Showing papers in "Hypertension in 1988"

Changes in autonomic regulation induced by physical training in mild hypertension.

Abstract: The adaptive effects of physical training on cardiovascular control mechanisms were studied in 11 subjects with mild hypertension. In these subjects we assessed the gain of the heart period-systolic arterial pressure relationship in the unfit and the fit state by using 1) an open loop approach, whereby the gain is expressed by the slope of the regression of heart period as a function of systolic arterial pressure, during a phenylephrine-induced pressure rise and 2) a closed loop approach with proper simplification, whereby the gain is expressed by the index alpha, obtained through simultaneous spectral analysis of the spontaneous variabilities of heart period and systolic arterial pressure. Both methods indicated that training significantly increased the gain of the relationship between heart period and systolic arterial pressure at rest and reduced arterial pressure and increased heart period significantly. This gain was drastically reduced during bicycle exercise both in the unfit and fit state. In a second group of normotensive (n = 7; systolic pressure, 133 +/- 3 mm Hg) and hypertensive (n = 7; systolic pressure, 180 +/- 10 mm Hg) subjects undergoing 24-hour diagnostic continuous electrocardiographic and high fidelity arterial pressure monitoring, the index alpha was significantly reduced in the hypertensive group at rest. Furthermore, when analyzed continuously over the entire 24-hour period, this index underwent minute-to-minute changes with lower values during the day and higher values during the night. We propose the index alpha as a quantitative indicator of the changes in the gain of baroreceptor mechanisms occurring with physical training in mild hypertension and during a 24-hour period in ambulatory subjects.

Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover.

Abstract: SINCE the sympathetic nervous system has such a central place in homeostasis in general, and in circulatory adaptation in particular, it is paradoxical that so little is known about the possible contribution of disturbed sympathetic nervous function to the development of human diseases. Clinical tests of sympathetic nervous system activity have, by and large, been routinely applied in one setting only: the detection of sympathetic nervous failure, from autonomic insufficiency syndromes, in patients with postural hypotension. A list of \"candidate\" diseases for sympathetic nervous system dysfunction might include, for example, essential hypertension, cardiac failure, coronary artery spasm, cirrhosis, mitral valve prolapse, and Raynaud's syndrome. Until very recently, the picture of sympathetic nervous pathophysiology for conditions such as these was particularly sketchy, mainly because of the rudimentary nature of the tests of sympathetic nervous system function available to investigative clinical medicine. Pertinent questions have gone incompletely answered at best — questions such as: Is the sympathetic nervous system directly involved in the early pathogenesis of essential hypertension? Is increased renal sympathetic activity a common cause of sodium retention in edematous states? Is increased cardiac sympathetic nerve firing an important element in the development of cardiac arrhythmias in humans?

Evaluation of the baroreceptor-heart rate reflex by 24-hour intra-arterial blood pressure monitoring in humans.

Abstract: The baroreceptor control of the sinus node was evaluated in 10 normotensive and 10 age-matched essential hypertensive subjects in whom ambulatory blood pressure was recorded intra-arterially for 24 hours and scanned by a computer to identify the sequences of three or more consecutive beats in which systolic blood pressure (SBP) and pulse interval (PI) progressively rose (+PI/+SBP) or fell (-PI/-SBP) in a linear fashion, according to a method validated in cats. In normotensive subjects, several hundred +PI/+SBP and -PI/-SBP sequences of 3 beats were found whereas the number of sequences of 4, 5, and more than 5 beats showed a progressive drastic reduction. The mean slopes of +PI/+SBP (7.6 +/- 2.0 msec/mm Hg) and -PI/-SBP (6.4 +/- 1.5 msec/mm Hg) sequences were similar, but in both instances there was a large scattering of the values around the mean (variation coefficients: 64.2 +/- 4.7 and 62.6 +/- 2.4%). The slopes decreased as a function of the sequence length and baseline heart rate and increased to a marked extent during the night as compared with daytime values. All sequences were more rare (-33.2% for +PI/+SBP and -31.7% for -PI/-SBP) and less steep in hypertensive subjects (-40.3 and -36.2%, respectively), who failed to show the marked nighttime increase in slope observed in normotensive subjects. To our knowledge, these observations provide the first description in humans of the baroreceptor-heart rate reflex in daily life. This reflex is characterized by marked within-subject variations in sensitivity due in part to hemodynamic, temporal, and behavioral factors.(ABSTRACT TRUNCATED AT 250 WORDS)

The discovery of nitric oxide as the endogenous nitrovasodilator.

