Impairment of the low-affinity state β 1-adrenoceptor- induced relaxation in spontaneously hypertensive rats

Abstract

In hypertension, a decrease of the vascular β-adrenergic relaxation has been described. However, the specific involvement of each β-adrenoceptor (β-AR) subtype, in particular the low-affinity state of β 1-AR, has not yet been evaluated. We investigated whether the low-affinity state of β 1-AR-induced relaxation was impaired in Spontaneously Hypertensive Rats (SHR). The relaxant responses to CGP 12177 and cyanopindolol, low-affinity state β 1-AR agonists (with β 1-/β 2-AR antagonistic and partial β 3-AR agonistic properties) were evaluated on thoracic aortic rings isolated from 12-weeks-old Wistar Kyoto rats (WKY) and SHR. In WKY, CGP 12177 and cyanopindolol produced an endothelium and nitric oxide (NO)-independent relaxation. CGP 12177-induced endothelium-independent relaxation was not modified either by β 1-, β 2-AR (nadolol) or β 3-AR (L-748337 or SR 59230A) antagonists but was significantly reduced by high concentrations of CGP 20712A (P < 0.05). This relaxation was also reduced by adenylyl cyclase inhibitors, SQ 22536 or MDL 12330A. In SHR, CGP 12177 produced mainly an endothelium and NO-dependent relaxation. This effect was not modified by nadolol, but was strongly reduced by β 3-AR blockade. Endothelium-independent relaxation to CGP 12177 was not altered by adenylyl cyclase inhibition, but was amplified in preparations from pertussis toxin-pretreated SHR. The immunohistochemical analysis revealed an upregulation of β 3-AR in the endothelial layer of SHR aorta, whereas the β 3-AR-induced relaxation was not modified. In conclusion, we demonstrated an impaired low-affinity state of the β 1AR-induced relaxation and an upregulation of the β 3-AR in hypertension. Some clinical implications of those findings are discussed.