Hypotensive effect of SA446, an angiotensin converting enzyme inhibitor, in 2-kidney, 1-clip renal hypertensive and normotensive dogs

Hypotensive effects of SA446, an angiotensin converting enzyme (ACE) inhibitor, and effects on the renin-angiotensin system were evaluated in conscious normotensive and 2-kidney, 1-clip renal hypertensive dogs. SA446 (1 mg/kg, p.o.) remarkably inhibited the pressor response to angiotensin (Ang) I between 1 and 6 hr after the administration in normotensive dogs. SA446 significantly decreased blood pressure at 10 mg/kg, p.o., in normotensive dogs. During repeated administration of SA446 (100 mg/kg/day, p.o.) for 13 weeks, the blood pressure was lowered, and the pressor response to Ang I and plasma ACE activity were strongly inhibited. ACE activities in the aorta and kidney were also inhibited. Plasma renin activity and plasma Ang I concentration increased by repeated SA446 application, while plasma aldosterone concentration decreased. The hypotensive effect of SA446 (5 mg/kg, p.o.) was more potent in 2-kidney, 1-clip renal hypertensive dogs than in normotensive dogs. SA446 had longer inhibitory effects on the pressor response to Ang I and more potent hypotensive effects than captopril. The hypotension caused by SA446 appears to be associated mainly with an inhibition of ACE in plasma and also in the vascular wall.     

Genistein prevents myocardial hypertrophy in 2-kidney 1-clip renal hypertensive rats by restoring eNOS pathway

Genistein has been shown to increase nitric oxide (NO) production derived from endothelial nitric oxide synthase (eNOS). This study was to investigate whether genistein could prevent myocardial hypertrophy in the 2-kidney 1-clip (2K1C) renohypertensive rat through the NO pathway and to clarify the underlying mechanisms. After the 2K1C operation, plasma angiotensin II increased, and the rats developed significant left ventricular hypertrophy (LVH) and increased collagen I expression. Phosphorylated eNOS, NOS activity, NO production and cGMP contents were markedly decreased in ventricular tissues of 2K1C rats. Chronic administration of genistein to 2K1C rats restored NO, NOS activity, phosphorylated eNOS expression, cGMP in ventricular tissues, and the restoration was parallel with the improvement of LVH and attenuated the excessive ventricular collagen I expression. Genistein also elevated angiotensin II type 2 receptor (AT2) expression, and the effects of genistein on LVH could be completely abolished by an AT2 antagonist, PD123319. The antagonist also reversed the increase in eNOS activity, NO and cGMP restored by genistein in hypertensive rats. We further explored the mechanisms by which genistein restored NO in hypertension and found that genistein significantly enhanced phosphorylated eNOS but left relatively unchanged total eNOS and the eNOS dimer/monomer ratio. In addition, genistein decreased the binding of eNOS with caveolin 3 and simultaneously promoted its binding with calmodulin and heat shock protein 90. We conclude that the preventive effects of genistein on cardiac remodeling induced by 2K1C hypertension are mediated by AT2-dependent NO production.     

Relaxation induced by acetylcholine involves endothelium-derived hyperpolarizing factor in 2-kidney 1-clip hypertensive rat carotid arteries

Acetylcholine induced relaxation in a concentration-dependent way in isolated phenylephrine-contracted carotid artery rings from normotensive two-kidney (2K) and hypertensive two-kidney one-clip (2K-1C) rats. In the presence of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NOARG, 100 micromol/l), the relaxation stimulated with acetylcholine was blocked in 2K arteries. However, in 2K-1C arteries, the relaxation was only partially inhibited. Indomethacin (3 micromol/l) had no effect in both groups. In 2K arteries, the combination of L-NOARG and indomethacin had similar effects to L-NOARG alone. On the other hand, in 2K-1C arteries, indomethacin further inhibited the maximum effect induced by acetylcholine. Endothelium-dependent relaxation induced by acetylcholine was markedly reduced in 2K arteries contracted with 90 mmol/l KCl, and it was abolished in 2K-1C arteries. The remaining response to acetylcholine in 2K arteries was blocked by L-NOARG. Thus, in addition to NO, a relaxing factor sensitive to extracellular K+ changes in the membrane potential contributes to endothelium-dependent relaxation in 2K-1C rat carotid artery. On the other hand, in arteries from 2K rats, only NO is involved in the relaxation induced by acetylcholine. The combination of 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 3 micromol/l), indomethacin (3 micromol/l) and L-NOARG (100 micromol/l) reduced the relaxation induced by acetylcholine in arteries from 2K-1C rats contracted with phenylephrine. On the other hand, in 2K arteries, the relaxation induced by acetylcholine was abolished. The combination of ODQ and K+ channel blockers charybdotoxin (100 nmol/l), apamin (500 nmol/l) and 4-aminopyridine (1 micromol/l) abolished the relaxation induced by acetylcholine in 2K and 2K-1C carotid arteries. These data indicate that the endothelium-derived relaxing factors that contribute to relaxation induced by acetylcholine are different in 2K and 2K-1C arteries. In 2K arteries, the only factor is NO, which involves the activation of K+ channels and the cGMP pathway. However, in 2K-1C arteries, the relaxation induced by acetylcholine is dependent on NO in addition to another factor, which is insensitive to indomethacin, but also activates the K+ channels and the cGMP pathway, presumably by membrane hyperpolarization through endothelium-derived hyperpolarizing factor.     

