Captopril in essential hypertension; contrasting effects of adding hydrochlorothiazide or propranolol.

Twenty-four patients with moderate to severe hypertension were treated for four weeks with captopril, an oral inhibitor of angiotensin-converting enzyme. The fall in blood pressure with captopril alone correlated with pretreatment plasma renin activity. The effect of adding either hydrochlorothiazide or propranolol to the captopril treatment was then studied. The addition of hydrochlorothiazide to captopril produced a dose-dependent fall in blood pressure. At the higher dose of the diuretic this fall in blood pressure correlated with weight loss, suggesting that when the diuretic-induced compensatory rise in angiotensin II is prevented by captopril the fall in blood pressure becomes dependent on loss of sodium and water. In contrast, the addition of propranolol to captopril produced no further fall in blood pressure, suggesting that inhibition of angiotensin-converting enzyme prevents the blood pressure lowering effect of propranolol. This may have implications for the mechanism whereby beta-blockers alone lower blood pressure. These contrasting effects of hydrochlorothiazide and propranolol in the presence of captopril indicate that in patients whose hypertension is not controlled by captopril alone the addition of increasing doses of diuretic is likely to control the blood pressure. The addition of a beta-blocker, however, is less likely to be effective.     

Combined administration of captopril with an antihypertensive Val-Tyr di-peptide to spontaneously hypertensive rats attenuates the blood pressure lowering effect

Some di-peptides have been proven to exert an antihypertensive effect in mild-hypertensive subjects. The aim of this study was to clarify whether combined administration of an ACE inhibitor, captopril, with an antihypertensive di-peptide Val-Tyr (VY) would alter their potent antihypertensive effects in spontaneously hypertensive rats (SHRs). Single oral administration of captopril (2.5 mg/kg), VY (25 mg/kg), or captopril (2.5 mg/kg)+VY (25 mg/kg) to 18-week-old male SHRs was performed. Systolic blood pressure (SBP) was measured up to 9 h, and plasma captopril concentrations were determined. A transport study of captopril and/or VY across living rat jejunum from SHRs was also performed to evaluate the kinetics of absorption. Combined administration of captopril with VY failed to lower the BP during the 9-h experiment. A transport study of captopril or VY revealed that VY inhibited captopril transport, and vice versa, in a competitive manner and exhibited an approximately 1/3-fold lower Ki value for captopril compared with that for VY; indicating that both compounds compete for the same membrane transport pathway. A 50% decrease in plasma captopril levels by combined administration with VY supported that the attenuation of the BP lowering effect was due to inhibition of captopril uptake by VY. Consequently, our findings suggest that subjects treated with ACE inhibitors for hypertension should avoid combined-intake with antihypertensive foods that are rich in small peptides due to the competitive inhibition of drug uptake by these peptides.     

Application of 2-halopyridinium salts as ultraviolet derivatization reagents and solid-phase extraction for determination of captopril in human plasma by high-performance liquid chromatography

A high-performance liquid chromatographic method was developed for the determination of captopril in human plasma. 1-Benzyl-2-chloropyridinium bromide (BCPB) was used as a precolumn derivatizing reagent. The mercapto group of captopril was arylated by the reagent to generate a stable UV-sensitive product. The derivative was solid-phase extracted (SPE), separated on a C₁₈ column using reversed-phase ion-paring chromatography and monitored by a spectrophotometric detector at 314 nm. The method enabled sensitive determination of captopril and its disulphides in human plasma in patients after oral administration. Disulphides of captopril with captopril itself and with endogenous thiol compounds are reduced with triphenylphosphine to form captopril, followed by derivatization with the same reagent. The quantification limit was 10 ng/ml. Calibration curves were prepared for human plasma samples spiked with captopril and captopril disulphide. The calibration curves were linear in the range of 10 to 500 ng/ml for captopril and 10 to 1000 ng/ml for captopril disulphide.     

Effect of captopril (SQ 14225) on blood pressure,plasma renin activity and angiotensin I converting enzyme activity.

Seven patients with essential hypertension and seven patients with hypertension associated with renal artery stenosis received captopril (SQ 14225), an inhibitor of angiotensin I converting enzyme. There was a significant reduction in mean blood pressure, from 176/113 +/- 4/3 mm Hg during the control period to 140/90 +/- 5/3 mm Hg during captopril administration. Five patients received captopril alone and nine patients needed hydrochlorothiazide in addition to control their blood pressure. Captopril produced a significant increase in peripheral plasma renin activity. When measured 12 hours after the administration of captopril the angiotensin I converting enzyme activity was found to be similar to that during the control period even though the blood pressure was at or near normal. These findings indicate that although captopril is an effective antihypertensive agent, its action does not depend only on inhibition of plasma angiotensin I converting enzyme activity.     

