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1. The effect of continuous infusion of captopril (80 microgram/h) for up to 5 days on blood pressure, adrenal angiotensin II receptors and vascular reactivity exogenous angiotensin II, arginine vasopressin and noradrenaline was studied in the rat. 2. In treated rats, blood pressure decreased transiently to a minimum after 2 days (-18 mmHg). Vascular reactivity to angiotensin II, but not to arginine vasopressin, was also increased significantly after 2 days, but vascular reactivity to noradrenaline decreased. After 5 days, vascular reactivity to angiotensin II had returned to normal and was similar to that of sham-treated controls. Adrenal angiotensin II receptor concentrations decreased significantly after 1 and 2 days, but at 5 days were again similar to controls There was no change in receptor affinity. 3. Converting enzyme inhibition with captopril causes transient specific changes in adrenal angiotensin II receptors and vascular reactivity. The receptor and vascular effects may facilitate and oppose, respectively, the early changes in blood pressure with captopril, but a long-term contribution from either is unlikely.

1. The acute effects of a single oral dose of captopril on blood pressure, pulse rate and circulating levels of angiotensin I (ANG I), angiotensin II (ANG II), renin, bradykinin and catecholamines were studied in three groups: eight normal subjects, six salt-depleted normal subjects and 16 patients with essential hypertension. 2. Captopril treatment did not cause any significant fall in supine blood pressure in salt-replete normal subjects or patients with untreated essential hypertension but was associated with a fall in mean blood pressure from 85 +/- 2 to 75 +/- 2 mmHg in salt-depleted normal subjects and from 131 +/- 7 to 117 +/- 5 mmHg in patients with essential hypertension treated with diuretics. There was no change in pulse rate in any group. 3. Hormonal responses to captopril were qualitatively similar in the three groups and consisted of significant falls in ANG II with corresponding increases in ANG I and plasma renin concentration. The changes in plasma renin concentration and ANG I were greater in salt-depleted normal subjects (mean values at 90 min were 1140% and 990% of basal levels respectively) than in salt-replete normal subjects (410%, 190%) and were blunted in patients with essential hypertension (140%, 120%). Blood bradykinin, noradrenaline and adrenaline concentrations did not change after captopril in any group. 4. The parallel fall in blood pressure and ANG II levels in salt-depleted normal subjects is consistent with maintenance of blood pressure by increased levels of ANG II in sodium depletion. 5. The failure of captopril to reduce acutely blood pressure in patients with essential hypertension despite suppression of plasma ANG II and without change in circulating bradykinin confirms that the renin-angiotensin system does not play a primary role in essential hypertension.

The fall in blood pressure produced by captopril is not accompanied by a compensatory tachycardia. Angiotensin converting enzyme may participate in the metabolism of endogenous opioids and these substances can lower blood pressure without reflex tachycardia. It is therefore possible that the hypotensive effect of captopril involves an action on endogenous opioid metabolism. The influence of naloxone, an opiate receptor antagonist, on the cardiovascular effects of captopril has been studied in nine normal volunteers. Mean blood pressure following a 70 degrees head up tilt 1.5 h after captopril was significantly lower than following placebo, but the blood pressure following the combination of captopril and naloxone differed from neither the placebo nor the captopril values. Blood pressures (mm Hg) were: placebo 97.7 +/- 5.9; captopril 83.3 +/- 14.2; captopril + naloxone 89.6 +/- 11.8. Heart rate (beats/min) following a 70 degrees head up tilt at 1.5 h was the same on all three treatments: placebo 83.4 +/- 21.1; captopril 83.3 +/- 16.5; captopril + naloxone 83.6 +/- 11.8. Maximum systolic blood pressure achieved during isometric exercise following captopril + naloxone was intermediate between, and did not differ significantly from, pressures obtained on the other two treatment days. We conclude that co-administration of naloxone may attenuate the effect of captopril on blood pressure and that endogenous opioids could be involved in the actions of this drug.

