Showing papers in "Hypertension in 1992"

Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension.

Abstract: Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginine orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angiotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164 +/- 6 mm Hg at 4-6 weeks, compared with 108 +/- 3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125 +/- 6 mm Hg, still elevated compared with rats receiving losartan alone (98 +/- 3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfusion, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment. Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomeruli. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes mellitus and hypertension.

Abstract: Diabetes mellitus and hypertension are common diseases that coexist at a greater frequency than chance alone would predict. Hypertension in the diabetic individual markedly increases the risk and accelerates the course of cardiac disease, peripheral vascular disease, stroke, retinopathy, and nephropathy. Our understanding of the factors that markedly increase the frequency of hypertension in the diabetic individual remains incomplete. Diabetic nephropathy is an important factor involved in the development of hypertension in diabetics, particularly type I patients. However, the etiology of hypertension in the majority of diabetic patients cannot be explained by underlying renal disease and remains "essential" in nature. The hallmark of hypertension in type I and type II diabetics appears to be increased peripheral vascular resistance. Increased exchangeable sodium may also play a role in the pathogenesis of blood pressure in diabetics. There is increasing evidence that insulin resistance/hyperinsulinemia may play a key role in the pathogenesis of hypertension in both subtle and overt abnormalities of carbohydrate metabolism. Population studies suggest that elevated insulin levels, which often occurs in type II diabetes mellitus, is an independent risk factor for cardiovascular disease. Other cardiovascular risk factors in diabetic individuals include abnormalities of lipid metabolism, platelet function, and clotting factors. The goal of antihypertensive therapy in the patient with coexistent diabetes is to reduce the inordinate cardiovascular risk as well as lowering blood pressure.

Orthostatic hypotension in older adults. The Cardiovascular Health Study. CHS Collaborative Research Group.

Abstract: The purpose of the present study was to assess the prevalence of orthostatic hypotension and its associations with demographic characteristics, cardiovascular risk factors and symptomatology, prevalent cardiovascular disease, and selected clinical measurements in the Cardiovascular Health Study, a multicenter, observational, longitudinal study enrolling 5,201 men and women aged 65 years and older at initial examination. Blood pressure measurements were obtained with the subjects in a supine position and after they had been standing for 3 minutes. The prevalence of asymptomatic orthostatic hypotension, defined as 20 mm Hg or greater decrease in systolic or 10 mm Hg or greater decrease in diastolic blood pressure, was 16.2%. This prevalence increased to 18.2% when the definition also included those in whom the procedure was aborted due to dizziness upon standing. The prevalence was higher at successive ages. Orthostatic hypotension was associated significantly with difficulty walking (odds ratio, 1.23; 95% confidence interval, 1.02, 1.46), frequent falls (odds ratio, 1.52; confidence interval, 1.04, 2.22), and histories of myocardial infarction (odds ratio, 1.24; confidence interval, 1.02, 1.50) and transient ischemic attacks (odds ratio, 1.68; confidence interval, 1.12, 2.51). History of stroke, angina pectoris, and diabetes mellitus were not associated significantly with orthostatic hypotension. In addition, orthostatic hypotension was associated with isolated systolic hypertension (odds ratio, 1.35; confidence interval, 1.09, 1.68), major electrocardiographic abnormalities (odds ratio, 1.21; confidence interval, 1.03, 1.42), and the presence of carotid artery stenosis based on ultrasonography (odds ratio, 1.67; confidence interval, 1.23, 2.26). Orthostatic hypotension was negatively associated with weight. We conclude that orthostatic hypotension is common in the elderly and increases with advancing age. It is associated with cardiovascular disease, particularly those manifestations measured objectively, such as carotid stenosis. It is associated also with general neurological symptoms, but this link may not be causal. Differences in prevalence of and associations with orthostatic hypotension in the present study compared with others are largely attributed to differences in population characteristics and methodology.

Renal injury from angiotensin II-mediated hypertension.

Abstract: Angiotensin II (Ang II)-mediated hypertension induces vascular smooth muscle cell hypertrophy and hyperplasia in systemic blood vessels, but the effects of Ang II on the intrinsic cell populations within the kidney have been less well characterized. We infused Ang II for 14 days into rats by minipump at doses (200 ng/min) that resulted in moderate hypertension (mean systolic blood pressure 156-172 mm Hg). Small renal arterial vessels of Ang II-infused rats demonstrated focal injury with fibrinoid necrosis and medial hyperplasia, whereas the glomerular capillaries demonstrated only rare segmental hyalinosis. Proliferation of vascular smooth muscle cells was pronounced (fourfold to 20-fold increase in [3H]thymidine incorporation) as opposed to a minimal proliferation of glomerular cells in Ang II-infused rats. In contrast, the principal effect of Ang II in glomeruli was to increase the expression of alpha-smooth muscle actin by mesangial cells and desmin by visceral glomerular epithelial cells. Ang II-infused rats also developed focal tubulointerstitial injury, with tubular atrophy and dilation, cast formation, an interstitial monocytic infiltrate, and mild interstitial fibrosis with increased type IV collagen deposition. The injury was associated with a proliferation of distal tubule, collecting duct, and interstitial cells as determined by immunostaining for proliferating cell nuclear antigen, and was accompanied by an increase in platelet-derived growth factor B-chain messenger RNA in the area of interstitial injury as localized by in situ hybridization. Renal interstitial cells also underwent phenotypic modulation in which they expressed alpha-smooth muscle actin. Vehicle-infused control rats displayed no tubular injury, proliferation, or phenotypic modulation. Thus, Ang II in doses that cause moderate hypertension induces marked vascular, glomerular, and tubulointerstitial injury with cell proliferation, leukocyte recruitment, phenotypic modulation with the upregulation of proteins normally associated with smooth muscle cells, and interstitial fibrosis.

Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats.

Abstract: An association between chronic high blood pressure and obstructive sleep apnea has been described. We hypothesized that repetitive episodic hypoxia patterned after the hypoxia seen in sleep apnea could contribute to diurnal elevation of blood pressure. Using 12-second infusions of nitrogen into daytime sleeping chambers, four groups of male rats (250-375 g) were subjected to intermittent hypoxia (3-5% nadir ambient oxygen) every 30 seconds, 7 hours per day for up to 35 days. In one group, blood pressure was measured weekly by the tail-cuff method in conscious animals during 5 weeks of episodic hypoxia. In the other three groups, blood pressure was measured in conscious animals via femoral artery catheters at baseline and after 20, 30, or 35 days of exposure. Additional groups served as controls: two sham groups housed in identical "hypoxia" chambers received compressed air instead of nitrogen (35 days) while two other groups remained unhandled in their usual cages (35 days). Both groups challenged with 35 days episodic hypoxia showed significant increases in blood pressure compared with controls: the tail-cuff rats showed a 21 mm Hg increase in systolic pressure (p less than 0.05) and the intra-arterially measured rats a 13.7 mm Hg increase in mean arterial pressure (p less than 0.05). The 30-day exposed rats also showed a 5.7 mm Hg increase in mean pressure over baseline (p less than 0.05). Blood pressure did not change significantly from baseline in the control groups. Left ventricle-to-body weight ratio was higher in both 35-day exposed groups than in unhandled or sham controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelium-derived contracting factors.

Abstract: The endothelium not only mediates relaxation but is a source of contracting factors. Endothelium-dependent contractions are elicited by physical and chemical stimuli (i.e., hypoxia, pressure, and stretch) and autacoids, local and circulating hormones. The mechanism of endothelium-dependent contractions to hypoxia involves withdrawal of nitric oxide. The endothelial cyclooxygenase pathway can produce thromboxane A2, prostaglandin H2, and superoxide anions. The peptide endothelin is a potent contracting factor; its production is stimulated by vasopressor hormones, platelet-derived factors, coagulation products, and cytokines, whereas endothelium-derived nitric oxide, prostacyclin, and a smooth muscle cell-derived inhibitory factor reduce endothelin production. In hypertension, the release of cyclooxygenase-dependent endothelium-derived contracting factors to stretch, acetylcholine, and platelet-derived products is augmented. Vascular endothelin production in hypertension remains controversial but appears mostly normal; it is augmented in the presence of vascular disease or renal insufficiency. The endothelium-dependent inhibition of endothelin-induced contractions is reduced in hypertension while the reactivity of vascular smooth muscle may be normal, increased, or reduced. The potentiating effects of low concentrations of endothelin on contractions to norepinephrine are augmented with aging and hypertension. In atherosclerosis, the production of the cyclooxygenase-dependent endothelium-derived contracting factors and endothelin is enhanced. Thus, endothelium-derived contracting factors can profoundly affect vascular tone and counteract relaxing factors produced within the endothelium. In hypertension and atherosclerosis, the role of contracting factors appears to become more dominant, leading to an imbalance of endothelium-dependent vascular regulation.

Induction of endothelin-1 gene by angiotensin and vasopressin in endothelial cells.

Abstract: To elucidate the cellular mechanism of endothelin-1 biosynthesis induced by angiotensin and vasopressin, we first cloned and sequenced full-length bovine preproendothelin-1 complementary DNA (cDNA) from a cultured bovine carotid artery endothelial cell cDNA library. The predicted bovine preproendothelin-1 consists of 202 amino acid residues and has a high percentage of homology to human, porcine, and rat preproendothelin-1 (70%, 81%, and 77%, respectively). Big endothelin-1, an intermediate form, consists of 39 residues differing only at position Val28 from porcine (Ile28) and His27 from rat (Arg27). The predicted 21-residue mature endothelin-1 is identical to human, porcine, rat, canine, and mouse endothelin-1. Northern blot analysis with the cloned cDNA as a probe demonstrated that a single 2.3-kb preproendothelin-1 messenger RNA (mRNA) is expressed not only in endothelial cells, but also in various bovine tissues, including lung, brain, heart, intestine, kidney, ovary, and urinary bladder. Angiotensin II and arginine vasopressin immediately and dose-dependently induced expression of preproendothelin-1 mRNA, whose effects were abolished by specific receptor antagonists. These findings suggest that stimulation of endothelin-1 secretion from endothelial cells by both agonists may be principally due to induction of preproendothelin-1 mRNA.

Prognostic significance of exercise blood pressure and heart rate in middle-aged men.

