Impairment of the low-affinity state beta1-adrenoceptor-induced relaxation in spontaneously hypertensive rats.

1 In hypertension, a decrease of the vascular beta-adrenergic relaxation has been described. However, the specific involvement of each beta-adrenoceptor (beta-AR) subtype, in particular the low-affinity state of beta1-AR, has not yet been evaluated. We investigated whether the low-affinity state of beta1-AR-induced relaxation was impaired in Spontaneously Hypertensive Rats (SHR). 2 The relaxant responses to CGP 12177 and cyanopindolol, low-affinity state beta1-AR agonists (with beta1-/beta2-AR antagonistic and partial beta3-AR agonistic properties) were evaluated on thoracic aortic rings isolated from 12-weeks-old Wistar Kyoto rats (WKY) and SHR. 3 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 beta1-, beta2-AR (nadolol) or beta3-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. 4 In SHR, CGP 12177 produced mainly an endothelium and NO-dependent relaxation. This effect was not modified by nadolol, but was strongly reduced by beta3-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. 5 The immunohistochemical analysis revealed an upregulation of beta3-AR in the endothelial layer of SHR aorta, whereas the beta3-AR-induced relaxation was not modified. 6 In conclusion, we demonstrated an impaired low-affinity state of the beta1-AR-induced relaxation and an upregulation of the beta3-AR in hypertension. Some clinical implications of those findings are discussed.