A novel renal hypertensive guinea pig model for comparing different inhibitors of the renin-angiotensin system.
The present study describes a novel renal hypertensive guinea pig model for comparing different inhibitors of the renin-angiotensin system (RAS). Renal hypertension was induced by a two-step procedure consisting of ligation of the left caudal renal artery and right nephrectomy. Sham-operated animals were used as controls. Arterial blood pressure and heart rate were monitored in conscious animals. Left caudal renal artery ligation and subsequent right nephrectomy led to a significant increase (32% over sham-operated controls, p < .05) in mean arterial blood pressure (MABP), 3 to 4 weeks following surgery. Renal hypertensive animals had increased urine production (from 63 +/- 8 mL/kg per day to 143 +/- 29 mL/kg per day, p < .05) and an increased incidence of proteinuria (11/13 animals had urine protein levels higher than 20 mg/kg per day). Five of the 13 renal hypertensive animals also had hematuria. On autopsy, an 83% increase in the left kidney/body weight ratio and a 37% increase in the heart/body weight ratio were observed in the renal hypertensive animals, compared to the sham-operated controls. Changes in blood pressure and heart rate were assessed before and after an intravenous bolus injection of the drug to be tested. Captopril reduced MABP in both sham-operated and renal hypertensive animals with equal efficacy (up to a maximum of 42%). In contrast, BILA 2157 BS, one of our human renin inhibitors, produced a similar maximum MABP decrease but only in renal hypertensive animals. This selective antihypertensive effect was also observed with enalkiren, another renin inhibitor. These results indicate that the renal hypertensive guinea pig is an useful model for comparing and contrasting different RAS inhibitors.
Duan
J
J
Department of Pharmacology, Bio-Méga/Boehringer Ingelheim Research Inc., Laval, Quebec, Canada.
Jaramillo
J
J
Jung
G L
GL
McLeod
A L
AL
Fernandes
B H
BH
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006977:Hypertension, Renal / Q000188:drug therapy / Q000209:etiology; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D012083:Renin / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology; D000092502:Renin Inhibitors
D000959:Antihypertensive Agents; D002216:Captopril; D004151:Dipeptides; D011725:Pyridines; D012083:Renin; D013844:Thiazoles; D000092502:Renin Inhibitors; C056622:enalkiren; C099058:BILA 2157 BS