Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats

1. The effects of an oral daily dose (10 mg kg(-1)) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. 2. Quercetin induced a significant reduction in systolic (-18%), diastolic (-23%) and mean (-21%) arterial blood pressure and heart rate (-12%) in SHR but not in WKY rats. 3. The left ventricular weight index and the kidney weight index in vehicle-treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin-treated SHR in parallel with the reduction in systolic blood pressure. 4. Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium-dependent relaxation to acetylcholine (E(max)=58+/-5% vs 78+/-5%, P<0.01) in isolated aortae. 5. The 24 h urinary isoprostane F(2 alpha) excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin-treated SHR rats both parameters were similar to those of vehicle-treated WKY. 6. These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug.     

Antihypertensive and hypothalamic depressant effects of tripamide in spontaneously hypertensive rats

When tripamide was added to the food of spontaneously hypertensive rats (SHR), there were no appreciable effects on heart rate, body weight, or food intake. Tail-cuff systolic pressures measured weekly were also unaffected in normotensive control rats (WKY), but the elevation expected in SHR was significantly reduced. Pressor responses to hypothalamic stimulation were also reduced selectively only in SHR. A peripheral inhibition of cardiovascular reactivity was considered unlikely, since pressor responses to injected norepinephrine, tyramine, or vasopressin were unaltered. Diminished pressor responsiveness was considered to be due to concurrent reduction of central sympathetic vasomotor activity, because sympathetic nerve responses to hypothalamic stimulation were appreciably lessened in tripamide-treated SHR. Although neither the site nor the mechanism causing sympathetic inhibition was determined exactly, our results are in accord with the interpretation that antihypertensive effects of tripamide in SHR depend, at least partly, on sympathetic inhibition.     

Cardiovascular effects of KRN2391, nitroglycerin and cromakalim in dihydroergotamine-treated pithed rats

1. The effects of KRN2391 on the cardiovascular system were compared with those of nitroglycerin and cromakalim in pithed rats treated with dihydroergotamine (DHE) in order to examine the effects of these drugs on venous blood vessels.2. DHE (100 μg/kg, i.v.) produced increases in mean blood pressure (MBP), cardiac output (CO) and central venous pressure (CVP) without changes in total peripheral vascular resistance (TPR) and heart rate (HR) based on venoconstriction. The DHE-treated pithed rats, nitroglycerin (30 μg/kg, i.v.) decreased CO and CVP whereas cromakalim (30 μg/kg, i.v.) produced a slight increase in CO followed by a decrease and did not affect CVP. KRN2391 (30 μg/kg, i.v.) produced a decrease in CVP without affecting CO. Decreases in MBP and TPR were induced by all drugs.3. These results suggest that nitroglycerin acts predominantly as a venodilator and KRN2391 and cromakalim showed a venodilating action in addition to an arterial dilating action in DHE treated pithed rats. However, the venodilating action of KRN2391 in this condition is more potent than that of cromakalim.     

Antihypertensive effects of captopril in combination with diuretics in spontaneously hypertensive rats

To examine the antihypertensive effects of captopril, when used in combination with diuretics, an oral dose of the agent (30 mg/kg) was given to spontaneously hypertensive rats pretreated for 1 week with trichlormethiazide (TCTZ), hydrochlorothiazide (HCTZ), furosemide, or water. One-week treatment with diuretics did not lower blood pressure, but potentiated the anti-hypertensive action of captopril in magnitude as well as duration. The degree of potentiation was in the following order: furosemide greater than or equal to HCTZ greater than TCTZ. Plasma renin concentration (PRC) prior to the administration of captopril was highest in the furosemide group, followed by the HCTZ, TCTZ, and control groups, in this order. When data from four groups were taken together, the reduction of blood pressure following captopril administration was closely related to PRC before administration. These data suggest that repeated administration of diuretics renders the maintenance of blood pressure more dependent on the renin-angiotensin system without affecting blood pressure and that this situation underlies the potentiation of the antihypertensive action of captopril by combined use of diuretics. There was no qualitative difference between furosemide and thiazides in the potentiation of anti-hypertensive action of captopril.     