Abstract: Endothelium-derived relaxing factor (EDRF) is a labile humoral agent released by vascular endothelium that mediates the relaxation induced by some vasodilators, including acetylcholine and bradykinin. EDRF also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to vascular endothelium. These actions of EDRF are mediated through stimulation of the soluble guanylate cyclase and the consequent elevation of cyclic guanosine 3',5'-monophosphate. EDRF has been identified as nitric oxide (NO). The pharmacology of NO and EDRF is indistinguishable; furthermore, sufficient NO is released from endothelial cells to account for the biological activities of EDRF. Organic nitrates exert their vasodilator activity following conversion to NO in vascular smooth muscle cells. Thus, NO may be considered the endogenous nitrovasodilator. NO is synthesized by vascular endothelium from the terminal guanido nitrogen atom(s) of the amino acid L-arginine. This indicates the existence of an enzymic pathway in which L-arginine is the endogenous precursor for the synthesis of NO. The discovery of the release of NO by vascular endothelial cells, the biosynthetic pathway leading to its generation, and its interaction with other vasoactive substances opens up new avenues for research into the physiology and pathophysiology of the vessel wall.

Mediators produced by the endothelial cell.

Abstract: This review discusses the role of three mediators, synthesized by vascular endothelial cells, that help to keep the surface of the normal endothelium nonthrombogenic. The first is prostacyclin, a product of arachidonic acid metabolism discovered in 1976. This labile prostanoid, with a half-life of approximately 3 minutes, relaxes vascular smooth muscle and inhibits the aggregation of blood platelets. Prostacyclin and its analogues are currently being tested clinically for use in cardiovascular diseases such as primary pulmonary hypertension. The second mediator discussed is endothelium-derived relaxing factor (EDRF), discovered in 1980, which also relaxes smooth muscle and inhibits the aggregation and adhesion of platelets. Substances that stimulate the release of EDRF include acetylcholine, bradykinin, and adenosine 5'-diphosphate. EDRF is even more labile than prostacyclin, with a half-life of about 6 seconds, and it has recently been identified as nitric oxide. Prostacyclin and EDRF are released together following stimulation of endothelial receptors and synergize to inhibit platelet aggregation. 13-Hydroxy-9,11-octadecadienoic acid, a third suggested mediator, is not released but acts from inside the cell to make the endothelial surface nonadhesive for circulating blood cells. It is proposed that these three mediators form the endothelial defense mechanism against blood-borne cells and chemicals and that breakdown of this barrier results in diseases such as hypertension and atherosclerosis.

Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects.

Abstract: We tested the hypothesis that sympathetic nerve responses to stimulation of chemoreceptors by hypoxia are exaggerated in borderline hypertensive humans. We compared responses to isocapnic hypoxia in eight borderline hypertensive subjects and eight normotensive control subjects matched for age, sex, weight, and height without a family history of hypertension. Measurements of heart rate, mean blood pressure, minute ventilation, and sympathetic nerve activity to muscle were made before and during hypoxia. We also measured responses to a period of voluntary apnea during hypoxia. There were no significant differences between the increases in heart rate, blood pressure, and ventilation in response to hypoxia in the two groups. However, during hypoxia sympathetic activity in the hypertensive subjects increased by 40.6 +/- 13.6% (mean +/- SE), greater than the increase of 20.4 +/- 5.0% in the control subjects (p less than 0.05). In six hypertensive and six control subjects, when apnea was performed during hypoxia, sympathetic activity increased by 605.0 +/- 294.3% in the hypertensive subjects and by only 52.8 +/- 17.3% in the control subjects (p less than 0.001). We conclude that the chemoreceptor reflex is enhanced in borderline hypertensive subjects and results in exaggerated increases in sympathetic nerve activity during hypoxia. This enhanced chemoreceptor reflex is especially obvious when the inhibitory influence of breathing and thoracic afferent activity is eliminated by apnea. This exaggerated response may contribute to excess sympathetic activity in borderline hypertensive subjects and to adverse consequences of sleep apnea in hypertensive subjects.

The reproducibility of average ambulatory, home, and clinic pressures.

Abstract: The reproducibility of ambulatory, home, and clinic blood pressures was compared in 13 untreated mildly hypertensive and 14 normotensive subjects. Each subject had two sets of daily ambulatory recordings, home self-measured readings (over 6 days), and clinic measurements taken 2 weeks apart. Comparisons over the 2 weeks within and among the methods of measurements were made using a repeated-measures analysis of variance. The results showed that there was no consistent average change in the ambulatory or home pressures and no change in clinic diastolic pressures, but the clinic systolic pressure of the hypertensive subjects dropped 6 mm Hg (p less than 0.05), while that of the normotensive subjects showed no significant change. Test-retest correlations of each of the three methods were similar in magnitude, indicating a similar level of reliability. Test-retest correlations of the ambulatory standard deviations, however, were low, indicating a low reliability of this measure of daily pressure variability. These results suggest that the reproducibility of ambulatory pressures may be as good or better than that of home or clinic measurements. They also suggest that the average ambulatory pressure may be preferable as the measurement in clinical trials, since it may be less influenced by measurement anxiety, particularly in hypertensive subjects.

Effects of moderate hypertension on cardiac function and metabolism in the rabbit.