Abstract: Systolic blood pressure and heart rate measured at rest and during a standardized exercise test were analyzed in the cohort of middle-aged male employees followed-up an average of 17 years in the Paris Prospective Study I. The population sample selected for the analysis included 4,907 men who completed at least 5 minutes of bicycle ergometry, who had no heart disease at entry, and whose resting blood pressure was less than or equal to 180/105 mm Hg. Exercise-induced increase in systolic blood pressure was positively correlated with resting systolic blood pressure (r = 0.104, p less than 0.0001), whereas the correlation of exercise-induced heart rate increase with resting heart rate was negative (r = -0.169, p less than 0.001). Using Cox regression analysis with the inclusion of resting systolic blood pressure and heart rate; exercise-induced elevations of systolic blood pressure and heart rate; and controlling for age, smoking, total cholesterol, body mass index, electrical left ventricular hypertrophy, and sports activities, cardiovascular mortality was found to be associated with the systolic blood pressure increase (p less than 0.05), whereas no association with resting systolic blood pressure was found. Total mortality was predicted by resting systolic blood pressure and its elevation (p less than 0.01 for both) and by resting heart rate (p less than 0.0001). The heart rate increase did not contribute to death prediction. In conclusion, the magnitude of the exercise-induced increase of systolic blood pressure, but not of heart rate, may represent a risk factor for death from cardiovascular as well as noncardiovascular causes, independently of resting blood pressure and heart rate.

Relation between job strain, alcohol, and ambulatory blood pressure.

Abstract: "Job strain" (defined as high psychological demands and low decision latitude on the job) has been previously reported to be associated with increased risk of hypertension and increased left ventricular mass index (LVMI) in a case-control study of healthy employed men, aged 30-60 years, without evidence of coronary heart disease. We hypothesized that job strain would be associated with increased ambulatory blood pressure (AmBP). A total of 264 men at eight work sites wore an AmBP monitor for 24 hours on a working day. In an analysis of covariance model, job strain was associated with an increase in systolic AmBP of 6.8 mm Hg (p = 0.002) and diastolic AmBP of 2.8 mm Hg at work (p = 0.03) after adjusting for age, race, body mass index, Type A behavior, alcohol behavior, smoking, work site, 24-hour urine sodium, education, and physical demand level of the job. Alcohol use also had a significant effect on AmBP. However, among subjects not in high-strain jobs, alcohol had no apparent effect on AmBP at work. Instead, alcohol use and job strain interacted such that workers in high-strain jobs who drank regularly had significantly higher systolic AmBP at work (p = 0.007). Among the other risk factors, only age, body mass index, and smoking had significant effects on AmBP. Job strain also had significant effects on AmBP at home and during sleep as well as on LVMI.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased systolic pressure in chronic uremia. Role of arterial wave reflections.

Abstract: To assess the role of arterial wave reflections in the mechanism of systolic hypertension and altered pulsatile arterial dynamics in patients with end-stage renal disease (ESRD), 79 ESRD patients were compared with 73 age-matched control subjects with normal renal function and similar mean blood pressure. Wave reflections were investigated from the carotid pulse contour recorded by applanation tonometry using a Millar micromanometer-tipped probe. Wave reflections were quantified as the ratio (augmentation index, %) of the height of the late systolic peak to the total height of carotid pulse wave. Travel time of the reflected wave was timed from the foot of the pressure wave to the foot of the late systolic peak. Systolic and pulse pressure were increased in ESRD patients (p less than 0.001) and was not attributable to differences in left ventricular ejection pattern. The augmentation index was increased in ESRD patients (23.2 +/- 15.0 versus 9.8 +/- 15.6%; p less than 0.001) in association with a shorter travel time of reflected wave (109 +/- 24 versus 131 +/- 30 msec; p less than 0.001). Multiple regression analysis showed two principal factors associated (p less than 0.001) with the increase in augmentation index and shortened travel time of reflected wave: increased aortic pulse wave velocity and smaller stature with shorter body height in ESRD patients. The study points to the role of arterial wave reflections in the mechanisms producing alterations in pulsatile arterial dynamics in ESRD and is the first, through the mechanisms of early wave reflections, to show in humans that the increase in systolic and pulse pressures is associated with lesser body size.

Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries

Abstract: In cultured endothelial cells, endothelin is produced after stimulation with angiotensin II. The effects of angiotensin II and endothelin-1 on vascular sensitivity to norepinephrine were studied in perfused rat mesenteric resistance arteries. Expression of endothelin messenger RNA (mRNA) was determined in endothelial cells obtained from the mesenteric circulation. Perfusion (5 hours) of the arteries with angiotensin II (10(-7) M) potentiated contractions in arteries with endothelium induced by norepinephrine in spontaneously hypertensive rats but not Wistar-Kyoto rats. The potentiation was inhibited by phosphoramidon and an endothelin antibody. Short-term stimulation (1 hour) with angiotensin II did not cause the potentiation. Stimulation with angiotensin I (10(-7) M; 5 hours) caused a potentiation prevented by captopril. In endothelial cells collected from the mesenteric arterial bed of spontaneously hypertensive rats, endothelin-specific mRNA was constitutively expressed, and the level of endothelin transcripts was increased by angiotensin II (10(-7) M). Threshold concentrations of exogenous endothelin-1 potentiated contractions induced by norepinephrine in arteries with and without endothelium of spontaneously hypertensive rats but not Wistar-Kyoto rats. Thus, angiotensin II stimulates the endothelial production of endothelin in situ and therapy potentiates contractions to norepinephrine in mesenteric resistance arteries of spontaneously hypertensive rats. This suggests that vascular endothelin production acts as an amplifier of the pressor effects of the renin-angiotensin system that may play an important role in hypertension.

The Zucker rat model of obesity, insulin resistance, hyperlipidemia, and renal injury.

