Synergistic effect on reduction in blood pressure with coadministration of the renin inhibitor, CP-80,794, and the angiotensin converting enzyme inhibitor, captopril.
The effects of coadministration of a renin inhibitor, CP-80,794, and an angiotensin converting enzyme inhibitor, captopril, on blood pressure of sodium-depleted guinea pigs was studied. Dose-response curves for CP-80,794 (0.3-3.0 mg/kg i.v.) and captopril (0.03-1.0 mg/kg i.v.) were obtained either alone or in the presence of a submaximal dose of the other inhibitor. The hypotensive response calculated for each compound individually was subtracted from the combined dose response. The results showed that statistically significant synergy with captopril and CP-80,794 occurred when the area rather than the peak drop or duration of change in blood pressure was measured. The degree of the synergy indicated that to achieve the same reduction in blood pressure, the dose of each drug, below the high end of its response range, could be decreased approximately sixfold when administered in combination. It was determined that the plasma pharmacokinetics of CP-80,794 were not altered during coadministration, as plasma concentrations of CP-80,794 were similar in the presence and absence of 0.1 mg/kg i.v. of captopril. These results indicate that by inhibiting sequential enzymes in the renin-angiotensin system, synergistic effects can be produced. The relative safety of each inhibitor could be improved by large reductions in dose when used concurrently.
Fossa
A A
AA
Department of General Pharmacology and Metabolic Diseases, Pfizer Central Research, Groton, Connecticut 06340.
Weinberg
L J
LJ
Barber
R L
RL
Rauch
A L
AL
Nocerini
M R
MR
Murphy
W R
WR
Swindell
A C
AC
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology*; D004151:Dipeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006168:Guinea Pigs; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000092502:Renin Inhibitors
D002216:Captopril; D004151:Dipeptides; D009025:Morpholines; D000092502:Renin Inhibitors; C076964:terlakiren