Abstract: To study the early effects of hypertension on the heart, we examined isolated hearts from rabbits with slowly developing hypertension of up to 64 weeks in duration after unilateral nephrectomy and renal artery stenosis. Normotensive animals kept under identical conditions served as controls. Mean arterial blood pressure rose from 83 to 155 mm Hg in the hypertensive group of longest duration, but the ratio of left ventricular weight to body weight was not different between the experimental and control groups. Although left ventricular hypertrophy was not present, left ventricular peak systolic pressure of perfused hearts was significantly higher in hypertensive than in normotensive hearts. Furthermore, while in hypertensive hearts the left ventricular end-diastolic volume was increased, the peak systolic pressure did not respond to an increase in left ventricular end-diastolic volume. Functional changes were accompanied by metabolic changes in the left ventricle. Rates of glucose utilization were increased and rates of ketone body utilization were decreased in hypertensive hearts. Activities of key enzymes of carbohydrate metabolism (phosphorylase, hexokinase, phosphofructokinase, and lactate dehydrogenase) were increased, while those of ketone body metabolism (3-oxoacid-CoA transferase, acetoacetyl-CoA synthase) were decreased and those of the citric acid cycle (citrate synthase, 2-oxoglutarate dehydrogenase) were not different between groups. In summary, moderate hypertension for a period of more than 1 year resulted in functional and metabolic changes of the left ventricle in hypertensive animals that were already manifest at 8 weeks of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelium-dependent and endothelium-independent vasodilation in resistance arteries from hypertensive rats.

Abstract: The endothelium-dependent and presumed endothelium-independent vasodilators acetylcholine and sodium nitroprusside, respectively, were used to characterize relaxation responses of mesenteric resistance arteries from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY). Vessels were preconstricted using concentrations of norepinephrine or 5-hydroxytryptamine, which reduced their diameters by 50 to 60%. Relaxation responses to acetylcholine (10(-8) - 10(-7) M) were significantly smaller (p less than 0.05) in vessel segments from SHRSP, but the maximal relaxations at higher concentrations were the same in both strains. However, SHRSP vessels relaxed to a greater extent than did those of the WKY at all concentrations of sodium nitroprusside. Endothelium removal significantly enhanced sodium nitroprusside-induced dilations in both rat strains, and the dilations were significantly greater in segments from SHRSP in the concentration range of 3 X 10(-8) to 10(-6) M. The decreased relaxation to acetylcholine in resistance arteries from adult hypertensive rats compared with those from the normotensive strain suggests that functional alterations in the endothelium may play a role in hypertensive disease.

Location and regulation of rat angiotensinogen messenger RNA.

Abstract: The presence of angiotensinogen messenger RNA (mRNA) was detected in rat vascular and adipose tissue. Angiotensinogen mRNA in rat aorta was localized in the adventitia and surrounding adipose tissue, and not in the vascular smooth muscle. Freshly dispersed and cultured endothelial and aortic smooth muscle cells did not contain detectable amounts of angiotensinogen mRNA. In addition to periaortic adipose tissue, angiotensinogen mRNA was present in other fat depots of both brown and white types. To examine regulation of angiotensinogen gene expression, Sprague-Dawley rats were treated with angiotensin converting enzyme inhibitor or underwent bilateral nephrectomy. Relative levels of angiotensinogen mRNA in brown adipose tissues increased dramatically by 48 hours after bilateral nephrectomy. However, only one source of brown adipose tissue showed increased angiotensinogen mRNA levels after animals were treated for 5 days with converting enzyme inhibitor. In addition, angiotensinogen was released into the medium from incubated adipose tissues with levels increasing over a 2-hour period. These results demonstrate that angiotensinogen is synthesized by adipose tissue in the rat and may play a role in the function of this tissue.

Altered circadian blood pressure rhythm in patients with Cushing's syndrome.

Abstract: The circadian blood pressure rhythm was compared in patients with Cushing's syndrome, essential hypertension, and primary aldosteronism. In patients with essential hypertension or primary aldosteronism, a clear nocturnal fall in systolic and diastolic blood pressure and heart rate was observed. This fall was seen in untreated subjects as well as in patients receiving combined treatment with a calcium antagonist, diuretic, converting enzyme inhibitor, alpha-blocker and beta-blocker, or sympatholytic drug. In these groups, there was a positive correlation between heart rate and systolic or diastolic blood pressure. On the other hand, in patients with Cushing's syndrome, there was no nocturnal fall in blood pressure but in some patients a rise was observed. In all patients there was a nocturnal fall in heart rate. Thus, there was no significant correlation between heart rate and blood pressure in these patients. Exogenous glucocorticoid eliminated the normal nocturnal fall of blood pressure in patients with chronic glomerulonephritis or systemic lupus erythematosus. These results suggest that the changed circadian blood pressure pattern in patients with Cushing's syndrome is not due to antihypertensive treatment or to the mineralocorticoid excess accompanying this disease, but it is attributable to excess glucocorticoid or the associated disturbance in the adrenocorticotropic hormone-glucocorticoid system (or both). This conclusion also implies that the normal circadian rhythm of blood pressure may be regulated at least in part by the adrenocorticotropic hormone-glucocorticoid system.

