氯沙坦对高血压病人肾素活性的影响

目的 :研究血管紧张肽II受体阻断剂氯沙坦对原发性高血压病人的降压疗效及其对肾素活性水平的影响。方法 :坐位舒张压 12 .7～ 15 .2kPa的原发性高血压病人 36例 ,经 1wk药物洗脱期 ,2wk安慰剂期后服用氯沙坦 5 0mg ,po ,qd ,4wk末坐位舒张压≥ 11.7kPa者剂量加至 10 0mg ,po ,qd× 4wk。服用氯沙坦前后测坐位血压和立位血浆肾素活性水平。结果 :8wk末平均动脉压从 15 .2kPa±1.1kPa下降至 13.7kPa± 1.1kPa(P <0 .0 1)。平均血浆肾素活性水平从 1.5 5 μg·L- 1·h- 1增加至5 .5 4 μg·L- 1·h- 1。结论 :氯沙坦使肾素活性水平增加 ,但其抗高血压疗效与基础肾素活性水平及肾素活性的变化幅度之间无相关性     

Effects of cadralazine on systemic blood pressure, renal function and plasma renin activity in anesthetized dogs

Renal effects of ethyl 6-[ethyl(2-hydroxypropyl)amino]-3-pyridazinecarbazate (cadralazine), a newly synthesized vasodilator with a pyridazine ring, were studied in anesthetized dogs. 30 min after intravenous (i.v.) injection of cadralazine in a dose of 1 mg/kg diastolic blood pressure (DBP) decreased from the control value of 115 +/- 4 mmHg to 108 +/- 3 mmHg. The decrease continued, being accompanied by an increase in heart rate, throughout the experimental period of 5 h. Renal vascular resistance was decreased significantly, while glomerular filtration rate and urine volume remained unchanged. Urinary excretions of sodium and potassium were increased about 1.5 to 2 times as compared to pre-injection control values. Hypotension and natriuresis were followed by increased plasma renin activity in the artery or renal vein. On the other hand, i.v. injection of hydralazine (0.3 mg/kg) promptly decreased DBP and urinary sodium excretion, 15 min after administration, with blood pressure tending to revert to the control value. These results indicate that cadralazine has hypotensive and renal vasodilating actions, characterized by a slow onset and long duration, when compared with hydralazine.     

The effects of combined angiotensin converting enzyme inhibition and beta-adrenoceptor blockade on plasma renin activity in anaesthetized dogs.

1. The effects of beta-adrenoceptor blockade on the changes in plasma renin activity (PRA) following angiotensin enzyme (ACE) inhibition were investigated in pentobarbitone-chloralose anaesthetized dogs. 2. ACE-inhibition, with enalapril (2 mg kg-1), caused a significant reduction in systemic arterial blood pressure (BP) with little or no effect on cardiac function, and a significant elevation of plasma renin activity (PRA). By contrast beta-adrenoceptor blockade with atenolol (1 mg kg-1), caused a similar reduction in BP but in addition, significantly reduced cardiac function and PRA. 3. A combination of enalapril with atenolol, caused a significant reduction in BP, cardiac function and PRA, hence there was no elevation of PRA, as was seen following ACE-inhibition with enalapril alone. 4. The observations with beta-adrenoceptor blockade alone, show that there is an important homeostatic role for the renal sympathetic innervation, mediated by beta-adrenoceptors, in controlling basal renin levels. Furthermore, the renal sympathetic innervation appears to be an important contributor to the renin release caused by an ACE-inhibitor as the additional presence of a beta-adrenoceptor blocking agent will prevent this release. 5. BW B385C (2 mg kg-1), which combines both ACE-inhibition and beta-adrenoceptor blocking properties, also produced reductions in BP and cardiac function similar to those seen with the enalapril/atenolol combination. In addition, for an equivalent degree of ACE-inhibition by BW 385C, to that seen with enalapril alone, the elevation of PRA was attenuated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of chronic sympatho-inhibition on reflex control of renal blood flow and plasma renin activity in renovascular hypertension

Background and purpose:

We determined if chronic sympatho-inhibition with rilmenidine has functional significance for the kidney by altering responses of renal blood flow (RBF) and plasma renin activity (PRA) to stress and acute hypotension in rabbits with renovascular hypertension.

Experimental approach:

RBF to each kidney and renal sympathetic nerve activity (RSNA) to the left kidney were measured in rabbits in which a renal artery clip induced hypertension (2K1C) and in sham-operated rabbits. After 2 weeks, a subcutaneous minipump was implanted to deliver rilmenidine (2.5 mg·kg⁻¹·day⁻¹) to 2K1C rabbits for 3 weeks.

