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PubMed2004

Renal targeting of captopril using captopril-lysozyme conjugate enhances its antiproteinuric effect in adriamycin-induced nephrosis.

INTRODUCTION: High-sodium intake blunts the renoprotective efficacy of angiotensin-converting enzyme (ACE) inhibitors. We investigated whether targeting the drug to the kidneys may attenuate the inferior response to ACE inhibitor (ACE-I) under high-sodium conditions. The ACE-I, captopril, was coupled to the low molecular weight protein (LMWP) lysozyme, yielding captopril-lysozyme conjugates that accumulate specifically in the proximal tubular cells of the kidneys. We compared the antiproteinuric efficacy of captopril to that of the captopril-lysozyme conjugate in adriamycin-induced proteinuric rats fed with a high-sodium diet. MATERIALS AND METHODS: Rats with adriamycin (single injection 2 mg/kg)- induced proteinuria were put on a high-sodium diet (HS; 3% NaCl). When stable proteinuria developed at 5.5 weeks, animals were assigned to the following subcutaneous treatments: (1) vehicle (n=7); (2) lysozyme (equivalent to the amount in conjugate) (n=7); (3) captopril (5 mg/kg/24 hours) (n=8); (4) captopril-lysozyme conjugate (captopril content equivalent to 1mg captopril/kg/24 hours) (n=7). Blood pressure and proteinuria were monitored. After 10 days of treatment the rats were sacrificed and kidneys and plasma were removed. RESULTS: Results are given as mean + S.E.M. After injection with adriamycin at t=0, stable proteinuria developed, amounting to 547+79 mg/24 hours at week 5.5. Subsequently, after seven and nine days of treatment, no reduction of proteinuria was observed in the captopril-treated group. In contrast, a significant reduction in proteinuria, amounting to 35+4% (day seven) and 25+2% (day nine), was observed in the captopril-lysozyme conjugate group (p<0.05 compared with the captopril group). In contrast, blood pressure was reduced in the captopril-treated group by 13.9+2.9 mmHg, while in the captopril-lysozyme treated group, an increase of 7.9+3.3 mmHg was found. Renal ACE activity was lowered by 30% in the captopril, as well as in the captopril-lysozyme conjugate treated group, compared with control. Furthermore, the ratio of kidney: plasma levels of captopril almost doubled as a consequence of coupling to lysozyme. CONCLUSION: In proteinuric rats fed with a high-sodium diet, captopril induced a reduction in blood pressure without an effect on proteinuria. In contrast, renal targeting of a five times lower dose of the ACE-I with the captopril-lysozyme conjugate reduced proteinuria without reducing blood pressure. Therefore, renal targeting of ACE-I may be a promising strategy to optimise the therapeutic response of ACE-I.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1986

Acute titration and chronic follow-up with captopril in hypertension. A one-year safety profile on combination therapy with captopril and a diuretic.

The present study examines acute titration with captopril and chronic follow-up data on captopril and a diuretic in patients with all forms of hypertension. Captopril was initiated in those patients in whom previous antihypertensive agents either failed to control high blood pressure or produced adverse reactions. Acute titration was done in 88 patients in whom average diastolic blood pressure was equal to or more than 95 mm Hg. Initial titration dosage was decided on the basis of initial blood pressure recordings. During initial titration, 5 patients received 12.5 mg, 51 received 25 mg, 28 received 50 mg, and the remaining 4 received 100 mg of captopril. Post-captopril blood pressure data were normalized by using pre-captopril data as 100% for each patient. The blood pressure-lowering effect of captopril on both systolic and diastolic blood pressure in all 88 patients was statistically significant (p less than 0.05), within forty-five minutes of captopril administration irrespective of the doses. No adverse reactions were seen during the acute titration. After the initial titration, in all 88 patients a diuretic was added to obtain a synergistic effect. Eleven patients were dropped from the study, for they could not follow the requirements of the protocol. In 77 patients the data for a one-year safety profile with captopril and diuretic were available. There were no overall significant statistical changes in serial white blood cell count, serum potassium, and serum creatinine values in those 77 patients. In 31 patients the initial and maintenance dosage of captopril and the diuretic remained unaltered for one year. Post-captopril blood pressure and heart rate data were normalized, pre-captopril data being considered as 100% in those 31 patients. The blood pressure data following captopril and a diuretic therapy compared with the pre-captopril data were statistically significant (p less than 0.05) throughout the study period. However, no significant changes in heart rates were observed during the study period. In all other patients, diuretic therapy was continued throughout the study period. In 6 severely hypertensive patients, an additional beta-blocker was needed for further control of high blood pressure. In 3 severe hypertensives with renal failure, besides a diuretic and a beta-blocker, minoxidil was needed to normalize their high blood pressure. In 4 of 77 patients, verapamil was used for treatment of either vasospastic angina or paroxsysmal supraventricular arrhythmia.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic beta-Antagonists↗

