Role of thromboxane A2 in the hypotensive effect of captopril in essential hypertension

We have previously reported that captopril stimulates thromboxane A2 synthesis in patients with essential hypertension. In the present study, the hypotensive effects of captopril and OKY-046, a selective inhibitor of thromboxane A2 synthetase, were studied in nine patients with essential hypertension to determine whether thromboxane A2 is involved in the regulation of blood pressure. A single oral dose of OKY-046 (400 mg) decreased urinary thromboxane B2 (a stable metabolite of thromboxane A2) excretion significantly (from 113 +/- 19.0 to 51.0 +/- 6.1 pg/min; p less than 0.01) and increased urinary sodium excretion significantly (from 73.0 +/- 15.3 to 113.0 +/- 14.4 microEq/min; p less than 0.01), but no change was observed in mean arterial pressure. The administration of OKY-046 (600 mg/day) for 3 days induced a significant and sustained decrease in urinary thromboxane B2 excretion, but it did not affect the mean arterial pressure. Although captopril (50 mg) alone induced a significant increase in urinary thromboxane B2 excretion (from 91.4 +/- 11.0 to 297.3 +/- 30.8 pg/min; p less than 0.001) and a significant decrease in mean arterial pressure (from 97.0 +/- 4.7 to 88.1 +/- 5.1 mm Hg; p less than 0.01), captopril in combination with OKY-046 induced a decrease both in urinary thromboxane B2 excretion (from 70.8 +/- 12.3 to 54.2 +/- 14.7 pg/min; p less than 0.01) and in mean arterial pressure (from 105.1 +/- 3.8 to 84.2 +/- 3.6 mm Hg; p less than 0.01). Thus, the hypotensive effect of captopril was potentiated by OKY-046. OKY-046 did not affect the changes in plasma renin activity and plasma aldosterone concentration and blunted urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion in response to captopril. These results indicate that thromboxane A2 counteracts the hypotensive effect of captopril in patients with essential hypertension.     

卡托普利联合美托洛尔治疗2型糖尿病合并高血压的疗效研究

目的 探讨美托洛尔联合卡托普利对2型糖尿病合并高血压患者血糖、血脂和血压水平的影响.方法 选取我院2009年6月-2011年6月收治的2型糖尿病合并高血压患者96例,均进行常规降血糖、调血脂治疗,根据不同的治疗方法将患者分为3组:卡托普利组30例,美托洛尔组33例,卡托普利联合美托洛尔组33例.观察3种不同的治疗方法对2型糖尿病合并高血压患者血糖、血压和血脂水平的影响.结果 治疗后,3组患者的血糖、血脂四项等比较差异均无统计学意义(P＞0.05).3组患者的血压和心率比较差异有统计学意义(P＜0.05),卡托普利联合美托洛尔组患者的血压和心率下降程度较其他两组更明显.结论 3种不同的治疗方案对血糖、血脂水平均无明显影响,均能有效降压,卡托普利联合美托洛尔具有协同降压作用,降压效果更明显.     

疏血通注射液联合卡托普利对老年高血压患者血压昼夜节律及血浆内皮素和一氧化氮的影响

目的 探讨疏血通注射液联合卡托普利对老年高血压患者血压昼夜节律及血浆内皮素、一氧化氮含量的影响.方法 将老年高血压病患者随机分为治疗组40例和对照组36例.治疗组采用疏血通注射液联合卡托普利治疗,对照组单用卡托普利治疗,疗程均为14天.治疗1疗程后观察并比较两组患者血压昼夜节律及血浆内皮素、一氧化氮水平的变化.结果 治疗组降压疗效优于对照组(P＜0.01),中西药联用在改善老年高血压患者昼夜节律变化方面优于对照组,且治疗组中的血浆内皮素、一氧化氮水平变化与对照组比较差异有显著性(P＜0.05).结论 疏血通注射液联合卡托普利能有效改善老年高血压患者血压昼夜节律变化.提高一氧化氮水平,降低血浆内皮素含量,具有较好的降压效果,值得在临床推广.     

