Antihypertensive Effect Of Captopril Research Articles

Abstract 077: Captopril-Induced Sustained Reduction in Blood Pressure is Associated With Alterations in Gut-Brain Axis in the Spontaneously Hypertensive Rats

Objective: The anti-hypertensive effect of captopril (CAP) is prolonged even when the treatment is discotinued. Our recent findings indicate the beneficial effect of CAP on hypertension-linked gut pathology. Given the roles of brain and gut/microbiota in hypertension, we hypothesized that prolonged anti-hypertensive effect of CAP is through impacts on the brain-gut axis. Accordingly, we tested if CAP induced alterations in the brain and the gut, and if the changes are preserved in the SHR following CAP withdrawal. Methods: Male SHR and normotensive Wistar Kyoto (WKY) rats were treated with CAP (250mg/kg/day) in water for 4 weeks followed by its withdrawal for 16 weeks (weeks 5-20). Systolic BP was measured by tailcuff at weeks 3, 5, and 9. Fecal microbiota was analyzed at week 4 and week 8. Brain neuronal activity was measured by manganese-enhanced MRI (MEMRI) at weeks 4 and 8. Gut pathology was assessed at week 20. Results: Unweighted principal coordinate analysis showed that CAP treatment significantly altered gut microbial composition, characterized by separate clusters between untreated and 4 weeks CAP-treated SHR. The composition change was preserved 4 weeks post-withdrawal of CAP. Sustained improvement in fibrotic area (untreated: 12.98±0.81% vs week 20: 10.23±0.69%, P=0.036), goblet cell number (untreated: 39±3.57 cells/villi vs week 20: 65±5.29 cells/villi, P=0.0006), and villi length (untreated: 271.4±9.85 μm vs week 20: 388.8±12.29 μm, P<0.0001) was observed at week 20 compared with untreated SHR. MEMRI demonstrated sustained decrease in neuronal activity in autonomic brain regions, with the most pronounced decrease in the posterior pituitary area in SHR treated with CAP (week 4) and withdrawal of CAP (week 8), compared with untreated control (untreated: 1.57±0.11 vs week 4: 1.14±0.074 vs week 8: 1.05±0.14, P=0.0162). In contrast, CAP-treated WKY showed little change in BP, gut pathology or neuronal activity, but distinct changes in gut microbiota. Conclusion: Oral CAP persistently lowered BP, altered gut microbiota, improved gut pathology and reduced posterior pituitary neuronal activity in the SHR even post-withdrawal of CAP, indicating persistent antihypertensive effect of CAP may result from altered brain-gut communication.

Ultrafine carbon black attenuates the antihypertensive effect of captopril in spontaneously hypertensive rats

Particulate matter (PM) has been associated with increased blood pressure (BP) by affecting renin-angiotensin system (RAS) on a systemic level in spontaneously hypertensive rats (SHR). RAS in SHR is also an important target for the angiotensin converting enzyme (ACE) inhibitors such as captopril. We aimed to determine if ultrafine carbon black (UCB) could affect antihypertensive effect of captopril in SHR. The rats were randomly divided into six groups. Group 1 did not receive intratracheal instillation; group 2 received saline instillation plus captopril administration; groups 3, 4 and 5 received 0.15 mg/kg, 0.45 mg/kg and 1.35 mg/kg UCB per instillation plus captopril administration, respectively; group 6 received 1.35 mg/kg UCB instillation only. Rats in the above groups were intratracheally instilled with saline or UCB once every two days for three times and captopril was administered to group 2–5 after the final UCB treatment, once a day for one week. The BP was measured 24 h after each intratracheal instillation. During captopril administration and 24 h after last captopril administration, we measured BP every two days for four times. Our results showed that UCB at the dose of 1.35 mg/kg induced pulmonary and systemic inflammation in SHR. Captopril reduced BP in rats exposed to 0, 0.15 and 0.45 mg/kg UCB seven and eleven days after the first UCB instillation, and had no effect on BP in rats exposed to 1.35 mg/kg UCB. Captopril also reduced angiotensin II (AngII) in rats exposed to saline. The reduction, however, was attenuated with increasing doses of UCB. We conclude that UCB attenuated the antihypertensive effect of captopril in SHR, and the effect was accompanied by a systemic increase in the concentration of AngII.