PubMed1985

Effect of probenecid on the disposition of captopril and captopril dimer in the rat.

The urinary excretion of captopril has been studied in a bladder-cannulated rat model and compared with that obtained after co-administration with probenecid. Probenecid reduced significantly the urinary excretion of captopril from 41% to 21% of the administered dose over a 3-hr period and significantly lowered urine flow rates. In addition, the effect of probenecid on plasma levels of captopril and total captopril (captopril plus disulfides) after oral administration of the disulfide prodrug captopril dimer (10 mg/kg) has been studied in a conscious rat preparation. Co-administration of probenecid (20 mg/kg) given either orally or intravenously increased both the plasma levels of captopril and total captopril (captopril plus captopril disulfides) over a 4-hr period. A prolonged significant inhibition of plasma ACE after co-administration of probenecid and captopril dimer suggests that probenecid may be useful to prolong the action of captopril or the prodrug captopril dimer.

Animals↗

PubMed1984

Captopril disulfide conjugates may act as prodrugs: disposition of the disulfide dimer of captopril in the rat.

The absorption and metabolism of the disulfide dimer conjugate of captopril has been studied in the rat following both oral and intravenous dosing and compared with that of the active monomer, captopril. Metabolism of the dimer to captopril has been shown after both oral and intravenous administration of the dimer (10 mg/kg) with peak plasma levels of captopril (154 ng/ml) occurring at 1 hr post dose. By contrast the peak plasma level of captopril after oral administration of captopril (10 mg/kg) at the same dose was much higher at 678 ng/ml and also occurred at 1 hr post dose. Plasma captopril disulfide species were much higher than the plasma levels of captopril after the administration of either dimer or captopril and tended to persist for much longer than for monomeric captopril particularly after administration of the dimer. Both the dimer and its pharmacologically active product captopril were found in relatively large amounts in lung, kidney and liver following the oral administration of the dimer.

Administration, Oral↗

PubMed1984

Combined gas chromatographic-mass spectrometric procedure for the measurement of captopril and sulfur-conjugated metabolites of captopril in plasma and urine.

A gas chromatographic-mass spectrometric method is described for the simultaneous measurement of the novel anti-hypertensive drug captopril, and the following metabolites: captopril disulfide dimer, S-methyl captopril, and S-methyl captopril sulfone. With this method all derivatives can be chromatographed using conventional gas chromatography of hexafluoroisopropyl esters in one temperature-programmed run and these can then be quantitated using selected-ion monitoring techniques. Using urine or plasma, captopril, S-methyl captopril and the disulfide dimer of captopril in concentrations as low as 1 ng/ml, 10 ng/ml and 25 ng/ml, respectively can be detected. The reproducibility of the method is satisfactory both within-assay and inter-assay. This technique has demonstrated that the pattern of urinary excretion of these compounds in both man and rat was similar. Excretion of unchanged captopril, S-methyl captopril and the disulfide dimer over 6 h in man given captopril (50 or 100 mg) chronically was 18.3%, 0.97% and 3.06%, respectively. Corresponding excretion of these three compounds in the rat following a single 10 mg/kg dose was 18.3%, 2.69% and 1.8%, respectively. A possible sulfone oxidation product of S-methyl captopril was not detected in the urine of either man or rat.