Role of Endogenous Angiotensin II and Prostaglandins in the Antihypertensive Mechanism of Angiotensin Converting Enzyme Inhibitor in Hypertension

The role of endogenous angiotensin II and prostaglandins (PGs) in the antihypertensive effect of converting enzyme inhibitor, captopril, was studied in essential hypertension by the separate and the combined administration of captopril and indomethacin. Although plasma angiotensin II was similarly suppressed by the separate and the combined administration of captopril and indomethacin, captopril lowered and indomethacin increased the mean blood pressure. There were negative correlations between the changes in mean blood pressure and in urinary sodium excretion as well as in urinary PGE excretion. These results suggest that endogenous PGs may be implicated in the antihypertensive effect of captopril through the alteration of sodium balance.     

The Hypotensive Effect of Single-Dose Captopril in Diabetics

To determine the role of the kallikrein-kinin(KK) system in patients with diabetes mellitus in relation to nephropathy and/or hypertension, the single-dose effects of captopril(25 mg, p.o.) were examined in 9 control subjects and 32 diabetics (group 1; 11 normotensives without nephropathy, group 2;10 hypertensives without nephropathy, group 3; 11 hypertensives with nephropathy). Significant hypotensive effects of captopril were found in groups 1 and 2 as well as in the control group, but not in group 3. These hypotensive effects were completely blocked by the infusion of ethyl-p-(6-guanidinohexanoyloxy) benzoate methanesulfonate (FOY), a kallikrein inhibitor. The administration of captopril during vehicle infusion induced a significant elevation of plasma renin activity(PRA) at 60 and 120 min after captopril in each group, except for group 3. FOY cancelled these captopril-induced effects on PRA in those groups. No correlation was found between pretreatment PRA and the changes in mean blood pressure(MBP) after captopril during vehicle infusion in whole diabetics. In addition, the daily urinary excretion of kallikrein in group 3 was significantly lower than that in groups 1 and 2 as well as in the control group. These results suggest that the hypotensive action of captopril in diabetics without nephropathy may be largely due to activating the KK system, and that the KK system may be suppressed in hypertensive diabetics with nephropathy.     

Effect of captopril on hemodynamics and physical exertion tolerance in patients with arterial hypertension

The hypotensive effect of captopril was assessed in patients with essential hypertension. Captopril-induced fall in arterial blood pressure was shown to be due to a decrease in total peripheral resistance. Treatment with captopril improved considerably physical stress tolerance, its combinations with a diuretic agent being particularly effective.     

Changes in the indicators of the renin-angiotensin-aldosterone system, kallikrein-kinin system and arterial blood pressure in elderly patients with essential hypertension treated with captopril

The magnitude of captopril hypotensive effect, and variation in renin-angiotensin-aldosterone and kallikrein-kinin parameters were examined in patients with advanced essential hypertension in the presence of normal and low plasma renin activity. The demonstrated differences in the patterns of arterial BP, renin-angiotensin and kallikrein-kinin change have suggested that low-renin essential hypertension is resistant to captopril in most cases.     

Technique for 24 Hour Recording of Continuous High Fidelity Arterial Pressure and Electrocardiogram in Ambulatory Patients

Angiotensin converting enzyme inhibition by MK 421, SA 446 or captopril (6 mg/kg/day ip) for up to 6 days induced significant fall in systolic blood pressure and plasma angiotensin II concentration. The hypotensive effect was greater in sodium depleted rats than in sodium repleted rats. The hypotensive effect was also accompanied by increased excretion of urinary prostaglandin E₂, however the levels of urinary prostaglandin E₂ in sodium repleted rats were not different from those in sodium depleted rats. Urinary kinin excretion was increased during infusion of MK 421, SA 446 or captopril in sodium depleted rats, whereas no significant change was found in sodium repleted rats. Thus the present results suggest that renal prostaglandin E system may not be essential for the hypotensive effect of these inhibitors. In addition, the greater hypotensive effect of these inhibitors in sodium depleted rats may be in part due to stimulated renal kinin system.     

