Elevated Blood Pressure In Spontaneously Hypertensive Rats Research Articles

The abnormalities of adrenomedullary hormonal system in genetic hypertension: Their contribution to altered regulation of blood pressure.

It is widely accepted that sympathetic nervous system plays a crucial role in the development of hypertension. On the other hand, the role of adrenal medulla (the adrenomedullary component of the sympathoadrenal system) in the development and maintenance of high blood pressure in man as well as in experimental models of hypertension is still controversial. Spontaneously hypertensive rats (SHR) are the most widely used animal model of human essential hypertension characterized by sympathetic hyperactivity. However, the persistence of moderately elevated blood pressure in SHR subjected to sympathectomy neonatally as well as the resistance of adult SHR to the treatment by sympatholytic drugs suggests that other factors (including enhanced activity of the adrenomedullary hormonal system) are involved in the pathogenesis of hypertension of SHR. This review describes abnormalities in adrenomedullary hormonal system of SHR rats starting with the hyperactivity of brain centers regulating sympathetic outflow, through the exaggerated activation of sympathoadrenal preganglionic neurons, to the local changes in chromaffin cells of adrenal medulla. All the above alterations might contribute to the enhanced release of epinephrine and/or norepinephrine from adrenal medulla. Special attention is paid to the alterations in the expression of genes involved in catecholamine biosynthesis, storage, release, reuptake, degradation and adrenergic receptors in chromaffin cells of SHR. The contribution of the adrenomedullary hormonal system to the development and maintenance of hypertension as well as its importance during stressful conditions is also discussed.

The Effects of Bradykinin B1 Receptor Antagonism on the Myocardial and Vascular Consequences of Hypertension in SHR Rats.

It is known that non-steroidal anti-inflammatory drugs increase cardiovascular (CV) morbidity and mortality. In this study, we examined whether a novel anti-inflammatory drug, bradykinin B1 receptor antagonist (FGY-1153) treatment could influence the development of hypertensive organ damages in spontaneously hypertensive rats (SHR). SHRs were treated with low (FGY-120) or high dose FGY-1153 (FGY-400) and with placebo (Control) for 26 weeks. Wistar–Kyoto rats were used as aged-matched, normotensive controls (WKY). Body weight, food consumption and blood pressure were measured regularly. Echocardiography was performed at the beginning and at the end of the study. Light and electron microscopic analysis of heart and great vessels were performed, and the extent of fibrotic areas was measured. The phosphorylation state of prosurvival Akt-1/glycogen synthase kinase (GSK)-3β pathway and the activation of signaling factors playing part in the fibrotic processes – mitogen activated protein kinases (MAPKs), and TGF-β/Smad2 – were monitored using Western-blot. Body weight and food consumption as well as the elevated blood pressure in SHRs was not influenced by FGY-1153 treatment. However, both doses of FGY-1153 treatment decreased left ventricular (LV) hypertrophy and diastolic dysfunction in hypertensive animals. Moreover systolic LV function was also preserved in FGY-120 group. Increased intima-media thickness and interstitial fibrosis were not significantly diminished in great vessels. FGY-1153 treatment inhibited the expression of TGFβ and the phosphorylation of SMAD2 in the heart. Our results suggest that the tested novel anti-inflammatory compound has no deleterious effect on CV system, moreover it exerts moderate protective effect against the development of hypertensive cardiopathy.

