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

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 1 ‐AR‐induced relaxation and an upregulation of the β 3 ‐AR in hypertension. Some clinical implications of those findings are discussed.British Journal of Pharmacology (2004) 143 , 599–605. doi: 10.1038/sj.bjp.0705990