Novel signal transduction pathway mediating endothelium‐dependent β‐adrenoceptor vasorelaxation in rat thoracic aorta

Abstract

1 Isoprenaline (3 x 10-8-I0-5M), salbutamol (3 x 10-7-10-4M) and forskolin (3 x 10-9-3 x 10-7M) relaxed rat isolated thoracic aortic rings contracted with noradrenaline (10-7 M). Removal of the endothelium from the aortic rings abolished the effect of acetylcholine (10-6 M) and completely prevented the vascular relaxation induced by isoprenaline, salbutamol or forskolin. 2 The isoprenaline concentration-relaxation curve was shifted in parallel to the right about 10 fold by propranolol (3 x 10-7 M) with no change in the maximum response, showing that the relaxation was mediated by a P-adrenoceptor.3 The inhibitor of nitric oxide synthesis, NG-nitro-L-arginine (L-NOARG; 10-5 M), shifted the isoprenaline relaxation curve to the right and reduced the maximum response. 4 Isoprenaline (10-6 M) relaxed noradrenaline-induced tone by approximately 95% and at the same time increased levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) 4 fold and guanosine 3':5'-cyclic monophosphate (cyclic GMP) 12 fold in the aortic rings. Sodium nitroprusside (3 x 10-8 M) relaxed noradrenaline-evoked tone by 82% without changing levels of cyclic AMP but raised cyclic GMP 19 fold.5 Forskolin (10-7 M) relaxed noradrenaline-induced tone by approximately 41% and, like isoprenaline, increased levels of cyclic AMP (2.5 fold) and cyclic GMP (12 fold) in the aortic rings. 6 Removal of the endothelium abolished the relaxant effects of isoprenaline (10-6 M) and also the associated accumulation of cyclic AMP and cyclic GMP. 7 L-NOARG (10-M) inhibited the relaxant responses and accumulation of cyclic GMP induced by isoprenaline (10-6 M) and forskolin (10-M) without affecting the associated cyclic AMP accumulation.8 It is concluded that, in the rat aorta, isoprenaline acts through a P-adrenoceptor on the endothelium to raise cyclic AMP and that this may, directly or indirectly, release nitric oxide to evoke vascular relaxation via the increase in cyclic GMP. The importance of this novel transduction pathway for cardiovascular regulation remains to be determined.

Noradrenaline, β‐adrenoceptor mediated vasorelaxation and nitric oxide in large and small pulmonary arteries of the rat

“…The proportion of NO-independent relaxation induced by isoprenaline in small pulmonary arteries was similar to that previously described in rat small mesenteric arteries (Graves & Poston, 1993). Our results are in clear agreement with previous studies on systemic arteries, that have suggested that isoprenaline-induced relaxation is at least partly dependent on NO and the endothelium (Gray & Marshall, 1992;Blankesteijn & Thien, 1993;Graves & Poston, 1993;Delpy et al, 1996).…”

“…The results suggest that in contrast to large conduit pulmonary arteries, where the propranolol-sensitive component of tension was only *20% at 10 mM noradrenaline, in small arteries the b-mediated response starts to predominate at concentrations of noradrenaline above 0.2 mM. It has been proposed that both a-and b-adrenoceptor activation can lead to release of NO (Gray & Marshall, 1992;Graves & Poston, 1993;Kaneko & Sunano, 1993;Ohgushi et al, 1993), and it has been shown that removal of the endothelium or inhibition of NO synthase potentiates noradrenaline induced-vasoconstriction in pulmonary arteries (Cederqvist et al, 1991;Leach et al, 1992;Shinozuka et al, 1992). In the present experiments the L-arginine analogue L-NMMA signi®cantly increased tension developed to noradrenaline in both large and small pulmonary arteries (Figure 1), but, the response to L-NMMA di ered substantially between large and small arteries.…”

“…In contrast to the results of Graves and Poston (1993), who showed that salbutamol-induced relaxation in small mesenteric arteries was una ected by L-NAME, we found that both salbutamol-induced relaxation ( Figure 6) and isoprenaline-induced relaxation in the presence of the b 1 -antagonist atenolol ( Figure 4) were reduced by L-NMMA, suggesting that b 2 -adrenoceptor-mediated relaxation also involves NO in the pulmonary vasculature. Gray & Marshall (1992) have previously demonstrated that removal of the endothelium abolished salbutamol-induced relaxation in rat thoracic aorta and, in large pulmonary arteries, we also found that the majority of the b 2 -mediated relaxation was inhibited by L-NMMA, leaving a very small NO-independent component. In small arteries this NO-independent component was larger, but in the case of salbutamol-induced relaxation was still less than 50% of the total.…”

“…If the NO-dependent component relates to a direct action on the endothelium, as proposed by Gray & Marshall (1992), this may re¯ect di erences in either b-adrenoceptor density or e cacy in the smooth muscle. It is worth noting that the total b 2 -adrenoceptor-mediated relaxation in these pulmonary arteries was greater than that mediated by b 1 -adrenoceptors, whereas in mesenteric arteries salbutamol-induced relaxation has been found to be relatively modest (Graves & Poston, 1993).…”

Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation

“…In addition, activation of b-adrenoceptors on the endothelium produces vasodilatation (Gray & Marshall, 1992;Brawley et al, 2000) that is mediated by the synthesis of nitric oxide (NO) (Ferro et al, 1999). It is possible that chronic b-adrenergic stimulation could induce adaptive alterations of vascular b-adrenoceptor signalling pathways resulting in endothelial dysfunction, impaired peripheral vasodilatation and/or inappropriate vasoconstriction.…”