Vascular smooth muscle calponin. A novel troponin T-like protein.

Abstract: In a search for additional Ca2+ regulatory components in vascular smooth muscle, a novel troponin T-like protein was purified from bovine aorta smooth muscle. The isolated protein was separated into several isoforms on isoelectric focusing. The major isoelectric variants were focused in the pH region of 8.4 to 9.1. The protein had slightly different molecular masses in the Mr range of 35,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Its molar ratio relative to tropomyosin in the muscle extract was estimated to be 0.9:1.0. The novel protein bound to the immobilized calmodulin and exhibited a number of common physicochemical properties with gizzard (Mr = 34,000) calmodulin-binding and F-actin-binding protein. The aorta and gizzard proteins were immunologically cross-reactive. Both proteins shared a common antigenic determinant with COOH-terminal segments of rabbit skeletal and bovine cardiac troponin T and bound to the immobilized smooth muscle tropomyosin. Both proteins interacted with rabbit skeletal troponin C in the presence and absence of Ca2+, but they did not interact with troponin I. These results suggest that the novel protein, which is designated calponin, may be a specialized component of smooth muscle thin filament involved in the regulation of contractile apparatus.

Effects of thyroid function on blood pressure. Recognition of hypothyroid hypertension.

Abstract: Hypothyroidism has been known to be associated, at times, with diastolic hypertension. We have found in 40 thyrotoxic patients that the induction of hypothyroidism by radioiodine therapy significantly increased diastolic blood pressure, raising it above 90 mm Hg in 16 (40%) of the patients. Restoration of euthyroidism with thyroxine administration significantly reduced the systolic and diastolic blood pressures in these patients, with a fall in diastolic pressure below 90 mm Hg in nine of 16 patients. The prevalence of hypothyroidism was determined by measurements of serum thyroxine and thyrotropin concentrations in 688 consecutive hypertensive patients, referred for evaluation and therapy of their hypertension. Hypothyroidism was found in 25 (3.6%) of the patients. Restoration of normal serum thyroxine and thyrotropin levels with thyroid hormone replacement therapy lowered diastolic blood pressure to levels below 90 mm Hg in 32% of these patients who could be followed up after withdrawal of all antihypertensive drug therapy when euthyroidism had been restored (i.e., 1.2% of the 688 patients). It is concluded that diastolic hypertension resulting from hypothyroidism is a relatively common disorder, present in 1.2% of our referred hypertensive patients, that should be sought and treated.

Arterial hypertension is associated with hypalgesia in humans.

Abstract: An association between increased blood pressure and hypalgesia has been reported in several studies in animals and in a few reports in humans. We investigated the relationship between hypertension and pain perception by comparing the response to graded electrical stimulation of the tooth pulp, which is thought to represent an exclusively nociceptive system. The test was performed with a commercial tooth pulp tester in a large series of subjects with borderline or established hypertension and in three groups of normotensive controls: volunteers, nonhypertensive patients, and medical students with a well-established or no family history of hypertension. Subjects had to report when they started to feel pulp stimulation (sensory threshold) and when this became painful (pain threshold). Sensory and pain thresholds were obtained as means of the measurements on four healthy, unfilled teeth. Sensory thresholds were significantly higher in subjects with borderline or established hypertension than in two of the three normotensive groups (volunteers and normotensive patients), whereas no significant difference was observed between the two hypertensive groups. The results for the pain threshold were qualitatively similar but less clear and less amenable to statistical analysis because this parameter could not be determined with accuracy in a number of subjects in whom the subjective pain threshold was above the upper range of stimulation of the instrument. The association between blood pressure levels and pain perception was further confirmed by the highly significant correlation found for the overall data between mean arterial blood pressure and both thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral circulation in chronic arterial hypertension.

Abstract: Several new concepts have emerged recently regarding the effects of chronic hypertension on cerebral blood vessels. First, hypertrophy of large cerebral arteries in chronic hypertension attenuates increases in pressure of downstream vessels and protects the cerebral microvasculature. Second, in contrast to large cerebral arteries, which become less distensible during chronic hypertension, distensibility of cerebral arterioles increases during chronic hypertension despite hypertrophy of the arteriolar wall. Third, dilatation of cerebral blood vessels with disruption of the blood-brain barrier, and not vasospasm, appears to be the critical factor in the pathogenesis of hypertensive encephalopathy. This concept is supported by the finding that cerebral edema in stroke-prone spontaneously hypertensive rats is preceded by vasodilatation and disruption of the barrier. Fourth, alterations of endothelium-mediated dilatation may impair vasodilator responses in chronic hypertension and predispose to ischemia. Finally, chronic hypertension impairs dilatation of collateral blood vessels in the cerebral circulation. The implication of this finding is that increased susceptibility to cerebral infarction in chronic hypertension may be related in part to compromised responses of the collateral circulation.