Antihypertensive effects of captopril and saralasin in essential and renal hypertension

The antihypertensive effect of captopril and its mechanism of action were studied in patients with essential and renal hypertension. In mild essential hypertension (n = 12), during monotherapy with captopril (50 to 450 mg, 4 to 12 weeks) blood pressure was normalized in seven, improved in two and remained unchanged in three patients, plasma levels of active and acid-activatable inactive renin significantly increased and angiotensin II decreased, whereas no consistent changes in urinary kallikrein excretion occurred. In severe renal (n = 14) and essential (n = 9) hypertension, blood pressure was normalized in eight (seven with renal hypertension), improved in seven and unchanged in eight patients, when captopril (50 to 450 mg, 3 to 15 months) was added to the antihypertensive medication. In one patient with stenosis in a transplanted renal artery reversible renal failure occurred during captopril therapy possibly because of a steep initial decrease in blood pressure, although a toxic effect of the drug cannot be excluded. In another series of 12 renal and 8 essential hypertensive patients, a significant correlation between the acute effect of captopril (within 90 minutes) and saralasin on blood pressure was demonstrated (r = 0.71, p < 0.001). The change in blood pressure after either drug was significantly related to the initial plasma renin concentration.In conclusion, captopril sems to be an effective antihypertensive agent in essential and renal hypertension. Renal function should be monitored during captopril therapy. Our studies suggest that captopril decreases blood pressure by inhibiting the vasopressor action of the renin-angiotensin system.     

Converting Enzyme Inhibition in Mild and Moderate Essential Hypertension. II

ABSTRACT. In 24 patients with mild/moderate essential hypertension, we studied the effects of captopril with/without hydrochlorothiazide (Htz) on blood pressure, the renin-angiotensin system, blood bradykinin concentration (BBK), plasma volume, exchangeable sodium and glomerular filtration. Daily captopril doses of 75 and 150 mg were equally effective in reducing the blood pressure. Addition of Htz caused further blood pressure reductions. Nineteen patients attained a diastolic blood pressure ≤90 mmHg. Angiotensin converting enzyme inhibition with captopril led to a fall in plasma concentrations of angiotensin II (PAII) and renin substrate, and an increase in plasma concentrations of renin and angiotensin I. Patients starting with Htz had a higher PAII and subsequently a larger fall in blood pressure on captopril than untreated patients. BBK remained unchanged, indicating that the hypotensive action of captopril does not involve an accumulation of circulating kinin. Body fluid volumes and renal function were not affected by the various treatment regimens.     

Responses of the kallikrein-kinin system to angiotensin converting enzyme inhibitors in the rat

Three structurally different drugs, MK421, SA446 and captopril, are angiotensin converting enzyme inhibitors. They induced a significantly greater fall in systolic blood pressure in sodium depleted rats than in sodium repleted ones. The combined administration of vasopressin or norepinephrine with MK421 eliminated the hypertensive effect of vasopressin or norepinephrine. Urinary kallikrein and kinin excretion were increased by MK421, SA446 or captopril in the sodium depleted rats whereas any significant changes in them were not observed in the sodium repleted rats. The combined administration of norepinephrine with MK421 induced further increases in urinary kallikrein and kinin excretion when compared to rats infused with norepinephrine alone, whereas the combined administration of vasopressin with MK421 did not induce any changes in them when compared to rats infused with vasopressin alone. Chronic infusion of captopril for up to 6 days in the rats induced a reduction of the vascular response to exogenous bradykinin; the blood pressure fall was less than that of the controls by 17% on Day 2 and by 18% on Day 6. These results indicate that the hypotensive response to angiotensin converting enzyme inhibitors was in part associated with the enhanced renal and vascular smooth muscle kallikrein-kinin system.     

Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients.

The antihypertensive effect of the orally active angiotensin-converting enzyme inhibitor captopril (SQ 14225) was assessed in 22 hypertensive patients of whom 17 were followed for periods ranging from 1 to 7 months. Of these, eight had essential hypertension, eight had renovascular hypertension, and six had hypertension associated with chronic renal failure. Blood pressure decreased markedly in all patients, including those with low renin levels. Nevertheless, the magnitude of blood pressure reduction correlated with the base-line plasma renin activity (r = 0.58, P less than 0.01). Increasing the dose of captopril from 25 to 200 mg did not enhance the amplitude of the antihypertensive effect but did increase its duration. Patients' blood pressure remained well controlled and free of side-effects with a maximal daily dose of up to 200 mg by mouth twice daily. Despite the blood pressure reduction, sodium excretion tended to increase, probably because of reduced aldosterone secretion. There was no evidence of orthostatic hypotension, and no escape from the antihypertensive effect was observed. These results indicate that chronic inhibition of the angiotensin-converting enzyme with an orally active compound offers a new, efficient, and well-tolerated approach to the treatment of hypertension.     