Involvement of prostaglandins in the action of captopril in type II diabetic patients.

Twelve well-controlled, type II diabetic patients without hypertension and advanced diabetic complications and 12 age-matched healthy control subjects were treated for 4 days with captopril 25 mg three times daily. The pretreatment values of plasma renin activity, plasma aldosterone, urinary 6-keto prostaglandin F1 alpha and thromboxane B2 were similar in both groups. Urinary prostaglandin E2 was significantly reduced in diabetics. After captopril plasma renin activity increased significantly in the diabetics and control subjects. Plasma aldosterone was not significantly decreased in both groups. Urinary prostaglandin E2 increased significantly in both diabetic and control groups. Other measured prostaglandins remained unchanged. After captopril systolic blood pressure decreased significantly in diabetics and not significantly in the control group. The results indicate that captopril was an effective drug for lowering blood pressure in diabetic patients, too. It is possible that the antihypertensive effect of captopril in diabetics could be due at least partly to prostaglandin E2.

Captopril bei essentieller Hypertonie

The antihypertensive effect of captopril was tested on 19 patients with essential hypertension, WHO grade I or II. In 11 patients blood pressure levels returned to normal over an observation period of 12 weeks at a dose of 3 C 50-150 mg daily (group A). In eight patients with grade II hypertension the absolute blood-pressure reduction was the same, but did not reach normal levels (group B). Although additional intake of propranolol, at a dose of 3 X 40 mg daily, achieved further reduction, normal pressures were still not attained. Initial blood pressure levels were higher and plasma-renin activity lower in patients of group B than of group A. There was a definite rise in plasma-renin activity with captopril, but corresponding to the suppression of plasma-renin in severe hypertension it was less. There was a fall in plasma-aldosterone levels, corresponding to a reduced angiotensin II level as a result of inhibition of the converting enzyme. The fall in plasma-aldosterone activity was less in severe hypertension, although there was the same inhibition of converting enzyme activity in both groups. Normochromic anaemia was noted in three patients, requiring further observation and explanation. No patient developed orthostatic hypotension or reflex tachycardia.

Late blood pressure reduction in shr subjected to transient captopril treatment in youth: possible mechanisms

Spontaneously hypertensive rats (SHR) are characterized by enhanced nifedipine-sensitive component of sympathetic vasoconstriction. Our study tried to elucidate the mechanisms responsible for long-term reduction of blood pressure (BP) in SHR subjected to early transient captopril treatment. Adult untreated SHR aged 30-34 weeks were compared with animals subjected to chronic captopril treatment for 6 weeks either in youth (between 4 and 10 weeks of age) or in adulthood (between 24 and 30 weeks of age). Antihypertensive effects of captopril were more pronounced in young than adult SHR. This was due to greater attenuation of sympathetic and nifedipine-sensitive BP components and prevention of residual BP rise in young captopril-treated SHR in which the reductions of nifedipine-sensitive BP component and residual BP persisted for 20 weeks after captopril withdrawal. The magnitude of nifedipine-sensitive component of sympathetic vasoconstriction is decisive for BP maintenance not only in untreated SHR but also in SHR during active captopril treatment by or after its withdrawal.