Animals↗

PubMed1983

A placebo-controlled trial of captopril in refractory chronic congestive heart failure. Captopril Multicenter Research Group.

Ninety-two patients with heart failure refractory to digitalis and diuretic therapy had captopril (n = 50) or placebo (n = 42) added to their therapeutic regimen in a randomized, double-blind trial. During a 2 week dosage titration period, one captopril-treated patient died of an intracerebral hemorrhage. Over the remaining 10 week evaluation period, 1 captopril-treated patient (2%) was excluded from the study because of treatment failure as compared with 12 discontinuations (4 deaths and 8 failures [29%]) among the placebo group (p less than 0.001). Eighty percent of patients in the captopril group exhibited some degree of clinical improvement, whereas only 27% in the placebo group did so (p less than 0.001). The therapeutic advantage of captopril over placebo was evidenced by a mean improvement of 0.52 (2.8 +/- 0.1 to 2.3 +/- 0.1) in the New York Heart Association functional class value as compared with 0.03 (2.9 +/- 0.1 to 2.8 +/- 0.1) with placebo (p less than 0.0001). There was a 24% mean increase in exercise tolerance with captopril (495 +/- 22 to 614 +/- 27 seconds) as compared with 0.4% with placebo (480 +/- 28 to 483 +/- 43 seconds) (p less than 0.01); the captopril group had an increase in the ejection fraction from a mean baseline value of 0.19 +/- 0.02 to 0.22 +2- 0.02 as compared with 0.19 +/- 0.02 to 0.18 +/- 0.002 (p less than 0.05) in the placebo group. A cohort analysis revealed that improvement in exercise tolerance with captopril was gradual and progressive throughout the 12 weeks. Improvement in specific symptoms of heart failure, that is, dyspnea, fatigue and orthopnea, and the reduction of edema also were greater in the captopril-treated patients (p less than 0.05 to p less than 0.001). Captopril therapy was well tolerated, although symptomatic hypotension after the first dose caused withdrawal of three patients (3%) from the study. It was concluded that captopril is an effective adjunctive treatment to digitalis and diuretic drugs for patients with refractory heart failure.

Adult↗

PubMed1996

Diagnosis of renovascular hypertension: feasibility of captopril-sensitized dynamic MR imaging and comparison with captopril scintigraphy.

OBJECTIVE: Angiotensin-converting enzyme inhibitors may decrease glomerular filtration rate when a significant renal artery stenosis is present. The purpose of this preliminary study is to evaluate the feasibility of captopril-sensitized, dynamic MR imaging of the kidney in a series of patients with a high suspicion of renovascular hypertension and to compare the results with those of captopril scintigraphy. SUBJECTS AND METHODS: Fifteen hypertensive patients with renal artery stenosis shown by angiography were studied with sequential gadolinium-enhanced MR imaging after oral administration of 50 mg of captopril, an inhibitor of angiotensin-converting enzyme. Symmetry of onset and evolution of tubular phases between the two kidneys were analyzed, and medullary signal intensity time curves were drawn for each kidney. When asymmetry between kidneys was noted, the same dynamic study was repeated 24 hr later, without captopril sensitization. All patients also underwent renal scintigraphy after administration of captopril to compare captopril-induced changes in both techniques. Three-dimensional time-of-flight MR angiography was also performed on all patients. RESULTS: MR imaging with normal and symmetric tubular phases showed that 11 patients had no impairment of glomerular filtration after administration of captopril. MR imaging showed that four had impairment of glomerular filtration: studies without captopril were symmetric (n = 2) or slightly asymmetric (n = 2), but administration of captopril induced severe functional impairment on the side of stenosis--that is, a delayed tubular phase with late corticomedullary decrease of signal intensity in the first two patients and absence of tubular phase in the other two. The results of scintigraphy were concordant in all but one case, in which the segmental distribution of filtration impairment, shown by MR imaging, was not shown by scintigraphy. The renal artery stenosis was shown by MR angiography in 10 of 15 patients (67%). CONCLUSION: Captopril-sensitized dynamic MR imaging of the kidney is feasible in patients with renovascular hypertension. However, captopril-induced changes are not present in all patients proven to have the disease. Scintigraphy provides similar results but may ignore segmental functional involvement.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1983

Metabolism of captopril-L-cysteine, a captopril metabolite, in rats and dogs.

