Evidence that different mechanisms underlie smooth muscle relaxation to nitric oxide and nitric oxide donors in the rabbit isolated carotid artery

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Abstract
The endothelium‐dependent relaxants acetylcholine (ACh; 0.03–10 μm) and A23187 (0.03–10 μm), and nitric oxide (NO), applied either as authentic NO (0.01–10 μm) or as the NO donors 3‐morpholino‐sydnonimine (SIN‐1; 0.1–10 μm) and S‐nitroso‐N‐acetylpenicillamine (SNAP; 0.1–10 μm), each evoked concentration‐dependent relaxation in phenylephrine stimulated (1–3 μm; mean contraction and depolarization, 45.8±5.3 mV and 31.5±3.3 mN; n=10) segments of rabbit isolated carotid artery. In each case, relaxation closely correlated with repolarization of the smooth muscle membrane potential and stimulated a maximal reversal of around 95% and 98% of the phenylephrine‐induced depolarization and contraction, respectively. In tissues stimulated with 30 mm KCl rather than phenylephrine, smooth muscle hyperpolarization and relaxation to ACh, A23187, authentic NO and the NO donors were dissociated. Whereas the hyperpolarization was reduced by 75–80% to around a total of 10 mV, relaxation was only inhibited by 35% (n=4–7 in each case; PG‐nitroarginine methyl ester (l‐NAME; 100 μm) or the inhibitor of soluble guanylyl cyclase 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ; 10 μm; 10 min; n=4 in each case; Pn=4 in each case; Pn=3–5; Pn=4 in each case; P>0.05). Charybdotoxin (ChTX; 50 nm) almost abolished repolarization to ACh (n=4; Pn=4–8; Pn=4 in each case; Pn=4; P>0.05). However, in the presence of tone induced by 1–3 μm phenylephrine (51.2±3.3 mN; n=4), ChTX significantly reduced relaxation to SIN‐1 by nearly 50% (maximum relaxation 53.2±6.3%, n=4; PBritish Journal of Pharmacology (1998) 123, 1351–1358; doi:10.1038/sj.bjp.0701746