Effect of a dopamine beta-hydroxylase inhibitor on tissue catecholamine levels in spontaneously hypertensive rats subjected to immobilization-cold stress.

A single administration of FD-008, a new dopamine β-hydroxylase inhibitor, lowered norepinephrine levels in the heart, spleen and various brain regions of spontaneously hypertensive rats, which were subjected to immobilization-cold stress, but FD-008 did not affect norepinephrine in the adrenal medulla. The effect of FD-008 was much stronger in stressed than in non-stressed spontaneously hypertensive rats. Dopamine levels in the cortex and striatum of the brain were not significantly affected by FD-008 in stressed spontaneously hypertensive rats.     

Pharmacological action of FD-008, a new dopamine beta-hydroxylase inhibitor. I. Effects on blood pressure in rats and dogs.

Hypotensive action of a new dopamine beta-hydroxylase (DBH) inhibitor, 5-(4'-chlorobutyl)picolinic acid (FD-008) was investigated in dogs and rats. FD-008, which is one of the most potent inhibitors among fusaric acid derivatives, decreased blood pressure in spontaneously hypertensive rats relatively parallel to DBH inhibition in vitro. The effect of FD-008 on blood pressure was stronger in hypertensive rats than in normotensive rats. No cumulative effect was observed in rats by repeated administration, On the other hand, repeated administration was required to lower blood pressure in normotensive dogs. The acute effect of FD-008 on blood pressure of anesthetized dogs was somewhat different from that of its mother compound, fusaric acid.     

Effect of dopamine beta-hydroxylase inhibition on systemic hemodynamics in conscious, spontaneously hypertensive rats

The acute and chronic effects of a potent and selective dopamine beta-hydroxylase inhibitor, SK&F 102698 [1-(3,5-difluorobenzyl)imidazole-2-thiol], on systemic hemodynamic variables were assessed in chronically instrumented spontaneously hypertensive and normotensive Wistar rats. The changes observed in the hypertensive rats were compared with those obtained by vehicle in a different group of rats. Following intragastric administration of SK&F 102698 (75 mg/kg), blood pressure and cardiac output decreased gradually in both strains of rats, while total peripheral vascular resistance remained unchanged. The antihypertensive effect of repeated daily administration of SK&F 102698 in the hypertensive rats was sustained for the duration of treatment. During the acute phase, the decrease in cardiac output was due to bradycardia. In addition, as a result of hemodynamic changes, SK&F 102698 significantly reduced the minute work output of the heart. The results indicate that SK&F 102698 lowers blood pressure primarily by decreasing cardiac output.     

Effect of intravenous dopamine on blood pressure and plasma insulin in hypertensive patients

Summary Eleven patients with moderate to severe hypertension were pre-treated with oral labetalol 800–1200 mg/day for one week, prior to receiving two IV infusions of dopamine 1–3 g/kg/min each of 30 min each, before and after the IV bolus injection of metoclopramide 30 mg. There were washout periods before and after the metoclopramide administration.Dopamine induced a significant decrease of blood pressure from 172/104 to 153/94 mm Hg without altering heart rate, and it increased the plasma insulin level from 8.3 to 12.1 U·ml^–1. Metoclopramide did not itself affect blood pressure or plasma insulin, but it did block the hypotensive response and rise in plasma insulin due to dopamine.We conclude that the pharmacological actions of intravenous dopamine on the cardiovascular system and on insulin secretion may be mediated by dopaminergic receptor stimulation.     

