Showing papers in "Clinical and Experimental Hypertension in 1998"
TL;DR: Low doses of CTS, including an endogenous ouabain-like compound, influence cytosolic Na+ and Ca2+ concentrations only in the cytoplasmic clefts between the PM and junctional SR (a functional unit the authors call the "plasmerosome").
Abstract: Arterial smooth muscle (ASM) contraction is triggered by agonist-evoked Ca2+ mobilization from sarcoplasmic reticulum (SR). The amount of Ca2+ released, and thus, the magnitude of the contractions, depends directly on SR Ca2+ content. Na+ pump inhibition by cardiotonic steroids (CTS) indirectly increases the Ca2+ content of the SR and, thus, contractility. This sequence of events does not, however, account for the multiple Na+ pump alpha subunit isoforms with different affinities for Na+ and for CTS, nor does it explain the cardiotonic and vasotonic effects of low doses of CTS that do not elevate cytosolic Na+ or Ca2+. We show that the Na+ pump high ouabain affinity (alpha3) isoform and the plasmalemmal (PM) Na/Ca exchanger are confined to PM domains that overlie junctional SR in ASM, while low ouabain affinity alpha1 and the PM Ca2+ pump are uniformly distributed in the PM. Thus, low doses of CTS, including an endogenous ouabain-like compound, influence cytosolic Na+ and (indirectly) Ca2+ concentrations only in the cytoplasmic clefts between the PM and junctional SR (a functional unit we call the "plasmerosome"). In turn, this modulates the Ca2+ content of the junctional SR and cell responsiveness.
117 citations
TL;DR: Only the 12 kD HAP band possessed all of the attributes of natriuretic hormone after extraction of the bands, with essentially no activity found in the 14 kD or 21 kD bands.
Abstract: We have previously demonstrated that a 12 kD hypertension-associated protein (HAP) is elevated in essential hypertension and that this protein has the characteristics of natriuresis, inhibition of Na-K-ATPase, displaces 3H-ouabain from binding sites, and is vasoconstrictive invitroIn the present study, plasma from 101 patients were examined [25 normals (N) age 50, 7 with acute congestive heart failure (CHF), 24 with chronic renal failure (CRF), on dialysis, 5 with idiopathic hyperaldoateronism (PA) and 27 with essential hypertension, untreated (EHT)]. Plasma was extracted with 32% acetonitrile, then analyzed by DELFIA for marinobufagenin and ouabain. In addition, from 32 patients (6 N 50, 5 CHF, 5 CRF, 6 EHT, and 4 PA) SDS gradient gels were obtained. The 12 kD bands were extracted, analyzed for Na-K-ATPase inhibition, marinobufagenin and ouabain, and compared to 14 kD and 21 kD bands. Marinobufagenin was found to be elevated in CRF, EHT, PA and CHF. Ouabain was increased only in P...
111 citations
TL;DR: It is suggested that at least one of the mammalian counterparts to the cardiac glycosides is a novel steroidal isomer of ouabain, which is secreted by the adrenal cortex, and augments cardiovascular function.
Abstract: The human circulation contains four readily distinguishable biologically active inhibitors of the sodium pump that appear to be endogenous to mammals. Of these, one has been purified to homogeneity and by numerous chromatographic, mass spectral, biochemical, and physiological analyses has been shown to be a novel steroidal isomer of ouabain in which the location and orientation of two or more steroidal hydroxyl groups differ. The human endogenous "ouabain" (EO) is a high affinity reversible inhibitor of the pump with inotropic and vasopressor activity. Circulating levels of EO depend upon the adrenal cortex and metabolic events preceding and following pregnenolone formation are involved in EO biosynthesis. Within the adrenal gland, the stimulus-secretion mechanisms for EO secretion are distinct from those for aldosterone highlighting different regulation. Among Caucasians with essential hypertension, 30-45% have elevated circulating levels of EO. Sustained elevation of plasma ouabain in rats induces chronic hypertension with characteristics similar to those in patients and whose severity is determined by inherited factors and renal function. In conclusion, at least one of the mammalian counterparts to the cardiac glycosides is a novel steroidal isomer of ouabain. The isomer is secreted by the adrenal cortex, and augments cardiovascular function. The observation of this entity in the human circulation, the demonstration of its biosynthesis, and the existence of specific receptors suggest to us that EO is a novel adrenocortical hormone and may be part of a broader family of novel mammalian steroids that regulate the sodium pump and other processes.
111 citations
TL;DR: It is demonstrated that EDLF response to VE includes stimulation of brain OLC and plasma bufodienolide and that marinobufagenin-like and ouabain-like immunoreactive material are stimulated by acute plasma volume expansion.