Role of hindbrain melanocortin-4 receptor activity in controlling cardiovascular and metabolic functions in spontaneously hypertensive rats

Although we previously demonstrated that activation of central nervous system (CNS) melanocortin3/4 receptors (MC3/4R) play a key role in blood pressure (BP) regulation, especially in spontaneously hypertensive rats (SHRs), the importance of hindbrain MC4R is still unclear. In the present study, we examined the cardiovascular and metabolic effects of chronic inhibition of MC3/4R in the hindbrain of SHRs and normotensive Wistar-Kyoto (WKY) rats. Male WKY rats (n = 6) and SHRs (n = 7) were implanted with telemetry probes to measure BP and heart rate (HR) 24 h/day, and an intracerebroventricular cannula was placed into the fourth ventricle. After 10 days of recovery and 5 days of control measurements, the MC3/4R antagonist (SHU-9119) was infused into the fourth ventricle (1 nmol/h) to antagonize hindbrain MC4R for 10 days, followed by a 5-day recovery period. Chronic hindbrain MC3/4R antagonism significantly increased food intake and body weight in WKY rats (17 ± 1 to 35 ± 2 g/day and 280 ± 8 to 353 ± 8 g) and SHRs (19 ± 2 to 35 ± 2 g/day and 323 ± 7 to 371 ± 11 g), and markedly increased fasting insulin and leptin levels while causing no changes in blood glucose levels (99 ± 4 to 87 ± 4 and 89 ± 5 to 89 ± 4 mg/dl, respectively, for WKY rats and SHRs). Chronic SHU-9119 infusion reduced mean arterial pressure and HR similarly in WKY rats (-8 ± 1 mmHg and -47 ± 3 b.p.m.) and SHRs (-11 ± 3 mmHg and -44 ± 3 b.p.m.). These results suggest that although hindbrain MC4R activity contributes to appetite and HR regulation, it does not play a major role in mediating the elevated BP in SHRs.

Abstract 439: Role of Hindbrain Endogenous Melanocortin Receptor Activity in Contributing to Hypertension in SHR

We previously demonstrated that activation of the central nervous system (CNS) melanocortin system plays a key role in the modulation of sympathetic nerve activity (SNA) and blood pressure (BP) regulation. In the present study, we examined whether chronic inhibition of melanocortin-4 receptors (MC4R) in the hindbrain attenuates the elevated blood pressure in spontaneously hypertensive rats (SHR). The long-term cardiovascular and metabolic effects of MC4R antagonism were assessed in SHR and normotensive Wistar-Kyoto (WKY) rats. Male WKY rats (n=6) and SHR (n=7) were implanted with telemetry probes to measure BP and heart rate (HR) 24-hrs/day, and an intracerebroventricular (ICV) cannula was placed into the fourth ventricle (4 th V). After 10 days of recovery and 5 days of control measurements, the MC4R antagonist (SHU-9119, 1 nmol/h, 4 th V) was infused for 10 days followed by a 5-day recovery period. Chronic hindbrain MC4R antagonism significantly increased food intake and body weight in WKY (17±1 to 35±2 g/day and 280±8 to 353±8 g) and SHR (19±2 to 35±2 g/day and 323±7 to 371±11 g). No changes were observed in blood glucose levels (99±4 to 87±4 and 89±5 to 89±4 mg/dl, respectively for WKY and SHR). Chronic SHU-9119 infusion reduced MAP and HR similarly in WKY (-5±1 mmHg and -47±3 bpm) and SHR (-8±3 mmHg and -44±3 bpm). These results suggest that although hindbrain MC4R activity is important for appetite and HR regulation, it does not play a major role in mediating the elevated blood pressure in SHR. (NHLBI-PO1 HL51971/AHA SDG5680016)

AT 1 angiotensin II receptor and novel non-AT 1, non-AT 2 angiotensin II/III binding site in brainstem cardiovascular regulatory centers of the spontaneously hypertensive rat