Abstract: Although the pathogenesis of obesity in OZR is unknown, the association among hyperinsulinemia, insulin resistance, and hyperlipidemia suggests that investigations using OZR may help define how a number of vascular disease risk factors interact to cause end-organ damage. Like other rat strains, OZR do not develop atherosclerosis spontaneously. Nevertheless, in an endothelial injury model, atherosclerosis was worse in OZR than in LZR. Perhaps more intriguing is the fact that OZR develop spontaneous glomerular injury. Although the mechanisms important in the development and progression of glomerular injury in OZR remain to be clarified, both lipid abnormalities and glomerular hemodynamic alterations could play a role.

Tissue-specific nutritional regulation of angiotensinogen in adipose tissue.

Abstract: Recent studies have found that angiotensinogen is expressed in white and brown fat pads, and adipocytes have been implicated as a primary source of angiotensinogen in several other tissues. The functional significance of this unexpected expression is unknown. To address this, we studied angiotensinogen messenger RNA (mRNA) expression and angiotensinogen secretion in adipose tissue and isolated adipocytes comparing fasted and refed rodents and those with genetic obesity with normal controls. Control 2-month-old Sprague-Dawley rats, those fasted for 3 days, or those fasted for 2 days and refed for 6 days were killed, and adipocytes were isolated from epididymal fat pads using collagenase digestion. Angiotensinogen mRNA was reduced to 14.6 +/- 2.3% of control levels under fasted conditions and increased to 228 +/- 53% of control levels after refeeding. Angiotensinogen release from adipocytes was reduced to 33% of control levels by fasting and increased to 183% by refeeding. These effects of fasting and refeeding on angiotensinogen regulation were tissue specific since liver angiotensinogen mRNA and serum angiotensinogen concentrations were unaffected. Systolic blood pressure, however, was modulated by fasting and refeeding in a manner parallel to adipocyte angiotensinogen expression. In related experiments, angiotensinogen secretion per epididymal fat pad of the ob/ob mouse model of obesity was increased an average of 3.4-fold compared with control. We conclude angiotensinogen expression in white adipocytes is regulated nutritionally in a tissue-specific manner. We propose that adipocyte angiotensinogen could play a previously unrecognized role in regulating adipose tissue blood supply and thereby fatty acid efflux from fat.(ABSTRACT TRUNCATED AT 250 WORDS)

Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats.

Abstract: Our previous studies demonstrated that the sexually dimorphic pattern of hypertension in the spontaneously hypertensive rat is androgen dependent. Gonadectomy retards the development of hypertension in young males, but not in females, and administration of testosterone propionate to gonadectomized spontaneously hypertensive rats of both sexes confers a male pattern of blood pressure development. The current study tested the hypothesis that renal and hepatic renin and angiotensinogen gene expression are also androgen dependent in the spontaneously hypertensive rat. Male and female spontaneously hypertensive rats underwent gonadectomy or a sham operation at 4 weeks of age. Subgroups of gonadectomized rats of both sexes were implanted with a 15-mm or 30-mm Silastic capsule filled with testosterone at the same time the gonadectomy was performed; a third group received an empty Silastic capsule. Northern and slot blot analyses were used to characterize and quantitate renin and angiotensinogen messenger RNA (mRNA) in the kidney and liver 18 weeks after the gonadectomy. Blood pressure, plasma renin activity, and hepatic angiotensinogen mRNA levels were higher in intact males than in females. Orchidectomy retarded the development of hypertension and lowered plasma renin and renal and hepatic angiotensinogen mRNA levels, and testosterone replacement restored the male pattern of hypertension and plasma renin and increased renal and hepatic angiotensinogen mRNA. Ovariectomy did not alter blood pressure or plasma renin but did lower renal renin and renal and hepatic angiotensinogen mRNA; testosterone increased blood pressure, plasma renin, renal renin and angiotensinogen mRNA, and hepatic angiotensinogen mRNA levels in ovariectomized females.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathetic denervation blocks blood pressure elevation in episodic hypoxia.

Abstract: We have previously described a rat model that responds to repetitive episodic hypoxia (FiO2 nadir 3-5% for 12 seconds every 30 seconds for 7 hr/day for 35 days) with chronic increase in arterial blood pressure. The purpose of the current study was to determine if peripheral sympathetic nervous system denervation blocks this persistent blood pressure elevation. Chemical sympathetic denervation was achieved and maintained by three intraperitoneal injections (100 mg/kg 6-hydroxydopamine) on days 1, 3, and 27 of a 47-day experiment in two groups of rats. One denervated group was subjected to episodic hypoxia for 40 consecutive days beginning on day 7 and the other remained unhandled in their usual cages. A third group was injected with vehicle only and subjected to the same episodic hypoxia while a fourth group remained unhandled for 40 days. The vehicle-treated, episodic hypoxia-exposed group showed a 7.7 mm Hg increase in mean arterial blood pressure (conscious, unrestrained) over the 40-day period, whereas all other groups showed a decrease in mean arterial pressure. The left ventricle and septum/whole body weight ratio was higher in both episodic hypoxia-exposed groups at the end of the study. Plasma epinephrine in both groups administered 6-hydroxydopamine was higher on day 6 than in the vehicle-injected rats. Measurement of catecholamines in cardiac muscle homogenate confirmed denervation in 6-hydroxydopamine animals. These results indicate that the peripheral sympathetic nervous system is necessary for the persistent increase in blood pressure in response to repetitive episodic hypoxia.