Abstract: The aim of the study was to further investigate the nature of endogenous digitalis-like factors stimulated by acute plasma volume expansion (VE), 10 male Fisher 344XNB rats were given intravenous (iv) saline infusion (4% of the body mass) for 30 min, which caused a fall in % hematocrit (35.9±0.69 vs. 41.8±1.05; vs. 10 controls, P<0.01). EDLF was measured in C-18 reverse-phase extracted (32%+80% acetonitrile) tissues. VE was associated with an increase in plasma marinobufagenin-like factor (MLF)(0.49±0.05 vs. 0.2±0.06 nmol/L, P<0.01) and pituitary ouabain-like compound (OLC) (30.9±3.12 vs. 3.2±2.3 pmol/g, P<0.01). Plasma OLC decreased (0.087±0.018 vs. 0.21±0.04 nmol/L, P<0.02), and pituitary MLF did not change (0.05±0.01 vs. 0.07±0.02 pmol/g) after VEChloroform extracted urine from 5 volume-expanded male mongrel dogs was fractionated on reverse-phase HPLC columns in a linear gradient of 0–80% acetonitrile. The material cross-reacting with marinobufagenin antibody eluted from HPLC column as a single peak, d...
100 citations
TL;DR: The results show that pretreatment with the NHE-subtype 1 inhibitor cariporide is cardioprotective by reducing infarct mass in rabbits in a dose-dependent manner and could be demonstrated over a broad range of doses.
Abstract: The aim of this study was to investigate the dose-dependent effect of pretreatment with the selective sodium-hydrogen exchange NHE-subtype 1 inhibitor cariporide on myocardial infarct mass in a rabbit model of coronary ligation and reperfusion. Furthermore, in a second part of the study, we tested the effect of cariporide in the rabbits when given prior to reperfusion.Rabbits (n=49) were randomized in 7 groups: saline vehicle, cariporide: 0.01, 0.03, 0.1 and 0.3 mg/kg, and subjected to a 30 min occlusion of a branch of the left coronary artery followed by 2 h reperfusion. Cariporide was given as a bolus intravenously 10 min before occlusion or 5 min before reperfusion. After reperfusion, myocardial infarct mass was determined by triphenyl tetrazolium chloride staining and expressed as a percent of area at risk.Cariporide given intravenously 10 min before occlusion in doses of 0.01, 0.03, 0.1, 0.3 mg/kg, led to a dose-dependent reduction in infarct mass from 58 ± 6% in controls to 48 ± 4% (-17 %, NS), 36 ±...
76 citations
TL;DR: Chronic oral treatment of genetically hypertensive rats by the AT1 receptors antagonist Telmisartan reveals a blood pressure lowering and reno-protective effect of this drug comparable to other AT1 receptor antagonists or converting enzyme inhibitors, and demonstrates a marked reduction of cardiac hypertrophy by TelmisArtan in this model.
Abstract: The aim of the study was to assess the effects of chronic angiotensin I receptor blockade on blood pressure, the renin-angiotensin system in plasma and kidney and the extent of renal damage in spontaneously hypertensive rats of the stroke prone strain (SHRsp). Four months old male SHRsp rats were orally treated with a high (10 mg/kg b.w. per day) or a low dose (1 mg/kg b.w. per day) of the AT1 receptor antagonist Telmisartan and compared to Losartan- (20 mg/kg b.w. per day), Captopril-treated (50 mgkg b.w. per day) or untreated control groups for 38 days. Despite a similar extent of blood pressure reduction in all groups (except low dose Telmisartan), high dose Telmisartan but not Losartan or Captopril significantly reduced left ventricular weight by 24% compared to controls (p<0.05). Renal damage as assessed by urinary albumin or glomerulosclerosis index was significantly reduced in all treatment groups (p<0.02). Plasma renin concentration was significantly elevated (p<0.02) and plasma angiotensinogen si...
58 citations
TL;DR: The results suggest that the activation of AT1 angiotensin II receptors stimulates Na+,K+-ATPase activity via a PTx-sensitive G protein-linked inhibition of adenylyl cyclase pathway, whereas the inhibition of Na+K-ATpase activity following AT1 receptor activation involves multiple signaling pathways which may include stimulation of adenosine cyclase and PLA2.
Abstract: The present study was designed to determine the cellular signaling mechanisms responsible for mediating the effects of angiotensin II on proximal tubular Na+,K+-ATPase activity. Angiotensin II produced a biphasic effect on Na+,K+-ATPase activity: stimulation at 10(-13) - 10(-10) M followed by inhibition at 10(-7) - 10(-5) M of angiotensin II. The stimulatory and inhibitory effects of angiotensin II were antagonized by losartan (1nM) suggesting the involvement of AT1 receptor. Angiotensin II produced inhibition of forskolin-stimulated cAMP accumulation at 10(-13) - 10(-10) M followed by a stimulation in basal cAMP levels at 10(-7) - 10(-5) M. Pretreatment of proximal tubules with losartan (1nM) antagonized both the stimulatory and inhibitory effects of angiotensin II on cAMP accumulation. Pretreatment of the proximal tubules with pertussis toxin (PTx) abolished the stimulation of Na+,K+-ATPase activity but did not affect the inhibition of Na+,K+-ATPase activity produced by angiotensin II. Pretreatment of the tubules with cholera toxin did not alter the biphasic effect of angiotensin II on Na+,K+-ATPase activity. Mepacrine (10microM), a phospholipase A2 (PLA2) inhibitor, reduced only the inhibitory effect of angiotensin II on Na+,K+-ATPase activity. These results suggest that the activation of AT1 angiotensin II receptors stimulates Na+,K+-ATPase activity via a PTx-sensitive G protein-linked inhibition of adenylyl cyclase pathway, whereas the inhibition of Na+,K+-ATPase activity following AT1 receptor activation involves multiple signaling pathways which may include stimulation of adenylyl cyclase and PLA2.