阿托伐他汀对老年高血压病患者降压作用的影响

目的探讨阿托伐他汀长期使用对已接受降压治疗的高血压病患者血压的影响。方法选取2007年8月至2008年4月在我院干部病房住院且出院后门诊随访、规律服用降压药物治疗的患者62例,按10年心血管危险分层及低密度脂蛋白胆固醇（LDL-C）水平分为治疗组（34例）和对照组（28例）,治疗组除常规降压治疗外,每日加服阿托伐他汀从10 mg开始,根据血脂水平调整剂量,平均为（13.9±6.1）mg.d-1,对照组给予常规降压治疗。比较两组在治疗前及治疗6个月时的动态血压变化。结果对照组治疗前后血压无明显变化（均P〉0.05）;治疗组24 h平均收缩压（24 h平均SBP）、24 h平均脉压（24 h平均PP）在治疗6个月时较治疗前均下降,差异均具有统计学意义（均P〈0.05）,24 h平均舒张压（24h平均DBP）治疗前后无显著变化（P〉0.05）。结论阿托伐他汀对高血压病患者具有降低24 h平均SBP、缩小24 h平均PP的作用。     

Effect of Korea red ginseng on the blood pressure in conscious hypertensive rats.

The change of blood pressure and heart rate after intravenous injection of Korea red ginseng (KRG) were studied in the conscious normotensive and one-kidney, one-clip Goldblatt hypertensive (1K, 1C-GBH) rats. Crude saponin (CS) of KRG (50, 100 mg/kg i.v.) induced a hypotensive effect and bradycardia in a dose-dependent manner in the anesthetized rats. On the other hand, CS of KRG (100 mg/kg) induced a hypotensive effect and reflex tachycardia in the conscious rats. Saponin-free fraction (SFF) of KRG did not affect them in the anesthetized normotensive rats (P>.05). The maximal hypotensive effect by CS of KRG in the conscious 1K, 1C-GBH hypertensive rats and L-nitroarginine methyl ester (L-NAME, 40 mg/kg)-treated conscious hypertensive rats was not different from that of conscious normotensive rats (Delta 31.6+/-6.3, Delta 27.5+/-5.8 vs. Delta 26.7+/-4.3 mmHg, P>.05). However, pretreatment of L-NAME significantly inhibited the reflex tachycardia by CS of KRG (70.8+/-7.0 vs. 30.6+/-15.0 bpm, P<.05). Hemolysate-sensitive nitric oxide (NO) current by the CS of KRG was greater than that of the SFF of KRG (651.9+/-128.2 pA for CS and 164.9+/-92.5 pA for SFF, P<.001). These findings suggest that KRG has a hypotensive effect and its effect may be due to saponin fraction of KRG in the conscious rats. The releasing effect of NO of KRG, like NO donor, may be partly contributed to the hypotensive effect of KRG.     

Occurrence and some properties of a protein-like inhibitor of dopamine beta-hydroxylase in rat liver.

Evidence of endogenous inhibitors of dopamine β-hydroxylase [3, 4-dihydroxyphenylethylamine, ascorbate:O₂ oxidoreductase (hydroxylating), EC 1.14.2.1] (DBH) in rat liver was obtained. At least two kinds of endogenous inhibitors were present in the 105,000 g supernatant of rat liver homogenate and their molecular weights were shown to be about 40,000 and 1200 by gel filtration.The higher molecular weight inhibitor was partially purified by ammonium sulfate fractionation, column chromatography of Sephadex G-100 or Sephadex G-200, and DEAE-Sephadex(A-25) treatment. The activity of this inhibitor was not diminished by boiling for 5 min, but was lost completely when the inhibitor was treated with trypsin, suggesting that it may be a protein. The inhibition of DBH by this protein-like inhibitor in the liver was completely protected by the addition of N-ethylmaleimide, indicating that it may contain functional sulfhydryl groups. The inhibition by this protein-like inhibitor was of the noncompetitive type with both the substrate and with ascorbic acid, one of the cofactors in this reaction.     

Effect of dopamine on renin secretion in the anesthetized dog.

Intrarenal perfusion of dopamine (6 mug/kg/min for 10 min) caused a significant increase of renin secretion, together with a significant increase in renal blood flow. This renin hypersecretion is not accompanied by any significant alteration in renal perfusion pressure, kalemia or natriuresis. The role of intrarenal dopaminergic receptors has been studied: (a) Haloperidol (intrarenal perfusion of 50 mug/kg/min for 20 min) suppresses the renal vasodilation and renin hypersecretion induced by dopamine. (b) Propranolol (intrarenal perfusion of 1 mg/kg in 15 min, then of 4 mg/kg/hr) alters neither the renal vasodilation nor the renin hypersecretion induced by dopamine. These observations support the assumption that the dopaminergic receptors are brought into play in the two renal responses to dopamine studied by us.     