Spontaneously hypertensive rats (SHR) have an activated brain angiotensin system that contributes to the elevation of blood pressure in this animal model. Physiological and pharmacological studies suggest that hyperactivation of brain AT 1 angiotensin receptors is a major pathophysiological factor. Consistent with these observations, radioligand binding studies indicate widespread up-regulation of brain angiotensin receptors in SHR. One key brainstem site in which AT 1 receptor stimulation appears to contribute to the elevated blood pressure in SHR is the rostral ventrolateral medulla (RVLM). However, no quantitative comparison of AT 1 receptor binding in the RVLM has been made in SHR versus normotensive rats. A novel, non-AT 1, non-AT 2 binding site, specific for angiotensins II and III, has recently been discovered in the brain. To determine if radioligand binding to either AT 1 receptors or this novel angiotensin binding site is altered in the RVLM and other caudal brainstem regions of SHR, a quantitative densitometric autoradiographic comparison of radioligand binding in SHR versus normotensive Wistar–Kyoto rats was made. In both the RVLM and caudal ventrolateral medulla (CVLM) as well as dorsomedial medulla (DMM), there was increased expression of AT 1 receptor binding in SHR (13%, 9%, and 23%, respectively). Conversely, expression of the novel, non-AT 1, non-AT 2, angiotensin II and III binding site was decreased in the RVLM and DMM of SHR (37% and 13%, respectively). This increased AT 1 receptor binding in the RVLM may contribute to the hypertension of SHR. Reduced radioligand binding to the novel, non-AT 1, non-AT 2, angiotensin binding site in the RVLM of SHR may indicate a role for this binding site to reduce blood pressure via its interactions with angiotensins II and III.

Reduced cerebrovascular remodeling and functional impairment in spontaneously hypertensive rats following combined treatment with suboptimal doses of telmisartan and ramipril: is less really more?

Reduced cerebrovascular remodeling and functional impairment in spontaneously hypertensive rats following combined treatment with suboptimal doses of telmisartan and ramipril: is less really more?

Hydroxyl Radical Mediates the Augmented Angiotensin II Responses in Thoracic Aorta of Spontaneously Hypertensive Rats

Aim: To investigate the role of hydroxyl radical in augmented angiotensin II (Ang II) responses in the thoracic aorta of spontaneously hypertensive rats (SHR). Methods: To elucidate the role of hydroxyl radical, we used edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) as a tool for our study. The vascular responses to Ang II (10^–10 to 10^–6 mol/l), tert-butyl hydroperoxide (tBHP; 10^–6 to 10^–2 mol/l) and H₂O₂ (10^–6 to 10^–2 mol/l) were constructed in aortic preparations obtained from control (WKY) and SHR in the absence and presence of edaravone. Results: The vascular responses to Ang II, tBHP and H₂O₂ were found to be enhanced in aortic preparations from SHR as compared to control WKY rats. Edaravone selectively attenuated the augmented responses to Ang II but not to tBHP and H₂O₂ suggesting that the ·OH radical is involved in the augmented responses to Ang II. The elevated blood pressure in SHR was restored to a near normal value after 2 weeks of edaravone (10 mg kg^–1 i.p., b.i.d.) treatment. Conclusion: From the results we infer that hydroxyl radical stress augments Ang II responses in the thoracic aorta of SHR and, by attenuating these enhanced vascular responses, edaravone could serve as an adjuvant antioxidant therapy for the vascular complications of hypertension.

Dietary vitamin E supplementation lowers blood pressure in spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHRs) excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes. Vitamin E increases tissue glutathione levels--a storage form of cysteine. The aim of the present study was to investigate whether a dietary supplementation of vitamin E lowers blood pressure and prevents renal vascular changes by normalizing tissue aldehyde conjugates and cytosolic [Ca2+] in SHRs. Starting at 12 weeks of age, animals were divided into three groups of six animals each. Animals in the WKY-control group and SHR-control group were given a normal diet and the SHR-vitamin E group a diet supplemented with vitamin E (34 mg/ kg feed) for the next 9 weeks. After 9 weeks, systolic blood pressure, platelet [Ca2+]i, and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared to WKY controls and the SHR-vitamin E group. SHR-controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidney. Dietary vitamin E supplementation in SHRs lowered the systolic blood pressure, cytosolic [Ca2+], tissue aldehyde conjugates and attenuated adverse renal vascular changes.