Converting enzyme activity and angiotensin metabolism in the dog brainstem.

Abstract: The concentrations of angiotensin converting enzyme (ACE) activity, norepinephrine, and serotonin were measured in microdissected regions of the dog's brainstem and spinal cord. In addition, we determined the in vitro metabolism of 125I-angiotensin I (Ang I) in homogenates of the same brain punch regions. High ACE-specific activity was found in the monoamine-containing regions of the brainstem and in the intermediolateral column of the spinal cord. In brainstem homogenates 125I-Ang I was metabolized to angiotensin II (Ang-[1-8]) and the N-terminal heptapeptide Ang-(1-7). In the presence of MK 422 (50 microM), Ang-(1-7) was still generated, while the production of Ang-(1-8) was inhibited. This study revealed the presence of high ACE activity in monoamine regions of dog brainstem and spinal cord, and showed that the metabolite Ang-(1-7) is the major product generated from Ang I in the presence and absence of ACE inhibition.

Baroreceptor reflex modulation by angiotensin II at the nucleus tractus solitarii

Abstract: This study characterized the effect of nucleus tractus solitarii (NTS) microinjection of the angiotensin II (Ang II) antagonist [Sar1, Thr8]Ang II on the baroreceptor control of heart rate in anesthetized rats. Reflex changes in heart rate were elicited by bolus intravenous injections of either phenylephrine or sodium nitroprusside before and after bilateral microinjection of [Sar1, Thr8]Ang II (100 pmol) or vehicle into the NTS. The slope of the relationship between the change in pulse interval and the change in mean arterial pressure was used as an index of baroreceptor reflex sensitivity. Bradycardia elicited by phenylephrine-induced increases in pressure was significantly greater after NTS injection of [Sar1, Thr8]Ang II. The slope of the pulse interval-arterial pressure relationship was 0.60 +/- 0.09 ms/mm Hg after injection, as compared with 0.42 +/- 0.07 ms/mm Hg before. In contrast, the baroreceptor reflex sensitivity index generated by decreases in pressure with nitroprusside was similar before and after injection. Vehicle injections did not alter the baroreceptor reflex index. Collectively, the data suggest that inhibition of endogenous Ang II in the NTS facilitates the baroreceptor reflex sensitivity to increases, but not decreases, in pressure. This new finding reveals the NTS as one site of action for the tonic effects of endogenous Ang II.

Left ventricular mass and exercise responses predict future blood pressure. The Muscatine Study.

Abstract: Increased blood pressure and left ventricular mass are associated with increased morbidity and mortality in adults with coronary heart disease. To define the predictors of subsequent childhood blood pressure and left ventricular mass, serial echocardiograms and blood pressure responses during exercise were studied in 274 children aged 6 to 15 years, whose systolic blood pressures were in the high, middle, or low range. Persistence of rank order for left ventricular mass and blood pressure, at rest and during exercise, was maintained over a mean follow-up period of 3.4 years, with correlations ranging from 0.33 to 0.44. Subsequent systolic blood pressure was best predicted from initial resting and maximal exercise systolic blood pressures and left ventricular mass. Subsequent left ventricular mass was best predicted from initial left ventricular mass and maximal exercise diastolic blood pressure, but resting systolic blood pressure did not add to this latter prediction. Since left ventricular mass relates best to exercise blood pressure and not to resting blood pressure, left ventricular mass may provide an integrated view of the effects of blood pressure both at rest and during stress. We speculate that increased left ventricular mass in childhood may be an important predictor of subsequent hypertension and its consequences.

Endothelium-dependent responses in carotid and renal arteries of normotensive and hypertensive rats.

Abstract: Endothelium-dependent relaxations are impaired in the aorta of various models of hypertension, but no data are available regarding the cerebral or renal circulation. Endothelium-dependent relaxations were studied in the carotid and renal artery of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Rings with and without endothelium were suspended in organ chambers for isometric tension recording. Acetylcholine and adenosine 5'-diphosphate (ADP) caused endothelium-dependent relaxations in both arteries that were impaired in the carotid, but not in the renal artery, of the SHR, similar to those to the endothelium-independent vasodilator sodium nitroprusside. Indomethacin did not affect relaxations to acetylcholine in the carotid artery, but it significantly augmented them in the renal artery. This finding suggests that an impaired vascular responsiveness to endothelium-derived relaxing factor is responsible for the decreased relaxations in the carotid artery of the SHR. In the renal artery, acetylcholine appears to release both endothelium-derived relaxing factor and a vasoconstrictor prostanoid. Carotid arteries of SHR were more sensitive to the constrictor effects of serotonin than were those of WKY. Endothelium removal caused a twofold to eightfold increase in sensitivity to serotonin in both strains. Thus, endothelium-dependent relaxations to acetylcholine and ADP are reduced and constrictions to serotonin are enhanced in the carotid, but not in the renal, artery of the SHR.

Attenuation of fructose-induced hypertension in rats by exercise training.