Pharmacology of smooth muscle cell replication.

Abstract: The suggestion that smooth muscle cell proliferation contributes to hypertension, atherosclerosis, and restenosis after angioplasty has led to a growing interest in the use of drugs to inhibit this process. This review summarizes pharmacological studies of smooth muscle cell proliferation in vitro and in vivo and identifies specific mediators of proliferation that are implicated by drugs binding with high affinity to enzymes or receptors.

Role of angiotensin subtype 2 receptor in neointima formation after vascular injury.

Abstract: The role of angiotensin receptor subtypes 1 and 2 was assessed on neointima formation after injury in rat carotid artery. The effects of angiotensin converting enzyme inhibition by perindopril (3 mg.kg-1 x day-1 p.o.) and selective blockade of angiotensin subtype 1 receptors by DuP 753 (5 and 30 mg.kg-1 x day-1 p.o.) were compared on proliferative response to balloon injury. In rats treated 6 days before and for 14 days after injury, perindopril significantly reduced (-76%, p < 0.01) myointimal hyperplasia. In contrast, DuP 753 at 5 mg.kg-1 x day-1 did not modify the hyperplastic response to balloon catheterization. Only at 30 mg.kg-1 x day-1 was DuP 753 able to reduce neointima formation (-47%, p < 0.05). This dose was equipotent to perindopril on the renin-angiotensin system as assessed by the pressor response to angiotensin II and angiotensin I. Therefore, blockade of subtype 1 receptors was a less effective means of suppression of myointimal growth than angiotensin converting enzyme inhibition, suggesting that another angiotensin receptor subtype or converting enzyme substrates are involved in this process. For the determination of whether angiotensin subtype 2 receptors were implicated, the specific subtype 2 receptor antagonist CGP 42112A (1 mg.kg-1 x day-1) was continuously infused perivascularly for 14 days in the vicinity of the injured carotid artery. CGP 42112A was as effective in preventing neointima formation as perindopril (-73%, p < 0.01, versus -76%, p < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans.

Abstract: We have previously demonstrated that physiological hyperinsulinemia in normotensive humans increases sympathetic nerve activity but not arterial pressure since it also causes skeletal muscle vasodilation. However, in the presence of insulin resistance and/or hypertension, insulin may cause exaggerated sympathetic activation or impaired vasodilation and thus elevate arterial pressure. This study sought to determine if insulin causes a pressor response in borderline hypertensive humans by producing exaggerated increases in sympathetic neural outflow or impaired vasodilation. We recorded muscle sympathetic nerve activity (microneurography, peroneal nerve), forearm blood flow, heart rate, and blood pressure in 13 borderline hypertensive subjects during a 1-hour insulin infusion (38 microunits/m2/min) while holding blood glucose constant. Plasma insulin rose from 12 +/- 3 microunits/ml (mean +/- SEM) during control to 73 +/- 7 microunits/ml during insulin infusion and fell to 9 +/- 2 microunits/ml 2 hours after insulin infusion was stopped. Muscle sympathetic nerve activity, which averaged 25 +/- 2 bursts per minute in control, increased significantly during insulin infusion (+9 bursts per minute) and remained elevated 1.5 hours into recovery (+7 bursts per minute, p less than 0.001). Despite increased muscle sympathetic nerve activity, there were significant (p less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during insulin infusion. Further, systolic and diastolic pressures fell approximately 3 and 6 mm Hg, respectively, during insulin infusion (p less than 0.01). This study suggests that acute physiological increases in plasma insulin elevate sympathetic neural outflow in borderline hypertensive humans but produce vasodilation and do not elevate arterial pressure.

Clustering of cardiovascular risk factors in confirmed prehypertensive individuals.

Abstract: Numerous studies have indicated that hypertensive subjects have an atherogenic lipoprotein pattern, hyperinsulinemia, and impaired glucose tolerance relative to normotensive individuals. These abnormalities could be due to adverse effects of certain antihypertensive agents, to pathophysiological concomitants of the hypertensive state itself, or to both. In this report, we describe the cardiovascular risk factor profile of 1,440 subjects who were normotensive and were not taking any antihypertensive medications when first examined and who subsequently participated in the 8-year follow-up of the San Antonio Heart Study. Hypertension developed in 130 subjects during the follow-up period. At baseline these prehypertensive individuals had significantly higher levels of blood pressure, fasting total and low density lipoprotein cholesterol, triglyceride, glucose, and insulin, and 2-hour glucose than those who remained free of hypertension. In addition, they had higher body mass indexes, a less favorable body fat distribution, and lower levels of high density lipoprotein cholesterol. In multiple linear regression analyses, baseline levels of triglyceride and blood pressure remained significantly higher and high density lipoprotein cholesterol remained significantly lower in the subjects who later converted to hypertension than in those who remained normotensive. Although baseline insulin levels were also higher in the prehypertensive subjects, this difference was not statistically significant. In nonobese subjects, however, those with high baseline insulin concentrations had an increased incidence of hypertension compared with those with low insulin concentrations. The present results suggest that the cluster of atherogenic changes associated with hypertension actually precede the development of the hypertensive state.

Role of nitric oxide in renal papillary blood flow and sodium excretion.

