EFFECTS OF BLOCKING THE ANGIOTENSIN-II RECEPTOR, CONVERTING-ENZYME, AND RENIN-ACTIVITY ON THE RENAL HEMODYNAMICS OF NORMOTENSIVE GUINEA-PIGS

The effects of three renin-angiotensin system (RAS) antagonists, DuP 753, a nonpeptide angiotensin II (Ang II) receptor antagonist, MK 521, an inhibitor of converting enzyme, and Ro 42-5892, a human renin inhibitor, renal function and hemodynamics were investigated in anesthetized, ventilated normotensive guinea pigs. This species was selected because this human renin inhibitor inhibits guinea pig renin. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by [H-3]inulin-methoxy and [C-14]aminohippuric acid clearances. Animals were perfused with isotonic saline at 0.2 ml/min. After a stabilization period of 1 h, drugs were given as an intravenous (i.v.) bolus (DuP 753, 1; MK 521, 0.1; Ro 42-5892, 1 mg/kg), followed by continuous infusion (DuP 753, 3; MK 521, 0.3; Ro 42-5892, 3 mg/kg/h). These doses have been used to induce slight but significant and similar decreases in mean arterial blood pressure (MABP). The mean changes during 1-h treatment showed similar decreases in MABP: vehicle, -2 +/- 1% (n = 10); DuP 753, -13 +/- 2% (n = 10); MK 521, -15 +/- 2% (n = 10); Ro 42-5892, -1-3 +/- 3% (n = 10), p < 0.001. Diuresis was unchanged in the four groups. GFR (vehicle, -0.2 +/8. 4%; DuP 753, +10.7 +/- 6.4%; MK 521, +13.2 +/- 8.6%; Ro 42-5g92, +37.2 +/- 7.5%, p < 0.01) and RBF (vehicle, -0.7 +/- 6.6%; DuP 753, +10.5 +/- 6.8%; MK 521, +16.4 +/- 6.8%; Ro 42-5892, +37.9 +/- 7.8%, p < 0.01) increased in parallel with the three drugs. Renal vascular resistance (RVR) decreased (vehicle, 2.8 +/- 6.9%; DuP 753, -12.5 +/- 8.5%; MK 521, -19.7 +/- 7.3%; Ro 42-5892, -33.9 +/- 4.5%, p < 0.01). Fractional excretion of sodium was s significantly increased. Plasma Ang II concentration (pg/ml) [vehicle, 36 +/- 7 (n = 12): DuP 753, 73 +/- 12 p < 0.01 (n = 12); MK 521, 8 +/- 3 p < 0.05 (n = 13); Ro 42-5892, 14 +/- 4, p < 0.05 (n = 12)] and plasma renin activity (ng Ang I/ml/h) (vehicle, 6.7 +/- 1.8; DuP 753, 16.3 +/- 3.5, p < 0.01; MK 521, 18.1 +/- 3.4, p < 0. 0 1; Ro 42-5892, 0.7 +/- 0.1, p < 0.05) changed according to the target of the pharmacologic blockade. These results demonstrate that the guinea pig is an appropriate species for testing human renin inhibitors and comparing their renal effects to non-species-specific inhibitors of the RAS, Ang II receptor antagonists and Ang I-converting enzyme (ACE) inhibitors. The renin inhibitor had the greatest renal hemodynamics effects, for a given fall in MAP.