Abstract: This study was initiated to see if the insulin resistance, hyperinsulinemia, and hypertension that follow feeding normotensive Sprague-Dawley rats a fructose-rich diet could be prevented by letting rats run spontaneously in exercise wheel cages. Blood pressure in sedentary rats increased from (mean +/- SEM) 125 +/- 2 to 148 +/- 3 mm Hg in response to 2 weeks of a high fructose diet, and this increment was significantly (p less than 0.001) attenuated in exercising rats (from 121 +/- 1 to 131 +/- 2 mm Hg). In addition, mean (+/- SEM) plasma insulin concentration was lower in fructose-fed rats allowed to run spontaneously (44 +/- 2 vs 62 +/- 5 microU/ml; p less than 0.01). Finally, resistance to insulin-stimulated glucose uptake was assessed by determining the steady state plasma glucose response to a continuous glucose and exogenous insulin infusion during a period in which endogenous insulin secretion was suppressed. The results of these studies indicated that the mean (+/- SEM) steady state plasma glucose concentration was significantly lower in the exercise-trained rats (127 +/- 5 vs 168 +/- 6 mg/dl; p less than 0.001), despite the fact that the steady state plasma insulin levels were also lower in rats allowed to run spontaneously (75 +/- 4 vs 90 +/- 5 microU/ml; p less than 0.05). Thus, the ability of exercise-trained rats to stimulate glucose disposal was enhanced as compared with that of sedentary rats fed the same fructose-rich diet. These data demonstrate that the insulin resistance, hyperinsulinemia, and hypertension produced in normotensive rats by feeding them a high fructose diet can be attenuated if rats are allowed to run spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)

The C1 area of the brainstem in tonic and reflex control of blood pressure. State of the art lecture.

Abstract: Recent studies have demonstrated that the neurons of the lower brainstem that are responsible for maintaining normal levels of arterial pressure reside in a specific area of the rostral ventrolateral medulla. In rat, the critical zone corresponds to a small region containing a subpopulation of the adrenergic C1 group, defined immunocytochemically by the presence of the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase. Neurons of this region (the C1 area), possibly including the adrenergic neurons, directly innervate preganglionic neurons in the spinal cord, and are tonically active and sympathoexcitatory. The excitatory transmitter released into the spinal cord is unknown. The discharge of C1 area neurons is locked to the cardiac cycle and, in turn, leads to firing of sympathetic preganglionic neurons. The C1 area neurons are inhibited by baroceptor input and mediate the vascular component of baroceptor reflexes. They also mediate somato-sympathetic pressor responses from skin and muscle and participate in reflex responses to hypoxia. The neurons are directly innervated by local neurons containing gamma-aminobutyric acid, acetylcholine, enkephalin, and substance P, all of which modulate arterial pressure. The C1 area is the site of the hypotensive actions of clonidine. Clonidine appears to act on imidazole receptors in the C1 area to lower arterial pressure. The natural ligand for these receptors may be a newly defined substance in brain, clonidine-displacing substance. Neurons of the C1 area appear to be the critical neuronal group governing the normal resting and reflex control of arterial pressure. They may play a critical role in the maintenance of elevated arterial pressure in hypertension and as a site of action of antihypertensive drugs.

Pressure-diuresis in volume-expanded rats. Cortical and medullary hemodynamics.

Abstract: This study evaluated whether pressure-diuretic and pressure-natriuretic responses are associated with alterations in vasa recta hemodynamics. Autoregulation of cortical and papillary blood flow was studied using a laser-Doppler flowmeter in volume-expanded and hydropenic rats. Superficial cortical flow and whole kidney renal blood flow were autoregulated in volume-expanded rats and decreased by less than 10% after renal perfusion pressure was lowered from 150 to 100 mm Hg. In contrast, papillary blood flow was not autoregulated and fell by 24 +/- 2%. The failure of papillary blood flow to autoregulate was due to changes in the number of perfused vessels as well as to alterations in blood flow in individual ascending and descending vasa recta. Pressure in vasa recta capillaries increased from 6.8 +/- 0.8 to 13.8 +/- 1.2 mm Hg after renal perfusion pressure was elevated from 100 to 150 mm Hg, and renal interstitial pressure rose from 7.4 +/- 0.8 to 12.3 +/- 1.4 mm Hg. In hydropenic rats, papillary blood flow was autoregulated to a significant extent, but it still decreased by 19% after renal perfusion pressure was lowered from 150 to 100 mm Hg. The pressure-diuretic and pressure-natriuretic responses in hydropenic rats were blunted in comparison to those observed in volume-expanded rats. These findings indicate that the pressure-diuretic and pressure-natriuretic responses are associated with changes in vasa recta hemodynamics and renal interstitial pressure.

Mechanisms underlying pressure-related natriuresis: the role of the renin-angiotensin and prostaglandin systems. State of the art lecture.

