Effect of Time and Dose on Angiotensin Converting Enzyme during Captopril Treatment in the Rat (original) (raw)
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Acta Pharmacologica et Toxicologica, 1983
Serum ACE activity increased as expected about three-fold following six weeks of captopril (30 mg/kg/day) treatment in Wistar rats (n=9). The effect on serum and lung ACE activity and concentration, respectively, was studied after captopril discontinuation. Serum ACE activity was measured at start and 3, 6 , and 12 days after captopril withdrawal. The approximal half-life of serum ACE activity was 72 hours as judged from the decrease rate after stimulated ACE biosynthesis induced by captopril. No differences in lung plasma membranes and lung homogenate ACE concentrations between treated and untreated rats were observed 12 days after discontinuation of captopril treatment. Serum ACE activity remained unchanged in the control rats (n=9). We conclude that induction of ACE biosynthesis in the rat is reversible after withdrawal of captopril.
Acta pharmacologica et toxicologica, 1981
Spontaneously hypertensive rats (SHR) of the Okamoto-Aoki strain (n = 40) were treated with captopril (SQ 14,225; D-3-mercapto-2-methylpropanoyl-L-proline) orally, dose 0.2 mg/ml in drinking water. The treatment was initiated early and later during the course of developing hypertension. Continuously treated rats did not develop hypertension. Rats receiving captopril for 12 weeks remained normotensive, whereas withdrawal of the drug resulted in hypertension. Captopril treatment was effective in the rats with established hypertension and decreased the blood pressures to nearly normal values. Serum angiotensin converting enzyme (ACE) activity rose 3-fold in captopril treated rats. ACE in lung plasma membranes increased during captopril treatment, indicating that captopril induced biosynthesis of pulmonary ACE. No qualitative differences were found in the ACE from treated and not treated animals. The dissociation of the antihypertensive effect of captopril and of increased ACE activity ...
Induction of angiotensin I-converting enzyme in rat lung with captopril: The effect of adrenalectomy
The American Journal of Cardiology, 1982
in spontaneously hypertensive rats, treatment with captoprii, 0.2 g/liter of drinking fluid for 12 to 24 weeks, caused a threefold increase in serum angiotensin i-converting enzyme activity. Angiotensin i-converting enzyme increased 25 to 120 percent in lung plasma membranes. The eiutiin profile of angiotensin i-converting enzyme on DEAE cellulose and after gel fiitration on Sepharose 48 was unchanged by captoprii. The K, value also remained unchanged. in Wistar rats subjected to bilateral adrenaiectomy, treatment with the same dose of captoprii for 3 days resulted in increased serum angiotensin i-converting enzyme activity in both sham-operated and adrenaiectomized rats, but angiotensin i-converting enzyme concentration increased in lung plasma membranes from sham-operated rats and captoprii-treated rats only. We conclude that captoprii causes induction of angiotensin-converting enzyme biosynthesis in spontaneously hypertensive and Wistar rats. The change is a quantitative one. intact adrenal glands may be important for the incorporation of angiotensin iconverting enzyme into lung membranes.
The American Journal of Cardiology, 1982
intravenous administration of captoprii (20 pg) produced inhibition of angiotensin I pressor responses by 70 percent and of plasma-converting enzyme activity by 72 percent. Oral treatment with captoprii (50 mg/ kg/day) for 1 week inhibited angiotensin I pressor responses more (84 percent) than plasma-converting enzyme activity (23 percent). Four month oral treatment of normotensive and spontaneously hypertensive rats with captoprii (50 mg/kg/day) led to a 88 and 7l'percent inhibition of angiotensin I pressor responses, but produced increases in piasmaconverting enzyme activity of 123 and 94 percent, respectively. in spontaneously hypertensive rats, elevated converting enzyme activity in the medulla obiongata was measured after this treatment. it is concluded that plasma-converting enzyme activity measurements can be dissociated from the in vivo inhibition of converting enzyme. Chronic oral captoprii treatment results in an induction of converting enzyme biosynthesis not only in peripheral tissue but also in the brain.