Dietary alpha-lipoic acid supplementation lowers blood pressure in spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHRs), excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes and normalizing membrane Ca2+ channels and cytosolic free calcium. The aim of the present study was to investigate whether a dietary supplementation of an endogenous fatty acid, alpha-lipoic acid, another thiol compound that is known to increase tissue cysteine and glutathione, can lower blood pressure and normalize associated biochemical and histopathological changes in SHRs. Starting at 12 weeks of age, animals were divided into three groups of six animals each. Animals in the Wistar- Kyoto (WKY) rat control group and the SHR control group were given a normal diet, and the SHR-lipoic acid group was given a diet supplemented with lipoic acid (500 mg/kg feed) for the next 9 weeks. After 9 weeks, systolic blood pressure, platelet [Ca2+]i, plasma insulin and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared with WKY rat controls and the SHR lipoic acid group. SHR controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary alpha-lipoic acid supplementation in SHRs lowered the systolic blood pressure, cytosolic [Ca2+]i, blood glucose and insulin levels, and tissue aldehyde conjugates, and attenuated adverse renal vascular changes.

Dietary vitamin B6 supplementation attenuates hypertension in spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHRs) excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels, increasing cytosolic free calcium and blood pressure. N-acetyl cysteine normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes. It is known that dietary vitamin B6 supplementation can increase the level of endogenous cysteine. Our objective was to investigate whether a dietary supplementation of vitamin B6 can prevent hypertension and associated changes in SHRs. Starting at 7 weeks of age, animals were divided into three groups of six animals each. Animals in WKY-control group and SHR-control group were given a normal vitamin B6 diet; and SHR-vitamin B6 group, a high vitamin B6 diet (20 times the recommended dietary intake; RDA) for the next 14 weeks. After 14 weeks, systolic blood pressure, platelet [Ca2+]i and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls compared to WKY controls. These animals also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin B6 supplementation attenuated the increase in systolic blood pressure, tissue aldehyde conjugates and associated changes. These results further support the hypothesis that aldehydes are involved in increased systolic blood pressure in SHRs and suggest that vitamin B6 supplementation may be an effective antihypertensive.

Influence of long-term treatment with the dihydropyridine-type calcium antagonist nicardipine on renal microanatomical changes in spontaneously hypertensive rats.

1. The influence of hypertension and treatment with the dihydropyridine-type Ca2+ antagonist, nicardipine, on the structure of the kidney was assessed in spontaneously hypertensive rats (SHR) of 12 weeks of age. Treatment went for 8 weeks with a daily oral dose of 1 mg/kg of nicardipine. 2. Control SHR exhibited hypertension and microanatomical vascular and glomerular changes. Vascular changes consisted of a thickening of the tunica media and decreased luminal area of medium- and small-sized intrarenal artery branches. Glomerular changes included glomerulosclerosis and atrophy of varying degrees. 3. Administration of nicardipine significantly reduced blood pressure. The drug also decreased the thickening of tunica media and luminal narrowing of renal artery branches as well as the degree of glomerular injury in SHR. 4. These data indicate that nicardipine treatment is able to control elevated blood pressure in SHR, and to counter hypertension-dependent microanatomical impairment of the kidney. This suggests that the compound exerts a protective effect on hypertensive kidney.

Dependence of elevated mesenteric arteriolar tone on glucocorticoids in spontaneously hypertensive rats.

This study is designed to explore the effect of adrenal glucocorticoids on arteriolar behavior under steady state conditions in spontaneously hypertensive rats (SHR) compared with their normotensive controls, the Wistar Kyoto (WKY) rats. Mesenteric arterioles were observed by intravital microscopy under general anesthesia and arteriolar diameters were measured. At the end of each experiment, papaverine was topically applied to determine maximum diameter of the vessels for which arteriolar tone was computed. The adrenal contribution to the atypical arteriolar tone in SHR was explored by subjecting them to bilateral adrenalectomy with or without glucocorticoid replacement therapy. Adrenalectomy led to a reduction in the elevated blood pressure in SHR to normotensive levels, which could be restored to its hypertensive level by treatment with dexamethasone. Adrenalectomy had so significant effect on blood pressure in WKY rats, although administration of dexamethasone but not aldosterone did lead to an elevation of the blood pressure in sham-operated WKY. Arteriolar tone in SHR was set at a higher steady state level than in WKY rats. In adrenalectomized SHR, tone fell to the levels observed in WKY rats. This decrease in arteriolar tone in the adrenalectomized SHR could in turn be restored to the hypertensive levels with dexamethasone but not aldosterone. Our results suggest that the enhancement of arteriolar tone, as well as the high blood pressure in SHR, may be related to the above normal levels of adrenal glucocorticoids present in the bloodstream.