55 citations
TL;DR: Experimental data providing evidence for physiological mechanisms involved in the regulation of blood pressure oscillations such as sympathetic nervous system, renin-angiotensin system, NO, respiration, heart function, and circulating blood volume are reviewed.
Abstract: Spectral analysis of blood pressure fast oscillations (short-term variability), both in humans and animals, reveals three major frequential domains: the very low-, low- and the high-frequency domain. In this paper, experimental data providing evidence for physiological mechanisms involved in the regulation of blood pressure oscillations such as sympathetic nervous system, renin-angiotensin system, NO, respiration, heart function, and circulating blood volume are reviewed. In addition, novel evidence is provided by the author for vasopressin modulation of the low- and high-frequency blood pressure components. This review suggests that the multiplicity of factors involved in the genesis of the blood pressure spectral components imply utmost caution in interpreting spectral results.
42 citations
TL;DR: This review addresses recent developments in the neurobiology of an endogenous inhibitor of brain Na+, K+ - ATPase, "ouabain", which mediates sympathoexcitatory and pressor responses to acute and chronic increases in cerebrospinal fluid sodium concentration.
Abstract: This review addresses recent developments in the neurobiology of an endogenous inhibitor of brain Na+, K+ - ATPase, "ouabain" "Ouabain" is present in hypothalamic and medullary neurons and mediates sympathoexcitatory and pressor responses to acute and chronic increases in cerebrospinal fluid (CSF) sodium concentration as well as mediates the sympathoexcitatory and pressor responses to high dietary sodium intake in SHR and Dahl-S rats, and sympathetic hyperactivity in the congestive heart failure Some of these actions of "ouabain" in the CNS take place in the median preoptic nucleus and ventral part of the AV3V region Despite recent advances in unveiling a biological role for "ouabain" its structure, biosynthetic and metabolic pathways as well as actual control mechanisms remain unresolved
41 citations
TL;DR: An antihypertensive compound which selectively antagonizes the pressor effect of OLF and corrects the ion transport defect is under development and can represent a new pharmacological approach to the treatment of hypertension.
Abstract: Endogenous ouabain-like factor (OLF) is present in mammai tissues and after standardized extraction procedure can be similarly quantified by two independent assays: RIA and Na-KATPase inhibition. OLF was quantified both from plasma and tissues obtained from MHS hypertensive and MNS normotensive rats, maintained under the same enviromental and dietary conditions, and from plasma of healthy volunteers and essential hypertensive patients. OLF biochemical characterization shows that it behaves like ouabain except for a 1000-fold higher affinity for the ouabain low-affinity Na-KATPase isoforms than ouabainTissue and plasma levels of OLF are higher in MHS than in MNS rats and are not influenced by exogenous OLF sources. Plasma OLF is also increased in a subgroup of hypertensive patients. Both in rats and humans a primary cell membrane alteration affecting ion transports seems to be linked to the increased levels of OLF. An antihypertensive compound which selectively antagonizes the pressor effect of OLF and cor...
31 citations
TL;DR: The abnormalities found in SHR at the mitochondrial level suggest a profound rearrangement of energy production mechanisms in this model of left ventricular hypertrophy; whether the defects are determined genetically, and then worsen with the hypertensive state, remains to be determined.
Abstract: The aim of this study was to investigate the oxidative phosphorylation and additional adenosinetriphosphate (ATP) production mechanisms in mitochondria isolated from hypertrophied left ventricles of spontaneously hypertensive rats (SHR). Measurements of adenosinediphosphate (ADP)/ ATP and inorganic phosphate (Pi) carrier activities showed a significant reduction of Vmax values thus suggesting a general decrease of ATP supply in the hypertrophied ventricles. Investigation of mitochondrial enzyme activities showed 45% and 90% increases of adenylate-kinase and 80% and 110% increases of creatine-phosphokinase in 5- and 24-week-old SHR, before and after the development of the hypertensive state, respectively. The abnormalities found in SHR at the mitochondrial level suggest a profound rearrangement of energy production mechanisms in this model of left ventricular hypertrophy; whether the defects are determined genetically, and then worsen with the hypertensive state, remains to be determined.
