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

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 (125)I]HPP-Hoe 140 and B(1) receptors (125)I]HPP-des-Arg(10) and Hoe140. 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, AcLysD-betaNal(7), Ile(8)]des-Arg(9)-BK (R-715). 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. Higher densities of specific (125)I]HPP-Hoe 140 labelling were found in discrete brain areas of SHR, especially in regions associated with cardiovascular function. Low levels of (125)I]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. 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.