Production of polyclonal antisera to parathyroid hypertensive factor from spontaneously hypertensive rats

Parathyroid hypertensive factor (PHF) is a newly described hypertensive factor which may cause elevation of blood pressure in approximately 40% of North American essential hypertensive patients. PHF is also found in several animal models of hypertension, including spontaneously hypertensive rats (SHR), deoxycorticosterone acetate-salt hypertensive rats and salt-sensitive Dahl rats. The objective of the present study was to raise an antibody to PHF, and to use this antibody to study the effect of PHF in SHR. Plasma and parathyroid gland culture media collected from SHR were used in the present study as the antigen in the production and analysis of a polyclonal antiserum to PHF. PHF is of low molecular weight (approximately 3000 daltons) and is sensitive to inactivation by trypsin. We used PHF partially purified from parathyroid gland culture media as the antigen to inoculate mice. The substance was bound to aminophenyl thioether paper discs to make it more antigenic. The discs were then emulsified in Freund's adjuvant (complete for first inoculation, incomplete for subsequent inoculations) for intraperitoneal implantation. Production of anti-PHF antisera was monitored by enzyme-linked immunosorbent assay. Antisera produced in mice reacted with purified PHF prepared from SHR plasma as well as with PHF prepared from parathyroid gland culture media. PHF treated with the PHF antiserum produced no characteristic hypertensive response in normotensive assay rats. The antisera did not crossreact with two forms of bovine parathyroid hormone, bPTH (1-84), bPTH (1-34) or with shorter parathyroid hormone fragments, or with any other vasoactive substance tested. Injection of an aliquot of the antiserum in anesthesized spontaneously hypertensive rats reduced mean arterial pressure to a normal range of approximately 110 mmHg. These results indicate that (1) polyclonal antisera to PHF can be raised in mice and (2) PHF may contribute significantly to the elevated blood pressure in SHR.

Enhanced Glucose Tolerance in Spontaneously Hypertensive Rats: Pancreatic β-Cell Hyperfunction With Normal Insulin Sensitivity

We used intravenous glucose tolerance tests in vivo and 3-O-methylglucose transport into skeletal muscle in vitro to assess glucose tolerance, pancreatic beta-cell function, and insulin action in 9- to 11-wk-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKY). Body weight was slightly higher in the WKY (P less than 0.001), while blood pressure was elevated in the SHR (P less than 0.001). Insulin responses to intravenous glucose after 4 or 12 h of fasting in SHR were 2-3 times the responses of WKY rats (P less than 0.001). The greater insulin responses in SHR were associated with accelerated glucose disappearance P less than 0.001 vs. WKY rats). A direct correlation (r = 0.49, P less than 0.05) between the peak plasma insulin responses to glucose and Kg values in SHR suggested that the exaggerated insulin responses contributed to the accelerated glucose disappearance in that group. 3-O-methylglucose transport rates into epitrochlearis muscles in vitro did not differ significantly between SHR and WKY groups in the absence of insulin (P less than 0.2) or in the presence of insulin at physiological (600 pM, P greater than 0.4) or pharmacological (120,000 pM, P greater than 0.9) concentrations. Thus, compared with WKY rats, SHR had exaggerated insulin responses to glucose, similar insulin-mediated glucose transport into skeletal muscle, and enhanced glucose tolerance. Our findings indicate that young, hypertensive SHR have hyperfunction of pancreatic beta-cells that is unrelated to insulin resistance. The resultant nutrient-stimulated hyperinsulinemia could play a role in the development or maintenance of elevated blood pressure in SHR.