Renal Kallikrein-Kinin System and the Depressor Effect of Angiotensin Converting Enzyme Inhibitors MK 421, SA 446, And Captopril In Rats

Responses in urinary kallikrein and kinin excretion and systolic blood pressure to MK 421, SA 446 or captopril were studied in normotensive rats fed on a regular or a low sodium diet to assess the role of renal kallikrein-kinin system in their hypotensive effect. MK 421, SA 446 or captopril were infused at a rate of 6 mg/kg/day by osmotic minipump implanted intraperito-neally for up to 6 days. The magnitude of fall in systolic blood pressure was greater on a low sodium diet when compared to on a regular diet, whereas the pattern of the fall was similar on both diets. The magnitude of falls in plasma angiotensin II and aldosterone concentration induced by MK 421, SA 446 and captopril was not significantly different between both regular and low sodium diets. Urinary kallikrein and kinin excretion and sodium excretion were increased during infusion of MK 421, SA 446 or captopril on a low sodium diet, however any significant changes were not found in each of them on a regular diet

The present results suggest that on a low sodium diet the augmented hypotensive response to angiotensin converting enzyme inhibitors in the rats might be due to the enhanced renal kallikrein-kinin system in addition to suppressed renin-angiotensin system     

Use of foridon in the treatment of arterial hypertension and hypertension of the lesser circulation

Hypotensive effect of foridon was evaluated in 68 patients with first- and second-stage essential hypertension, 17 patients with renal hypertension and 18 patients with pulmonary hypertension. Changes in clinical condition, central hemodynamics, pulmonary arterial systolic pressure, inhalation and exhalation intensity were assessed. Foridon effect was shown to be largely due to reduced peripheral resistance. Foridon (30-60 mg) was effective in first-stage essential hypertension. In second-stage hypertension, foridon alone did not always produce an effect. In such cases, foridon-clofelin combination where clofelin hypotensive effect is enhanced can produce a marked hypotensive effect. Foridon is not indicated for the treatment of renal hypertension. Its use as part of combined treatment for chronic nonspecific pulmonary diseases where it is to reduce pulmonary hypertension, is justified.     

Vasoactive Peptides and Hypertension: Role of Angiotensin Converting Enzyme

Abstract: Angiotensin converting enzyme plays a key role in the hormonal regulation of blood pressure. It is responsible for the production of the vasconstrictor hormonal peptide angiotensin II as well as the destruction of the vasodilator peptide bradykinin. Recently, orally active specific inhibitors of angiotensin converting enzyme have become available. Captopril (SQ14225) blocks angiotensin I and potentiates bradykinin effects in vitro and in vivo. In man it leads to a fall in endogenous plasma angiotensin II , a rise in blood angiotensin I and renin, but no change in blood bradykinin can be detected .
In sodium deplete normal subjects it lowers the blood pressure, but in sodium replete subjects it is without effect. Similarly, it will acutely lower blood pressure in renovascular and accelerated hypertension but not in essential hypertension. The acute hypotensive effect of captopril may therefore be due to inhibition of the renin-angiotensin system .
However, in the long term, it is effective in lowering the blood pressure in patients with essential hypertension, especially when combined with a diuretic. This suggests that the long-term hypotensive effect differs from the short term effect, and involves mechanisms other than inhibition of the renin-angiotensin     

Acute hypotensive and renin-stimulating actions of captopril before and during treatment with a beta-blocking drug

There is no general agreement on the relation between the hypotensive effect of captopril and the pretreatment plasma renin levels of hypertensive patients. To determine whether the hypotensive effect of captopril was directly related to plasma renin, the angiotensin-converting enzyme inhibitor was administered acutely to 10 essential hypertensive patients with normal or suppressed plasma renin activity before and after inhibition of renin secretion with propranolol. Captopril was equally effective in reducing blood pressure both when administered alone (25 mg: -29/-17; 50 mg: -37/-23 mm Hg) and after chronic treatment with propranolol (25 mg: -33/-20; 50 mg: -30/-20 mm Hg). The increase in renin induced by captopril was not decreased by propranolol therapy. The persistence of the hypotensive effect of captopril after renin suppression by propranolol suggests that this drug has some blood pressure decreasing properties independent of plasma renin.     