Abstract: Renal medullary interstitial infusion of NG-nitro-L-arginine (120 micrograms/hr, n = 7) decreased papillary blood flow to 71 +/- 5% of control without altering outer cortical flow. Before NG-nitro-L-arginine infusion, interstitial acetylcholine administration (200 micrograms/hr) increased cortical and papillary blood flow to 134 +/- 6% and 113 +/- 2% of control, respectively. After NG-nitro-L-arginine administration, the vasodilator response to acetylcholine was abolished. In clearance experiments, renal medullary infusion of NG-nitro-L-arginine (120 micrograms/hr, n = 7) significantly decreased total renal blood flow by 10%, renal interstitial fluid pressure by 23%, sodium excretion by 34%, and urine flow by 39% without altering glomerular filtration rate, fractional sodium and water excretion, blood pressure, or urine osmolality. These data indicate that selective inhibition of nitric oxide in the renal medullary vasculature reduces papillary blood flow, which is associated with decreased sodium and water excretion. We conclude that nitric oxide exerts a tonic influence on the renal medullary circulation.

Conduit artery compliance and distensibility are not necessarily reduced in hypertension.

Abstract: The goal of this study was to investigate whether the elastic behavior of conduit arteries of humans or rats is altered as a result of concomitant hypertension. Forearm arterial cross-sectional compliance-pressure curves were determined noninvasively by means of a high precision ultrasonic echo-tracking device coupled to a photoplethysmograph (Finapres system) allowing simultaneous arterial diameter and finger blood pressure monitoring. Seventeen newly diagnosed hypertensive patients with a humeral blood pressure of 163/103 +/- 4.4/2.2 mm Hg (mean +/- SEM) and 17 age- and sex-matched normotensive controls with a humeral blood pressure of 121/77 +/- 3.2/1.9 mm Hg were included in the study. Compliance-pressure curves were also established at the carotid artery of 16-week-old anesthetized spontaneously hypertensive rats (n = 14) as well as Wistar-Kyoto normotensive animals (n = 15) using the same echo-tracking device. In these animals, intra-arterial pressure was monitored in the contralateral carotid artery. Mean blood pressures averaged 197 +/- 4 and 140 +/- 3 mm Hg in the hypertensive and normotensive rats, respectively. Despite the considerable differences in blood pressure, the diameter-pressure and cross-sectional compliance-pressure and distensibility-pressure curves were not different when hypertensive patients or animals were compared with their respective controls. These results suggest that the elastic behavior of a medium size muscular artery (radial) in humans and of an elastic artery (carotid) in rats is not necessarily altered by an increase in blood pressure.

Reactivity of small blood vessels in hypertension: relation with structural changes. State of the art lecture.

Abstract: Small blood vessels, particularly small arteries of 150-300 microns in lumen diameter and larger arterioles of 50-150 microns in lumen diameter, are the most important location of the arterial bed that undergoes changes resulting in the increased peripheral resistance that characterizes elevated blood pressure. This article reviews these morphological and functional alterations of small blood vessels. Study of mesenteric small arteries with a lumen diameter of 220-260 microns revealed consistently a reduced external and lumen diameter in renal and deoxycorticosterone acetate-salt hypertensive rats early in the evolution of hypertension. The media of the vessel wall was significantly thickened in the hypertensive rats, and the media/lumen ratio was increased. Although the tension that developed in response to different vasoconstrictors was not elevated or was even decreased in hypertensive rats, exaggerated transmural pressures resulted in the isolated blood vessels as a consequence of the law of Laplace because of the narrowed lumen. Similar findings were obtained in small resistance arteries from subcutaneous gluteal biopsies of hypertensive humans. In arterioles, on the other hand, decreases in the density of blood vessels (rarefaction) and in vasomotion amplitude may play a more important role than reductions in lumen diameter. As a consequence of the design of small resistance blood vessels and as a result of functional and structural alterations, which may be primary to or a consequence of high blood pressure, the pressor effect of vasoconstrictors is amplified and interacts with other factors to contribute to the maintenance of elevated blood pressure even if the intrinsic response of vascular smooth muscle to these agents is not exaggerated.

Regulation of contraction and relaxation in arterial smooth muscle

Abstract: Intracellular calcium concentration ([Ca2+]i)-dependent activation of myosin light chain kinase and its phosphorylation of the 20-kd light chain of myosin is generally considered the primary mechanism responsible for regulation of contractile force in arterial smooth muscle. However, recent data suggest that the relation between [Ca2+]i and myosin light chain phosphorylation is variable and depends on the form of stimulation. The dependence of myosin phosphorylation on [Ca2+]i has been termed the "[Ca2+]i sensitivity of phosphorylation." The [Ca2+]i sensitivity of phosphorylation is "high" when relatively small increases in [Ca2+]i induce a large increase in myosin phosphorylation. Conversely, the [Ca2+]i sensitivity of phosphorylation is "low" when relatively large increases in [Ca2+]i are required to induce a small increase in myosin phosphorylation. There are two proposed mechanisms for changes in the [Ca2+]i sensitivity of phosphorylation: Ca(2+)-dependent decreases in the [Ca2+]i sensitivity of phosphorylation induced by phosphorylation of myosin light chain kinase by Ca(2+)-calmodulin protein kinase II and agonist-dependent increases in the [Ca2+]i sensitivity of phosphorylation by inhibition of a myosin light chain phosphatase. I will review the proposed mechanisms responsible for the regulation of [Ca2+]i and the [Ca2+]i sensitivity of phosphorylation in arterial smooth muscle.

