Evidence for reduced beta-adrenoceptor coupling to adenylate cyclase in femoral arteries from spontaneously hypertensive rats

Abstract

1. Arterial relaxant responses via beta-adrenoceptors have been demonstrated to be decreased in spontaneously hypertensive rats (SHR) when compared with normotensive Wistar-Kyoto rats (WKY). To determine which process of the beta-adrenoceptor.adenylate cyclase (AC) system is involved in the decreased responsiveness to beta-adrenoceptor stimulation, relaxant responses to forskolin and dibutyryl cyclic AMP (db cyclic AMP) were compared strips of femoral and mesenteric arteries isolated from 13 week-old SHR and age-matched WKY. 2. The relaxant response to either forskolin, an activator of AC, or db cyclic AMP was not significantly different between the SHR and WKY, when the strips of both arteries from both strains were contracted with K+ to an equivalent magnitude (85% of the maximum). 3. Under the same conditions, however, the relaxant response to noradrenaline (NA) via beta-adrenoceptors was significantly decreased in the SHR arteries. 4. When the strips of femoral arteries were contracted with the same concentration of K+, there was a precontraction of greater magnitude in response to the K+ and a decreased relaxation in response to forskolin, db cyclic AMP or NA in the SHR. On the other hand, when the strips of mesenteric arteries were contracted with the same concentration of K+, the precontraction was smaller in magnitude and there was an increased relaxation in the SHR. 5. The relationship between the relaxant responses and the K+-induced precontractions clearly showed that the ability of forskolin and NA to relax the K+-contracted strips depends on the magnitude of precontraction. Therefore, a difference in magnitude of precontraction between the two groups may produce a meaningless difference. 6. The relaxant responses to forskolin and NA were significantly potentiated by the addition of isobutyl methylxanthine (IBMX), an inhibitor of cyclic AMP phosphodiesterase. Even in the presence of IBMX, relaxant responses to forskolin were the same for the two strains. The difference in the pD2 value for NA-induced relaxation between the two strains was the same in the presence and absence of IBMX. 7. The relaxant effect of either nitroprusside or nifedipine, agents which are independent of this system, was not significantly different between the strips from SHR and WKY. These relaxations were not potentiated by IBMX. 8. From these results, it is concluded that the reduced beta-adrenoceptor coupling to AC is mainly involved in the decreased responsiveness to beta-adrenoceptor stimulation. Furthermore, for an accurate comparison to be made, it is necessary to minimize the influence of variations in the magnitude of precontraction on the relaxant responses.