Humoral and hemodynamic effects of increasing doses of captopril in patients with essential hypertension

To compare the hemodynamic and humoral effects of increasing doses of captopril, blood pressure, heart rate, plasma renin activity, plasma aldosterone and angiotensin-converting enzyme activity were measured in 10 patients with mild uncomplicated essential hypertension before and after captopril given in an increasing dose of 25, 50 and 100 mg twice a day, with each dose given for 3 days. The maximal decrease in blood pressure, which was predicted both by basal plasma renin activity values and by the hypotensive response to the first dose, was found after the lowest (25 mg) dose; this effect was detectable for 12 hours independently of the dose administered. Similarly, plasma renin activity was already maximally increased and plasma aldosterone maximally decreased at the lowest dose, while angiotensin-converting enzyme activity showed a dose-dependent inhibition. These data suggest that (1) neither the magnitude nor the duration of the hypotensive effect nor the resin-stimulating and aldosterone-inhibiting actions of captopril are enhanced by drug doses above 25 mg (at least up to 100 mg), and (2) there was no apparent correlation between the degree of angiotensin-converting enzyme inhibition with increasing doses of captopril and the hypotensive effects of the drug.     

Effects of converting enzyme inhibition on blood pressure, plasma renin activity (PRA) and plasma aldosterone in hypertensive diabetics compared to patients with essential hypertension

Hypertension with diabetes mellitus has been associated with suppression of the renin-angiotensin-aldosterone system. We have studied the effects of the converting enzyme inhibitor, captopril, on blood pressure, plasma renin activity (PRA) and plasma aldosterone in 10 stable hypertensive diabetic subjects and 10 age-matched patients with essential hypertension. There was no clinical evidence of complication in the diabetic subjects and their diabetic treatment remained unchanged throughout the study. Mean captopril doses used were similar in both groups. In the diabetics and the essential hypertensives, treatment resulted in a significant and similar decrease in blood pressure. Pre-treatment basal and stimulated PRA and the change of PRA with captopril were also similar. Pre-treatment stimulated plasma aldosterone and the response of aldosterone to postural stress was significantly lower in the diabetic group, suggesting an impaired adrenal responsiveness to stress. Despite this, our findings indicate that the hypotensive action of captopril is at least as effective in hypertension associated with otherwise uncomplicated diabetes mellitus as in essential hypertension.     

Double-blind comparison between propranolol and bendroflumethiazide in captopril-treated resistant hypertensive patients

In a double-blind crossover trial, 15 captopril (daily dose 600 mg) treated patients received in addition to the converting enzyme inhibitor, placebo, propranolol (240 mg), or bendroflumethiazide (7.5 mg). Propranolol produced an additional hypotensive effect, while pulse rate slowed, indicating effective beta-adrenoceptor blockade. Plasma renin activity decreased, but the hypotensive effect of propranolol was not accompanied by changes in the plasma angiotensin II and aldosterone levels or in the urinary aldosterone excretion. Also bendroflumethiazide lowered blood pressure, while body weight decreased slightly. During captopril-bendroflumethiazide treatment, serum sodium and potassium decreased while the plasma renin-angiotensin-aldosterone system was stimulated. In these captopril-treated patients, the hypotensive response to bendroflumethiazide tended to be somewhat larger than the response to propranolol, but the difference was small and statistically not significant.     

Acute effects of captopril on the baroreflex of normotensive and spontaneously hypertensive rats

When captopril was injected intravenously in urethane anesthetized rats, a hypotensive effect accompanied by bradycardia was obtained, while an intravenous (i.v.) injection of prostaglandin I2 (PGI2), which induced hypotension of the same magnitude as the hypotensive effect obtained with captopril, caused a marked tachycardia. Simultaneously, sympathetic nerve activity recorded from abdominal sympathetic nerves was unchanged following injection of captopril, while it was significantly increased during hypotension induced by PGI2. The bradycardia, but not the hypotensive effects induced by captopril was abolished by i.v. pretreatment with atropine. Intracisternal injection of a small dose of captopril inhibited reflex tachycardia during hypotension induced by PGI2 and prolonged the hypotensive effect, while intravenous administration of this dose did not inhibit the reflex tachycardia induced by PGI2. In spontaneously hypertensive rats (SHR), the hypotensive effect of captopril was increased partly, however, the accompanying bradycardia was significantly reduced. These findings suggest that captopril inhibits the baroreflex and centrally activates the cardiac vagal nerve. Moreover in SHR, the effect of captopril on cardiac vagal activity was disturbed.