Effects of continuous angiotensin I-converting enzyme blockade on blood pressure, sympathetic activity and renin-angiotensin system in stroke-prone spontaneously hypertensive rats

The purpose of this study was to examine the effects of continuous angiotensin converting enzyme (ACE) blockade in stroke-prone spontaneously hypertensive rats (sp-SHR) on the renin-angiotensin system and on sympathetic activity. The pressor response to angiotensin II (AII) and norepinephrine (NE) were also examined after chronic blockade of ACE and compared to that of saline-treated controls. Captopril treatment had no effect on body weight. Serum ACE was significantly reduced on day 1; an effect that persisted through day 6 and day 10. Plasma renin activity (PRA) was elevated significantly on day 1 and remained at this high level throughout the 10 day observation period. Plasma NE was not altered by the chronic ACE blockade except on day 1, where there was a slight elevation of plasma NE in both groups. Pressor responses to AII and NE were not changed after chronic captopril treatment. It is observed that chronic inhibition of the renin-angiotensin system with captopril in sp-SHR resulted in a reduction of blood pressure, reduced serum ACE activity and elevated PRA. The constant plasma NE levels suggest that chronic inhibition of the renin-angiotensin system does not affect sympathetic activity. This study also indicates that long term inhibition of ACE does not alter pressor responses to either AII or NE.     

Antioxidant activity of propionyl-L-carnitine in liver and heart of spontaneously hypertensive rats

Oxidative stress plays an important role in arterial hypertension and propionyl-L-carnitine (PLC) has been found to protect cells from toxic reactive oxygen species. In this work, we have evaluated the antioxidant capacity of chronic PLC treatment in spontaneously hypertensive rats (SHR) by measuring the activity of antioxidant enzymes and the lipid peroxidation in liver and cardiac tissues. The activity of glutathione peroxidase was decreased in liver and cardiac tissues of SHR when compared with their normotensive controls, Wistar- Kyoto (WKY) rats, this alteration being prevented by PLC treatment. Glutathione reductase activity was increased in hypertensive rats and no effect was observed after the treatment. No significant changes in superoxide dismutase activity were observed among all experimental groups. Liver of hypertensive rats showed higher catalase activity than that of normotensive rats, and PLC enhanced this activity in both rat strains. Thiobarbituric acid reactive substances, determined as a measure of lipid peroxidation, were increased in SHR compared with WKY rats, and PLC treatment decreased these values not only in hypertensive rats but also in normotensive ones. The content of carnitine in serum, liver and heart was higher in PLC-treated rats, but PLC did not prevent the hypertension development in young SHR. In addition, triglyceride levels, which were lower in SHR than WKY rats, were reduced by chronic PLC treatment in both rat strains. These results demonstrate: i) the hypotriglyceridemic effect of PLC and ii) the antioxidant capacity of PLC in SHR and its beneficial use protecting tissues from hypertension-accompanying oxidative damage.     

Tissue angiotensin I-converting enzyme activity in spontaneously hypertensive hamsters.

The purpose of this study was to measure angiotensin I-converting activity in heart, kidney, lung and cheek pouch tissue homogenates of spontaneously hypertensive and normotensive hamsters. We also determined inhibitor sensitivity and the effects of chloride anion concentration on kidney angiotensin I-converting activity in these animals. We found no significant differences in angiotensin I-converting activity between hypertensive and normotensive hamsters in all tissues tested. Inhibitor sensitivity of kidney angiotensin I-converting activity with captopril and lisonopril was similar in both groups. Finally, kidney angiotensin I-converting activity increased significantly in both groups as chloride anion concentration in the assay buffer increased. Substituting chloride anion for citrate abrogated the increase in angiotensin I-converting enzyme activity.     