The metabolism of [14C]captopril-L-cysteine was studied in spontaneously hypertensive rats and pure-bred beagles after a single i.v. dose (4 mg/kg). During the first 24 h, concn. of total radioactivity in blood were similar in both species. Captopril was found in small amounts in the blood of both species. In rats, captopril, bound covalently but reversibly to plasma proteins (CP-PR), was the major component in blood (70%), whereas captopril-L-cysteine was a minor component (23%) of the total radioactivity. In dog blood, CP-PR constituted a smaller fraction (45%) of the total radioactivity than in the rat and captopril-L-cysteine was the major component (53%). In 72 h, 89-91% of the dose was excreted in the urine of rats and dogs. Captopril-L-cysteine accounted for 7% (rat) and 68% (dog) of the radioactivity in urine; captopril accounted for 75% (rat) and 7% (dog). Other metabolites were present in the urine of both species. The greater net conversion of captopril-L-cysteine to CP-PR and to captopril in rats helps explain why captopril-L-cysteine is excreted in urine as a major metabolite of captopril in dogs but only a minor one in rats.

Animals↗

PubMed1984

Quantitative determination of captopril in blood and captopril and its disulfide metabolites in plasma by gas chromatography.

A sensitive, quantitative gas chromatographic-electron capture (GC-EC) method for the determination of captopril in blood and captopril and its disulfide metabolites (collectively) in plasma was developed. After addition of an internal standard and N-ethylmaleimide to the biological samples, excess N-ethylmaleimide and naturally occurring interfering substances were removed by extraction with benzene followed by acidification and extraction with hexane. The N-ethylmaleimide adducts of captopril and of the internal standard were then extracted with benzene and converted to their hexafluoroisopropyl esters. For the assay of captopril and its disulfide metabolites, tributylphosphine was used to reduce the disulfide metabolites to captopril prior to derivatization. The hexafluoroisopropyl esters of the N-ethylmaleimide adducts of captopril and of the internal standard, the 4-ethoxyproline analogue of captopril, were separated by GC on a column packed with 3% OV-101 on Chromosorb W-HP. The lower limits of sensitivity were 20 ng/mL for captopril in blood and 50 ng/mL for captopril and its disulfide metabolites in plasma. Linearity, precision, and accuracy were excellent. The method was validated by comparison of results obtained for total captopril in dog plasma by the GC-EC assay with results obtained by a published GC-MS method. The assay was applied to dog and human samples to explore its general utility.

Administration, Oral↗

PubMed1985

Plasma free captopril concentrations during short and long term treatment with oral captopril for heart failure.

Plasma free captopril concentrations and haemodynamic response to captopril were studied in 20 patients with severe chronic heart failure. A 25 mg oral dose of captopril produced a 36% reduction in systemic vascular resistance, with individual responses varying from 13% to 64%. Mean systemic pressure fell by 20% and cardiac output rose 28%. The absorption of captopril was rapid. Peak plasma free captopril concentration occurred at 45 minutes after the dose and was followed by a smaller second peak. Peak plasma free captopril concentrations varied more than 20-fold but did not correlate with the maximal reduction in systemic vascular resistance. Elimination half life was seven hours. Fourteen patients were restudied after 1-2 months of captopril treatment and 12 showed symptomatic benefit. There was a sustained improvement in haemodynamic state and in non-invasive indices of myocardial function. During long term treatment the predose plasma free captopril concentration correlated well with dosage, but steady state captopril concentrations did not show a significant relation with haemodynamic response. On a dosage regimen of 25-50 mg three times daily the morning predose plasma free captopril concentration and plasma renin activity were relatively low and suggested that maximal inhibition of the renin-angiotensin system was not maintained throughout the dosage interval.

Aged↗

PubMed1999

Specific delivery of captopril to the kidney with the prodrug captopril-lysozyme.

