Contribution of the central dopaminergic system in the anti-hypertensive effect of kinin B1 receptor antagonists in two rat models of 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.
De Brito Gariepy
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Département de Physiologie, Faculté de Médecine, Université de Montréal, C.P. 6128 Succursale Centre-ville, Montréal, QC, Canada H3C 3J7.
Carayon
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Ferrari
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Couture
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D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065169:Bradykinin B1 Receptor Antagonists; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043783:Receptor, Bradykinin B1 / Q000378:metabolism
D065169:Bradykinin B1 Receptor Antagonists; D018492:Dopamine Antagonists; D043783:Receptor, Bradykinin B1; D020891:Raclopride; D006220:Haloperidol; D004298:Dopamine