Impairment of the low-affinity state _1-adrenoceptor-induced relaxation in spontaneously hypertensive rats-

Authors
M. Y. Mallem, G. Toumaniantz, S. Serpillon, F. Gautier, M. Gogny et al.

Lab
UPSP 5304 de Physiopathologie Animale et de Pharmacologie Fonctionnelle, Ecole Nationale Vétérinaire, Nantes, France ; Institut du Thorax, Inserm U533, Nantes, France ; Faculté des Sciences et Techniques, Nantes, France.

Journal
British Journal of Pharmacology

Abstract
In hypertension, a decrease of the vascular _-adrenergic relaxation has been described. However, the specific involvement of each _-adrenoceptor (_-AR) subtype, in particular the low-affinity state of _1-AR, has not yet been evaluated. We investigated whether the low-affinity state of _1-AR-induced relaxation was impaired in Spontaneously Hypertensive Rats (SHR). The relaxant responses to CGP 12177 and cyanopindolol, low-affinity state _1-AR agonists (with _1-/_2-AR antagonistic and partial _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 _1-, _2-AR (nadolol) or _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 _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 _3-AR in the endothelial layer of SHR aorta, whereas the _3-AR-induced relaxation was not modified. In conclusion, we demonstrated an impaired low-affinity state of the _1-AR-induced relaxation and an upregulation of the _3-AR in hypertension. Some clinical implications of those findings are discussed.

BIOSEB Instruments Used:
Non Invasive Pressure Measurement (LE5001)