TL;DR: Attenuation in the Ach induced NO release and augmentation in the superoxide radical generation seems to play an important role in the modulation of vasoreactivity following renal hypertension in rats.
Abstract: Objectives:Present study was undertaken to investigate involvement of nitric oxide (NO) and superoxide radicals in the modulation of vasoreactivity in a model of renal hypertensionMethod:Hypertension was induced in the male Sprague Dawley rats by aortic banding just above the left kidney. Relaxation or contraction following cumulative addition of acetylcholine (Ach, 1 × 10-8to 1 x-5M) or phenylephrine (PE, 1 × 10-8to 1 × 10-5mol/1) was studied in the aortic rings obtained from sharn operated normotensive, hypertensive and captopril pretreated rats. Ach and PE responses were taken in the presence or absence of NO synthase inhibitor (L-NAME; 1 × 10-5and 1 × 10-4mol/1). Spontaneous release of NO from the aortic rings was evaluated by studying the inhibition of adenosine phosphate stundated platelet aggregation, while superoxide radcals were estunated by cytochrome c reduction methodResults:Ach induced vasorelaxation in PE precontracted rings was impaired followmg 8 wk alter aorbc bandmg, while spontaneous re...
TL;DR: Efonidipine attenuates SBP increase and ameliorates glomerular injury as well as nifedipine and enalapril on proteinuria suggest that different mechanisms mediate the improvement of proteinuria.
Abstract: We investigated the effects of a calcium antagonist, efonidipine, which was reported to dilate not only afferent arterioles but also efferent arterioles, on progression of renal failure in salt-loaded partially nephrectomized spontaneously hypertensive rats (SHR). Forty-four SHR's with 5 of 6 nephrectomy were divided into four groups: group 1 as control (n=20); group 2, efonidipine-treated (n=8); group 3, enalapril-treated (n=8); and group 4, nifedipine-treated (n=8). The rats were given these drugs and a high-salt diet (5% NaCl) for 8 weeks. During the experiment, systolic blood pressure (SBP) and daily urinary protein excretion were measured eveiy 2 weeks. At the end of the study. seniin creatinine was deteimined, and renal tissues were obtained for light microscopic examination. SBI was markedly reduced by 8-week antihypertensive treatment. (control, 267±7 mmHg: efonidipine, 181 ± 7 mmHg; enalapril, 200±12 mmHg; nifedipine, 184±6 mmHg). Glomerular sclerosis developed markedly in the control group, but ...
TL;DR: It is suggested that early, long-term treatment with captopril can prevent alterations in endothelial function observed in SHR even after ACE-inhibitor therapy has been stopped.
Abstract: Angiotensin converting enzyme inhibitors (ACE-I) have been shown to prevent impairment of endothelial cell function in Spontaneous Hypertensive rats (SHR). The purpose of this study was to examine the effects of early, long-term captopril (ACE-I) treatment and its withdrawal on vascular reactivity in SHR. Three groups of male SHR were studied: 1) untreated SHR; 2) SHR treated with captopril in-utero and maintained on oral treatment post-weaning (SHRCAP); and 3) SHR treated with captopril in-utero followed by withdrawal of drug therapy at two months of age (OFFCAP). All rats were studied at six months of age. Isolated aortic ring segments were suspended in tissue chambers for measurement of isometric force. Ring segments were exposed to cumulative concentrations of serotonin or phenylephrine (3 x 10(-9)-3 x 10(-5) M). SHR demonstrated an enhanced sensitivity to serotonin induced contraction. EC50 value were: SHR 3.6+/-1.4 x 10(-7)M, SHRCAP 9.5+/-0.5 x 10(-7) and OFFCAP 8.1+/-0.9 x 10(-7). Endothelium-dependent relaxation to acetylcholine (ACh) was markedly impaired in the SHR. Maximum relaxation (Rmax) to ACh was 61.1+/-1.6% of serotonin induced contraction versus 91.4 +/- 1.2% and 90.7 + 1.8% relaxation in SHRCAP and OFFCAP, respectfully (p<0.05). These data suggest that early, long-term treatment with captopril can prevent alterations in endothelial function observed in SHR even after ACE-inhibitor therapy has been stopped.
TL;DR: Results suggest that Na+, K+-ATPase inhibitors which interact with ouabain antibodies, but not those which interaction with bufalin antibodies, are synthesized in bovine and rat adrenals.
Abstract: The biosynthesis of digitalis-like compounds (DLC) was determined in bovine and rat adrenal homogenates by following changes in the concentration of DLC using three independent sensitive bioassays: inhibition of [3H]-ouabain binding to red blood cells and competitive ouabain and bufalin ELISA. The amounts of DLC in bovine and rat adrenal homogenates, as measured by the two first bioassays, increased with time when the mixtures were incubated under tissue culture conditions. These results suggest that Na+, K+-ATPase inhibitors which interact with cuabain antibodies, but not those which interact with bufalin antibodies, are synthesized in bovine and rat adrenals
TL;DR: A unified hypothesis for blood pressure control is outlined via a combination of the plasma volume regulating pressure-natriuresis mechanism and the powerful antihypertensive actions of the "medullipins" (i.e. vasodilatation, inhibition of sympathetic drive and a diuretic action).