Key results:

After 5 weeks of renal artery stenosis, mean arterial pressure (MAP) was 23% higher and PRA 3-fold greater than in sham-operated rabbits. Blood flow and renal vascular conductance in the stenosed kidney were lower (−75% and −80%) compared with sham, and higher in the non-clipped kidney (68% and 39%). Responses of RBF and PRA to hypotension were similar in 2K1C and sham rabbits. Airjet stress evoked a greater increase in MAP in 2K1C rabbits than sham controls. Chronic rilmenidine normalized MAP, reduced RSNA and PRA, and did not reduce RBF in the stenosed kidney. Responses of RBF (clipped and non-clipped kidney), RSNA and PRA to hypotension and airjet were little affected by rilmenidine.

Conclusions and implications:

Our observations suggest that chronic sympatho-inhibition is an effective antihypertensive therapy in renovascular hypertension. It normalizes MAP and reduces basal PRA without compromising blood flow in the stenosed kidney or altering responses of MAP, haemodynamics and PRA to acute hypotension and stress.     

卡维地洛对麻醉犬血流动力学的影响

目的　观察国产卡维地洛（ｃａｒｖｅｄｉｌｏｌ,Ｃａｒ）对动物血流动力学的影响,全面了解该药对心血管系统的作用。方法　杂种家犬麻醉下ｉｖ０－１、０－３、１ｍｇ·ｋｇ－１Ｃａｒ,记录心电、血压、左心室内压、心输出量。结果　Ｃａｒｉｖ给药可引起麻醉犬平均动脉压、心率、左心室内压及其最大变化速率、左心室做功及总外周血管阻力明显下降,给药后１ｍｉｎ即开始起效,给药后１～５ｍｉｎ达最大效能,并具有剂量依赖性,１ｍｇ·ｋｇ－１剂量药效可持续至给药后４５ｍｉｎ,Ｃａｒ对心输出量及左室舒张末压无明显影响。结论　Ｃａｒ具有较广泛的心血管效应,除通过扩张外周阻力血管降低血压外,尚具有降低心率、抑制心肌收缩性能的作用;试验结果同时提示国产Ｃａｒ兼具α肾上腺素受体和β肾上腺素受体拮抗作用,支持该药为具有Ｓ（－）和Ｒ（＋）构型的外消旋化合物。     

The effects of intravenous L-dopa on plasma renin activity, renal function, and blood pressure in man

Summary L-dopa 7 µg·kg^–1·min^–1 was given intravenously over 2 h to six healthy subjects, controlled by an infusion of saline on a separate occasion, with measurement of plasma renin activity (PRA), urinary sodium and potassium excretion, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), blood pressure, and pulse rate.Mean PRA fell by 50% following L-dopa, which was significantly different from the slight rise which occurred after saline infusion. There was a significant increase in urinary sodium excretion and effective renal plasma flow on infusion of L-dopa. Mean diastolic blood pressure fell during L-dopa infusion, in contrast to the slight increase which occurred during the control study.These observations confirm the anticipated renal dopaminergic effects of L-dopa and also suggest a dopaminergic influence on renin release in man.     

A comparison of the effects of prazosin and hydrallazine on blood pressure,heart rate and plasma renin activity in conscious renal hypertensive dogs

Prazosin, a novel antihypertensive agent, and hydrallazine have been compared in renal hypertensive dogs. I.v. prazosin (0.1 mg/kg) produced greater falls in blood pressure than hydrallazine (1 mg/kg i.v.) but, in contrast to hydrallazine, did not cause any significant alteration in heart rate or plasma renin activity in these animals. When given orally, prazosin (0.1 mg/kg) produced falls in blood pressure equivalent to those observed with i.v. hydrallazine (1 mg/kg) again without significant tachycardia or plasma renin activation.     