Low-molecular-weight proteins (LMWPs) accumulate in the proximal tubular cells of the kidney, which makes these proteins interesting tools for renal drug targeting. We studied this approach using the LMWP lysozyme as a carrier for the angiotensin-converting enzyme inhibitor captopril. Captopril was conjugated to lysozyme via a disulfide bond. The pharmacokinetics of the captopril-lysozyme conjugate was studied in the rat. Only intact conjugate could be detected in the circulation. The total amount of captopril disulfides in the kidney was six times higher after administration of the conjugate than after the administration of an equivalent amount of free captopril. The conjugate was recovered in the urine partially as intact conjugate and partially as low-molecular-weight disulfides. The excretion of conjugate in the urine was not a consequence of the coupling of captopril to lysozyme because an equivalent bolus dose of native lysozyme was similarly excreted into the urine. By determination of the renal angiotensin-converting enzyme activity, we showed that the conjugate was degraded to the pharmacologically active captopril in vivo. We conclude that the coupling of captopril to the LMWP lysozyme results in increased captopril concentrations in the kidney and reduced captopril concentrations in the circulation.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1992

Furosemide-induced natriuresis is augmented by ultra-low-dose captopril but not by standard doses of captopril in chronic heart failure.

BACKGROUND: Ten chronic heart failure patients were studied on three occasions in randomized double-blind fashion to compare the acute hemodynamic, neurohormonal, and renal sodium-handling responses to 1 mg captopril versus 25 mg captopril, both in the absence of loop diuretic therapy and during furosemide-stimulated natriuresis. METHODS AND RESULTS: Compared with placebo, 1 mg captopril caused nonsignificant decreases in mean arterial pressure and circulating angiotensin II level and had no effect on glomerular filtration rate as determined by 51Cr-EDTA elimination. Captopril (25 mg) produced marked suppression of serum angiotensin II with or without oral furosemide (both p less than 0.002), a marked decrease in mean arterial pressure (p less than 0.001) that was accentuated by furosemide (p less than 0.00001), and a decrease in glomerular filtration rate (p = 0.0007). No difference from placebo in renal sodium excretion was noted with either 1 or 25 mg captopril in the absence of furosemide. In contrast, while 25 mg captopril caused slight attenuation of the natriuretic response to furosemide, 1 mg captopril significantly enhanced furosemide-induced natriuresis (p less than 0.05). No correlation was found in our patients between the natriuretic effect of furosemide and either absolute mean arterial pressure or change in mean arterial pressure during the furosemide phase of each study session. This suggests that blood pressure is not the important factor mediating the divergent renal responses to furosemide of the two captopril dosage regimens. CONCLUSIONS: We propose that in the face of furosemide-induced postglomerular vasodilatation in chronic heart failure, captopril at a starting dose of 1 mg (but not 25 mg) preserves enough circulating angiotensin II to maintain efferent arteriolar tone and thus glomerular filtration, while offsetting the antinatriuretic renal tubular effects of angiotensin II.

Aged↗

PubMed2001

Detection of renal artery stenosis: prospective comparison of captopril-enhanced Doppler sonography, captopril-enhanced scintigraphy, and MR angiography.

OBJECTIVE: The objective of our study was to compare the value of captopril-enhanced Doppler sonography, captopril-enhanced renal scintigraphy, and gadolinium-enhanced MR angiography for detecting renal artery stenosis. SUBJECTS AND METHODS: Forty-one patients with suspected renovascular hypertension were prospectively examined with captopril-enhanced Doppler sonography, captopril-enhanced renal scintigraphy, gadolinium-enhanced MR angiography, and catheter angiography. The sensitivity and specificity of each technique for detecting renal artery stenosis measuring 50% or greater and 70% or greater were compared using the McNemar test. Positive and negative predictive values were estimated for populations with 5% and 30% prevalence of renal artery stenosis. Kappa values for interobserver agreement were assessed for both gadolinium-enhanced MR angiography and catheter angiography. RESULTS: For detecting renal artery stenosis measuring 50% or greater, the sensitivity of gadolinium-enhanced MR angiography (96.6%) was greater than that of captopril-enhanced Doppler sonography (69%, p = 0.005) and captopril-enhanced renal scintigraphy (41.4%, p = 0.001). No significant difference in specificity was observed among modalities. For renal artery stenosis measuring 50% or greater, positive and negative predictive values were respectively 62% and 86% for captopril-enhanced Doppler sonography, 49% and 76% for captopril-enhanced renal scintigraphy, and 53% and 98% for gadolinium-enhanced MR angiography. Interobserver agreement was high for both gadolinium-enhanced MR angiography (kappa = 0.829) and catheter angiography (kappa = 0.729). CONCLUSION: Gadolinium-enhanced MR angiography is the most accurate noninvasive modality for detecting renal artery stenosis greater than or equal to 50%. The use of captopril-enhanced Doppler sonography in combination with gadolinium-enhanced MR angiography for identifying renal artery stenosis needs to be evaluated with a cost-effectiveness analysis.

