1997-05-01·Journal of Cardiovascular Pharmacology4区 · 医学
Differential inhibition of plasma versus tissue ACE by utibapril: biochemical and functional evidence for inhibition of vascular ACE activity
4区 · 医学
作者: Buikema, Hendrik ; Pinto, Yigal M. ; Van Geel, Peter Paul ; Rooks, Gerrit ; De Langen, Cees D. J. ; De Graeff, Pieter A. ; Van Gilst, Wiek H.
Utibapril is an angiotensin-converting enzyme (ACE) inhibitor with a proposed tissue-specific inhibitory profile. This implies that at a certain dose, utibapril should be able to inhibit tissue ACE activity without affecting plasma ACE. Moreover, if tissue ACE activity is rate limiting, functional conversion of angiotensin I should be decreased. Accordingly, we studied the dose-dependent effect of long-term treatment with utibapril on plasma and tissue ACE. Normal Wistar rats were randomly allocated to oral treatment with different doses of utibapril (0, 2, 10, 50, or 250 micrograms/kg/day) for 30 days. Tissue inhibition of ACE was assessed biochemically, whereas functional conversion of angiotensin I was determined in the isolated organ. Utibapril significantly inhibited plasma, renal, and vascular ACE but not ventricular ACE activity. Notably, however, only treatment with the highest dose of utibapril resulted in a significant inhibition of plasma ACE, whereas vascular ACE activity was already significantly inhibited after treatment with a lower dose of utibapril. In accordance, utibapril dose-dependently inhibited the contraction of isolated aortic rings to angiotensin I. Furthermore, angiotensin I-induced decreases in coronary flow in the isolated heart were significantly inhibited after treatment with the higher doses of utibapril. These data suggest the preferential inhibition of vascular ACE by utibapril in normal rats. Furthermore, the dose-dependent inhibition of the functional conversion of angiotensin I indicates that the tissue ACE activity may be rate limiting in vascular beds in rats.
1991-10-01·Hypertension1区 · 医学
Cardiac and aortic effects of angiotensin converting enzyme inhibitors
1区 · 医学
作者: Frohlich, Edward D. ; Horinaka, Shigeo
The effects of six angiotensin converting enzyme inhibitors (captopril, CGS-16617, cilazapril, enalapril, utibapril, and quinapril) on cardiovascular structure, systemic hemodynamics, left ventricular end-diastolic pressure, left ventricular pumping ability, and aortic distensibility were assessed in male normotensive Wistar-Kyoto and spontaneously hypertensive rats 16-19 weeks of age. Rats (10 in each group) were treated for 3 weeks with drugs or control diluents administered daily by gavage. The agents, in general, had similar hemodynamic effects, although these effects on cardiac mass were variable; some agents reduced left ventricular mass and some produced no change. These effects occurred in hypertrophied as well as nonhypertrophied chambers. Furthermore, changes in left ventricular pumping ability were not necessarily related to the ability of these agents to change left ventricular mass; this dissociation in performance was neither related to change in structure nor to changes in aortic distensibility. Thus, even within a same class of antihypertensive agents (i.e., angiotensin converting enzyme inhibitors), similarly induced hemodynamic alterations were associated with inconsistent changes in left ventricular pumping ability or aortic distensibility regardless of whether the structure was hypertrophied before therapy. These dissociated responses in cardiovascular structure and function may be related to pharmacodynamic or pharmacokinetic differences; alternatively, they also may be related to these differences in action on local myocytic renin-angiotensin systems or in intramyocytic biological responses.
1991-01-01·Journal of Medicinal Chemistry1区 · 医学
Design, synthesis, and physicochemical properties of a novel, conformationally restricted 2,3-dihydro-1,3,4-thiadiazole-containing angiotensin converting enzyme inhibitor which is preferentially eliminated by the biliary route in rats
1区 · 医学
作者: Bennion, Colin ; Brown, Roger C. ; Cook, Anthony R. ; Manners, Carol N. ; Payling, David W. ; Robinson, David H.
Two novel series of dihydrothiadiazole ring containing inhibitors of angiotensin converting enzyme have been designed and synthesized. The compounds are highly potent enzyme inhibitors and, as a consequence of conformational restriction, chemically stable with respect to undesirable cyclization reactions. The most interesting compound from this series, 5a (FPL 63547), is the monoethyl ester prodrug of the highly potent "aminocarboxy" inhibitor 5b (FPL 63674). It produces an antihypertensive effect of long duration in animal models after oral dosing. Unlike other ACE inhibitors, 5b is eliminated almost entirely by biliary clearance in the rat. The favorable pharmacological properties of 5a and 5b are rationalized in terms of their unique physicochemical profiles. The clear preference for biliary clearance seen with 5b is consistent with its lipophilicity and its high degree of net ionization at physiological pH, which results from the very low pKa of the C-terminus carboxylic acid function. FPL 63547 is presently undergoing clinical investigation in man.