Dose effect of captopril on renal hemodynamics and proteinuria in conscious, partially nephrectomized rats

The effect of varying doses of captopril, an angiotensin I-converting enzyme inhibitor, on renal hemodynamics, systemic arterial pressure, and the progression of chronic renal disease in conscious, three-quarter nephrectomized adult male Sprague-Dawley rats was studied. Six weeks following nephrectomy (Week 0), rats were randomly divided into five groups. Group 2 (n = 8), 3 (n = 8), 4 (n = 9), and 5 (n = 5) were given 5, 10, 20, and 40 mg/kg captopril, respectively, daily in drinking water. Group 1 (n = 7) and sham-operated controls (n = 7) were given water only. On Weeks -6, 0, 2, and 4, renal function was assessed by 24-hr urinary protein excretion and plasma creatinine. Systolic blood pressure was measured at these times by the tail cuff method. Following Week 4, glomerular filtration rate and effective renal plasma flow were measured in conscious rats by single injection clearance of [3H]inulin and [14C]tetraethylammonium bromide, respectively. Group 1 had significantly higher (P less than 0.05) 24-h urinary protein excretion, plasma creatinine, and systolic pressure compared with Group 5 and controls by Week 4, whereas values for these parameters for Groups 2-4 ranged between these extremes. Although systolic pressures were not significantly different (P greater than 0.05), Group 2 had significantly lower proteinuria than Group 1 (P less than 0.05) at Week 4. Total kidney glomerular filtration rate was similarly decreased in Groups 1-5 compared with control rats. Total kidney effective renal plasma flow was higher in captopril-treated groups than in Group 1, whereas systolic blood pressure was similar or lower, indicating that captopril reduced renal vascular resistance. Furthermore, unlike Groups 1-3, the groups receiving higher doses of captopril (4 and 5) did not develop anemia associated with chronic renal disease. In conclusion, captopril attenuated renal functional deterioration in a dose-related manner. The effect on proteinuria was evident at low doses of captopril which did not significantly reduce systemic blood pressure and was accompanied by an increase in effective renal plasma flow and a decrease in renal vascular resistance.     

Hinokitiol, a metal chelator derived from natural plants, suppresses cell growth and disrupts androgen receptor signaling in prostate carcinoma cell lines

Diabetic patients are often treated with a lipid lowering statin and an ACE inhibitor or angiotensin receptor antagonist against hypertension or albuminuria. These drugs may also improve glucose tolerance, but the mechanism for this remains elusive. We now studied whether these drugs and the fatty acid palmitate influence insulin secretion in vivo in rats through effects on islet blood perfusion. Whole pancreatic blood flow was markedly increased by captopril and irbesartan, and decreased by palmitate. Islet blood flow was significantly and preferentially enhanced by captopril, irbesartan, and pravastatin, and suppressed by palmitate. Both captopril and irbesartan raised serum insulin concentrations significantly. However, glycemia was not affected in any group. In conclusion, the present study suggests that a local pancreatic RAS and pravastatin may be selectively controlling pancreatic islet blood flow and thereby influencing insulin secretion. The antidiabetic actions of statins and RAS inhibitors might in part occur through the beneficial direct islet effects shown here. Conversely, free fatty acids that are elevated in type 2 diabetic patients may contribute to an impaired nutritive islet blood flow and thereby further aggravate the diabetic state by limiting the supply of insulin needed to curb hyperglycemia.     

Effect of the arterial hypertension and captopril treatment on the angiotensin II content in the subfornical organ. A study in SHR rats

We studied the effects of spontaneous high blood pressure and the captopril treatment on the subfornical organ (SFO) of rats. The brains of control Wistar-Kyoto rats (WKY), WKY rats treated with captopril (WKY-T), spontaneously hypertensive rats (SHR) and SHR rats treated with captopril (SHR-T) were processed immunohistochemically using anti-angiotensin II as primary antibody. Immunorective material (IRM) for angiotensin II was observed in a group of neurons and some cells of the ependymal layer of the SFO in WKY rats. The angiotensin II immunoreactive (AGII-ir) in the SHR rats was decreased, showing positive reaction only in a few neurons, while captopril treatment induced an increase in immunoreactive material in hypertensive rats, but contrarily, the expression of AGII-ir in the WKY-T group was scarce. The variations of the angiotensin II observed in the SFO could be owing to an interaction between the hypertension and its captopril treatment.     

