Evidence for reduced β‐adrenoceptor coupling to adenylate cyclase in femoral arteries from spontaneously hypertensive rats

Abstract

1 Arterial relaxant responses via fi-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 f-adrenoceptor adenylate cyclase (AC) system is involved in the decreased responsiveness to fi-adrenoceptor stimulation, relaxant responses to forskolin and dibutyryl cyclic AMP (db cyclic AMP) were compared between 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 fi-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 f-adrenoceptor coupling to AC is mainly involved in the decreased responsiveness to ,B-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.

Decreased arterial responsiveness to multiple cyclic AMP‐generating receptor agonists in spontaneously hypertensive rats

“…Strips were treated with 2 x 10-6M Pbz during the first 60 min of the 90 min equilibration period. Using these Pbz-treated strips, relaxant responses to NA via P-adrenoceptors could be consistently demonstrated (Asano et al, 1982;1988a).…”

“…Male SHR, 13 weeks of age, and age-matched male WKY were used (Asano et al, 1988a). The rats were stunned and exsanguinated.…”

“…were quickly dissected and placed in the Krebs-bicarbonate solution of the following composition (in mm): NaCl 115.0, KCl 4.7, CaCl2 2.5, MgCl2 1.2, NaHCO3 25.0, KH2PO4 1.2 and dextrose 10.0. Helical strips (0.8mm in width and 7mm in length) of these arteries were prepared according to the method described previously (Asano et al, 1988a). The size of the strips of renal arteries was somewhat smaller (0.6mm x 5mm).…”

“…The size of the strips of renal arteries was somewhat smaller (0.6mm x 5mm). To avoid the possible effects of the endothelium-derived relaxing factor, the endothelium of the strip was removed (Asano et al, 1988a). Arterial strips were mounted vertically between hooks in water-jacketed (37 + 0.5°C) muscle baths containing 20ml of the Krebs-bicarbonate solution.…”

“…To compare agonists that relax blood vessels, arterial strips were contracted with K+ to an equivalent magnitude of tension (85% of the maximum contraction developed by 60mm K+) before challenge with the agonists (Asano et al, 1988a). These contractions induced by ED85 K were well sustained for at least 3 h. Cumulative dose-response curves for the arterial relaxant responses to agonists were determined by producing a stepwise increase in the concentration of the agonist as soon as a stable response to the preceding dose had been obtained.…”