Inhibition of tissue angiotensin converting enzyme. Quantitation by autoradiography
Hypertension, 1988
Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after administration of lisinopril, an ACE inhibitor. Tissue ACE was assessed by quantitative in vitro autoradiography using the ACE inhibitor [ I25 I]351A, as a ligand, and serum ACE was measured by a fluorimetric method. Following oral administration of lisinopril (10 mg/kg), serum ACE activity was acutely reduced but recovered gradually over 24 hours. Four hours after lisinopril administration, ACE activity was markedly inhibited in kidney (11% of control level), adrenal (8%), duodenum (8%), and lung (33%; p<0.05). In contrast, ACE in testis was little altered by lisinopril (96%). In brain, ACE activity was markedly reduced 4 hours after lisinopril administration in the circumventricular organs, including the subfornical organ (16-22%) and organum vasculosum of the lamina terminalis (7%; p < 0.05). In other areas of the brain, including the choroid plexus and caudate putamen, ACE activity was unchanged. Twenty-four hours after administration, ACE activity in peripheral tissues and the circumventricular organs of the brain had only partially recovered toward control levels, as it was still below 50% of control activity levels. These results establish that lisinopril has differential effects on inhibiting ACE in different tissues and suggest that the prolonged tissue ACE inhibition after a single oral dose of lisinopril may reflect targets involved in the hypotensive action of ACE inhibitors. (Hypertension 11: 230-238, 1988) KEY WORDS • angiotensin converting enzyme inhibitors • hypotensive action lisinopril • blood-brain barrier • renin ANGIOTENSIN converting enzyme (ACE; / \ EC3.4.15.1) is a peptidyl dipeptidase that is X \. responsible for the conversion of angiotensin I to angiotensin II. High concentrations of ACE are found in vascular endothelial cells, 1 renal proximal tubules, 2 intestinal mucosa, 3 the male reproductive system, 4 and some specific areas of the brain. 5-6 Recently, ACE inhibitors such as captopril and enalapril have been found to be effective for the treatment of hypertension and congestive heart failure. 7 The mechanism of the hypotensive action of these drugs is unclear. Although the circulating renin-angiotensin system was initially considered the primary target for ACE inhibitors, this possibility must be reevaluated
Journal of Pharmacology and Experimental Therapeutics, 2002
We have synthesized a prodrug of the angiotensin-converting enzyme (ACE) inhibitor captopril by coupling this drug covalently to the low molecular weight protein (LMWP) lysozyme. Such drug-LMWP conjugates can be used for renal drug delivery, since LMWPs accumulate specifically in the proximal tubular cells of the kidney. In the present study, we compared the effects of captopril-lysozyme and free captopril in male Wistar rats. ACE activity in plasma and the kidney was measured after intravenous bolus injection of either the captoprillysozyme conjugate (33 mg ⅐ kg Ϫ1 , corresponding to 0.2 mg ⅐ kg Ϫ1 captopril) or equivalent dosages of free captopril and lysozyme. The administration of the captopril-lysozyme conjugate resulted in less plasma ACE inhibition and a longer-lasting renal ACE inhibition compared with the free drug. Effects on
Clinical and Experimental Pharmacology and Physiology, 1992
1. The effects of angiotensin-converting enzyme (ACE) inhibitors on the tissue ACE were assessed by quantitative in vitro autoradiography after acute and chronic administrations of the drugs. 2. Following acute administration of lisinopril, perindopril or benazepril, ACE was markedly inhibited in the lung, kidney and blood vessels but not in the testis. In the brain, ACE was inhibited mainly in structures with a deficient blood brain barrier. 3. High doses of perindopril progressively inhibited ACE in other brain structures. Tissue ACE inhibition persisted after serum levels of the enzyme had returned to control levels. In the case of perindopril, the time course of tissue ACE inhibition correlated with the inhibition of the pressor responses to exogenous angiotensin I. 4. After chronic administration of lisinopril or perindopril for 14 days, a similar pattern of ACE inhibition was observed in the kidney, lung and blood vessels. In the lung, however, lisinopril was found to increase total ACE by 30%, while plasma ACE was increased two-threefold by both lisinopril and perindopril. Testicular ACE remained unaltered by chronic lisinopril treatment. 5. Overall, the changes in tissue ACE after the administration of inhibitors more closely parallel the drugs' biological effects than changes in plasma ACE or drug levels. ACE in the testis and brain is protected by permeability barriers that limit access of the drugs.