Captopril, an orally active angiotensin-converting enzyme (ACE) inhibitor, was effective in the long-term reduction of blood-pressure in 17 patients with essential hypertension. The addition of hydrochlorothiazide produced a further hypotensive effect, and the combined treatment produced satisfactory control of the blood-pressure for eight months. Captopril prevented and reversed the secondary hyperaldosteronism and hypokalaemia induced by simultaneous diuretic administration, thus eliminating the need for potassium supplements. The fall in plasma-angiotensin-II and urinary aldosterone and rise in angiotensin I and plasma-renin provide biochemical evidence that captopril inhibits ACE in vivo. No change in circulating venous bradykinin levels could be detected. The hypotensive action of captopril is not mediated by changes in blood-bradykinin but may involve inhibition of the renin-angiotensin and kallikrein-kinin systems locally within the kidneys or blood vessels.

The use of captopril in pregnancy has not previously been reported. We describe a patient who presented in the third trimester of pregnancy with severe hypertension secondary to renal artery fibromuscular hyperplasia and who was successfully treated with captopril alone and in combination with labetalol and frusemide.

Angiotensin II exerts an inhibitory influence on active renin release from the kidney. To assess a possible role for angiotensin II in the release of inactive renin, levels in the circulation were measured before and at regular intervals after the administration of captopril, an orally active inhibitor of angiotensin I-coverting enzyme, to 12 salt-replete and six salt-deplete normal subjects. Concurrent measurements of active renin, angiotensin I and angiotensin II were also performed. Basal inactive renin in the salt-deplete group was increased compared with the salt-replete subjects, but inactive renin remained constant in both groups after treatment with captopril. There were significant increases in concentrations of both active renin and angiotensin I after treatment with captopril in all subject and corresponding decreases in angiotensin II. These results suggested that angiotensin II does not influence the release of inactive renin, in contrast with its role in the release of active renin.

1. In rats treated continuously with captopril (80 microgram/h, i.p.), for 2 days, blood pressure decreased and adrenal angiotensin II receptor concentration was decreased from 160 fmol/mg protein (s.e.m. = 9) in controls to 131 fmol/mg protein (s.e.m. 7, P < 0.01, n = 10). However, after 5 days of continuous treatment, blood pressure had returned to normal and adrenal receptor concentrations in treated rats were not significantly different from controls (180 fnol/mg, s.e.m. = 11 and 203 fmol/mg protein s.e.m. = 14 respectively, 0.1 > P > 0.05). 2. Vascular reactivity, defined as the pressor response to exogenous angiotensin II, increased concurrently by 166 and 33% respectively. 3. In anaesthetized dogs (n = 8), captopril (1.5 mg/kg, i.v.) caused a fall in blood pressure, and uring bradykinin excretion increased from 1-08 (s.e.m. = 0.14) to 1.64 microgram/h (s.e.m. = 0.33, P < 0.025) at 15 min. Renal blood flow increased significantly (P < 0.01) with no change in glomerular filtration rate, and there was no change in either renal venous or arterial blood bradykinin levels. 4. Thus, converting enzyme inhibition produces transient secondary changes in angiotensin receptors and vascular reactivity. Increased urine bradykinin probably reflects decreased catabolism of intrarenal bradykinin. The hypotensive effect of captopril may be due in part to raised levels of bradykinin in the kidney.

To test a possible role of endogenous opioids in the blood pressure (BP) and heart rate (HR) responses to the converting enzyme inhibitor captopril in man, nine normal subjects were given captopril (50 mg) or placebo with and without the opioid antagonist naloxone (0.2 mg/kg i.v.). Treatments were given in random order and under double-blind conditions. BP and HR were measured supine and after a 5 min head-up tilt to 60 degrees before, 90, and 360 min after captopril. BP and HR responses to Valsalva's manoeuvre and isometric exercise (sustained hand grip) were also measured, as indirect tests of baroreceptor reflex function. After captopril alone, there was a significant decrease in supine diastolic and tilt systolic and diastolic BP at 90 min (7.8, s.d. = 6; 15.4, s.d. = 13; and 7.0, s.d. = 12 (s.d. = 9), 0 (s.d. = 15) and 3 (s.d. = 7) mmHg. The effect of naloxone on the changes in supine diastolic and tilt systolic BP were significant (P = 0.017, P = 0.030 respectively; analysis of variance). No significant effects of treatment on supine or tilt HR were seen. BP and HR changes during Valsalva's manoeuvre and isometric exercise were not altered by active treatment. These results suggest that the BP but not the HR responses to converting enzyme blockade are mediated by endogenous opioids.