Pressor actions of arginine vasopressin in pithed Sprague-Dawley, Wistar-Kyoto and spontaneously hypertensive rats before and after treatment with nifedipine or pertussis toxin.

The pressor actions of arginine vasopressin (AVP) were examined in pithed Sprague-Dawley and Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Prior to pithing, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded via an intra-arterial catheter from sodium pentobarbital anaesthetized rats. SBP and DBP recorded from SHR were significantly greater than those from Sprague-Dawley and WKY rats. However, after pithing, there were no significant differences between DBP among the various strains. Pertussis toxin pretreatment significantly reduced the prepithing SBP and DBP of the SHR but not Sprague-Dawley or WKY rats. Administration of nifedipine significantly reduced DBP of pithed rats. The dose-diastolic pressure response curves obtained from infusion of AVP in Sprague-Dawley and WKY rats were not significantly different from one another, but the maximal vasopressor responses to AVP in pithed SHR were enhanced. Administration of nifedipine to Sprague-Dawley and WKY rats did not affect the dose-response curve to AVP, but nifedipine administration in SHR led to a significant inhibition of the pressor responses to AVP. Furthermore, pertussis toxin pretreatment of rats significantly reduced a component of the AVP pressor effect in SHR but not Sprague-Dawley or WKY rats. We speculate that, in SHR, vasopressin receptors are coupled to a pertussis toxin-sensitive G protein that, in turn, may couple to a dihydropyridine-sensitive calcium channel and also to a pertussis-insensitive G protein that is probably coupled to the phospholipase C/intracellular calcium release process. A component of the elevated blood pressure in SHR is also regulated by a pertussis toxin-sensitive process.(ABSTRACT TRUNCATED AT 250 WORDS)

Malfunction of arterial sarcoplasmic reticulum leading to faster and greater contraction induced by high-potassium depolarization in young spontaneously hypertensive rats.

The contribution of sarcoplasmic reticulum was studied with regard to the increase in arterial contraction induced by a high-potassium depolarization in spontaneously hypertensive rats (SHR). The 20 mmol/l potassium-induced contraction of femoral arteries was faster and greater in 6-week-old SHR than in age-matched normotensive Wistar-Kyoto (WKY) rats. Relaxation after washing the arteries with a Krebs solution was slower in SHR than in WKY rats. When the sarcoplasmic reticulum of SHR arteries had been depleted of calcium by caffeine in a calcium-free solution, the rate of high-potassium-induced contraction of the calcium-depleted SHR arteries was slowed, the same result as that with non-calcium-depleted WKY arteries. In ryanodine-treated arteries, the rate and magnitude of high-potassium-induced contraction were enhanced slightly in SHR and greatly in WKY rats, resulting in no final difference between SHR and WKY rats. Ryanodine slowed the relaxation rate in WKY rats but not in SHR. These results suggest that the diminution in ability of sarcoplasmic reticulum to sequester calcium may be responsible for the faster rate and greater magnitude of high-potassium-induced contraction with the slower relaxation in SHR arteries. We postulated that genetic malfunction of sarcoplasmic reticulum causes the increased contraction of arterial smooth muscle leading to the enhanced vasoconstriction and elevated blood pressure in SHR.