Effects of chronic quercetin treatment on hepatic oxidative status of spontaneously hypertensive rats

The effects of chronic administration of an oral daily dose of quercetin (10 mg Kg^–1), the most abundant dietary flavonoid, were investigated on hepatic oxidative status in spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Decreased liver glutathione peroxidase activity, increased liver total glutathione levels and increased both hepatic and plasmatic malondialdehyde concentrations were observed in spontaneously hypertensive rats when compared to Wistar Kyoto rats. In spontaneously hypertensive rats, treatment with quercetin for 5 weeks reduced blood pressure, increased glutathione peroxidase activity and reduced both plasma and hepatic malondialdehyde levels. However, none of these effects were observed in Wistar Kyoto rats. In conclusion, quercetin shows both antihypertensive and antioxidant properties in this model of genetic hypertension.     

Intravenous epoprostenol sodium does not increase hepatic microsomal enzyme activity in rats

Previous studies have indicated that epoprostenol may increase hepatic microsomal enzyme activity both in animals and humans. However, interpretation of the results of these studies may be confounded by the route of epoprostenol administration or small sample sizes. The primary objective of the present investigation was to evaluate the effects of epoprostenol (given as a continuous intravenous infusion) on hepatic microsomal enzyme activity in rats. Male Sprague Dawley rats (220–290 g) received infusions of either vehicle (glycine buffer, 1 mL/hr) or 0.2 μg/kg/min epoprostenol through a jugular vein cannula for 24 hr or 7 days. At the end of the infusion, a 25 mg/kg ix. bolus of antipyrine was administered and blood samples were collected over 6 hr. Serum antipyrine concentrations were determined by HPLC. Twenty-four hr post-infusion, hepatic microsomes were prepared, and cytochrome P-450 content was determined by difference spectroscopy. Cytochrome P-450 content and antipyrine clearance values determined from serum antipyrine concentration-time profiles were not significantly different between treatment groups. Antipyrine clearance [mean (SD)] in the 24-hr vehicle-treated group was 3.68 (0.49) mL/min/kg versus 4.35 (1.1)mL/min/kg in the epoprostenol-treated group. In the 7-day vehicle-treated rats, antipyrine clearance was 5.43 (1.0) mL/min/kg compared to 4.68 (0.61)mL/min/kg in epoprostenol-treated rats. A statistically significant effect of infusion duration was observed in the control group, i.e., antipyrine clearance in rats treated with vehicle for 7 days was significantly greater than that observed in rats treated with vehicle for 24 hr. However, the increase was less than 50%. These data suggest that when epoprostenol is administered as an intravenous infusion to rats, no significant alterations in hepatic microsomal enzyme activity occur. Based on these data, long term changes in heparic metabolism in response to chronic epoprostenol administration are nor expected.     

Plasma catecholamines and dopamine-beta-hydroxylase activity in spontaneously hypertensive rats.

Levels of plasma norepinephrine and total catecholamines in spontaneously hypertensive rats bred from a normotensive Kyoto strain of Wistar rats increase between their 8th to 12th week post utero concomitant with the development of hypertension, but levels of plasma norepinephrine are not significantly different between the spontaneously hypertensive strain, a normotensive Kyoto strain and a N.I.H. strain of Wistar rats at either 8 or 12 weeks of age. Plasma total catecholamine levels in the spontaneously hypertensive strain are significantly higher at 12 weeks of age than those in either control strain, while plasma levels of dopamine-β-hydroxylase show no consistant relationship between the three strains. It, therefore, appears unlikely that increased sympathetic neuronal activity is an etiological factor in this form of hypertension.     

Basic fibroblast growth factor increases collateral blood flow in spontaneously hypertensive rats

