raclopride and Hypertension

Kinins are neuroactive peptides that could play a role in central autonomic control of blood pressure. Whereas kinin B1R binding sites were increased in specific brain areas of spontaneously hypertensive rats (SHR) and Angiotensin II (AngII)-hypertensive rats, the contribution of kinin B1R in hypertension remains controversial. The aims of the study were to determine: (a) the effects on mean arterial blood pressure (MAP) of centrally and peripherally administered B1R antagonists in SHR (16weeks) and AngII-hypertensive rats (200ng/kg/minx2weeks, s.c.); (b) the contribution of central dopamine in the effects of SSR240612. The rationale is based on the overactivity of the dopaminergic system in hypertension. In both models, SSR240612 (1, 5 and 10mg/kg, gavage) reduced dose-dependently MAP (-75mm Hg at least up to 6-8h) and this therapeutic effect was resolved after 24h. At the dose of 5mg/kg, SSR240612-induced anti-hypertension was prevented by two dopamine receptor blockers, namely raclopride (0.16mg/kg, i.v.) and haloperidol (10mg/kg, s.c.). I.c.v. SSR240612 (1mug) decreased rapidly MAP in both models (1-6h) via a raclopride sensitive mechanism. In comparison, peripherally acting B1R antagonists (R-715 and R-954, 2mg/kg, s.c.) caused shorter and very modest decreases of MAP (from -20 to -30mm Hg). Centrally or peripherally administered B1R antagonists had no effect on MAP in control Wistar-Kyoto rats. Data provide the first pharmacological evidence that the up-regulated brain kinin B1R contributes through a central dopaminergic mechanism (DA-D2R) to the maintenance of arterial hypertension in genetic and experimental animal models of hypertension.

Topics: Analysis of Variance; Animals; Blood Pressure; Bradykinin B1 Receptor Antagonists; Brain; Disease Models, Animal; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Haloperidol; Hypertension; Male; Raclopride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Bradykinin B1

Intracerebroventricularly injected tachykinin NK(3) receptor (R) antagonists normalize mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHR). This study was pursued to define the role played by NK(3)R located on dopamine neurones 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 cannulae. 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(3)R agonist (senktide) and antagonists (SB222200 and R-820) were measured before and after systemic administration of selective antagonists for D(1)R (SCH23390), D(2)R (raclopride) or non-selective D(2)R (haloperidol), and after destruction of the VTA with ibotenic acid.. I.c.v. or VTA-injected SB222200 and R-820 (500 pmol) evoked anti-hypertension, which was blocked by raclopride. Senktide (10, 25, 65 and 100 pmol) elicited greater increases of MAP and HR when injected in the VTA, and the cardiovascular response was blocked by R-820, SCH23390 and haloperidol. 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. Destruction of the VTA prevented the pressor response to i.c.v. senktide and the anti-hypertension to i.c.v. R-820.. The NK(3)R in the VTA is implicated in the maintenance of hypertension by increasing midbrain dopaminergic transmission in SHR. Hence, this receptor may represent a therapeutic target in the treatment of hypertension.

Topics: Animals; Benzazepines; Blood Pressure; Dopamine; Haloperidol; Heart Rate; Hypertension; Ibotenic Acid; Indoles; Male; Oligopeptides; Peptide Fragments; Quinolines; Raclopride; Rats; Rats, Inbred SHR; Receptors, Neurokinin-3; Substance P; Ventral Tegmental Area

We studied the differential involvement of central dopaminergic activation and autonomic nervous system regulatory mechanisms in the cardiovascular responses to cocaine in conscious rats. Sprague-Dawley rats, Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were instrumented with catheters in the jugular vein and abdominal aorta at least 5 days before the experiment. Intravenous administration of cocaine (0.1-3.0 mg/kg) caused a dose-dependent increase in blood pressure that was biphasic, with a large and rapid increase peaking at 10 s, followed by a mild sustained pressor response. Pressor responses to cocaine were significantly greater in SHR when compared to WKY rats. However, pretreatment with dopamine D1 receptor antagonist SCH 23390 or the D2 receptor antagonist raclopride did not influence the effects of cocaine. Pretreatment with the alpha-adrenoceptor antagonist phentolamine or the ganglion blocker pentolinium blocked the peak response and reversed the more sustained response into a depressor effect. While pretreatment with propranolol alone did not alter the responses to cocaine, in rats pretreated with phentolamine and propranolol neither a pressor response nor a depressor response was observed. In conclusion, cocaine administration caused marked, but short lasting pressor responses that were mediated by sympathetic activation and alpha-adrenoceptor vasoconstriction with little involvement of central dopaminergic mechanisms. The rapid return of blood pressure towards baseline may be mediated by sympathoinhibition and beta-adrenoceptor-mediated vasodilatation, the latter of which being particularly prominent when alpha-adrenoceptor activation was prevented.

Topics: Acute-Phase Reaction; Animals; Blood Pressure; Cardiovascular System; Cocaine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Male; Pressoreceptors; Raclopride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Dopamine; Salicylamides; Sympathetic Nervous System; Time Factors