Heparin lowers blood pressure and vascular calcium uptake in hypertensive rats

Increased calcium uptake by vascular tissue, leading to elevated cytosolic calcium, has been implicated in the pathophysiology of hypertension. Heparin treatment of hypertensive rats has been known to lower blood pressure but its mechanism is not known. This study examined the effect of chronic heparin treatment on systolic blood pressure, aortic calcium and 86Rubidium (86Rb) uptake of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Starting at 12 weeks of age SHR and WKY rats were given either sodium heparin 300 units s.c. or equal amounts of saline once a day for a period of 6 weeks. At 18 weeks, systolic blood pressure, uptakes of calcium and 86Rb by aortae were significantly higher (p<0.01) in saline-treated SHR compared with heparin-treated SHR and WKY. Heparin treatment lowered the elevated calcium and 86Rb Uptake and blood pressure in SHR but had no effect on WKY. The parallel increase in systolic blood pressure and vascular calcium uptake suggests that increased calcium uptake mechanisms are associated with hypertension in SHR. Heparin appears to lower elevated blood pressure in SHR by lowering elevated vascular calcium uptake.

Heparin lowers blood pressure and vascular calcium uptake in hypertensive rats

Increased calcium uptake by vascular tissue, leading to elevated cytosolic calcium, has been implicated in the pathophysiology of hypertension. Heparin treatment of hypertensive rats has been known to lower blood pressure but its mechanism is not known. This study examined the effect of chronic heparin treatment on systolic blood pressure, aortic calcium and 87Rubidium (86Rb) uptake of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Starting at 12 weeks of age SHR and WKY rats were given either sodium heparin 300 units s.c. or equal amounts of saline once a day for a period of 6 weeks. At 18 weeks, systolic blood pressure, uptakes of calcium and 86Rb by aortae were significantly higher (p less than 0.01) in saline-treated SHR compared with heparin-treated SHR and WKY. Heparin treatment lowered the elevated calcium and 86Rb Uptake and blood pressure in SHR but had no effect on WKY. The parallel increase in systolic blood pressure and vascular calcium uptake suggests that increased calcium uptake mechanisms are associated with hypertension in SHR. Heparin appears to lower elevated blood pressure in SHR by lowering elevated vascular calcium uptake.

Growth hormone responses to clonidine and GRF in spontaneously hypertensive rats: Neuroendocrine evidence for an enhanced responsiveness of brain alpha 2-adrenoceptors in genetical hypertension

Clonidine induces growth hormone (GH) release in rat. According to previous investigations this effect is mediated by postsynaptic alpha 2-adrenoceptors in the hypothalamus exerting a stimulatory influence of the recently discovered GH releasing factor (GRF). In the present study it is demonstrated that spontaneously hypertensive rats (SHR) of the Wistar-Kyoto strain display enhanced GH responses to clonidine as compared to normotensive Wistar-Kyoto control rats. In contrast, the GH responses to GRF are similar in hypertensive and normotensive animals. These findings indicate that brain alpha 2-adrenoceptors are move responsive in SHR than in normotensive controls. Since the enhanced GH responses to clonidine were observed also in young, prehypertensive SHR they are probably not secondary to the elevated blood pressure. The possible importance of an altered alpha 2-adrenergic neurotransmission for the development of elevated blood pressure in SHR is discussed.

Ultrastructural changes in mesenteric arteries from spontaneously hypertensive rats. A morphometric study.

Morphometric measurements at the electron microscope level were carried out on three categories of mesenteric arteries representing elastic (superior mesenteric), muscular and arteriolar vessels, from 10- to 12-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto normotensive rats (WKY). Changes were observed only in muscular and arteriolar vessels of SHR, mainly as thickening of the vessel wall due to hypertrophy of the media. In muscular arteries, hypertrophy of the endothelial cells, widening of the subendothelial space, increased volume of the internal elastic lamina (IEL), and both hyperplasia and hypertrophy of the smooth muscle cells (SMC) in the media contributed to the wall thickening. In arteriolar vessels, increase in the subendothelial space and IEL, and hyperplasia of the SMC in the media were involved in the increased thickness of the vessel wall. There was no difference in the collagen content in all vessels, but elastin was increased in the muscular and arteriolar vessels of SHR. Nerve density was also increased in arteriolar vessels of SHR. These changes, especially the increase of SMC in muscular and arteriolar vessels, may be related to the elevated blood pressure in SHR.