Polymorphisms of ACE2 Gene are Associated With Essential Hypertension and Antihypertensive Effects of Captopril in Women

ACE2 appears to counterbalance the vasopressor effect of angiotensin I converting enzyme (ACE) in the reninangiotensin system. We hypothesized that ACE2 polymorphisms could confer a high risk of hypertension and have an impact on the antihypertensive response to ACE inhibitors. The hypothesis was tested in two casecontrol studies and a clinical trial of 3,408 untreated hypertensive patients randomized to Atenolol, Hydrochlorothiazide, Captopril, or Nifedipine treatments for 4 weeks. ACE2 rs2106809 T allele was found to confer a 1.6-fold risk for hypertension in women (95% confidence interval (CI), 1.132.06), whereas when combined with the effect of the ACE DD genotype, the risk was 2.34-fold (95% CI, 1.754.85) in two independent samples. The adjusted diastolic blood pressure response to Captopril was 3.3 mm Hg lower in ACE2 T allele carriers than in CC genotype carriers (P=0.019) in women. We conclude that the ACE2 T allele confers a high risk for hypertension and reduced antihypertensive response to ACE inhibitors.

Involvement of Ras-Regulated Myosin Light Chain Phosphorylation in the Captopril Effects in Spontaneously Hypertensive Rats

Early treatment with captopril prevents the development of hypertension by inhibiting the generation of angiotensin II and smooth muscle contraction. Although smooth muscle contraction is regulated by myosin light chain phosphorylation (MLC-P), the role of MLC-P in captopril effects in hypertension has not been described. Therefore, we treated spontaneously hypertensive rats (SHR) with captopril and investigated the effects of this agent on downstream signaling. Male SHR (n = 12) were treated with captopril (3.7 mmol/L in drinking water) beginning in utero and continuing up to 12 weeks of age. Age- and sex-matched untreated SHR and Wistar-Kyoto (WKY) rats were used as controls. Rats were split into three subgroups and were sacrificed at 12, 18, or 24 weeks of age. Systolic blood pressure, left ventricular weight, and body weight were measured. Mesenteric arteries were removed for histologic and biochemical studies. At 12 weeks, captopril significantly decreased systolic blood pressure (from 198 +/- 10 to 125+/-16 mm Hg), reduced left ventricular weight-to-body weight ratios (from 2.94 +/- 0.06 to 2.17 +/- 0.08 mg/g), and prevented vascular remodeling in mesenteric arteries in SHR. Ras expression, extracellular receptor kinase phosphorylation (ERK-P), myosin light chain kinase (MLCK) expression, and MLC-P were all significantly increased in mesenteric arteries in untreated SHR compared with WKY rats. Early captopril treatment in SHR significantly inhibited Ras and MLCK expression at all ages and decreased ERK-P and MLC-P at 12 and 18 weeks in mesenteric arteries. These data demonstrate that the antihypertensive effects of captopril are correlated with inhibition of Ras-regulated ERK activation, MLCK expression, and MLC-P.

Involvement of ras-regulated myosin phosphorylation in the long-term antihypertensive effects of captopril

Involvement of ras-regulated myosin phosphorylation in the long-term antihypertensive effects of captopril

Possible impact of nitric oxide on the antihypertensive effect of captopril and zaprinast.

The interaction between the renin-angiotensin system and nitric oxide (NO) is undeniable, but its nature is not fully known. This study investigated the contribution of NO to the acute hypotensive effect of captopril in conscious normotensive rats and the effect on blood pressure of dual administration of captopril and the phosphodiesterase-5 inhibitor zaprinast. In two separate experiments, rats were pretreated with the NO inhibitor L-arginine methyl ester (L-NAME) and with the NO enhancer zaprinast. Pretreatment with L-NAME attenuated and pretreatment with zaprinast potentiated the hypotensive effect of captopril. The hypotensive effect of captoril was not associated with a significant change in the plasma level of cyclic guanosine monophosphate (cGMP). These findings suggest that NO contributes to the blood pressure-lowering effect of captopril. The inability of captopril to alter plasma cGMP levels is not consistent with this view, however, and leads to the conclusion that NO contributes to the acute hypotensive effect of captopril, although the mechanism is not fully understood. Zaprinast potentiates the hypotensive effect of captopril, and an adjustment in dose should be considered when this combination is administered.