Abstract: It has long been recognised that the kidneys take part in blood pressure control via both their exocrine and endocrine functions. An endocrine antihypertensive function of the renal medulla has been proposed. The renal medullary depressor substances (“medullipins”), are released in response to increased renal perfusion pressure. It has been suggested that the release of “medullipin” is controlled via changes in renal medullary blood flow. Recent observations also suggest that renal medullary blood flow is involved in the control of the pressure/natriuretic-diuretic action of the kidneyIn this review we outline a unified hypothesis for blood pressure control via a combination of the plasma volume regulating pressure-natriuresis mechanism and the powerful antihypertensive actions of the “medullipins” (i.e. vasodilatation, inhibition of sympathetic drive and a diuretic action). It is hypothesised that the activity of both these systems are under control by renal medullary blood flow
TL;DR: Investigation of the effects of erythro-9-(2-hydroxyl-3-nonyl) adenine (EHNA), an adenosine deaminase inhibitor, on hemodynamic and renal parameters in 16-week-old and 36- week-old SHR and normotensive Wistar Kyoto rats and 1,3-dipropyl-8-p-sulfopheznylxanthine (DPSPX) blocked the anti
Abstract: Adenosine is an ubiquitously occurring endogenous nucleoside that via cell surface receptors exerts multiple antihypertensive actions, and mediates a number of biological responses that may reduce cardiovascular disease risk. Therefore modulation of endogenous levels of adenosine may offer beneficial effects in hypertension. The objective of this study was to determine whether inhibition of adenosine deaminase lowers blood pressure in spontaneously hypertensive rats (SHR). We investigated the effects of erythro-9-(2-hydroxyl-3-nonyl) adenine (EHNA), an adenosine deaminase inhibitor, on hemodynamic and renal parameters in 16-week-old and 36-week-old SHR and normotensive Wistar Kyoto rats (WKY) and in 36-week-old SHR and WKY pretreated with 1,3-dipropyl-8-p-sulfopheznylxanthine (DPSPX, an adenosine antagonist that does not enter the brain and is restricted to the extracellular space). Adenosine deaminase inhibition with EHNA (10 m a g, iv.) produced a marked fall in arterial blood pressure in older (MABP 16...
TL;DR: A protein of Mr = 60 kDa has been found in bovine serum by affinity-labeling with N-hydroxysuccimidyl digoxigenin-3-O-methylcarbonyl-epsilon-aminocaproate, consistent with the postulate that endogenous ouabain and proscillaridin A immunoreactivities may belong to a new class of cardiotonic steroid hormones.
Abstract: A material crossreacting with antibodies against the bufadienolide proscillaridin A and inhibiting the sodium pump was found in human blood plasma. The concentration of the material with a retention time similar to ouabain in a reversed phase HPLC correlated to systolic blood pressure and pulse pressure. Affinity purification of this compound from bovine adrenals resulted in the isolation of a compound with molecular mass of 600 Da that was not identical with ouabain. Consistent with the postulate that endogenous ouabain and proscillaridin A immunoreactivities may belong to a new class of cardiotonic steroid hormones, a protein of Mr = 60 kDa has been found in bovine serum by affinity-labeling with N-hydroxysuccimidyl digoxigenin-3-O-methylcarbonyl-epsilon-aminocaproate.
TL;DR: It is concluded that insulin has independent direct and indirect effects on LSNA, RSNA, MAP and HR that are modulated by glycemia and the baroreflex.
Abstract: In this study we measured simultaneously and sequentially the lumbar sympathetic nerve activity (LSNA) or renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) in response to insulin with co-existing hypoglycemia or with glucose replacement in normal rats. Sinoaortic denervation (SAD) was used to evaluate the influence of the baroreflex. LSNA, RSNA, MAP and HR were determined using an acquisition processor and computer software. Bolus insulin infusion where the blood glucose was allowed to decrease resulted in an immediate decrease in MAP. The HR decreased for approximately 15 min and subsequently increased. The LSNA increased immediately after insulin infusion peaking at 25 minutes and then recovered toward baseline. Insulin infusion with glucose replacement resulted in a decrease in MAP and HR. The LSNA progressively increased and was maintained throughout the experimental period. Insulin infusion with hypoglycemia increased RSNA and when hypoglycemia was prevented the RSNA decreased. SAD attenuated the decrease in MAP and LSNA response to insulin. Thus, insulin acts to decrease MAP while simultaneously increasing HR, LSNA and RSNA when hypoglycemia is allowed to occur. However, insulin acts to decrease HR and RSNA when euglycemia is maintained. The insulin-induced increase in LSNA is modulated by the baroreflex mechanism. We conclude that insulin has independent direct and indirect effects on LSNA, RSNA, MAP and HR that are modulated by glycemia and the baroreflex.
