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(Hypertension. 1995;26:1186-1189.)
© 1995 American Heart Association, Inc.

Articles

Cardiovascular Effects of a Specific Nonpeptide Antagonist of Substance P (NK-1) Receptor in DOCA-Salt Hypertension

Osvaldo Kohlmann, Jr; Milton Ginoza; Mario Luis Cezaretti; Maria Tereza Zanella; Artur Beltrame Ribeiro; Agostinho Tavares; Oswaldo Luiz Ramos; Susan E. Leeman; Irene Gavras; Haralambos Gavras

From the Nephrology Division, Escola Paulista de Medicina-Federal University of São Paulo (Brazil) (O.K., M.G., M.L.C., M.T.Z., A.B.R., A.T., O.L.R.) and Boston University Medical Center, Mass (S.E.L., I.G., H.G.).

Correspondence to Osvaldo Kohlmann, Jr, Nephrology Division, Federal University of São Paulo, Escola Paulista de Medicina, Rua Botucatu, 740, 04023-900, São Paulo, SP, Brazil.

Abstract The neurotransmitter substance P acts also as a potent vasodilator. Its participation in the pathogenesis of deoxycorticosterone acetate (DOCA)–salt hypertension was evaluated by an acute infusion of a newly synthesized, potent, specific nonpeptide antagonist of substance P at the 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 nonsignificant rises in blood pressure of sham-treated control rats. The rise in blood pressure was not accompanied by changes in heart rate. Maximal blood pressure increase in DOCA-salt rats was 31.7±14.8 mm Hg. In a second series of experiments, the hemodynamic effects of this antagonist were evaluated under anesthesia in both DOCA-salt and sham-treated control rats by the thermodilution method. During CP 96 345 infusion, sustained increases in cardiac index and stroke volume and decreases in total peripheral resistance were observed in both DOCA-salt and control rats. In DOCA-salt rats, cardiac index rose by 79.4%, while total peripheral resistance fell by 27.9% of the baseline values. In control rats, the changes were smaller (+27.2% and -22.5%, respectively). Stroke volume changed in parallel to cardiac output in both groups. The data suggest that acute blockade of NK-1 receptors increases blood pressure in DOCA-salt rats mainly by an increase in cardiac output. We conclude that endogenous substance P tends to counteract the DOCA-salt–induced elevation of blood pressure by modulating both cardiac output and peripheral resistance.

Key Words: substance P • neuropeptides • tachykinins • hypertension, sodium-dependent

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