ROLE OF SUBSTANCE-P IN BLOOD-PRESSURE REGULATION IN SALT-DEPENDENT EXPERIMENTAL-HYPERTENSION

The participation of substance P in the pathogenesis of five models of experimental hypertension, ie, DOCA-salt, subtotal nephrectomy, one-k idney-one clip renovascular, two-kidney-one clip renovascular, and spo ntaneous hypertension, was evaluated via an acute infusion of a newly synthesized potent, specific nonpeptide antagonist of substance P at t he NK-1 receptor, the agent CP 96,345. In conscious unrestrained rats, CP 96,345 induced significant and sustained increases in mean arteria l pressure of DOCA-salt, subtotal nephrectomy, and one-kidney-one clip renovascular hypertensive rats but only small and nonsignificant chan ges in blood pressure of two-kidney-one clip renovascular and spontane ously hypertensive rats. CP 96,345 had no effect on the blood pressure of sham-treated controls and Wistar-Kyoto rats. This NK-1 receptor an tagonist did not significantly affect the heart rate of any experiment al model studied. The data suggest that endogenous substance P may act as a partial counterregulatory mechanism against vasoconstriction in models of salt-dependent hypertension.