Double-blind placebo-controlled trial of terazosin effect on blood pressure and urinary output of dopamine in hypertensive patients.

In a parallel, double-blind study, 12 untreated hypertensive patients received terazosin (2-4 mg/day for 4 weeks), and 12 received placebo during the same period. Systolic and diastolic blood pressure decreased significantly in the terazosin group, from 150 +/- 5.0 mmHg systolic and 99.6 +/- 2.0 diastolic before treatment, to 134.0 +/- 7.0 systolic and 85.6 +/- 3.0 mmHg diastolic at week 4 of treatment. No significant blood pressure changes occurred in the placebo group. Blood pressure decrease showed a positive correlation (r = .62 and r = .52 for systolic and diastolic blood pressure, respectively) with the patient's age (P less than .05). Total plasma cholesterol decreased 18% in the terazosin group (P less than .05) and 9% in the placebo group (P greater than .05). Urinary dopamine excretion decreased significantly from 692.8 +/- 180.0 to 330.5 +/- 52.0 micrograms/24 hours in the terazosin group (P less than .05) and showed a nonsignificant increase in the placebo group. Compared with 22 age- and sex-matched healthy volunteers, urinary dopamine excretion in the hypertensive group before treatment was not statistically different (779.3 +/- 83.1 micrograms/24 hours). Dopamine excretion was higher in untreated hypertensive men and in male healthy volunteers compared with women. The decrease of urinary dopamine excretion observed under terazosin treatment could be due to a decrease of kidney dopamine synthesis or release induced by blood pressure reduction, or secondarily to the blockade of kidney alpha 1-receptors, modulating dopamine excretion. No significant changes were observed in urinary excretion of noradrenaline and adrenaline.     

Effects of alpha-methyldopa on blood pressure in the anaesthetized dog.

Intravenous infusion over 1 h of 20 mg kg(-1) of alpha-methyldopa produced hypotension in the anaesthetized dog. The magnitude of this effect was, however, inversely correlated with bodyweight. Either rapid intravenous injection of alpha-methyldopa or slow infusion of alpha-methyldopate, was less effective in lowering blood pressure than infusion of free alpha methyldopa in dogs of equivalent bodyweight. Infusion of alpha-methyldopa into a vertebral or internal carotid artery produced hypotensive responses but these were no greater and generally less than those obtained to intravenous infusion. alpha-Methyldopa was therefore capable of producing hypotension in the dog but no evidence was obtained for this being the result of an action within the brain.     

Effect of intracerebroventricular 5,6-dihydroxytryptamine on blood pressure of spontaneously hypertensive rats.

The effects of intracerebroventricular injections of 5,6-DHT on the development and maintenance of hypertension in spontaneously hypertensive rats has been investigated. 5,6-DHT, injected into 6 week old rats, retarded the development of hypertension for at least 6 weeks; this effect was not accompanied by inhibition of the pressor response produced by stimulation of the total peripheral sympathetic outflow. 5,6-DHT, injected into 14-15 week old rats with established hypertension, produced a short-lived fall in blood pressure. These findings suggest that central 5-HT neurones are involved in the development of hypertension in spontaneously hypertensive rats.     

Effect of dietary taurine on blood pressure in spontaneously hypertensive rats

Previous studies have shown the dietary supplementation with sulfur amino acids modified the development of hypertension in rats. In the current study, it was found that the addition of taurine (3%) to the drinking water of rats during the period of 4–14 weeks of age had little effect on blood pressure in normotensive Wistar-Kyoto rats (WKR), and slightly retarded the development of hypertension in spontaneously hypertensive rats (SHR). In the stroke-prone substrain (SHR-SP), however, there is a highly significant reduction in the development of hypertension. The endogenous content of taurine in the liver of SHR-SP is less than 50 per cent of that measured in WKR. The livers of the SHR contain an intermediate amount of taurine. The cysteic acid decarboxylase activity of liver is similar in all three strains. The tissues of animals treated chronically with taurine contain only slightly greater amounts of taurine, with small but significant increases in brain taurine being noted. It appears that genetically hypertensive rats, particularly the SHR-SP substrain, have a defect in taurine metabolism, and that this may be related to the severity of hypertension. There is no evidence to suggest that taurine plays a normal regulatory role in blood pressure maintenance.