TL;DR: Vascular ET-1 content but not plasma levels are increased in uremic rats treated with r-HuEPO suggesting an increase in blood vessel ET- 1 production which may play a role in the pathogenesis of r- HuEPO-induced hypertension.
Abstract: The present study was designed to evaluate whether changes in plasma and blood vessel endothelin-1 (ET-1) concentrations may play a role in the enhanced blood pressure response to recombinant human erythropoietin (r-HuEPO) replacement therapy in uremia. Renal failure was induced by 5/6 nephrectomy (Nx). Uremic rats received either r-HuEPO (100 u s.c. three times a week) or the vehicle for 5 weeks. They were compared to control rats receiving the vehicle. Systolic blood pressure (tail cuff method), hematocrit, serum creatinine, plasma and tissue ET-1 were measured at the end of the protocol. Immunoreactive ET-1 (ir-ET-1) was determined by radioimmunoassay of acid-extracts from the plasma, thoracic aorta and mesenteric arterial bed. Creatinine increased about three fold in Nx animals. Blood pressure in control rats was 120 ± 3 mmHg compared to 161 ± 6 mmHg in the Nx + vehicle group (p<0.01) and 199 ± 9 mmHg in the Nx + r-HuEPO group (p±0.01). Plasma ir-ET-1 levals were similar in the Nx + vehicle and Nx + r...
TL;DR: The inhibitor which acts on the sodium pump in arteries appears to be present only in low renin hypertension.
Abstract: Three lines of evidence led to our suggestion in 1976 that sodium pump inhibitors are involved in volume expanded hypertension. These were 1) pressor activity of low renin hypertensive blood 2) natriuretic and sodium pump inhibiting activities of volume expanded blood and 3) potassium vasoactivity which was blocked by ouabain and suppressed potassium vasodilatation, myocardial Na-K-ATPase, and artery, vein and WBC sodium pumps in low renin hypertension. This led to bioassay of plasma from acutely volume expanded dogs and from dogs with one-kidney, one wrapped hypertension for sodium pump inhibiting activity that acts on arteries. Positive results were reported in 1980. The assay was also positive in rats with one-kidney, one clip and reduced renal mass hypertension (but not in rats with spontaneous or salt sensitive hypertension) and in humans with acute volume expansion and low renin essential hypertension (but not in humans with normal renin hypertension). Thus the inhibitor which acts on the sodium pump in arteries appears to be present only in low renin hypertension.
TL;DR: Results suggest that vasodilatory /3 -blockers such as nipradilol and long-acting Ca channel blockers such as barnidipine may be usefull for insulin sensitivity in patients with essential hypertension.
Abstract: Objectives To assess the effects of a vasodilatory β -adrenoceptor blocker, nipradilol, and a long-acting Ca channel blocker, barnidipine, on insulin sensitivity.Design Insulin sensitivity was determined using a euglycemic hyperinsulinemic clamp technique before and after a 12-week treatment period in eighteen patients with essential hypertension.Results Both drugs decreased blood pressure without affecting any serum parameters of glucose and lipid metabolism. Nipradilol significantly augmented glucose infusion rate (GIR) from 3.11 ± 0.28 to 4.69 ± 0.57 mg/kg/min (p=0.027). Barnidipine also increased GIR from 3.91 ± 0.43 to 5.29 ± 0.43 mg/kg/min (p=0.028). Plasma norepinephrine concentrations significantly increased with barnidipine treatment, while nipradilol had no effect on plasma norepinephrine levels. No adverse events were reported during the study.Conclusions These results suggest that vasodilatory /3 -blockers such as nipradilol and long-acting Ca channel blockers such as barnidipine may be usefui...
TL;DR: The data suggest that chronic central sympathetic suppression with clonidine in CHF results in significant functional amelioration and improved electrophysiologic stability.
Abstract: Previous short-term studies demonstrated that treatment with clonidine produced significant hemodynamic improvement in patients with congestive heart failure (CHF). In this study we followed 12 CHF patients (10 M, 2 F age 63 ± 11, 10 with ischemic cardiomyopathy and 2 with dilated cardiomyopathy) treated with 0.15 or 0.075 mg oral clonidine twice daily for 13 ± 5 months (range 6-23), with functional evaluation at baseline, 6 weeks and 6 months. There was suppression of circulating cateholamines, associated with significant ameliorations in NYHA class, in duration of exercise tolerance (from 246 ± 68 sec to 362 ± 30 and 459 ± 70 sec, respectively p < 0.02), in ejection fraction (from 32 ± 7% to 35 ± 5 and 39 ± 7% p < 0.04) and in left ventricular enlargement as assessed echocardiographically. There were also improvements in a number of electrophysiologic parameters calculated by computerized analysis of ambulatory ECG tapes, such as heart rate variability, indicating diminished propensity to malignant arrh...