Hormonal and renal responses to converting enzyme inhibition during maximal exercise

The role of angiotensin II in the hormonal and renal responses to maximal exercise was investigated by using the angiotensin-converting enzyme inhibitor captopril. Nine male subjects performed a standardized maximal treadmill test with and without acute captopril treatment (25 mg orally). At rest, captopril elevated plasma renin activity and lowered aldosterone levels. With maximal exercise, captopril treatment reduced the increase in mean arterial blood pressure by 8 mmHg and the increase in plasma renin activity by 3.0 ng ANG I.ml-1.h-1. The responses of adrenocorticotropin (ACTH), cortisol, and vasopressin to maximal exercise were not altered by captopril treatment. Although aldosterone levels were reduced at rest with captopril, during maximal exercise no difference was noted between treatments. Captopril treatment had no effects on the renal handling of salts or water during exercise. In conclusion, angiotensin II plays a role in the increase in mean blood pressure during maximal exercise in normal subjects but has no effect on the exercise responses of ACTH, vasopressin, and aldosterone or on the renal handling of salts and water.     

Specificity of renal vasodilation with captopril: Saralasin prevents the response in the doca-treated,salt-loaded rabbit

A prominent action of converting enzyme inhibitors, such as captopril, is a reduction in angiotensin II formation, but interpretation of responses has been complicated by the potential for such agents to reduce bradykinin degradation and promote prostaglandin release. To assess the specificity of the action of captopril, we pretreated rabbits with desoxycorticosterone and a high sodium intake, to suppress the renin-angiotensin system and thus maximize the renal vascular responses which might be unrelated to angiotensin II. Captopril was infused intravenously in graded dosage from 10 to 3,000 μg/kg, and renal blood flow measured with an electromagnetic flowmeter. Despite suppression of the renin system, captopril increased renal blood flow from 3.7 ± 0.5 to 5.3 ± 0.8 ml/g/min (p < .001) in 7 rabbits. In 6 additional rabbits, captopril was superimposed on a saralasin infusion (1.0 μg/kg/min) in a dose sufficient to block responses to endogenous angiotensin II. Saralasin prevented entirely the renal vasodilator response to captopril. Two surprising conclusions derive from this study: first, the renal vasodilator response to captopril appears to be specific for a reduction in angiotensin II formation; second, endogenous angiotensin appears to contribute to renal vascular tone, at least when anesthesia is employed, even when the renin system has been suppressed by a combination of a high sodium intake and desoxycorticosterone.     

ACE activity during the hypotension produced by standardized aqueous extract of Cecropia glaziovii Sneth: A comparative study to captopril effects in rats

To evaluate the effect of the standardized aqueous extract (AE) of Cecropia glaziovii Sneth on the plasma angiotensin I converting enzyme (ACE-EC 3.4.15.1) activity, rats were treated with a single dose of AE (1 g/kg, p.o.) or repeatedly (0.5 g/kg/bid, p.o.) for 60 days. Captopril (50 mg/kg, p.o.) was used as positive control on the same animals. The effects on the blood pressure were recorded directly from the femoral artery (single dose), or indirectly by the tail cuff method (repeated doses) in conscious rats. The plasma ACE activity was determined spectrofluorimetrically using Hypuril-Hystidine-Leucine as substrate. The arterial blood pressure, heart rate and plasma ACE activity were not significantly modified within 24 h after a single dose administration of AE. Comparatively, blood pressure in captopril treated rats was reduced by 7-16% and heart rate was increased by 10-20% from 30 min to 24 h after drug administration. ACE activity after captopril presented a dual response: an immediate inhibition peaking at 30 min and a slow reversal to 32% up-regulation after 24 h. To correlate the drug effects upon repeated administration of either compound, normotensive rats were separated in three groups: animals with high ACE (48.8+/-2.6 nmol/min/ml), intermediate ACE (39.4+/-1.4 nmol/min/ml) and low ACE (23.5+/-0.6 nmol/min/ml) activity, significantly different among them. Repeated treatment with AE reduced the mean systolic blood pressure (121.7+/-0.5 mm Hg) by 20 mm Hg after 14 days. The hypotension was reversed upon washout 60 days afterwards. Likely, repeated captopril administration decreased blood pressure by 20 mm Hg throughout treatment in all groups. After 30 days treatment with AE (0.5 g/kg/bid, p.o.) the plasma ACE activity was unchanged in any experimental group. After captopril (50 mg/kg/bid, p.o.) administration the plasma ACE activity was inhibited by 50% within 1 h treatment but it was up-regulated by 120% after 12 h in all groups. It is concluded that the hypotension produced by prolonged treatment with AE of C. glaziovii is unrelated to ACE inhibition.     

