Correlation between brain bradykinin receptor binding sites and cardiovascular function in young and adult spontaneously hypertensive rats

1 Intracerebroventricular (i.c.v.) effects of bradykinin (BK) B-1 and B-2 receptor agonists and antagonists were assessed on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR, aged of 8 and 16 weeks) and age-matched Wistar Kyoto rats (WKY). Quantitative in vitro autoradiographic studies were also performed on the brain of both strains with specific radioligands for B-2 receptors [I-125]HPP-Hoe 140 and B-1 receptors [I-125]HPP-des-Arg(10) and Hoe140. 2 MAP increased linearly with doses of BK (81-8100 pmol) and the amplitudes were significantly greater in SHR, particularly at 16 weeks. While BK evoked a negative linear trend on HR (bradycardia) in WKY, a positive one (tachycardia) was observed in adult SHR. In both strains, BK-induced pressor response was blocked by equimolar doses of B-2 receptor antagonist, D-Arg-[Hyp(3) Thi(5), D-Tic(7), Oic(8)]-BK (Hoe 140), but not by B-1 receptor antagonist, AcLys[D-betaNal(7), Ile(8)]des-Arg(9)-BK (R-715). 3 B-1 receptor agonists (Sar-[D-Phe(8)]-des-Arg(9)-BK, des-Arg(9)-BK, des-Arg(10)-Kallidin) and antagonist (R-715 alone or with Hoe 140) had no or marginal effect on MAP and HR at doses up to 8100 pmol in SHR and WKY. 4 Higher densities of specific [I-125]HPP-Hoe 140 labelling were found in discrete brain areas of SHR, especially in regions associated with cardiovascular function. Low levels of [I-121]HPP-[des-Arg(10)]-Hoe140 binding sites were seen in WKY and SHR, yet densities were significantly greater in midbrain and cortical regions of SHR aged of 16 weeks. Contrary to SHR, ageing caused a downregulation of B-2 and B-1 receptor binding sites in specific brain nuclei in WKY. 5 It is concluded that the hypersensitivity of the pressor response to i.c.v. BK in SHR occurs during both the early and established phases of hypertension in parallel with the enhancement of B-2 receptor binding sites in various cardiovascular brain centres. In contrast, brain B-1 receptors do not seem to participate in the central pressor effects of kinins nor in the maintenance of hypertension in SHR.