Treatment of hypertensive and hypercholesterolaemic patients in general practice: The effect of captopril, atenolol and pravastatin combined with life style intervention

Objective - To elucidate the effect on blood pressure and blood lipids of an angiotensin converting enzyme inhibitor (captopril), and a beta-receptor blocking agent (atenolol), given alone or in combination with a cholesterol reducing drug, the beta-hydroxy-methylglutaryl-coenzyme A reductase inhibitor pravastatin, in patients who were also encouraged to improve their lifestyle.Design - A longitudinal study consisting of three phases. I: Lifestyle intervention alone. II: Continued lifestyle intervention combined with captopril or atenolol. III: Continued lifestyle intervention combined with the same drugs as in phase II and in addition pravastatin or placebo. Setting - Fifty-four general practice surgeries in Norway. Participants - Hypertensive patients, 210 females and 160 males, treated or untreated with antihypertensive drugs with a sitting diastolic blood pressure between 95 and 115 mmHg and a serum total cholesterol between 6.5 mmol/l (7.0 for those age 60-67 years) and 9.0 mmol/l.Results - The antihypertensive effect of captopril and atenolol was not influenced by concurrent administration of pravastatin. The effect of pravastatin was not limited by concurrent medication with captopril or atenolol. Improvement in lifestyle seemed to reduce the need for supplementary treatment with diuretics.Conclusion - Pravastatin can be used in combination with captopril or atenolol in the treatment of hypertensive and hypercholesterolemic patients.

The influence of restraint on blood pressure in the rat

We examined the influence of procedures used in blood pressure measurement on blood pressure and the effects of antihypertensive agents. Subjects were spontaneously hypertensive rats (SHR) and their Wistar/Kyoto (WKY) controls. Blood pressure was recorded by telemetry. Twenty-four h baseline pressure were measured, and the effect of minor handling on blood pressure and heart rate was examined. The influence of restraint such as is used for tail-cuff blood pressures was examined. The effects of three different antihypertensive drugs was also examined in the SHR. In the home-cage environment, the SHRs showed higher systolic blood pressures, but had similar hypertensive responses to minor handling as the WKYs. Both strains had elevated heart rate and blood pressure when restrained in the manner used for tain-cuff readings. The antihypertensive effects of captopril and losartan in the SHR were unchanged when the animals were restrained but the hypotensive effect of hydralazine was greater. These results confirm that significant changes in heart rate and blood pressure can occur as a result of the minor procedures frequently used in blood pressure recording in both SHR and WKY rats. This suggests that telemetry may have significant advantages as a method for continous blood pressure monitoring. The pharmacological profile of antihypertensive drugs may well be different in animals where telemetry is employed and are not subject to the stresses involved in previous methods of monitoring blood pressure.

Antihypertensive effect of captopril and enalapril in endothelin-infused rats.

Comparative effects of angiotensin converting enzyme inhibitors and calcium channel blockers were assessed in rats infused chronically with synthetic endothelin. When 50 mg/kg/day of captopril orally or 6 mg/kg/day of enalapril intraperitoneally was administered simultaneously with 60 micrograms/kg/day of endothelin, the systolic blood pressure was on Day 1 142.7 +/- 5.9 mmHg (p less than 0.05) or 128.7 +/- 6.7 mmHg (p less than 0.05), respectively, compared to the rise to 163.8 +/- 4.7 mmHg when endothelin alone was infused. The antihypertensive effect of captopril or enalapril was sustained for the entire experimental period and was not associated with a significant change in urinary sodium excretion, whereas both drugs induced a significant increase in urine volume. Chronic infusion of angiotensin II intraperitoneally at a subpressor dose (400 micrograms/kg/day) reversed the antihypertensive effect of captopril in endothelin-infused rats. When 6 mg/kg/day of benidipine or 10 mg/kg/day of nilvadipine orally was administered simultaneously with 60 micrograms/kg/day of endothelin, the systolic blood pressure was on Day 1 137.0 +/- 2.4 mmHg (p less than 0.05) or 119.7 +/- 5.9 mmHg (p less than 0.05), respectively, compared to the rise when endothelin alone was infused. The antihypertensive effect of benidipine or nilvadipine was sustained for the entire experimental period and was not associated with any significant changes in urine volume and urinary sodium excretion. These results indicate that the reduced sensitivity of the peripheral arteries to endothelin may be involved in the mechanism of the hypotensive action of angiotensin converting enzyme inhibitors, dependent on the suppressed angiotensin II formation.