重组降血压肽缓释微球对自发性高血压大鼠的降压作用

目的考察重组降血压肽聚乳酸(rAHP-PLA)缓释微球对自发性高血压大鼠(SHR)的降压作用。方法采用口服和皮下注射两种给药方式,分别给予按体质量和血压均衡分组的自发性高血压大鼠rAHP-PLA缓释微球,空白组给予等量生理盐水。结果口服给予降血压肽缓释微球后10 h,自发性高血压大鼠的血压降至最低,且药效可以持续36 h;皮下注射rAHP-PLA缓释微球后30 h,血压降至最低,且可以持续约9 d。rAHP-PLA缓释微球对正常血压无影响。结论 rAHP-PLA缓释微球具有显著的降压效果,并有明显的缓释作用。     

Antihypertensive activity of alacepril in spontaneously hypertensive rats and deoxycorticosterone acetate-salt hypertensive rats and dogs

Antihypertensive activity of alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine, DU-1219), an orally active angiotensin converting enzyme (ACE) inhibitor, was investigated in hypertensive models with normal or low plasma renin activity (PRA). After single oral administration in spontaneously hypertensive rats (SHR), alacepril (1-30 mg/kg) showed a dose related antihypertensive effect with a gradual onset and long lasting action. The maximum hypotensive effect was about 3 times more potent than that of captopril (3-100 mg/kg) on a weight basis. When comparing the AOC (area over the antihypertensive curve) values, the overall antihypertensive activity of alacepril was 8 times stronger than that of captopril. In deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats, alacepril (10-100 mg/kg) produced a significant and sustained hypotensive effect. The maximum hypotensive potency and the overall antihypertensive activity of alacepril were remarkably stronger than those of captopril (30, 100 mg/kg). During once daily successive oral administration for 10 days in SHR, alacepril (3-10 mg/kg/d) reduced dose relatedly the daily starting blood pressure. In DOCA-salt hypertensive rats and dogs, alacepril (30 mg/kg/d) produced a significant antihypertensive effect, while captopril (30 mg/kg/d) did not reduce daily starting blood pressure. Therefore, it may be expected that alacepril is a more effective antihypertensive agent than captopril in various hypertensions of different etiology.     

Antihypertensive effects of SA446, hydralazine and the combination on renal hypertensive rats and spontaneously hypertensive rats by long-term treatment

SA446 [(2R, 4R)-2-(o-hydroxyphenyl)-3-(3-mercaptopropionyl)-4- thiazolidinecarboxylic acid] (30 mg/kg/day), an orally active angiotensin-converting enzyme inhibitor, lowered significantly indirect systolic blood pressure (SBP) of 2-kidney, 1-clip renal hypertensive rats (RHR) by consecutive oral administration over a 14 week period. Daily oral dosing of hydralazine (2 mg/kg/day) for 14 weeks had little or no effect on SBP, but potentiated the antihypertensive effect of SA446. One to two weeks after discontinuation of the drugs, SBP in SA446 and the combination groups returned to the control level. Survival rates were 64%, 30% in the control and hydralazine group, respectively, but no death was observed in the SA446 group and the combination group throughout the administration period. Twenty-four hour urine volume and water intake tended to increase in the hydralazine group through the administration period, but increased apparently in the SA446 group and the combination group after discontinuation of the drugs. Daily oral dosing of SA446 (45 mg/kg/day) for over 16 weeks completely prevented the development of hypertension in spontaneously hypertensive rats (SHR). Daily oral dosing of hydralazine (2 mg/kg/day) similarly prevented the development. The combined effect with SA446 and hydralazine on the development was also observed. SBP in the SA446 group and the combination group increased gradually after discontinuation of the drugs, but were maintained at a low level as compared with the control group 3 weeks after discontinuation, while hydralazine gave a rapid return. No influences were observed in 24 hr-urine volume and water intake during and after the administration period in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive effect of docosahexaenoic acid in stroke-prone spontaneously hypertensive rats

