cardiovascular-agents and perindoprilat

We compared the relationships between the plasma concentrations (C) of perindoprilat, active metabolite of the angiotensin I-converting enzyme inhibitor (ACEI) perindopril, and the effects (E) induced on plasma converting enzyme activity (PCEA) and brachial vascular resistance (BVR) in healthy volunteers (HV) and in congestive heart failure (CHF) patients after single oral doses of perindopril.. Six HV received three doses of perindopril (4, 8, 16 mg) in a placebo-controlled, randomized, double-blind, crossover study whereas 10 CHF patients received one dose (4 mg) in an open study. Each variable was determined before and 6-12 times after drug intake. E (% variations from baseline) were individually related to C (ng ml(-1)) by the Hill model E=Emax x Cgamma/(CE50gamma + Cgamma). When data showed a hysteresis loop, an effect compartment was used.. (means+/-s.d.) In HV, relationships between C and E were direct whereas in CHF patients, they showed hysteresis loops with optimal k(e0) values of 0.13 +/- 0.16 and 0.13 +/- 0.07 h(-1) for PCEA and BVR, respectively. For PCEA, with Emax set to -100%, CE50 = 1.87 +/- 0.60 and 1.36 +/- 1.33 ng ml(-1) (P = 0.34) and gamma = 0.90 +/- 0.13 and 1.11 +/- 0.47 (P = 0.23) in HV and CHF patients, respectively. For BVR, Emax= -41 +/- 14% and -60 +/- 7% (P = 0.02), CE50 = 4.95 +/- 2.62 and 1.38 +/- 0.85 ng ml(-1) (P = 0.02), and gamma = 2.25 +/- 1.54 and 3.06 +/- 1.37 (P = 0.32) in HV and CHF patients, respectively.. Whereas concentration-effect relationships were similar in HV and CHF patients for PCEA blockade, they strongly differed for regional haemodynamics. This result probably expresses the different involvements, in HV and CHF patients, of angiotensinergic and nonangiotensinergic mechanisms in the haemodynamic effects of ACEIs.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Brachial Artery; Cardiovascular Agents; Cross-Over Studies; Double-Blind Method; Female; Heart Failure; Hemodynamics; Humans; Indoles; Male; Middle Aged; Peptidyl-Dipeptidase A; Perindopril; Vascular Resistance

Recent data indicate that bradykinin participates in the regulation of neonatal glomerular function and also acts as a growth regulator during renal development. The aim of the present study was to investigate the involvement of bradykinin in the maturation of renal function. Bradykinin beta2-receptors of newborn rabbits were inhibited for 4 days by Hoe 140. The animals were treated with 300 microg/kg s.c. Hoe 140 (group Hoe, n = 8) or 0.9% NaCl (group control, n = 8) twice daily. Clearance studies were performed in anesthetized rabbits at the age of 8-9 days. Bradykinin receptor blockade did not impair kidney growth, as demonstrated by similar kidney weights in the two groups, nor did it influence blood pressure. Renal blood flow was higher, while renal vascular resistance and filtration fraction were lower in Hoe 140-treated rabbits. No difference in glomerular filtration rate was observed. The unexpectedly higher renal perfusion observed in group Hoe cannot be explained by the blockade of the known vasodilator and trophic effect of bradykinin. Our results indicate that in intact kallikrein-kinin system is necessary for the normal functional development of the kidney.

Topics: Adrenergic beta-Antagonists; Animals; Animals, Newborn; Blood Gas Analysis; Bradykinin; Bradykinin Receptor Antagonists; Cardiovascular Agents; Hematocrit; Indoles; Inulin; Kidney; p-Aminohippuric Acid; Rabbits; Receptors, Bradykinin; Urine

Topics: Angiotensin II; Cardiovascular Agents; Drug Synergism; Humans; Indoles; Norepinephrine; Renin-Angiotensin System; Sympathetic Nervous System; Vasoconstriction; Vasoconstrictor Agents; Vasodilation