Abstract: It has long been known that increments in renal perfusion pressure can induce an elevation of urine sodium excretion without changing renal blood flow or glomerular filtration rate. The mechanism underlying this pressure-related natriuresis remains undefined, although the interest in its elucidation has been stimulated by the notion that it may constitute the central phenomenon through which the kidney regulates blood volume and, thereby, blood pressure. Recently, the use of novel experimental techniques has disclosed some important clues about changes in renal hemodynamics that, along with changes in renal humoral regulators, allow us to visualize a possible sequence of events responsible for pressure-related natriuresis. According to this hypothesis, the autoregulatory responses responsible for maintaining glomerular filtration rate are elicited in preglomerular vasculature by changes in renal perfusion pressure. These myogenic responses are coupled through Ca2+ entry in juxtaglomerular cells with inversely related changes in the release of renin and, consequently, with the amount of angiotensin II generated in renal interstitium. The release of renin from juxtaglomerular cells is modulated by the synthesis of prostaglandin I2 from the adjacent endothelial cells. Interstitial angiotensin II could influence sodium tubular reabsorption directly by stimulating sodium transport in proximal renal tubules and indirectly by altering medullary blood flow and, thereby, medullary interstitial pressure. In the renal medulla, the effects of interstitial pressure on sodium reabsorption can be amplified by the release of prostaglandin E2 from interstitial cells. A deficient regulation of this relationship could result in a shift of the pressure-natriuresis curve, leading to hypertension.

Sexual dysfunction in hypertensive men. A critical review of the literature.

Abstract: Sexual dysfunction is common in hypertensive men and often is first reported by patients while receiving hypotensive therapy, leading to a widespread belief by patients and physicians that the sexual dysfunction is caused by a specific antihypertensive medication. However, it is unclear from the literature whether this problem is related to hypertension or to its therapy. Further, whether the erectile failures reported during therapy are a result of 1) reduced penile blood flow secondary to reduction of blood pressure after antihypertensive treatment or to obstructive vascular disease (or both) or 2) specific drug effects has not been well studied. Because of these unresolved issues, this common problem is not well managed and contributes to noncompliance with therapy by hypertensive male patients, which impedes the attainment of satisfactory blood pressure control. The present article reviews the literature related to hypertension and sexual function in men and outlines a management strategy for clinicians that attempts to document normalcy of sexual function before initiating treatment in newly diagnosed hypertensive patients. Further, it does not ascribe causality to specific antihypertensive agents for the sexual dysfunction reported by treated hypertensive patients but attempts instead to delineate the pathogenesis of the dysfunction. Once the pathogenesis is established, treatment plans can be implemented to restore normotension and maintain adequate sexual function among treated hypertensive men. The article also discusses how applied research in this area may be performed.

Serotoninergic mechanisms in hypertension. Focus on the effects of ketanserin.

Abstract: Aggregating platelets release serotonin, which induces contraction of most vascular smooth muscle by activation of S2-serotoninergic receptors. Serotonin released in the circulation may contribute to the increase in peripheral resistance of hypertension as the responsiveness of blood vessels from hypertensive animals and humans to the vasoconstrictor action of the monoamine is augmented. The data obtained with the new antihypertensive agent ketanserin may favor that interpretation. Ketanserin is a selective S2-serotoninergic antagonist with additional alpha 1-adrenergic blocking properties. In humans, it has a terminal half-life of 12 to 25 hours and is eliminated predominantly by the liver. The hemodynamic profile of ketanserin is that of a vasodilator drug with actions on both resistance and capacitance vessels. On short-term intravenous administration, it lowers blood pressure in hypertensive patients with minimal reflex changes in cardiovascular function. When given orally long term to hypertensive patients, ketanserin causes a sustained reduction in arterial blood pressure, comparable to that obtained with either beta-adrenergic blockers or diuretics. Several studies have shown a greater efficacy in older (greater than 60 years of age) than in younger patients independent of starting pressure. Side effects mainly consist of dizziness, somnolence, and dry mouth, but they are usually not severe. The mechanism underlying the antihypertensive effect of ketanserin is unclear. It cannot be attributed to either S2-serotoninergic or alpha 1-adrenergic blockade alone, but an interaction between the two effects appears to be required.

Cardiopulmonary reflex before and after regression of left ventricular hypertrophy in essential hypertension.