The effect of acetylsalicylic acid and captopril on uterine and ovarian blood flow during the estrous cycle in mares

In previous studies, transrectal color Doppler sonography was used to demonstrate an increase in genital blood flow resistance in subfertile mares. The objectives of the present study were to determine the effects of an anticoagulant (acetylsalicylic acid) and a vasodilator (captopril) on uterine and ovarian perfusion and plasma progesterone concentrations in cycling mares. From Day 1 to 11 of an estrous cycle (Day 0=day of ovulation following prostaglandin-induced luteolysis), five Trotter mares were given 2500 mg lactose, 2500 mg ASA, or 50 mg captopril twice daily in their feed (one compound per cycle, in random order). Transrectal color Doppler sonography was used to examine both uterine arteries and the ovarian artery ipsilateral to the corpus luteum once daily, immediately prior to administration of the drug. Blood flow resistance was determined semiquantitatively using the pulsatility index (PI) and plasma progesterone concentrations were determined with an enzyme immunoassay. Compared to the placebo, both ASA and captopril decreased mean PI values of both uterine arteries of all mares. On average, ASA decreased the PI of the uterine arteries by 25%; this was more (P<0.05) than the average decrease (13%) caused by captopril. Both drugs decreased (P<0.05) blood flow resistance in the ovarian arteries, although there was no difference (P<0.05) in their efficacy. In addition, both ASA and captopril increased (P<0.0001) plasma progesterone concentrations (18 and 17%, respectively). In conclusion, either ASA or captopril improved uterine and ovarian perfusion; however the effects on fertility were not determined.     

Effect of diabetes on aortic nitric oxide synthesis in spontaneously hypertensive rats; does captopril modulate this effect?

Nitric oxide (NO) is a potent regulator in the cardiovascular system; it is generated by the nitric oxide synthase (NOS) family of proteins. NO produced in endothelial cells plays a crucial role in vascular functions. The aim of this study was to clarify the effect of diabetes on aortic NO synthesis in a model of genetic hypertension and determine whether captopril modulates this effect. Diabetes was induced in ten weeks old spontaneously hypertensive rats (SHR) by streptozotocin injection. The rats were allocated into 3 groups: control group 1, non-diabetic SHR; group 2, diabetic SHR; group 3, diabetic SHR group receiving captopril at 80 mg/kg in drinking water for 4 weeks. Mean blood pressure (MBP) was measured once a week by tail-cuff method. Aortic NO metabolities (nitrite/nitrate) and endothelial NOS (NOS-3) were assayed by Griess reaction and by immunoblotting and immunohistochemistry, respectively. There was a significant decrease in nitrite/nitrate (NOx) in aortas of diabetic SHR compared with controls. The decrease of aortic NOx in diabetic SHR was accompanied by a decrease in NOS-3 expression. Captopril treatment reduced MBP without affecting either NOx level or NOS-3 expression in aortas of diabetic SHR. We conclude that STZ-induced diabetes decreased NO in aortas of SHR that may reflect endothelial cell dysfunction; captopril administration decreased MBP without affecting NO level in aortas of diabetic SHR which suggest that the blood pressure-lowering effects of captopril were independent of NO.     

Increased sensitivity of the cardiovascular system to captopril after microsphere embolization of the coronary vessels]

Changes in captopril sensitivity as a result of coronary embolization by 15 um microspheres were studied in rats. Selective coronary embolization was produced by injection of microspheres into the left ventricle during ascending aorta occlusion. The hemodynamic data were examined in conscious rats 21 days after embolization or sham operation before and after captopril bolus injection (1 mg/kg) by using microspheres method. Captopril injection caused a significant increase of the blood flow in the heart, kidneys, skin and some intestinal organs.     