Docosahexaenoic acid (DHA) is an n-3 unsaturated fatty acid derived from fish oils. The precise mechanisms of DHA actions are still obscure. Especially, the antihypertensive effect of DHA has not yet been elucidated. Stroke-prone spontaneously hypertensive rats (SHRSP) provide the best available model for essential hypertension and stroke. The present study was undertaken to elucidate the effects of long term administration of DHA on blood pressure and stroke-related behavior in SHRSP. The blood pressure of DHA-treated SHRSP was lowered significantly as compared with that of non-treated SHRSP. DHA produced an ameliorative effect on the decreased passive avoidance response in SHRSP. DHA also improved the behavioral changes in spontaneous motor activity of SHRSP. DHA-treated SHRSP produced a significant decrease in the levels of total cholesterol, low density lipoprotein, triglycerides, lipid peroxide, serum creatinine and blood urea nitrogen as compared with those in non-treated SHRSP. These findings indicate that the DHA-induced antihypertensive action may be associated with the amelioration of both serum lipid alteration and renal dysfunction in non-treated SHRSP. Moreover, DHA-treated SHRSP maintain the normal levels of acetylcholine and choline concentrations in the hippocampus and cerebral cortex. These findings demonstrated that DHA produced an ameliorative effect on cholinergic nerve dysfunction in SHRSP. The improved cholinergic nerve function induced by DHA might have an inhibitory effect on stroke-related behavior in SHRSP. The present study suggests that long term administration of DHA may suppress the development of hypertension and stroke-related behavioral changes in SHRSP.     

Antihypertensive effects of continuous oral administration of nattokinase and its fragments in spontaneously hypertensive rats

To determine whether the antihypertensive effect of nattokinase is associated with the protease activity of this enzyme, we compared nattokinase with the fragments derived from nattokinase, which possessed no protease activity, in terms of the effect on hypertension in spontaneously hypertensive rats (SHR). In the continuous oral administration test, the groups were given a basic diet alone (control), the basic diet containing nattokinase (0.2, 2.6 mg/g diet) or the basic diet containing the fragments derived from nattokinase (0.2, 0.6 mg/g diet). The group fed the basic diet containing high-dosage nattokinase (2.6 mg/g diet) showed significant reductions in systolic blood pressure (SBP), diastolic blood pressure (DBP) and plasma fibrinogen level, compared with control group and no influence on activities of renin and angiotensin-converting enzyme (ACE, EC 3.4.15.1), and plasma angiotensin II level in the renin-angiotensin system. The treatment of the basic diet containing high-dosage fragments (0.6 mg/g diet) significantly decreased SBP, DBP and plasma angiotensin II level in plasma but the treatment did not influence on plasma fibrinogen level. These results suggest that nattokinase and its fragments are different from each other in the mechanism to reduce hypertension. Nattokinase, retained its protease activity after absorbance across the intestines, may decrease blood pressure through cleavage of fibrinogen in plasma. The fragments, which absorbed as nattokinase-degradation products, prevents the elevation of plasma angiotensin II level to suppress hypertension.     

Antihypertensive effect of peptides from royal jelly in spontaneously hypertensive rats

We have shown that Protease N treated Royal Jelly (ProRJ) and peptides from ProRJ (Ile-Tyr (IY), Val-Tyr (VY), Ile-Val-Tyr (IVY)) inhibited angiotensin I-converting enzyme (ACE) activity and they have an antihypertensive effect in repeated oral administration for 28 d on spontaneously hypertensive rats (SHR). We investigated the contributive ratio of these peptides in ProRJ for antihypertensive effect in single oral administration on SHR. In single oral administration of each peptide and peptides mixture (MIX; IY, VY and IVY) at doses of 0.5, 1 and 10 mg/kg, systolic blood pressure (SBP) of SHR was reduced dose-dependently. This antihypertensive effect was held for 8 h. These results suggest that peptides contributed to the antihypertensive effect of ProRJ. And the contributive ratio of MIX in ProRJ for antihypertensive effect was computed to be about 38%. Therefore it is considered that intake of peptides, as a functional food would be beneficial for improving blood pressure in people with hypertension.     

Antihypertensive and hormonal activity of MK 954 in spontaneously hypertensive rats.

MK 954 (DuP 753), a recently developed angiotensin II (Ang II) receptor antagonist, was administered orally for 2 weeks to spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). Whereas the basal levels of plasma Ang II were lower in SHR than in WKY, treatment with MK 954 markedly reduced blood pressure in SHR but not in WKY. Plasma renin activity, Ang I and Ang II were increased, while plasma aldosterone was decreased in both strains. These results no only indicate therapeutic efficacy of this agent in the chronic treatment of human hypertension, but also support the idea that the renin-angiotensin system plays an important role in the control of blood pressure in SHR.     