Antihypertensive Effect of Captopril on Essential Hypertension

Antihypertensive Effect of Captopril on Essential Hypertension

Effects of Indomethacin on Hormonal and Blood Pressure Responses to Captopril in Spontaneously Hypertensive Rats

The possible role of vasodilatory prostanoids in the antihypertensive action of captopril was investigated in spontaneously hypertensive rats (SHR). Captopril (100 mg/kg/day for 5 days) decreased systolic blood pressure and increased water consumption, urine excretion and plasma renin activity (PRA). It also enhanced the urinary excretion of the prostacyclin metabolite 6-keto-PGF1 alpha, but did not change the excretion of PGE2. Indomethacin (3 mg/kg/day), given both alone and in combination with captopril, reduced markedly the urinary excretions of 6-keto-PGF1 alpha and PGE2 but did not alter PRA, compared with corresponding groups without indomethacin. The suppression of prostanoid synthesis caused by indomethacin did not affect the antihypertensive effect of captopril or the basal blood pressure in SHR. Neither did indomethacin influence drinking or urine excretion in SHR not receiving captopril, but it reduced the dipsogenic and diuretic effects of captopril. The results suggest that captopril augments the production of vasodilatory prostacyclin. Yet prostanoids have no significant role in the antihypertensive mechanism of captopril in SHR.

Acute oral captopril inhibits angiotensin converting enzyme activity in human cerebrospinal fluid.

Angiotensin converting enzyme (ACE) activity in human plasma and cerebrospinal fluid (CSF), was measured by a fluorimetric method, following an acute oral dose (75 mg) of captopril. A decrease of approximately 60% in enzyme activity was observed in CSF, suggesting that the drug penetrates the blood/brain barrier (BBB) in sufficient amounts to inhibit the ACE in CSF. The activity of CSF enkephalinase, an enzyme present in human brain and inhibited in vitro by an elevated concentration of captopril, was, however, unaffected by the acute drug administration. It is proposed that the antihypertensive effect of captopril in humans may be due, at least in part, to the inhibition of ACE contained within brain structures.

Captopril + hydrochlorothiazide 24 h ambulatory monitoring effects.

The purpose of this study was to evaluate over a 24 h period the antihypertensive effect of captopril 50 mg + hydrochlorothiazide (HCTZ) 25 mg once a day in mild to moderate hypertension. Ambulatory recordings over 24 h of the blood pressure using the Spacelabs system were performed, at the end of a 15-day placebo period and after giving captopril + HCTZ for 45 days. Captopril + HCTZ significantly decreased (P less than 0.001) systolic and diastolic blood pressures for both the diurnal period (8 h to 22 h) and the nocturnal period (22 h to 8 h). No change in heart rate was observed. For further analysis, the mean hour values of blood pressure and heart rate were calculated. A constant decrease of the systolic and diastolic blood pressure throughout the 24 h was obtained after captopril + HCTZ without any change in heart rate and in nyctohemeral variations. The study provided evidence that, in patients with mild to moderate essential hypertension, captopril + HCTZ once a day decreased systolic and diastolic blood pressure all day long without any change in the heart rate and the blood pressure nyctohemeral cycle.

