MECHANISMS OF THE CIRCADIAN REGULATION OF BETA-ADRENOCEPTOR DENSITY AND ADENYLYL-CYCLASE ACTIVITY IN CARDIAC TISSUE FROM NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS

Circadian variation in beta-adrenoceptor density and adenylyl cyclase activity was studied in myocardium from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In SHR cardiac beta-adrenoceptor density was significantly lower than in WKY. This reduction in total beta-adrenoceptors was exclusively due to a loss in the beta(1)-subtype. Total and beta(1)-adrenoceptor density in ventricles from both strains exhibited significant circadian variation with peaks occurring in the middle of the light and dark periods, whereas the beta(2)-subtype did not show rhythmicity. Similarly, stimulation of adenylyl cyclase via total beta-adrenoceptors and via the beta(1)-subtype was circadian time dependent, but circadian peaks occurring at the beginning of the light and dark periods were 6h apart from those in beta-adrenoceptor density. Rhythmicity in the formation of cAMP was observed under basal conditions and after stimulation by isoprenaline or a forskolin derivative, whereas addition of manganese-ions abolished the circadian variation. In conclusion, the present study demonstrates that in ventricular tissue from WKY and SHR circadian rhythms observed in total beta-adrenoceptor density are due exclusively to variations in the beta(1)-subtype. Since peaks in cAMP formation coincided with troughs in beta-adrenoceptor number, cAMP mediated phosphorylation of beta-adrenoceptors enhancing their down-regulation, could be involved in the circadian regulation of myocardial beta-adrenoceptor density. Rhythmicity in cAMP formation itself seems to involve coupling of G-proteins, because manganese ions abolished the circadian variation.