Adult↗

PubMed1987

The pharmacokinetics of captopril and captopril disulfide conjugates in uraemic patients on maintenance dialysis: comparison with patients with normal renal function.

We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function. The mean peak plasma concentration of captopril was 2.5 times higher (0.447 micrograms X ml-1 vs 0.181 micrograms X ml-1) and the concentrations of the disulfides 4 times higher (3.62 micrograms X ml-1 vs 0.924 micrograms X ml-1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46 +/- 19 h. Only 15% of these conjugates were removed by dialysis. This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37 +/- 7 mmHg and 24 +/- 9 mmHg respectively, occurring 6 h after the dose, compared with 8 +/- 7 and 8 +/- 1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.

Adult↗

PubMedDate not supplied

Usefulness of captopril renography to predict the benefits of renal artery revascularization or captopril treatment in hypertensive patients with diabetic nephropathy.

This retrospective study aimed to use captopril renography (CR) for predicting the benefits of captopril treatment in hypertensive patients with diabetic nephropathy. CR was utilized in 60 hypertensive patients with diabetic nephropathy for detecting the probability of renovascular hypertension (RVH) and predicting the benefits of renal artery revascularization or captopril treatment. Ten of the 60 patients showed a high probability of RVH with marked changes of the renogram curve after an oral intake of 50-mg captopril compared to baseline findings. All of the 10 patients confirmed significant main renal artery stenosis in all of them, bilaterally in four patients and unilaterally in the remaining six patients by renal angiographic findings. After successful revascularization, blood pressure was well controlled and renal function was preserved in all of the 10 patients. The other 50 patients showed a low or intermediate probability of RVH with normal findings or unchanged on CR after 50-mg captopril. Then, captopril alone or combination treatment started and continued on 50 patients. After monitoring for at least 6 months, blood pressure was well controlled and renal function was preserved in all the 50 patients on captopril treatment. We conclude that CR should be considered as the standard diagnostic criteria of RVH and may be helpful in predicting the beneficial impact of captopril treatment in hypertensive patients with diabetic nephropathy.

Age of Onset↗

PubMed1998

Enhanced reduction of atherosclerosis in hamsters treated with pravastatin and captopril: ACE in atheromas provides cellular targets for captopril.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and angiotensin-converting enzyme (ACE) reduce experimental atherosclerosis by different mechanisms. To determine whether dual-drug therapy additively retards the progression of early lesions, control hyperlipidemic hamsters were compared with those treated with pravastatin, captopril, and pravastatin plus captopril. After 8 weeks of treatment, pravastatin (34 mg/kg/day) reduced plasma total cholesterol and triglycerides by 41 and 84%, respectively, whereas captopril (100 mg/kg/day) reduced normal blood pressure by 21%. The combination of pravastatin and captopril (33 and 100 mg/kg/day) decreased plasma total cholesterol and triglycerides by 44 and 84%, and blood pressure was decreased by 14%. In the aortic arch, pravastatin reduced macrophage-foam cell size and fatty streak area by 21 and 31%, respectively, whereas captopril decreased macrophage-foam cell number and fatty streak area by 34 and 35%. Pravastatin plus captopril decreased macrophage-foam cell number, foam cell size, and fatty streak area by 38, 24, and 67%. ACE inhibitors were previously reported to retard atherosclerosis without affecting blood pressure, suggesting that these agents acted on the artery wall. Therefore the expression of arterial ACE was determined in normal and atherosclerotic hamster aortas. ACE messenger RNA (mRNA) and protein were detected in endothelial cells, intimal macrophage-foam cells and medial smooth-muscle cells of atherosclerotic arteries indicating an upregulation of ACE expression with hyperlipidemia and atherosclerosis. In conclusion, dual-therapy with pravastatin and captopril produced an additive reduction in fatty streak area compared with either drug alone and suggested that atherogenesis can be retarded beyond the level achieved with monotherapy. The presence of ACE in endothelial cells and intimal macrophage-foam cells provides cellular targets for captopril to directly modify the formation of early atherosclerotic lesions.