Effects of combined administration of captopril and DMSA on arsenite induced oxidative stress and blood and tissue arsenic concentration in rats

We compared the therapeutic efficacy of captopril and a thiol chelating agent, meso 2,3-dimercaptosuccinic acid (DMSA) either individually or in combination against arsenite induced oxidative stress and mobilization of metal in rats. Animals were exposed to 100 ppm arsenite as sodium arsenite in drinking water for six weeks followed by treatment with DMSA (50 mg/kg, orally), captopril (50 mg/kg, intraperitoneally) either alone or in combination, once daily for 5 consecutive days. Arsenite exposure led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity, glutathione and platelet levels while significantly increased the level of reactive oxygen species (in RBCs). Hepatic reduced glutathione (GSH) level showed a significant decrease while, thiobarbituric acid reactive substances (TBARS) levels increased on arsenite exposure indicating arsenite induced hepatic oxidative stress. Kidney GSH, GSSG, catalase and TBARS remained unchanged on arsenite exposure. Treatment with DMSA was effective in increasing ALAD activity while, captopril was ineffective when given alone. Captopril when co-administered with DMSA also provided no additional beneficial effect on blood ALAD activity but significant brought altered platelet counts back to the normal value. In contrast, administration of captopril alone provided significant beneficial effects on hepatic oxidative stress, and in combination with DMSA provided a more pronounced recovery in the TBARS level compared to the individual effect of DMSA and captopril. Renal biochemical variables remained insensitive to arsenite and any of the treatments. Interestingly, combined administration of captopril with DMSA had a remarkable effect in depleting total arsenic concentration from blood and soft tissues. These results lead us to conclude that captopril administration during chelation treatment had some beneficial effects particularly on the protection of inhibited blood ALAD activity, and depletion of arsenic level. The study supports our earlier conclusion that a co-administration of an antioxidant is more beneficial than monotherapy with the chelating agents, in order to achieve optimal effects of chelation in arsenite toxicity.     

Effect of captopril on kidney function in insulin-dependent diabetic patients with nephropathy.

The influence of angiotensin II on kidney function in diabetic nephropathy was assessed by studying the effect of 12 weeks'' monotherapy with captopril (25-50 mg twice a day) in 16 hypertensive insulin dependent diabetic patients with persistent albuminuria. In an initial one week randomised single blind trial of captopril versus placebo, captopril (for nine patients) reduced arterial blood pressure from 148/94 (SD11/6) to 135/88 (8/7) mm Hg (p less than 0.05) and albuminuria from 1549 (range 352-2238) to 1170 (297-2198) micrograms/min (p less than 0.05), while glomerular filtration rate remained stable. No significant changes occurred in seven patients treated with placebo. During the 12 weeks of captopril treatment arterial blood pressure in all patients fell from 147/94 (11/6) to 135/86 (13/7) mm Hg (p less than 0.01), albuminuria fell from 1589 (range 168-2588) to 1075 (35-2647) micrograms/min (p less than 0.01), and glomerular filtration rate fell from 99 (SD19) to 93 (25) ml/min/1.73 m2 (p less than 0.01). The renin-angiotensin system showed suppressed plasma concentrations of angiotensin II and increased concentrations of angiotensin I and renin. The study showed that glomerular filtration rate is not dependent on angiotensin II, that captopril reduces albuminuria, probably by lowering glomerular hypertension, and that captopril represents a valuable new drug for treating hypertension in diabetics dependent on insulin with nephropathy.     

Acute and chronic arterial and venous effects of captopril in congestive cardiac failure.

OBJECTIVE--To determine whether captopril alters peripheral venous tone in patients with congestive cardiac failure. DESIGN--Open study of patients at start of captopril treatment and three months later. SETTING--A hospital gamma camera laboratory. PATIENTS--16 Men with congestive cardiac failure in New York Heart Association class II or III, aged 57-73. INTERVENTIONS--Patients were initially given 500 micrograms sublingual glyceryl trinitrate followed by 25 mg oral captopril. The study was then repeated after three months'' captopril treatment. MAIN OUTCOME MEASURES--Previously validated non-invasive radionuclide techniques were used to measure changes in central haemodynamic variables and peripheral venous volumes in the calf. RESULTS--After 25 mg captopril there were falls in blood pressure and relative systemic vascular resistance and increases in cardiac index and left ventricular ejection fraction. This was accompanied by a 16% increase in peripheral venous volume (95% confidence interval 13.4% to 18.4%, p less than 0.01), which compared with an 11% increase after 500 micrograms glyceryl trinitrate (10% to 12%, p less than 0.01). Eleven patients were restudied after three months'' continuous treatment with captopril. The resting venous volume was higher than it had been initially, by about 10%, and increased by a further 8.4% after 25 mg captopril (5.4% to 11.4%, p less than 0.05). CONCLUSIONS--Captopril is an important venodilator. Venous and arterial dilatation are produced short term and during long term treatment.     

