BLOCKADE OF TACHYKININ NK-3 RECEPTOR REVERSES HYPERTENSION THROUGH A DOPAMINERGIC MECHANISM IN THE VENTRAL TEGMENTAL AREA OF SPONTANEOUSLY HYPERTENSIVE RATS: PP.29.161

Abstract

Intracerebroventricularly (i.c.v.) injected tachykinin NK-3 receptor (R) antagonists normalized mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHR). This study was pursued to define the role played by NK-3R located on dopamine (DA) neurons of the ventral tegmental area (VTA) in the regulation of MAP in SHR. SHR (16 weeks) were implanted permanently with i.c.v. and/or VTA guide cannula. Experiments were conducted 24 h after catheterization of the abdominal aorta to measure MAP and heart rate (HR) in freely behaving rats. Cardiovascular responses to i.c.v. or VTA injected NK-3R agonist (senktide) and antagonists (SB222200 and R-820) were measured before and after systemic administration of selective DA antagonists for D-1R (SCH23390), D-2R (raclopride) or non-selective D-2R (haloperidol) and after destruction of the VTA with ibotenic acid. Senktide (10, 25, 65 and 100 pmol) elicited more prominent increases of MAP and HR when injected in the VTA than i.c.v. and this cardiovascular response was blocked by R-820, SCH23390 and haloperidol. I.c.v. or VTA injected SB222200 and R-820 (500 pmol) evoked anti-hypertension, which was blocked by raclopride. Destruction of the VTA prevented the pressor response to i.c.v. senktide and the anti-hypertension to i.c.v. R-820. VTA injected SB222200 prevented the pressor response to i.c.v. senktide, and vice versa, i.c.v. senktide prevented the anti-hypertension to VTA SB222200. Repeated i.c.v. injection of R-820, once a day for 5 days, caused a sustained anti-hypertensive effect in SHR. Tachykinin NK-3R in the VTA is implicated in the maintenance of hypertension by increasing midbrain DA transmission in SHR. Hence, these receptors may represent a therapeutic target in the treatment of arterial hypertension.