Comparative studies on differential inhibition of the renin - angiotensin system in the anesthetized guinea pig.
The present study compares the hemodynamic effects and mechanisms of action of angiotensin II (AngII) antagonists, angiotensin converting enzyme (ACE) inhibitors, and renin inhibitors in the guinea pig, an animal with high similarity to primates in terms of in vitro and in vivo responses to several human renin inhibitors. Animals were anesthetized with urethane and ketamine. The carotid artery was catheterized for monitoring blood pressure and heart rate. After 30 min stabilization, drug (or vehicle) effects were monitored for 1 h following each increasing dose (i.v. bolus injection). Drugs tested include losartan, an AngII receptor antagonist; two renin inhibitors, BILA 2157 BS and PD-134672; and captopril, an ACE inhibitor. All drugs dose dependently decreased blood pressure. Diastolic blood pressure was reduced more than systolic blood pressure, suggestive of vasodilation. The maximum decrease (32 +/- 6%, p < 0.05 vs. vehicle) in mean arterial blood pressure (MABP) by losartan was achieved with a dose of 1 mg/kg. A similar decrease in MABP was observed with renin inhibitors at a dose of 3 mg/kg, without affecting heart rate. A further increase in the dose of renin inhibitors (6 mg/kg) decreased not only blood pressure but also heart rate. Captopril decreased MABP with a maximum of 48 +/- 3% (p < 0.05 vs. vehicle, losartan, and PD-134672). In the presence of HOE-140, a bradykinin antagonist, the MABP decrease by captopril was only 35 +/- 4%, (p < 0.05 vs. captopril alone). Bilateral nephrectomy reduced the peak MABP effect of PD-134672 by 67%, while the effects of captopril on MABP were affected to a lesser degree (57%). Therefore, captopril remains more effective in reducing MABP (p < 0.05 vs. that of PD-134672). These results suggest that renin inhibitors and AngII antagonists act more specifically on the renin - angiotensin system cascade, while captopril acts partially by a bradykinin-dependent mechanism. The small animal model described provides a novel tool for the comparative pharmacologic assessment of different renin - angiotensin system inhibitors.
Duan
J
J
Department of Pharmacology, Bio-Mega/Boehringer Ingelheim Research Inc., Canada.
Jaramillo
J
J
Jung
G L
GL
McLeod
A L
AL
Fernandes
B H
BH
Mathis
D
D
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology*; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D009392:Nephrectomy; D011725:Pyridines / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D000092502:Renin Inhibitors
D000409:Alanine; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D001920:Bradykinin; D002216:Captopril; D007093:Imidazoles; D019808:Losartan; D011725:Pyridines; D013777:Tetrazoles; D013844:Thiazoles; D000092502:Renin Inhibitors; C099059:PD 134672; C099058:BILA 2157 BS; C065679:icatibant