Variability between current definitions of 'normal' ambulatory blood pressure. Implications in the assessment of white coat hypertension.

Abstract: The assessment of white coat hypertension is complicated by the lack of generally agreed-on normal limits of ambulatory blood pressure. To assess the influence of four of these limits on the prevalence of white coat hypertension and the corresponding distribution of left ventricular hypertrophy, we performed 24-hour ambulatory blood pressure monitoring and echocardiographic studies in 346 untreated patients with essential hypertension and 47 age-matched normotensive control subjects. The upper limits of normal daytime ambulatory blood pressure were lower using standards drawn from clinically normotensive populations than using standards drawn, partly or entirely, from general populations. The prevalence of white coat hypertension differed markedly using the different standards, being 12.1%, 16.5%, 28.9%, and 53.2% (chi 2 = 346.0, p less than 0.0001). Left ventricular mass index averaged 77 g/m2 in the control group, 85 g/m2 in the two groups with white coat hypertension defined by using standards drawn from normotensive populations (both comparisons not significant versus control group), and 90 and 98 g/m2 in the two groups with white coat hypertension defined by using the other two standards (both p less than 0.01 versus control group). The prevalence of echocardiographic left ventricular hypertrophy was 0% in the control group, 2.4% and 3.5% in the two groups with white coat hypertension defined by using standards drawn from normotensive populations, and 9.0% and 14.7% in the other two groups with white coat hypertension (p less than 0.05 and p less than 0.01, respectively, versus control group).(ABSTRACT TRUNCATED AT 250 WORDS)

Aftereffects of exercise on regional and systemic hemodynamics in hypertension.

Abstract: Several studies have indicated that a single bout of physical exercise induced a significant antihypertensive effect during the hours after the activity. However, little information is presently available on the underlying hemodynamic changes. We examined 13 essential hypertensive patients and nine normotensive subjects in a randomized, crossover study design during 3 hours after a 30-minute period of upright leg cycling at 50% of peak aerobic capacity and during 3 hours after a 30-minute control period of rest. Blood pressure, heart rate, cardiac output, total peripheral resistance, and regional vascular resistance in the forearm as well as venous plasma catecholamine concentrations were measured repeatedly. After exercise, systolic (-11 +/- 2 mm Hg) and diastolic (-4 +/- 1 mm Hg) blood pressures, total peripheral resistance (-27 +/- 5%), forearm vascular resistance (-25 +/- 6%), and plasma norepinephrine levels (-21 +/- 7%) were significantly (p less than or equal to 0.05) decreased, and cardiac output was increased (+31 +1- 8%) compared with control in hypertensive subjects. In contrast, in normotensive subjects blood pressure, forearm vascular resistance, and plasma norepinephrine were unchanged, and systemic hemodynamics changed to a lesser extent than in hypertensive subjects after exercise. It is concluded that a decrease in regional vascular resistance in skeletal muscles and possibly in the skin in hypertensive patients may contribute importantly to the antihypertensive effect of prior exercise. A decreased sympathetic nervous activity, as seen from lower plasma norepinephrine levels, may be involved in this effect.

Brain atrophy in hypertension. A volumetric magnetic resonance imaging study.

Abstract: To determine whether hypertension, the predominant risk factor for stroke and vascular dementia, is associated with brain atrophy, magnetic resonance imaging (MRI) scans were performed to quantify brain volumes and cerebrospinal fluid spaces. Eighteen otherwise healthy, cognitively normal older hypertensive men (mean +/- SD age, 69 +/- 8 years, duration of hypertension 10-35 years) and 17 age-matched healthy, normotensive male control subjects were studied in a cross-sectional design. Axial proton-density image slices were analyzed using region-of-interest and segmentation analyses. The hypertensive subjects had significantly larger mean volumes of the right and left lateral ventricles (p less than 0.05, both absolute volume and volume normalized to intracranial volume) and a significantly smaller normalized mean left hemisphere brain volume (p less than 0.05) with a trend toward significance for a smaller normalized mean right hemisphere volume (p less than 0.09). Four hypertensive subjects and one healthy control subject were found to have severe periventricular hyperintensities on T2-weighted MRI images. When data for these subjects were removed from the analyses, the normalized lateral ventricle volumes remained significantly larger in the hypertensive group. Lateral ventricle enlargement was not related to age or use of diuretics in the hypertensive group nor to duration of hypertension between 10 and 24 years. Our findings suggest that long-standing hypertension results in structural changes in the brain. Longitudinal studies will determine whether MRI-associated changes are progressive and if such changes identify hypertensive subjects at increased risk for clinically apparent brain dysfunction.

Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients.

Abstract: Animal studies suggest that some angiotensin converting enzyme inhibitors augment endothelium-dependent vasorelaxation. We aimed to determine if captopril augments endothelium-dependent vasodilation in middle-aged hypertensive patients. By using strain-gauge plethysmography, forearm vasodilation evoked with intra-arterial acetylcholine (4, 8, 16, and 24 micrograms/min) or nitroprusside (0.2, 0.4, 0.8, and 1.2 micrograms/min) was examined before and after captopril administration (25 mg per os). Before captopril, forearm vasodilation with acetylcholine was less in hypertensive patients (n = 12) than in age-matched (n = 7) or young (n = 7) normotensive subjects, but forearm vasodilation with nitroprusside did not differ among the three groups. Captopril improved forearm vasodilation in hypertensive patients (n = 7) with acetylcholine but nitroprusside did not. In contrast, nifedipine (10 mg per os) did not alter forearm vasodilation with acetylcholine or nitroprusside in hypertensive patients (n = 5). The decreases in mean blood pressure caused by captopril and nifedipine in hypertensive subjects were comparable. Captopril did not alter forearm vasodilation with acetylcholine or nitroprusside in young normotensive subjects (n = 7). These results suggest that captopril in hypertensive patients may acutely improve impaired endothelium-dependent forearm vasodilation that does not result from reduction in blood pressure per se.