Ischemia-induced angiogenic response is reduced in spontaneously hypertensive rats (SHR). To study whether exogenous basic fibroblast growth factor (bFGF) infusion is effective in expanding collateral circulation in frankly hypertensive SHR, femoral arteries of male SHR (weighing approximately 250 g) were kept intact (nonoccluded control; n = 9) or occluded for 4h(n = 12) or for 16 days with vehicle (n = 14) or bFGF [0.5 (n = 17), 5.0 (n = 13), and 50.0 (n = 14) microg. kg-1. day-1 for 14 days] intraarterially. Maximal collateral-dependent blood flows (BF) to the hindlimbs were determined with 85Sr- and 141Ce-labeled microspheres during running at 20 and 25 m/min (15% grade). Preexercise heart rates (approximately 530 beats/min) and blood pressures (BP; approximately 200 mmHg) were similar across groups except in the high-dose bFGF group, where BP was reduced by approximately 12% (P < 0.05). Femoral artery occlusion for 4 h resulted in approximately 95% reduction of BF in calf muscles [199 +/- 18.7 (nonoccluded group) to 10 +/- 1.0 ml. min-1. 100 g-1; P < 0.001]. BF to calf muscles of the vehicle and low-dose bFGF (0.5 microg. kg-1. day-1) groups increased to 36 +/- 3.2 and 45 +/- 2.0 ml. min-1. 100 g-1, respectively (P < 0.001). bFGF infusion at 5.0 and 50.0 microg. kg-1. day-1 further increased (P < 0.001) BF to calf muscles (62 +/- 4.6 and 62 +/- 2.2 ml. min-1. 100 g-1, respectively). Our results show that bFGF can effectively increase BF in hypertensive rats. The reduced hypertension with high-dose bFGF suggests that a critical signal in arteriogenesis (nitric oxide bioavailability) may be restored. These findings suggest that the dulled endothelial nitric oxide synthase of SHR does not preempt collateral vessel remodeling.     

Elastase-like enzyme in the aorta of spontaneously hypertensive rats

In an attempt to obtain information regarding vascular elastase in arterial hypertension, we examined biochemical changes in elastase-like enzyme activity, and the intravascular localization of elastase by immunohistochemical techniques in the aorta of spontaneously hypertensive rats (SHR). In the biochemical study, aortic elastase-like enzyme activity was significantly higher in SHR than in controls. Using an antibody against rat pancreatic elastase raised in the rabbit, it was demonstrated immunohistochemically that the enzyme was localized in the endothelial cells and subendothelial spaces in the aorta of control animals. In SHR, elastase was also demonstrated in medial smooth muscle cells and particularly in the modified smooth muscle cells in areas of intimal thickening. Some vacuoles in the smooth muscle cells also showed positive enzyme staining. Elastase seems to play an important role in the development of hypertensive vascular changes.     

Effects of antenatal,postpartum and post-weaning melatonin supplementation on blood pressure and renal antioxidant enzyme activities in spontaneously hypertensive rats

Although melatonin lowers blood pressure in spontaneously hypertensive rats (SHR), its effect following antenatal and postpartum supplementation on the subsequent development of hypertension in SHR pups remains unknown. To investigate this, SHR dams were given melatonin in drinking water (10 mg/kg body weight/day) from day 1 of pregnancy until day 21 postpartum. After weaning, a group of male pups continued to receive melatonin till the age of 16 weeks (Mel-SHR), while no further melatonin was given to another group of male pups (Maternal-Mel-SHR). Controls received plain drinking water. Systolic blood pressure (SBP) was measured at 4, 6, 8, 12 and 16 weeks of age, after which the kidneys were collected for analysis of antioxidant enzyme profiles. SBP was significantly lower till the age of 8 weeks in Maternal-Mel-SHR and Mel-SHR than that in the controls, after which no significant difference was evident in SBP between the controls and Maternal-Mel-SHR. SBP in Mel-SHR was lower than that in controls and Maternal-Mel-SHR at 12 and 16 weeks of age. Renal glutathione peroxidase (GPx) and glutathione s-transferase (GST) activities, levels of total glutathione and relative GPx-1 protein were significantly higher in Mel-SHR. GPx protein was however significantly higher in Mel-SHR. No significant differences were evident between the three groups in the activities of superoxide dismutase, catalase and glutathione reductase. In conclusion, it appears that while antenatal and postpartum melatonin supplementation decreases the rate of rise in blood pressure in SHR offspring, it however does not alter the tendency of offspring of SHR to develop hypertension.     