Effects of prostaglandins and nitric oxide on the renal effects of angiotensin II in the anaesthetized rat

1. The potential influences of nitric oxide (NO) and prostaglandins on the renal effects of angiotensin II (Ang II) have been investigated in the captopril-treated anaesthetized rat by examining the effect of indomethacin or the NO synthase inhibitor, N^ω-nitro-L-arginine methyl ester (L-NAME), on the renal responses obtained during infusion of Ang II directly into the renal circulation.
2. Intrarenal artery (i.r.a.) infusion of Ang II (1–30 ng kg⁻¹ min⁻¹) elicited a dose-dependent decrease in renal vascular conductance (RVC; −38±3% at 30 ng kg⁻¹ min⁻¹; P<0.01) and increase in filtration fraction (FF; +49±8%; P<0.05) in the absence of any change in carotid mean arterial blood pressure (MBP). Urine output (Uv), absolute (UNaV) and fractional sodium excretion (FENa), and glomerular filtration rate (GFR) were unchanged during infusion of Ang II 1–30 ng kg⁻¹ min⁻¹ (+6±17%, +11±17%, +22±23%, and −5±9%, respectively, at 30 ng kg⁻¹ min⁻¹). At higher doses, Ang II (100 and 300 ng kg⁻¹ min⁻¹) induced further decreases in RVC, but with associated increases in MBP, Uv and UNaV.
3. Pretreatment with indomethacin (10 mg kg⁻¹ i.v.) had no significant effect on basal renal function, or on the Ang II-induced reduction in RVC (−25±7% vs −38±3% at Ang II 30 ng kg⁻¹ min⁻¹). In the presence of indomethacin, Ang II tended to cause a dose-dependent decrease in GFR (−38±10% at 30 ng kg⁻¹ min⁻¹); however, this effect was not statistically significant (P=0.078) when evaluated over the dose range of 1–30 ng kg⁻¹ min⁻¹, and was not accompanied by any significant changes in Uv, UNaV or FENa (−21±12%, −18±16% and +36±38%, respectively).
4. Pretreatment with L-NAME (10 μg kg⁻¹ min⁻¹ i.v.) tended to reduce basal RVC (control −11.8±1.4, +L-NAME −7.9±1.8 ml min⁻¹ mmHg⁻¹×10⁻²), and significantly increased basal FF (control +15.9±0.8, +L-NAME +31.0±3.7%). In the presence of L-NAME, renal vasoconstrictor responses to Ang II were not significantly modified (−38±3% vs −35±13% at 30 ng kg⁻¹ min⁻¹), but Ang II now induced dose-dependent decreases in GFR, Uv and UNaV (−51±11%, −41±14% and −31±17%, respectively, at an infusion rate of Ang II, 30 ng kg⁻¹ min⁻¹). When evaluated over the range of 1–30 ng kg⁻¹ min⁻¹, the effect of Ang II on GFR and Uv were statistically significant (P<0.05), but on UNaV did not quite achieve statistical significance (P=0.066). However, there was no associated change in FENa observed, suggesting a non-tubular site of interaction between Ang II and NO.
5. In contrast to its effects after pretreatment with L-NAME alone, Ang II (1–30 ng kg⁻¹ min⁻¹) failed to reduce renal vascular conductance in rats pretreated with the combination of L-NAME and the selective angiotensin AT₁ receptor antagonist, {"type":"entrez-nucleotide","attrs":{"text":"GR117289","term_id":"238364164","term_text":"GR117289"}}GR117289 (1 mg kg⁻¹ i.v.). This suggests that the renal vascular effects of Ang II are mediated through AT₁ receptors. Over the same dose range, Ang II also failed to significantly reduce GFR or Uv.
6. In conclusion, the renal haemodynamic effects of Ang II in the rat kidney appear to be modulated by cyclooxygenase-derived prostaglandins and NO. The precise site(s) of such an interaction cannot be determined from the present data, but the data suggest complex interactions at the level of the glomerulus.

     

Effect of captopril on renin and blood pressure in cirrhosis

Summary In hepatic cirrhosis neurohumoral vasoconstrictor systems are activated to compensate for circulatory disturbances. To study the renin-angiotensin-aldosterone system in more detail, angiotensin converting enzyme in 15 patients with advanced liver disease was inhibited with captopril after moderate sodium restriction.Captopril caused an increase in plasma renin activity (p<0.005) and a decrease in plasma aldosterone (p<0.025) from an elevated baseline, and a moderate drop in systolic (p<0.025) and diastolic (p<0.05) blood pressure. Hyperreninaemia after captopril was inversely related to the prevailing plasma sodium level (r=–0.66,p<0.01), and the changes in both systolic and diastolic blood pressure were correlated with baseline plasma renin activity (r=0.49,p<0.05 for systolic andr=0.71,p<0.01 for diastolic blood pressure). No change occurred in heart rate or in stimulated plasma noradrenaline and vasopressin levels.The data suggest that in these cirrhotic patients the reactivity of the renin-angiotensin-aldosterone system was still intact, although it occurred at a higher level. They confirm the importance of the renin-angiotensin-aldosterone system in arterial blood pressure regulation in cirrhosis.     