Systemic antioxidant properties of L-carnitine in two different models of arterial hypertension

In spite of a wide range of drugs being available in the market, treatment of arterial hypertension still remains a challenge, and new therapeutic strategies could be developed in order to improve the rate of success in controlling this disease. Since oxidative stress has gained importance in the last few years as one of the mechanisms involved in the origin and development of hypertension, and considering that L-carnitine (LC) is a useful compound in different pathologies characterized by increased oxidative status, the aim of the present study was to investigate the systemic antioxidant effect of LC and its correlation to blood pressure in two experimental models of hypertension: (1) spontaneously hypertensive rats (SHR) and (2) rats with hypertension induced by N^ω-nitro-L-arginine methyl ester (L-NAME). Treatment with captopril was also performed in SHR in order to compare the antioxidant and antihypertensive effects of LC and captopril. The antioxidant defense capacity, in terms of antioxidant enzyme activity, glutathione system availability and plasma total antioxidant capacity, was measured in both animal models with or without an oral, chronic treatment with LC. All the antioxidant parameters studied were diminished in SHR and in L-NAME-treated animals, an alteration that was in general reversed after treatments with LC and captopril. In addition, LC produced a significant but not complete reduction of systolic and diastolic blood pressure levels in these two models of hypertension, whereas captopril was able to normalize blood pressure. Both LC and captopril prevented the reduction in nitric oxide (NO) levels observed in hypertensive animals. This suggests a decrease in the systemic oxidative stress and a higher availability of NO induced by LC in a similar way to captopril’s effects, which could be relevant in the management of arterial hypertension eventually.     

Essential hypertension: effect of an oral inhibitor of angiotensin-converting enzyme.

Captopril, a specific oral inhibitor of angiotensin-converting enzyme, was given to 18 unselected patients with moderate essential hypertension. Mean blood pressure fell by 14.5% at the maximum dose given, and this fall was significantly correlated with the initial plasma renin activity. The main fall in blood pressure occurred two hours after the first dose of captopril. These results suggest that captopril effectively lowers blood pressure in patients with essential hypertension and that the renin-angiotensin aldosterone system may maintain blood pressure in essential hypertension. This does not necessarily imply that the renin-angiotensin system is the cause of the high blood pressure.     

Effects of long-term treatment with captopril on the isomyosin profile of the heart from SHR and Wistar rats

Heart myosin isoforms and arterial blood pressure changes were studied in 30 SHR rats following a long-term treatment with captopril. 30 Wistar rats were included in the same trial as control. Twelve week old SHR rats with an already established hypertension and ventricular hypertrophy were orally administered with between 25 and 100 mg/Kg/die of captopril. After a ten-week treatment, animals were sacrificed and heart myosin isoforms (V1, V2, V3) analysed by polyacrylamide gel electrophoresis. Our results showed that captopril can: a) reduce blood pressure; b) reduce the cardiac hypertrophy; c) reverse the isomyosin enzymes (V1 V3) previously altered by the hypertrophy condition (V3 V1) to normal value. Furthermore we have detected an increase of V myosin isoform in SHR rats (35%) and to a lower extent in treated Wistar rats (17%). Since SHR and Wistar rats usually do not express V isoform, our results suggest that captopril may be responsible for this phenomenon by acting directly on myocardial cells.     

Factors related to first dose hypotensive effect of captopril: prediction and treatment.

The blood pressure response to the first dose of captopril (6.25 mg, 12.5 mg, or 25 mg) was measured in 65 treated, severely hypertensive patients. Mean supine blood pressure was 187/108 mm Hg immediately before captopril was given. Twenty one patients experienced a fall in supine systolic pressure greater than 50 mm Hg, including five whose pressure fell more than 100 mm Hg and two whose pressure fell more than 150 mm Hg. Six patients developed symptoms of acute hypotension, including dizziness, stupor, dysphasia, and hemiparesis. Percentage reductions in blood pressure were greatest in those with secondary hypertension (p less than 0.05), high pretreatment blood pressure (p less than 0.05), and high concentrations of plasma renin and angiotensin II (p less than 0.01). No significant correlation was found between fall in blood pressure and serum sodium concentration, age, renal function, and the dose of captopril given. A severe first dose effect cannot be consistently predicted in individual patients who have received other antihypertensive drugs for severe hypertension. Such patients should have close medical supervision for at least three hours after the first dose of captopril.