Effects of praeruptorin C on blood pressure and expression of phospholamban in spontaneously hypertensive rats

BackgroundThe traditional Chinese medicine Praeruptorin c (Pra-c) has many physiological and pharmacological effects, including antagonistic effects on blood pressure and calcium levels, maintenance of cellular calcium homeostasis, and improved cardiac systolic and diastolic function. It is potentially a novel and versatile drug for the treatment and prevention of cardiovascular diseases.ObjectiveTo explore the possible impact of Pra-c on blood pressure in SHR and its mechanism of action.Materials and methodsTwenty SHR were randomly divided into a Pra-c group [Pra-c was administered intragastrically, 20 mg kg⁻¹ d⁻¹, n = 10] or an untreated control group (n = 10), containing 10 age-matched SD rats. Each group of rats was followed for 8 weeks. Before and during the treatment, tail artery systolic blood pressure was measured using a tail-cuff every 2 weeks. After 8 weeks, the rats were sacrificed and RNA was extracted from homogenates of cardiac tissue. Tissue from the left ventricle was fixed, sectioned and H&E stained to assess possible changes in myocardial cell structure and morphology. Semi-quantitative RT-PCR was used to assess changes in phospholamban gene expression in treated and untreated rats.ResultsSHR treated with Pra-c for 8 weeks had a lower systolic pressure than untreated SHR (p < 0.05), two measures of cardiac damage, the heart mass index and left ventricle mass index (HMI and LVMI, respectively) were improved, and the level of PLB mRNA expression was lower in the untreated SHR group (p < 0.05).Discussion and conclusionWith continuous hypertension, SHR gradually formed or developed cardiac hypertrophy and fibrosis. Pra-c had a clear effect on blood pressure in SHR, and reversed SHR ventricular remodeling by upregulating the gene expression of sarcoplasmic reticulum PLB.     

A hypertensive substance found in the blood of spontaneously hypertensive rats

A substance has been obtained from the blood of spontaneously hypertensive rats which produces a hypertensive elevation of the blood pressure in normotensive rats. The substance is dialyzable and is associated with the erythrocyte membrane. It appears to be relatively long-lived in its effect on arterial pressure. The erythrocyte fractions that exhibit pressor activity also stimulate the in vitro uptake of calcium by aortas obtained from normotensive animals. This suggests that the hypertensive factor or related substances may influence the calcium metabolism of vascular tissue.     

Differential effects of blood insulin levels on microsomal enzyme activities from hepatic and extrahepatic tissues of male rats.

Microsomal glutathione S-transferase, UDP-glucuronyl transferase, and aniline hydroxylase activities were determined in liver, renal cortex, and small intestine of control, streptozotocin-diabetic, alloxan-diabetic, and untreated insulin-injected male Wistar rats. Renal microsomal glutathione S-transferase activity showed a direct linear relationship with insulin blood levels, in agreement with our previous report on cytosolic glutathione S-transferase. This result suggests a possible regulatory mechanism of insulin that needs to be further examined. The hepatic microsomal UDP-glucuronyl transferase was only decreased in streptozotocin-diabetic rats and was not restored by insulin treatment. Intestinal UDP-glucuronyl transferase exhibited an opposite response in streptozotocin-treated animals that was not normalized by the administration of insulin. Hepatic aniline hydroxylase showed the same behaviour as intestinal UDP-glucuronyl transferase. These results suggest that streptozotocin and (or) its metabolites have a direct effect on hepatic and intestinal UDP-glucuronyl transferase activity and on hepatic aniline hydroxylase activity. On the other hand, insulin regulation of enzyme activity varies from one organ to another.     

Effect of Vaccinium ashei reade leaves on angiotensin converting enzyme activity in vitro and on systolic blood pressure of spontaneously hypertensive rats in vivo

The hypotensive effects of Vaccinium ashei reade (blueberry) leaves were studied in vitro and in vivo. Blueberry leaf showed a strong inhibitory effect on angiotensin-converting enzyme activity in vitro. Additionally, feeding of blueberry leaf suppressed the development of essential hypertension in spontaneously hypertensive rats in vivo. These results promise the use of blueberry leaf as a source of dietary hypotensive components.     