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 role of renal hemodynamics in the antihypertensive effect of captopril

To evaluate the role of regional hemodynamics in mediating the long-term depressor effect of the converting enzyme inhibitor, captopril, at a low dose (37.5 mg/day), for 2 weeks, its systemic, renal, and forearm circulatory actions were determined in 12 patients with mild to moderate essential hypertension. After administration of captopril, there was a significant decline in mean blood pressure (average −12.1 ± 1.9%) accompanied by a decrease in systemic vascular resistance (−9.1 ± 3.3%), but cardiac output did not change. Although forearm vascular resistance was not altered, renal vascular resistance decreased considerably (−17.1 ± 5.0%). Moreover, there was a highly significant ( r = 0.891) correlation between the changes in mean blood pressure and renal vascular resistance. Plasma renin activity increased after therapy as plasma aldosterone decreased, while plasma norepinephrine slightly increased. The change in renal vascular resistance significantly ( r = −0.617) correlated with the pretreatment level of plasma renin activity. These findings suggest that suppression of the renin-angiotensin system in essential hypertension induces selective vasodilation in the renal vasculature, which may play an important role in the long-term antihypertensive effect of the converting enzyme inhibitor. This renal vasodilator action appears to be the feature that distinguishes the converting enzyme inhibitor from conventional vasodilator drugs.

Pharmacokinetics and pharmacodynamics of captopril in patients undergoing continuous ambulatory peritoneal dialysis.

Pharmacokinetics and pharmacodynamics of captopril were studied in 5 continuous ambulatory peritoneal dialysis (CAPD) patients (including 2 hypertensive patients) after single oral administration of 50 mg captopril. The pharmacokinetic parameters for plasma free unchanged captopril were time to maximal concentration 1.1 +/- 0.3 h, maximal plasma concentration 387 +/- 75 ng X ml-1, elimination half-life 1.0 +/- 0.3 h, and the area under the concentration-time curve 711 +/- 144 ng X h X ml-1. For plasma total captopril (the sum of free unchanged captopril and its disulfide compounds) the values were time to maximal concentration 3.5 +/- 0.6 h and maximal plasma concentration 2,777 +/- 429 ng X ml-1. Captopril was detected in the dialysis fluid in all CAPD patients. Blood pressures in the 2 hypertensive CAPD patients were lower at 24 h after than before captopril administration. These results suggest that captopril may be eliminated by CAPD. In addition, there is a possibility that the antihypertensive effects of captopril may be prolonged in hypertensive CAPD patients.

Captopril Versus Enalapril Maleate

Summary: The antihypertensive effects of captopril and enalapril maleate were studied over a 10-week period in 24 hypertensive patients randomized into captopril or enalapril treatment groups. Prestudy blood pressure was 171 ± 4/109 ± 1 mm Hg and after 4 weeks of hydrochlorothiazide 160 ± 4/103 ± 1 (p < 0.05). With the addition of converting enzyme inhibitor to hydrochlorothiazide the blood pressure decreased at 3 h to 132 ± 3/87 ± 2 in the subjects. The diastolic blood pressure decreased acutely more with captopril (− 24) than with enalapril (− 17) (p < 0.05). After 10 weeks of combined therapy the depressor response was maintained (134 ± 3/83 ± 1) and there was no difference between the diastolic blood pressure in the two groups treated with captopril and enalapril. Acute and chronic responses of plasma renin activity, plasma aldosterone, and converting enzyme to the angiotensin-converting enzyme inhibitor were determined. There was a significant correlation between the acute fall in diastolic blood pressure and rise in plasma renin activity in patients treated with captopril but not with enalapril. In conclusion, there is an acute depressor response with converting enzyme inhibition which is more pronounced with captopril than with enalapril and which correlates with an increase in plasma renin activity. With more prolonged treatment, the two drugs show equivalent efficacy in reducing blood pressure, inhibiting angiotensin-converting enzyme, reducing aldosterone, and stimulating plasma renin activity.