TL;DR: The HSLK diet is associated with inappropriate activation of the sympathetic nervous system and increased arterial pressure in both strains, and it is suggested that the observed abnormalities in calcium and magnesium metabolism might independently promote hypertension development in the S strain.
Abstract: Dietary combination of high salt with low potassium (HSLK) exacerbates hypertension development in Dahl salt-sensitive (S) rats, and produces a mild degree of hypertension in otherwise salt-resistant (R) rats. Increased blood pressure in both strains is associated with increased urinary excretion of calcium and magnesium. The objective of this study was to determine the effect of blood pressure on body balance of these ions in Dahl rats on HSLK diet. Two groups of S and two groups of R weanlings were all placed on HSLK diet (NaCl=8%, K=0.2%) for eight weeks. One group of each strain was subjected to chemical sympathectomy with 6-hydroxydopamine (6-OHDA) to counteract hypertension development. Urinary norepinephrine was used to determine efficacy of 6-OHDA treatment. Systolic blood pressures of conscious animals were measured daily throughout the study. The last three days on the diet were used to determine total dietary intake and urinary as well as fecal excretion of sodium, calcium and magnesium. At the end of the study, extracellular fluid volume, serum aldosterone and parathyroid hormone were analyzed. Final systolic blood pressures in the 4 groups were as follows: S=235+/-9 mmHg (n=9); R=155+/-3 mmHg (n=8); 6-OHDA S=151+/-6 mm Hg (n=8); 6-OHDA R=117+/-6 mm Hg. Chemical sympathectomy decreased blood pressure in both S and R rats. There was no indication of sodium accumulation in S rats. Associated with reduced parathyroid hormone levels the S strain had significantly less positive balance for calcium than the R strain, primarily due to increased urinary excretion. A less positive balance for magnesium was also observed, due mainly to relatively reduced intestinal absorption of the ion. We conclude that the HSLK diet is associated with inappropriate activation of the sympathetic nervous system and increased arterial pressure in both strains. In addition, since divalent cations may influence blood pressure, we suggest that the observed abnormalities in calcium and magnesium metabolism might independently promote hypertension development in the S strain.
TL;DR: Data indicate an excitatory effect of ouabain on baroreceptor nerve activity in normotensive and markedly in hypertensive rats which could contribute to the reflex arterial pressure regulation, besides the known inotropic action on the heart.
Abstract: The effect of acute ouabain treatment was evaluated on afferent baroreceptor nerve activity in spontaneously hypertensive rats (SHR) compared with Wistar Kyoto rats (WKY). Under urethane anesthesia (1.2 mg/Kg) the discharge of the recurrent laryngeal nerve was utilized as index of arterial baroreceptor activity (BNA) in rats with the ipslateral vagus cut at a proximal level. The ouabain (30 μg, i.v.) treatment produced an excitatory effect on BNA without changes in basal arterial pressure in both groups studied. This effect was larger in SHR (92±10%) than WKY (37±4%, P < 0.01)The arterial pressor response to phenylephrine was similar in both SHR and WKY before (20±1 and 22±1.2 mmHg) and after (18±1.4 and 20±2 mmHg, respectively) ouabain. The BNA under phenylephrine-induced peaks of high arterial pressure was significantly higher in SHR (61±15%) than in WKY (41±5% P < 0.01) but after ouabain treatment the opposite was observed (31±5 vs. 61±4% P < 0.01). The inhibitory effects of sodium nitroprusside on art...
TL;DR: These findings are the first demonstration of a direct and modulatory action of des-Asp-angiotensin I on the blood vessels of the SHR and raise the possibility of its involvement in blood pressure control, its exact role remains to be further studied.
Abstract: The actions of des-Asp angiotensin I, a nine aminoacid peptide, on the contractility of the aortic rings of the normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were studied. In the presence of captopril which prevented its degradation to angiotensin III by angiotensin converting enzyme, des-Asp-angiotensin I exerted direct concentration-dependent contractile action on the aortic rings. The contractile action was concentration-dependently attenuated by the AT1 receptor antagonist, losartan, but was not affected by the AT2 receptor antagonist, PD123319; indicating that angiotensin AT1 receptors mediate the direct contractile action. The response to des-Asp-angiotensin I was qualitatively different from that to angiotensin III i.e. lower potency and a likely higher efficacy suggesting that the two angiotensins act on different subtypes of angiotensin receptor. The response of the aortic rings to angiotensin III and des-Asp-angiotensin I in the SHR was significantly lower than the corresponding responses in WKY. Des-Asp-angiotensin I attenuated in a concentration-dependent and U-shape manner the response of the aortic ring to angiotensin III in the SHR but not in the WKY. Significant attenuation occurred in the pico to nano molar range of des-Asp-angiotensin I which is within the physiological concentration of the nonapeptide. Although these findings are the first demonstration of a direct and modulatory action of des-Asp-angiotensin I on the blood vessels of the SHR and raise the possibility of its involvement in blood pressure control, its exact role remains to be further studied.