Atrial natriuretic factor attenuates prostaglandin E2-stimulated plasma renin activity in humans

The effect of atrial natriuretic factor (ANF) 99-126 3 or 10 pmol/kg/min on increase in plasma renin activity (PRA) stimulated by a 30-min infusion of prostaglandin E2 (PGE2) 80 ng/kg/min was studied in healthy salt-replete male volunteers. PGE2 increased PRA to approximately 230% of basal levels (p less than 0.001). Concomitant infusion of ANF 3 pmol/kg/min significantly attenuated this rise in PRA to approximately 130% of baseline values (p = 0.02, n = 10). A quantitatively similar effect was observed with ANF 10 pmol/kg/min (n = 5). We suggest, in light of previous findings, that this inhibitory effect of ANF probably represents a nonspecific action rather than a specific effect of ANF on PGE2-mediated increases in PRA.     

Acute effects of lead on renal electrolyte excretion and plasma renin activity

Since lead accumulates in the kidney and interferes with the renal transport of amino acids and glucose, we tested the hypothesis that acute doses of lead also reduce tubular electrolyte reabsorption and alter the secretion of renin. In sodium pentobarbital-anesthetized dogs, acute iv lead increased the excretion of sodium, potassium, calcium, and water, despite a constant glomerular filtration rate; therefore lead reduced the tubular reabsorption of these substances. Lead also caused an increase in plasma renin activity. The threshold dose of acutely administered lead necessary to elicit these responses was determined in dose-response experiments on unanesthetized rats; a dose of 0.1 mg of lead/kg was sufficient to cause significant increases in plasma renin and the renal excretion of sodium. Lead concentrations in the tissues of the rats were measured in samples taken immediately at the conclusion of the study; the threshold dose of lead was associated with very low blood lead (< 5 μg/100 ml) and kidney lead (1.2 μg/g wet wt). These effects of lead are discussed with regard to their possible clinical significance.     

Autoregulation of renal blood flow during the infusion of acetylcholine or carbachol in anaesthetized dogs

Whether renal blood flow autoregulation is abolished by acetylcholine was re-examined by kidney perfusion experiments in anaesthetized dogs. Renal blood flow was dose-dependently increased by the renal arterial infusion of acetylcholine (2 and 5 micrograms min-1) or another muscarinic agent, carbachol (2 and 5 micrograms min-1) and was maintained at an increased level during the infusion. When perfusion pressure was changed stepwise between 60 and 200 mmHg, the infusion of acetylcholine or carbachol caused no impairment of autoregulation. It is concluded that autoregulation is independent of muscarinic stimulation of vascular smooth muscle in the kidney.     

Immediate effects of catecholamines on plasma fibrinogen in conscious and anaesthetized dogs

Adrenaline, noradrenaline, and isoprenaline were injected into dogs and the levels of plasma fibrinogen were estimated for up to 90 min. No changes in the concentrations of circulating plasma fibrinogen were found following the administration of any of the agents. These results do not support the view that hyperfibrinogenaemia occurs immediately following injection of adrenaline or that changes in fibrinogen concentration are related to alterations in blood pressure.     

Hypotensive effects of sodium volume depletion and 1-sar-8-ala-angiotensin II in relation to plasma renin in hypertensive patients

Summary The hypotensive effect of acute sodium volume depletion, produced by chlorthalidone and a low sodium diet, was inversely related to the plasma renin concentration (PRC) in 13 hypertensive patients of varying aetiology (r=0.61; p<0.05); weight reduction induced by this therapy was not related to PRC (r=0.12; p>0.1). The angiotensin II antagonist 1-sar-8-ala-angiotensin II failed to reduce arterial pressure when the patients ingested 130 mEq sodium per day, but pressure fell when it was infused during sodium volume depletion, except when PRC remained low; the changes in pressure were related to the plasma renin level (r=0.78; p<0.005). The combined hypotensive response to acute sodium volume depletion and to angiotensin II blockade during sodium volume depletion was not related to PRC (r=0.15; p>0.1). The results demonstrate that acute sodium volume depletion caused similar weight loss in patients with high and low PRC values, and it would have had similar hypotensive effects but for angiotensin-induced vasoconstriction in the high renin patients. Since 1-sar-8-ala-angiotensin II also reduced arterial pressure in 6 patients during chronic diuretic therapy, angiotensin II must still induce vasoconstriction in these circumstances.     