Angiotensin-Converting Enzyme Inhibitors↗

PubMedDate not supplied

Pre- and postjunctional inhibition of vascular sympathetic function by captopril in SHR. Implication of vascular angiotensin II in hypertension and antihypertensive actions of captopril.

The present study was designed to examine the effects of treatment of SHR with captopril, teprotide, and saralasin on vascular and cardiac responses to sympathetic nerve stimulation and angiotensin I and II (AI, AII) and norepinephrine (NE). A single dose of captopril (10 mg/kg i.v. as well as 10 and 100 mg/kg p.o.) caused significant and marked inhibition of pressor responses to sympathetic nerve stimulation in pithed SHR but cardiac responses were unaffected. Pressor responses to AI were abolished but those to AII and NE were not significantly altered. Neither teprotide nor saralasin caused consistent inhibition of sympathetic responses despite total blockade of AI and AII response respectively. Selective inhibition of pressor but not cardiac responses to sympathetic nerve stimulation was obtained after 2 weeks, 3 and 6 months of daily oral doses of captopril. In addition, postjunctional pressor responses to AI, AII, and NE were also significantly inhibited by chronic captopril treatment. Infusion of AII, bilateral nephrectomy, or pretreatment with indomethacin alone in pithed SHR receiving captopril had no effect on the inhibition of pressor responses to sympathetic stimulation. However, the combination of pretreatment of indomethacin and infusion of AII completely restored sympathetic function in SHR receiving captopril. These studies suggest that captopril has a selective inhibitory effect on vascular responses to sympathetic nerve stimulation but not on cardiac responses. Moreover, this effect may have a prejunctional component since, after acute treatment, there is no inhibitory effect on responses to AII or NE. Since, under appropriate conditions, the inhibition can be reversed by AII infusion but not nephrectomy, it is suggested that this inhibition occurs at the vascular level by inhibition of local AII formation by captopril, a site not accessible to teprotide or saralasin.

Angiotensin II↗

PubMed1997

[Usefulness of angiotensin converting enzyme inhibitors in the diagnosis of renovascular hypertension. III. Evaluation of the validity of the captopril test and the reno-scintigraphic captopril test in the diagnosis of renovascular hypertension according to accepted criteria].

The aim of the study was to evaluate diagnostic validity of captopril test and scintigraphic test before and after captopril for the detection of renovascular hypertension (RVH) according to applied criteria. Employing blood pressure response to captopril as a criteria sensitivity was 37.0%, specificity 92.1%, positive predictive value 75.0% and negative predictive value 70.2% in the captopril test. Applying plasma renin activity (PRA) response to captopril as a criteria sensitivity was 92.5%, specificity 100%, positive predictive value 100% and negative predictive value 96.0% in the same test. Renin captopril test has excellent sensitivity and positive predictive value, is easy to perform and inexpensive and therefore may be a useful screening test for RVH in unselected population. With the own criteria used, captopril renoscintigraphy detected RVH with 87.5% sensitivity, 91.7% specificity, 87.5% positive predictive value and 91.7% negative predictive value. Captopril renoscintigraphy is an accurate diagnostic test for the identification of RVH in a clinically selected high-risk population. Common evaluation of both tests does not improve their accuracy in diagnosis of RVH.

Angiotensin-Converting Enzyme Inhibitors↗