To determine whether endogenous nitric oxide (NO) opens the ATP-sensitive K+ channel (KAV channel), we investigated the effect of nonendothelialderived NO on this channel in cultured smooth muscle cells of the porcine coronary artery by the patch-clamp technique. In the cells pretreated with endotoxin, the addition of lo-" M L-arginine generated NO and activated the KATp channel. Activation of this channel was suppressed by pretreatment with 10e3 M NG-methyl-L-arginine or 10m3 M N"-nitro+arginine methyl ester, each of which is a specific antagonist of the L-arginme-NO pathway, and by 10" M Methylene blue, which blocks guanylate cyclase. The activation of the K ATp channel by L-arginine-NO pathway is expected to produce hyperpolarixation of the cell membrane and relaxation of vascular smooth muscle cells.
1 Adenosine-induced dilatation of rat aorta was present in aorta taken from 4 week-old rats, attenuated with increase in age of rats to 8 weeks, and was virtually absent in the aorta from 12 week-old rats. 2 Removal of the endothelium by mechanical rubbing attenuated adenosine-induced dilatation. 3 Haemoglobin and methylene blue partly reversed the adenosine-induced endothelium-dependent dilatation. 4 The order of potency of adenosine derivatives was 5'-(N-ethylcarboxamido)indicating that adenosine receptors mediating the dilatation are of the A2 subtype. 5 [3H]-NECA bound to preparations of membranes from rats of 4 weeks old; it was displaced more effectively by NECA and the A2 ligand CV-1808 than by the A1 ligands CHA and S-PIA. ligands CHA and S-PIA. 6 The number but not affinity of specific binding sites for NECA decreased considerably with increase in age of rats to 8 weeks, and binding sites for [3H]-NECA were hardly detected in membrane preparations from rats of 20 weeks old. 7 Adenosine caused a marked increase in cyclic GMP production, but did not induce an increase in the cyclic AMP level. 8 This increase in cyclic GMP production induced by adenosine was abolished by methylene blue or 8-phenyltheophylline, or by removal of the endothelium. 9 The age-associated decrease in adenosine-induced dilatation was found to be associated with a reduction in the formation of cyclic GMP, but not of cyclic AMP. 10 These results suggest that adenosine causes dilatation via A2 receptors by inducing production of an endothelium-derived relaxing factor (EDRF), which in turn stimulates soluble guanylate cyclase, and so increases production of cyclic GMP. It is also suggested that the main reason for the age-associated decrease in adenosine-induced dilatation is a decrease in the number of A2-receptors or the ability of the endothelium to produce EDRF, leading to decreased production of cyclic GMP.
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