Effects of acute exercise and prolonged exercise training on blood pressure, vasopressin and plasma renin activity in spontaneously hypertensive rats

The purpose of this study was to investigate the effect of swimming training on systolic blood pressure (BPs), plasma and brain vasopressin (AVP), and plasma renin activity (PRA) in spontaneously hypertensive rats (SHR) during rest and after exercise. Resting and postexercise heart rate, as well as blood parameters such as packed cell volume (PCV), haemoglobin concentration (Hb), plasma sodium and potassium concentrations ([Na+], [K+]) osmolality and proteins were also studied. Hypophyseal AVP had reduced significantly after exercise in the SHR, whereas PRA had increased significantly in the Wistar-Kyoto (WKY) strain used as normotensive controls. Plasma AVP concentration increased in both strains. By the end of the experiment, training had reduced body mass and BPs by only 10% and 6%, respectively. Maximal oxygen uptake was increased 10% and plasma osmolality 2% by training. The postexercise elevation of heart rate was not significantly attenuated by training. A statistically significant reduction in postexercise plasma osmolality (10%) and [Na+] (4%) was observed. These results suggested that swimming training reduced BPs. Plasma and brain AVP played a small role in the hypertensive process of SHR in basal conditions because changes in AVP contents did not correlate with those of BPs. Moreover, there were no differences between SHR and WKY in plasma, hypophyseal and hypothalamic AVP content in these basal conditions. Finally, during moderate exercise a haemodilution probably occurred with an increase of plasma protein content. This was confirmed by the exercise-induced increase of plasma AVP and the reduction of hypophyseal AVP content, suggesting a release of this hormone, which probably contributed to the water retention and haemodilution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of diphenylhydantoin on blood pressure of spontaneously hypertensive rats

Diphenylhydantoin (DPH) has been shown to elicit direct peripheral vasodilatory effects in anaesthetised animals. Since spontaneously hypertensive (SH) rats exhibit many features similar to human essential hypertension, the effect of DPH on blood pressure of these rats was studied. DPH given orally for 5 days elicited dose-dependent fall in systolic blood pressure in conscious SH rats. In addition, repeated administrations of DPH increased the noradrenaline concentration in the hypothalamus. These results suggest that the central noradrenergic mechanisms might be involved in the hypotensive action of DPH in SH rats, probably at the supramedullary level.     

Effects of captopril on acute phase in two-kidney Goldblatt hypertensive rats and spontaneously hypertensive rats]

Effects of continuous oral administration of captopril were investigated on acute phase in two-kidney Goldblatt hypertensive (2 KGH) rats and spontaneously hypertensive rats (SHR). Systolic blood pressure gradually rose throughout the experimental period of 7, 14, 21 and 28 days in both 2 KGH rats and SHR. These gradual increases of systolic blood pressure were reduced by administration of captopril in both rats. Plasma renin activity were markedly increased throughout the experimental period in both rats treated with captopril, and were modestly increased in 2 KGH rats. In contrast, those changes in plasma renin activity were not obvious in SHR. In 2 KGH rats, juxtaglomerular index (JGI) and juxtaglomerular cell count (JGCC) of the clipped kidneys increased whereas JGI of the opposite kidneys decreased. In contrast, those changes in JGI and JGCC were not obvius in SHR. On the other hand, JGI and JGCC of the clipped kidneys increased in 2 KGH rats treated with captopril and those of the both kidneys increased in SHR treated with captopril. These results suggested that juxtaglomerular cells were related to the development of hypertension in 2 KGH rats, but were not clear in SHR. And these results were found that captopril showed antihypertensive effects, in spite of rises in JGI and JGCC of both 2 KGH rats and SHR.     