TL;DR: The results suggest that there is a connection between RVLM cholinergic systems and cardiovascular baroreflexes and it is probable that neurons in the CVLM are involved in mediating the release of ACh in the RVLM.
Abstract: We examined whether baroreceptor activation causes a release of acetylcholine (ACh) in the rostral ventrolateral medulla (RVLM) of the rat, in order to investigate a possible connection between RVLM cholinergic systems and cardiovascular baroreflexes. Male Wistar rats were anesthetized, paralyzed and artificially ventilated. Either electrical stimulation of aortic nerve or baroreceptor activation by intravenous phenylephrine produced an increase of the release of ACh in the RVLM, whereas baroreceptor denervation and tetrodotoxin (TTX) microinfusion in the RVLM inhibited the increase in ACh release induced by phenylephrine. TTX injected in the caudal ventrolateral medulla (CVLM) inhibited the phenylephrine-induced increase of ACh release. The excitatory amino acid L-glutamate microinfused in the CVLM produced an release in ACh release in the RVLM. These results suggest that there is a connection between RVLM cholinergic systems and cardiovascular baroreflexes. It is probable that neurons in the CVLM are involved in mediating the release of ACh in the RVLM.
TL;DR: The acetylcholine-induced vasodilation in the kidney and the heart was attenuated in theSHR compared to the WKY, which might suggest a difference in the endothelial response between the SHR and the W KY in some, but not in all, tissues.
Abstract: This study was performed to investigate the in vivoeffects of acetylcholine, a stimulator of endogenous NO production, and nitroprusside, an exogenous NO-donor, on hemodynamics in the normotensive (WKY) and the hypertensive (SHR) rat. Anesthetized rats were given microspheres for the measurement of cardiac index (CI), total vascular resistance (TPRI), regional blood flow and vascular resistance. Infusion of acetylcholine (2 μg/kg/min) caused a marked decrease in TPRI by (−35±5%, ±SEM) in the WKY (n=8), whereas in the SHR (n=8) a less pronounced reduction was seen (−14±3%, p<0.01 between groups). CI increased by 27±9% in the WKY, but was unaltered in the SHR. Blood pressure decreased similarily (17–20%). Acetylcholine significantly increased blood flow by about 40% in the kidneys and the heart in the WKY, but had no significant effect in the SHR. Other tissues, such as skeletal muscle and cerebral tissues, showed no major changes. Infusion of nitroprusside (1μg/kg/min) reduced blood pressure by 5 to 10% in...
TL;DR: It was demonstrated that RAS was playing a significant role in cardiac hypertrophy and renal disorders of THM and that lisinopril had inhibitory effects on cardiac hyperTrophy and kidneys glomerular sclerosis by inhibiting RAS.
Abstract: Tsukuba hypertensive mice (THM) are a hypertensive model prepared by mating a transgenic mice with human renin gene and a transgenic mice with human angiotensinogen gene. In the present study, we examined effects of renin-angiotensin system (RAS) on cardiac hypertrophy and renal disorders using Tsukuba hypertensive mice. While THM showed an increase of about 30 mmHg in systolic pressure compared to C57BL/6 mice employed as normal control animals, the increase in blood pressure was not observed in the mice to which either gene was transferred. Urinary volume, water intake volume, urinary albumin excretion, heart to body weight ratio and renal glomerular sclerosis index increased significantly in THM, but none of these parameters showed a significant difference from the C57 mice when they were examined in mice to which either of the genes was transferred. In contrast, when lisinopril was administered to THM, all the parameters decreased significantly without lowering the systolic pressure. From these findin...
TL;DR: These mutations have the potential to alter the type and/or affinity of transcriptional factors for the SHR renin gene in vivo, and result in renin overproduction at an extra-renal tissue site subserving blood pressure control.
Abstract: We and others have reported elevated levels of renin mRNA in extrarenal tissues of the spontaneously hypertensive rat (SHR) of the Okamoto strain. We hypothesise that this is due to mutations we have found in putative, cis-regulatory regions in the first intron of its renin gene. Here we report two G-A mutations at position +502 and +934 of the first intron of the SHR renin gene, when compared to normotensive Wistar Kyoto (WKY) and Sprague Dawley (SD) rats. These mutations fall within consensus sequences for the well described E2A and peroxisome proliferator-activated receptor (PPAR) transcription factors. We used electrophoretic mobility shift assays to determine if these mutations alter the pattern or affinity of nuclear protein binding to oligonucleotides homologous to these regions of the renin gene. Both mutations significantly altered the intensity and pattern of nuclear protein binding to oligonucleotides homologous with the renin gene regions bearing these putative transcription factor binding sites. Thus these mutations have the potential to alter the type and/or affinity of transcriptional factors for the SHR renin gene in vivo, and result in renin overproduction at an extra-renal tissue site subserving blood pressure control.