SUMMARY The role of renin-angiotensin system has been examined in the maintenance of hypertension in acute and chronic two-kidney (36 weeks) and chronic one-kidney (12 weeks) Goldblatt hypertensive rats using three inhibitors of this system. The inhibitors used were URI-73A, a synthetic analog of lysopbosphatidylethanolamine, which inhibits renin both in vivo and in vitro, SQ14.225, a potent conrerting enzyme inhibitor, and [Sar 1 , Thr*] angiotensin II, an angiotensin II antagonist. When the inhibitors were administered in acute (high renin) hypertensive rats, they all lowered blood pressure significantly. However, in the chronic (low renin) hypertensive phase, both renin and converting enzyme inhibitors lowered blood pressure, whereas, Sar', Thr* failed to lower Mood pressure. The renin inhibitor lowered plasma renin activity ( system there haVe been continued efforts to determine whether or not it is instrumental in maintaining blood pressure elevation in various forms of experimental or clinical hypertension. Interruption of the system by blocking renin, either with antibodies to renin 12 or with a • phospholipid renin inhibitor purified from kidney,' 1 * lowered blood pressure in most instances in botfOhort-(acute) and long-term (chronic) one-and two-kidney models of renal hypertensive rats. A major criticism of experiments involving either active or passive immunization to renin was the lack of homogeneity of renin used for antibody production. Use' of the lipid renin inhibitor has been limited and it remains to be determined whether or not this compound has effects in vivo other than renin blockade. Hosoki et al. 6 reported the synthesis of a renin inhibitor, 2-[4-(4-chlorophenoxy) phenoxyacetylamine]-ethyl phosphorylethanolamine (PE-104), which is an analog of the natural phospholipid renin inhibitor. PE-104 inhibits the reaction between renin and renin substrate in vitro and in vivo, and reduces the concentration of circulating angiotensin I in normotensive and renal hypertensive rats. It also lowered blood pressure in renal hypertensive rats when administered in a dose of 20 mg/kg/min.5 Turcotte et al. 9 synthesized a large series of phospholipid analogs and examined their structure-activity relationship for inhibiting renin. Of the compounds tested, eicosatetraenyl (3-aminopropyl) phosphonate (URI-73A), which is an analog of lyosphosphatidyl ethanolamine, was found to be the most potent inhibitor of renin both in vivo and in vitro. ' In recent work 7 utilizing specific angiotensin II inhibitors, the concept has been developed that in twokidney hypertensive animals, the renin-angiotensin system plays a role in maintenance of hypertension but in the one-kidney model, where the contralateral kidney has been removed, it does not. The latter is generally believed to be more volume-dependent than renin-dependent.