In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously hypertensive rats.

Abstract: We investigated the processing enzymes involved in the formation of circulating angiotensin-(1-7) after intravenous administration of angiotensin I to conscious spontaneously hypertensive and Wistar-Kyoto rats. Immunoreactive products, including angiotensin I, angiotensin II, and angiotensin-(1-7), were measured in arterial blood by three specific radioimmunoassays. Angiotensin I infusion (2 nmol) induced a rapid increase in immunoreactive angiotensin II and angiotensin-(1-7). Pretreatment with the angiotensin converting enzyme inhibitor enalaprilat (2 mg/kg) eliminated angiotensin II formation and augmented circulating levels of angiotensin I and angiotensin-(1-7) in spontaneously hypertensive and Wistar-Kyoto rats. The elevated levels of angiotensin-(1-7) in enalaprilat-treated rats were blocked by concurrent treatment with the neutral endopeptidase (EC 3.4.24.11) inhibitor SCH 39,370 (15 mg/kg) in both strains. Administration of SCH 39,370 alone decreased angiotensin-(1-7) levels in spontaneously hypertensive rats, whereas angiotensin II levels increased in both strains (p less than 0.01). Comparisons of the metabolism of angiotensin I in the two rat strains showed increased formation of angiotensin-(1-7) in spontaneously hypertensive rats not given any of the enzyme inhibitors. In addition, levels of angiotensin I were higher after administration of SCH 39,370 in hypertensive rats. These novel findings reveal that neutral endopeptidase EC 3.4.24.11 participates in the conversion of angiotensin I to angiotensin-(1-7) and in the metabolism of angiotensin II in the circulation of both spontaneously hypertensive and Wistar-Kyoto rats. Our results suggest that neutral endopeptidase EC 3.4.24.11 is a major enzymatic constituent of the circulating renin-angiotensin system.

Obesity, the sympathetic nervous system, and essential hypertension.

Abstract: There is ample evidence that the sympathetic nervous system is important in the etiology of essential hypertension. Plasma catecholamines such as norepinephrine and epinephrine are the most common indexes of sympathetic function used in studies of essential hypertension. Plasma norepinephrine is higher in young essential hypertensive patients than in normotensive subjects. Other methods to examine sympathetic activity, such as blood pressure response to sympatholytic agents, measurement of regional sympathetic activity, vascular reactivity to sympathetic agonists, power spectral analysis, and microneurography, have all provided further evidence for enhanced sympathetic activity in essential hypertension, especially in younger subjects. Certain groups that make up a substantial part of the essential hypertensive population, such as obese subjects, have heightened sympathetic activity that could contribute to hypertension. Plasma norepinephrine levels are significantly higher in obese compared with nonobese subjects, and the remarkable fall in blood pressure with weight loss in obese subjects is correlated with reductions in plasma norepinephrine. Antihypertensive agents have variable effects on sympathetic activity; some agents (diuretics and direct vasodilators) have elevating effects, some agents (centrally acting agents and alpha-antagonists) have lowering effects, and others (converting enzyme inhibitors, calcium blockers, and beta-blockers) have mixed effects. Tailoring therapy toward agents that reduce sympathetic activity for specific groups perceived as having neurogenic hypertension, such as obese subjects, is a goal yet to be attained.

Oxygen free radicals and cardiac reperfusion abnormalities.

Abstract: Oxygen free radicals are highly reactive compounds causing peroxidation of lipids and proteins and are thought to play an important role in the pathogenesis of reperfusion abnormalities including myocardial stunning, irreversible injury, and reperfusion arrhythmias. Free radical accumulation has been measured in ischemic and reperfused myocardium directly using techniques such as electron paramagnetic resonance spectroscopy and tissue chemiluminescence and indirectly using biochemical assays of lipid peroxidation products. Potential sources of free radicals during ischemia and reperfusion have been identified in myocytes, vascular endothelium, and leukocytes. In several different experimental models exogenous free radical-generating systems have been shown to produce alterations in cardiac function that resemble the various reperfusion abnormalities described above. Injury to processes involved in regulation of the intracellular Ca2+ concentration may be a common mechanism underlying both free radical-induced and reperfusion abnormalities. Direct effects of free radicals on each of the known Ca(2+)-regulating mechanisms of the cell as well as the contractile proteins and various ionic membrane currents have been described. Free radicals also inhibit critical enzymes in anaerobic and aerobic metabolic pathways, which may limit the metabolic reserve of reperfused myocardium and contribute to intracellular Ca2+ overload. Inhibiting free radical accumulation during myocardial ischemia/reperfusion with free radical scavengers and inhibitors has been demonstrated to reduce the severity of myocardial stunning, irreversible injury, and reperfusion arrhythmias in many, but not all, studies. This evidence strongly implicates free radical accumulation during myocardial ischemia/reperfusion as an important pathophysiological mechanism of reperfusion abnormalities, although many issues remain unresolved.