Abstract: Studies that have examined the cardiopulmonary receptor control of circulation in hypertension have produced conflicting results. In 10 normotensive subjects and in age-matched essential hypertensive subjects without (n = 10) or with left ventricular hypertrophy (n = 12), as well as in seven subjects of the latter group restudied after 1 year of treatment that induced regression of cardiac hypertrophy, we examined the cardiopulmonary reflex by increasing central venous pressure and stimulating cardiopulmonary receptors through passive leg raising and by reducing central venous pressure and deactivating cardiopulmonary receptors through nonhypotensive lower body negative pressure. Reflex responses were measured as changes in forearm vascular resistance (mean blood pressure divided by plethysmographically measured blood flow), plasma norepinephrine concentration, and plasma renin activity. In hypertensive subjects without left ventricular hypertrophy, stimulation and deactivation of cardiopulmonary receptors caused changes in forearm vascular resistance, norepinephrine concentration, and plasma renin activity that were modestly reduced as compared with those in normotensive subjects. However, all these changes were markedly reduced in hypertensive subjects with left ventricular hypertrophy. Following regression of left ventricular hypertrophy, the changes in vascular resistance, plasma norepinephrine, and plasma renin activity induced by cardiopulmonary receptor manipulation all improved markedly. These results demonstrate that cardiopulmonary receptor regulation of peripheral vascular resistance and of neurohumoral variables is impaired in essential hypertension and that the impairment is much more pronounced when this condition is associated with cardiac structural alterations. Therapeutic regression of these alterations, however, leads to a marked improvement of this reflex, with consequent favorable effects on circulatory homeostasis.

Factors influencing blood pressure and heart rate variability in hypertensive humans

Abstract: We examined the influence of baroreceptor reflex sensitivity (the increase in pulse interval in response to a phenylephrine-induced increase in blood pressure), age, blood pressure, and beta-adrenergic receptor blockade on the variability of blood pressure and heart rate in essential hypertension. Fifty-six subjects were studied before treatment; intra-arterial blood pressure was recorded outside the hospital for 24 hours. Variability was defined (from all beats occurring while subjects were awake) as the standard deviation about the average waking value for mean arterial pressure (MAP) or pulse interval. The correlation (r) between baroreceptor reflex sensitivity and blood pressure variability was -0.47 (p less than 0.0002). Baroreceptor reflex sensitivity was the only independent determinant of blood pressure variability on multiple regression analysis. Thirty subjects were restudied after 5 months of beta-adrenergic receptor blockade. Ambulatory blood pressure was lower during treatment, whereas pulse interval, its variability, and baroreceptor reflex sensitivity were higher. Blood pressure variability was unchanged. The variability of MAP was inversely correlated with baroreceptor reflex sensitivity before (r = -0.42, p less than 0.02) and during (r = -0.45, p less than 0.02) treatment, but it was unrelated to the average ambulatory MAP or to the variability of pulse interval either before or during beta-blockade. Sixteen subjects whose average waking ambulatory blood pressure was 140/90 mm Hg or less were not treated. This group of borderline hypertensive subjects had less variable MAP than did the remaining 40 subjects (12.4 +/- 2.3 [SD] vs 14.5 +/- 2.5 mm Hg; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of dietary sodium, potassium, calcium, and magnesium with blood pressure. Belgian Interuniversity Research on Nutrition and Health.

Abstract: From 1979 through 1984, a randomized epidemiological survey in Belgium assessed the dietary intake of sodium, potassium, calcium, and magnesium using 24-hour food records checked by trained dietitians. Dietary cation intake levels were correlated with blood pressure both in the total group (4167 men and 3891 women) and in the group not taking antihypertensive medication (3814 men and 3329 women). Serum sodium, potassium, calcium, and phosphorus were also measured. Multiple regression analysis adjusting for age, body mass index, heart rate, alcohol intake, and total caloric intake revealed a significant positive correlation between sodium intake and blood pressure in the group not treated for hypertension except for diastolic blood pressure in women. A significant negative correlation was found between dietary calcium intake and diastolic blood pressure in men and between dietary magnesium intake and systolic blood pressure in women. No independent effect of dietary potassium intake on blood pressure could be established. Significant but weak correlations were found between the dietary intake of sodium, potassium and calcium and their serum values. The study confirms the hypothesis that at the population level dietary cations are related to the regulation of blood pressure.

Plasma and urinary catecholamines in salt-sensitive idiopathic hypertension.

Abstract: Nineteen patients with normal renin idiopathic hypertension were arbitrarily classified as salt-sensitive or salt-resistant depending on whether their mean arterial pressure did or did not increase by 8% or more when sodium intake was increased. The responses of the two subsets and of five normal subjects to sodium intakes of 9, 109, and 249 mEq/day given for 7 days were as follows: The salt-sensitive subjects retained more sodium than normal and plasma or urinary norepinephrine did not decrease when they were given a high sodium intake; urinary dopamine was normal but did not increase normally when sodium intake was increased. The salt-resistant subjects excreted sodium normally and plasma and urinary norepinephrine was decreased by 30 and 37%, respectively, when they were given a high sodium intake; urinary dopamine was supernormal and did not increase further when sodium intake was increased. Cumulative sodium retention during the high sodium intake was directly related to the percentage of change in plasma norepinephrine in the hypertensive subjects, suggesting that renal adrenergic activity was a factor in the impaired sodium excretion in the salt-sensitive patients. Cumulative sodium retention and the percentage of change in plasma norepinephrine were inversely related to urinary dopamine in the hypertensive subjects, suggesting that increased formation of dopamine in renal and neural tissue in the salt-resistant subjects may have been responsible for the differences between the subsets in renal and adrenergic responses to a high sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)