Implication of nigral tachykinin NK3 receptors in the maintenance of hypertension in spontaneously hypertensive rats: a pharmacologic and autoradiographic study.

1. The role of nigral tachykinin NK(1), NK(2) and NK(3) receptors in central cardiovascular regulation was studied by measuring the effects of selective agonists and antagonists on mean arterial pressure (MAP) and heart rate (HR) after bilateral microinjection into the substantia nigra of spontaneously hypertensive rats (SHR). Quantitative in vitro autoradiography was also performed in the midbrain of SHR and Wistar-Kyoto (WKY) with the NK(3) receptor ligand [(125)I]-HPP-Senktide. 2. Tachycardia was elicited by the NK(1) ([Sar(9),Met(O(2))(11)]SP) and NK(2) ([betaAla(8)]NKA(4-10)) agonists at 25 and 100 pmol while the NK(3) agonist (senktide, 50 and 100 pmol) had no significant effect. The three agonists had no effect on behaviour, and increases in MAP were elicited by the NK(1) agonist only. 3. Whereas antagonists at NK(1) (RP 67580, 500 pmol) and NK(2) (SR 48968, 500 pmol) receptors had no significant effect on MAP and HR, the NK(3) antagonist (R-820, 500 pmol) reduced MAP for over 3 h in SHR. That anti-hypertensive effect did not occur after intracerebroventricular or intravenous injection of R-820. Also, R-820 had no cardiovascular effect in WKY. 4. The affinity (K(D): 0.7 nM) and densities of specific NK(3) receptor binding sites measured in the substantia nigra, ventral tegmental area, hippocampus and amygdala were not significantly different in SHR and WKY. 5. It is concluded that endogenous tachykinins exert a tonic activity on NK(3) receptors in the substantia nigra of SHR to maintain high blood pressure. Hence, nigral tachykinin NK(3) receptors may represent a promising therapeutic target in the treatment of arterial hypertension.