Effects of angiotensin II on the spontaneous activity of rostral ventrolateral medullary cardiovascular neurons and blood pressure in spontaneously hypertensive rats

The interactive role of rostral ventrolateral medulla (RVL) cardiovascular neurons and brain angiotensin II (Ang II) in regulating the arterial blood pressure was examined by recording simultaneously the spontaneous activity of these spinal projecting neurons and the arterial blood pressure in the pentobarbital-anesthetized spontaneously hypertensive rat (SHR) and its normotensive control, the Wistar Kyoto rat (WKY). It was found that Ang II elicited dose-dependent excitatory responses in a subpopulation of RVL cardiovascular neurons, followed by a subsequent increase in blood pressure. These effects of Ang II were significantly greater in SHR than in WKY. The effects were attenuated or abolished by co-administration of Ang II antagonist, [Sar¹, Ile⁸]-Ang II. Pre-administration of [Sar¹, Ile⁸]-Ang II to RVL using bilateral microinjection attenuated the blood pressure effects of intracerebroventricularly administered Ang II by as much as 70%. These results indicated that spinal projecting RVL cardiovascular neurons are important in mediating the pressor action of Ang II. The enhanced sensitivity and responsiveness of RVL cardiovascular neurons to Ang II may be pertinent to the genesis of hypertension in adult SHR.     

Nitric oxide synthase activity in blood vessels of spontaneously hypertensive rats: antioxidant protection by gamma-tocotrienol.

Involvement of free radicals and nitric oxide (NO) has long been implicated to the pathogenesis of essential hypertension. Several studies using antioxidants as the radical scavenger have shown to confer protection against free radical mediated diseases. This study is designed to investigate the role of antioxidant gamma-tocotrienol on endothelial nitric oxide synthase (NOS) activity in spontaneously hypertensive rats (SHR). SHR's were divided into four groups namely untreated SHR (HC), treatment with 15 mg gamma-tocotrienol/kg diet (gammal), 30 mg gamma-tocotrienol/kg diet (gamma2) and 150 mg gamma-tocotrienol/kg diet (gamma3) and studied for three months. Wister Kyoto (WKY) rats were used as the control (C). Blood pressure was recorded every fortnightly by tail plethysmography. Animals were sacrificed and NOS activity in blood vessels was measured by [3H]arginine radioactive assay. Nitrite concentration in plasma was determined by Greis assay and lipid peroxides in the blood vessels by spectrofluorometry. This study showed that gamma-tocotrienol significantly reduced systolic blood pressure (SBP) in SHRs with a maximum reduction in group treated with gamma-tocotrienol 15 mg/kg diet (HC: 210 +/- 9 mmHg, gammal:123 +/- 19 mmHg). Blood vessels from untreated SHR showed a reduced NOS activity compare to that of WKY rats (C: 1.54 +/- 0.26 pmol/mg protein, HC: 0.87 +/- 0.23 pmol/mg protein; p<0.001). Gamma-tocotrienol improves NOS activity in all the groups with more significance in group gamma2 (p<0.001) and gamma3 (p<0.05). Plasma level of nitrite was reduced in SHR from 55 +/- 3 microM/ml in WKY to 26+/-2 muM/ml (p<0.001). Plasma nitrite level was reversed by treatment with gamma-tocotrienol. (gammal: p<0.001, gamma2: p<0.005, gamma3: p<0.001, respectively). In all the treatment groups, NOS activity showed significant negative correlation with blood pressure (gammal: r=-0.716, p<0.05; gamma2: r=-0.709, p<0.05; gamma3: r=-0.789, p<0.05). For plasma nitrite, although it shows a negative correlation with blood pressure it was significant only in gammal (r=-0.676, p<0.05) and gamma2 (r=-0.721, p<0.05). From this study we found that compared to WKY rats, SHR has lower NOS activity in blood vessels, which upon treatment with antioxidant gamma-tocotrienol increased the NO activity and concomitantly reduced the blood pressure. These findings further strengthen the hypothesis that free radicals and NO play critical role in pathogenesis of essential hypertension.