Pharmacological analysis of the vasodepressor effect of KRN2391 in pithed rats

• 1.1. The antagonism by glibenclamide of the vasodepressor effects of KRN2391, cromakalim and nitroglycerin was compared in pithed rats with blood pressure supported by an infusion of phenylephrine.
• 2.2. Cumulative administration of KRN2391 (3–300 μg/kg, i.v.), cromakalim (3–300 μg/kg, i.v.) and nitroglycerin (1–300 μg/kg, i.v.) produced dose-dependent decreases in diastolic blood pressure.
• 3.3. In rats given glibenclamide (20 mg/kg, i.v.), the dose-vasodepressor curves for KRN2391 and cromakalim were shifted to the right. However, glibenclamide had no effect on the vasodepressor effect of nitroglycerin.
• 4.4. The ED_{50 mmHg} values increased about 5.9 fold for KRN2391 and 9.5 fold for cromakalim in glibenclamide-treated rats.
• 5.5. These results suggest that the vasodepressor effect of KRN2391 is due to both glibenclamide-sensitive and insensitive mechanisms. This glibenclamide-insensitive effect of KRN2391 is thought to reflect its nitrate action.

     

Antihypertensive effect of bopindolol on stroke-prone spontaneously hypertensive rats (SHRSP)

The antihypertensive effect of bopindolol, a long-acting beta-adrenoceptor blocking agent, was investigated in stroke-prone spontaneously hypertensive rats (SHRSP). One group received tap water during the period of 8 to 32 weeks of age. The average dose of bopindolol administered was calculated from water intake to be approximately 1.4 mg/kg/day. The lowering effect in blood pressure of bopindolol was apparent at the age of 14 weeks, and this continued up to the end of the experiment. Bopindolol significantly reduced the heart rate. Plasma levels of urea nitrogen (BUN), triglyceride, and phospholipid of SHRSP treated with bopindolol were lower than those of the control SHRSP. One of the 8 control SHRSP died, and no rats treated with bopindolol died during the experiment. The histopathological study revealed that three of the control SHRSP had cerebral apoplexy, whereas there was no evidence of cerebral apoplexy in the treated SHRSP. Chronic treatment of bopindolol clearly alleviated myocardial fibrosis and hypertrophic changes in the left ventricular wall of the heart. Decreases in the incidence of proliferative arteritis and malignant nephrosclerosis in the kidney and necrotizing arteritis of the mesenteric arteries were observed in SHRSP treated with bopindolol. The data presented indicate that bopindolol is a powerful antihypertensive agent.     

Cardioprotective effects of KRN2391 and nicorandil on ischemic dysfunction in perfused rat heart.

The cardioprotective effect of KRN2391 (N-cyano-N-(2-nitroxymethyl)-3- pyridinecarboximidamide methanesulfonate), a novel vasodilator, was studied in the isolated perfused rat heart and compared with that of nicorandil. The isolated buffer-perfused rat heart was subjected to 25 min ischemia followed by 30 min reperfusion. The heart was pretreated with 0.1-10 microM KRN2391, 10-1000 microM nicorandil or vehicle. Before ischemia, KRN2391 (1-10 microM) and nicorandil (10-1000 microM) increased coronary flow, but did not modify the cardiac mechanical function. KRN2391 (1-10 microM) and nicorandil at high doses (300-1000 microM) resulted in significant improvements of cardiac functions and coronary flow during reperfusion and significantly reduced the release of cytosolic enzymes. The protective effects of 3 microM KRN2391 and 300 microM nicorandil were completely reversed by 3 microM glibenclamide, a blocker of ATP-sensitive potassium channels. Thus, KRN2391 and nicorandil at high doses have a direct cardioprotective effect, which may be related to activation of ATP-sensitive potassium channels.     

