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The relationship between plasma angiotensin and the reduction of blood pressure with the angiotensin converting enzyme inhibitor enalapril was studied in rats. Blood pressure was measured in conscious rats with indwelling arterial catheters. To measure angiotensin II, plasma was analyzed by physical separation of angiotensins using high performance liquid chromatography followed by radioimmunoassay. The effects of both single (acute) and long-term (chronic) dosages of enalapril were measured. After a single oral dose of enalapril (10 mg/kg), mean arterial pressure fell from 111 ± 3 to 86 ± 3 nun Hg (p<0.005). Despite the blood pressure reduction, plasma angiotensin II was unaffected (control, 9.9 ± 1.8 vs 9.7 ±1.1 pg/ml). After a higher single oral dose of enalapril (30 mg/kg), there was a reduction in both mean arterial pressure (81 ± 5 mm Hg, p<0.005) and plasma angiotensin II concentration (2.3 ± 0.6 pg/ml, p<0.01). The chronic effects of converting enzyme inhibition were evaluated in rats given enalapril in their drinking water (30 mg/kg/24 hr) for 1 week or 2 months. Mean arterial pressure remained equally low after chronic administration (for 1 week or 2 months), but plasma angiotensin II increased above normal (after 1 week, 28.9 ±8.7, p<0.01 vs control; after 2 months, 43.1 ± 16.2 pg/ml, p< 0.05 vs control). Although plasma angiotensin converting enzyme activity was undetectable at any time after enalapril administration, there was a partial return of the angiotensin I pressor response with chronic administration. The data are most compatible with actions of converting enzyme inhibitors independent of the blockade of plasma angiotensin II formation. (Hypertension 9 [Suppl III]: III-42- III-48, 1987) KEY WORDS • angiotensin II • converting enzyme inhibition • high performance liquid chromatography • radioimmunoassay • enalapril A NGIOTENSIN converting enzyme (ACE) in-/ \ hibitors were designed to lower blood pres-A. V . sure by blocking the formation of the potent vasopressor, angiotensin II (ANG II). 1 -2 Evidence from many studies seems to confirm this mechanism of ACE inhibitor action. The acute administration of ACE inhibitors lowers blood pressure, decreases levels of immunoreactive ANG II in plasma, 3 " 5 and prevents blood pressure rise in the two-kidney, one clip Goldblatt model. 6 Several recent observations suggest that the mechanism of action of ACE inhibitors is more complex than

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Previous autoradiographic studies have delineated the renal medullas the predominant site of renal endothelin (ET) receptors. Accordingly, cultured rat renal medullary interstitial cells (RMICs) were studied as a target tissue for ET action. Scatchard analysis revealed presence of a single class of high-affinity receptor sites (Kd, 57 +/- 10 pM; receptor density, 749 +/- 124 fmol/mg protein). Relative potency order for displacing 125I-ET-1 was ET-1 greater than ET-2 greater than sarafotoxin greater than big endothelin (human) = big endothelin (porcine). ET-3, unrelated pressor substances, vasodilators, Ca2+ channel antagonists, atrial natriuretic factor, GTP, and GppNHp did not inhibit binding. Challenge of monolayers with ET-1 evoked a biphasic elevation in cytosolic free Ca2+ concentration [Ca2+]i). Initial transient rise in [Ca2+]i observed in absence of extracellular Ca2+ and accumulation of inositol trisphosphate (IP3) was consistent with activation of phosphatidylinositol-specific phospholipase C (PI-PLC). Half-maximal activation concentration of ET-1 for the process was 0.5 and 1 nM for [Ca2+]i and IP3, respectively. The late sustained phase in [Ca2+]i elevation was completely blocked by Ni2+, unperturbed by nimodipine, and accompanied by influx of Mn2+, indicating presence of receptor-operated Ca2+ channels. Ca2+ channel opening was detected at 10(-16) MET-1, whereas greater than 10(-12) M agonist was required to mobilize Ca2+ from intracellular stores and/or stimulate phosphoinositol hydrolysis, indicating that ET activation of PI-PLC and Ca2+ channel opening were independent events. ET-1 markedly stimulated prostaglandin E2 synthesis in a concentration-dependent manner that paralleled PI-PLC activation and mobilization of [Ca2+]i. In summary, cultured rat RMICs possess ET receptors that are linked to PI-PLC, Ca2+ channels, and perhaps phospholipase A2.