高血压与肾脏疾病中肾脏局部肾素血管紧张素系统的激活及病理生理作用

肾脏存在独立调节的肾素-血管紧张素系统(RAS).多数高血压与肾脏疾病患者均存在肾脏RAS活性的上调,这对维持机体水钠平衡有重要作用,但同时也促进了高血压的发生,并加速了肾损害的进展.本文结合最近一些基础及临床研究结果,着重讨论疾病状态下肾脏RAS激活的机制、后果及RAS阻断剂的干预意义,这对认识肾脏局部RAS功能,探讨延缓慢性肾脏病进展的治疗策略具有重要意义.     

金鸡菊有效部位对高血压小鼠的血压和肾素-血管紧张素系统的影响

目的观察金鸡菊提取物70%乙醇洗脱物对高血压小鼠血压、血浆血管紧张素Ⅰ（AngⅠ）、血浆血管紧张素Ⅱ（AngⅡ）和组织中AngⅡ浓度的影响。方法采用高盐（80mg/mLNaCl溶液）冷激法,连续20d,形成小鼠高血压模型;将实验小鼠分为正常组、模型组、卡托普利组（40mg/kg）和金鸡菊提取物70%乙醇洗脱物低、中、高剂量（40、80、160mg/kg）组。连续ig给药28d后,采用颈动脉插管法测定小鼠血压并取血,放射免疫法测定血浆AngⅠ、AngⅡ、及肾组织中AngⅡ的含量。结果模型组血浆AngⅠ和组织中AngⅡ含量均明显高于正常组（P〈0.05）,其血压和血浆AngⅡ含量显著高于正常组（P〈0.01或P〈0.001）;与模型组相比,金鸡菊提取物70%乙醇洗脱物中、高剂量（80、160mg/kg）组血浆AngⅠ含量明显升高（P〈0.05）,血浆AngⅡ含量极显著降低（P〈0.001）,肾组织中的AngⅡ含量显著降低（P〈0.01）。结论金鸡菊提取物70%乙醇洗脱物可明显升高AngⅠ水平,减少AngⅡ生成,推测其降压机制主要是通过影响肾素–血管紧张素系统,发挥AngⅠ拮抗剂或血管紧张素转化酶抑制剂的作用。     

Effect of pinacidil on blood pressure,plasma catecholamines and plasma renin activity in essential hypertension

Summary Pinacidil, a new cyanoguanidine derivative, is an antihypertensive agent with arteriolar vasodilating properties, which acts on precapillary resistance vessels. A trial was carried out in 30 patients with essential hypertension WHO I-II. The treatment period was divided into three phases. Hydrochlorothiazide (HCTZ) and amiloride were administered for 4 weeks in Phase 1 and supine and standing blood pressure decreased significantly. During Phase 2 pinacidil was added to HCTZ/amiloride for the following 3 months. A further significant reduction in blood pressure was obtained. In the next period of treatment (Phase 3) patients were divided into two groups. For 1 month Group A (15 patients) received pinacidil alone and Group B (15 patients) received HCTZ/amiloride. Conventional laboratory blood tests in all patients remained unchanged during treatment. Reported side effects during Phase 2 were headache (2 patients), dizziness (3 patients), palpitations (2 patients) and ankle oedema (2 patients). Plasma renin activity was slightly increased at the end both of Phases 1 and 2. Plasma catecholamines were increased but not significantly at the end of Phase 2 as compared to Phase 1. The results indicate that pinacidil is effective in lowering blood pressure in mild to moderate essential hypertension.     

Drug effects on plasma renin activity in the mouse

To investigate the possible effects of newly synthesized beta-adrenergic blockers on plasma renin activity, an assay was developed using unanesthetized mice and radioimmunoassay. Renin activity was significantly increased by the administration of hydralazine (1 mg/kg, i.p.), furosemide (20 mg/kg, i.v.), and isoproterenol (0.1 mg/kg, s.c.). Unlike isoproterenol, norepinephrine (1 mg/kg, s.c.) and epinephrine (1 mg/kg, s.c.) were active but considerably less effective stimulants. The increase caused by isoproterenol was blocked by clonidine, pindolol, bunolol, atenolol, and l-propranolol, but not d-propranolol. The beta-blockers with intrinsic sympathomimetic activity such as pindolol were found to increase renin activity when given alone, but blocked an increase in renin activity when given prior to isoproterenol. In general, nonselective beta-blocking drugs possessing both beta 1- and beta 2-(vascular) blocking activity were found to be most effective in blocking plasma renin activity on oral administration.