CARDIOVASCULAR EFFECTS OF A SPECIFIC NONPEPTIDE ANTAGONIST OF SUBSTANCE-P (NK-1) RECEPTOR IN DOCA-SALT HYPERTENSION

The neurotransmitter substance P acts also as a potent vasodilator. It s participation in the pathogenesis of deoxycorticosterone acetate (DO CA)-salt hypertension was evaluated by an acute infusion of a newly sy nthesized, potent, specific nonpeptide antagonist of substance P at th e NK-1 receptor, the agent CP 96 345. In conscious unrestrained rats, CP 96 345 induced significant and sustained increases in mean arterial pressure of DOCA-salt rats but only small, transient, and nonsignific ant rises in blood pressure of sham-treated control rats. The rise in blood pressure was not accompanied by changes in heart rate. Maximal b lood pressure increase in DOCA-salt rats was 31.7+/-14.8 mm Hg. In a s econd series of experiments, the hemodynamic effects of this antagonis t were evaluated under anesthesia in both DOCA-salt and sham-treated c ontrol rats by the thermodilution method. During CP 96 345 infusion, s ustained increases in cardiac index and stroke volume and decreases in total peripheral resistance were observed in both DOCA-salt and contr ol rats. In DOCA-salt rats, cardiac index rose by 79.4%, while total p eripheral resistance fell by 27.9% of the baseline values. In control rats, the changes were smaller (+27.2% and -22.5%, respectively). Stro ke volume changed in parallel to cardiac output in both groups. The da ta suggest that acute blockade of NK-1 receptors increases blood press ure in DOCA-salt rats mainly by an increase in cardiac output. We conc lude that endogenous substance P tends to counteract the DOCA-salt-ind uced elevation of blood pressure by modulating both cardiac output and peripheral resistance.