Effect of KRN2391 on canine ventricular arrhythmia models

• 1.1. KRN2391 (3–30 μg/kg, i.v.) produced a decrease in mean blood pressure (MBP) with concomitant increase in heart rate (HR) and change in electrocardiogram (ECG) such as the shortening of PP and PQ intervals and the prolongation of QTc and these changes in HR and ECG were attenuated by pretreatment with propranolol (1 mg/kg) in normal dogs.
• 2.2. KRN2391 at 30 μg/kg induces neither suppression nor aggravation of ventricular arrhythmias caused by adrenaline and digitalis.
• 3.3. In two-stage coronary ligation-induced arrhythmia, KRN2391 inhibited arrhythmia at 48 hr.
• 4.4. These results suggest that KRN2391 may be effective on arrhythmia related to ischemia. In addition, it is considered that arrhythmia is not induced even by a high dose of KRN2391 in the normal condition.

     

Antihypertensive effect of cattle bone collagen-derived peptides in ovariectomized stroke-prone spontaneously hypertensive rats

1. The effect of food collagen, cattle bone collagen-derived (CBC) peptides, on ovariectomy induced increases in blood pressure was examined in stroke-prone spontaneously hypertensive rats (SHRSP). 2. Long-term administration of CBC peptides to ovariectomized SHRSP suppressed the hypertension compared with ovariectomized SHRSP fed standard chow. 3. The CBC peptides showed an inhibitory activity (IC50 = 40 microg/mL) for angiotensin I-converting enzyme (ACE) in vitro. Furthermore, pre-incubation of CBC peptides with gastrointestinal proteases did not change this inhibitory activity of CBC for ACE. 4. These results indicate that CBC peptides may prevent increases in blood pressure in ovariectomized SHRSP by a possible mechanism of an inhibitory action against ACE.     

Antihypertensive effect of spirapril and felodipine during repeated administration to spontaneously hypertensive rats

The antihypertensive activity of spirapril given alone or in combination with felodipine was investigated in spontaneously hypertensive rats (SHR) during a 3-week treatment regimen and for one week after drug withdrawal. Systolic blood pressure and heart rate were recorded once a week just before dosing and at varying time intervals up to 6 hr thereafter. Recordings were continued for one week after drug withdrawal. Spirapril alone at 1 and 5 mg/kg p.o. was found to produce dose-related antihypertensive effects throughout the treatment period. Felodipine alone at 5 mg/kg p.o. reduced blood pressure slightly more than did the low dose of spirapril. The combination of spirapril and felodipine induced a marked antihypertensive response which was greater than that observed in rats treated with either drug alone. One week after treatment withdrawal, blood pressure was at initial levels with no evidence of rebound phenomena. No significant heart rate changes were observed in the treated groups, as compared with the controls, except for an increase on the 1st day of treatment in rats given felodipine. These findings indicate that the combination of an angiotensin converting enzyme (ACE) inhibitor with a calcium antagonist leads to an effective control of hypertension over a prolonged period of treatment. Since the combination allows effectiveness with lower doses of ACE inhibitor, it is expected that the antihypertensive efficacy might be associated with a lower liability to untoward effects.     

Neurotensin-induced myocardial noradrenergic effects in spontaneously hypertensive rats

Although increases in myocardial synaptic norepinephrine concentrations contribute toward the progression to heart failure in hypertension, the stimuli for norepinephrine release are unclear. In this study we explored whether neurotensin, a neuropeptide found in heart tissue, could modify myocardial norepinephrine release in spontaneously hypertensive rats (SHR). Prior to the development of cardiac decompensation, baseline coronary effluent norepinephrine concentrations were higher in isolated heart preparations of spontaneously hypertensive rats than in Wistar Kyoto (WKY) control rat hearts. Neurotensin increased coronary effluent norepinephrine concentrations and induced positive inotropic responses, effects that were enhanced in spontaneously hypertensive rats compared with Wistar Kyoto rats. Although the neurotensin receptor antagonist, SR 48692, did not modify either baseline coronary effluent norepinephrine concentrations or left ventricular systolic function in spontaneously hypertensive rats, it dose dependently abolished neurotensin-induced cardiac norepinephrine release and contractile responses. Neurotensin-mediated inotropic responses were also abolished by co-administration of the beta-adrenoreceptor blockers, propranolol and atenolol. Inotropic responses to exogenous norepinephrine were similar in SHR and WKY rats. In summary, in the hypertensive heart there is an increased sensitivity to neurotensin's actions on myocardial norepinephrine release and subsequent contractile changes. Therefore, neurotensin receptor blockade may represent a novel therapeutic target in preventing the progression to heart failure in hypertension.