1 The mechanisms involved in the mechano-inhibitory effects of acetylcholine (ACh) have been compared with those of sodium nitroprusside (SNP) and cromakalim on the rat isolated thoracic aorta.2 Relaxations produced by ACh were endothelium-dependent, whereas those produced by SNP or cromakalim were endothelium-independent. 3 ACh, cromakalim and SNP relaxed established contractions produced by noradrenaline (NA) and KCl (20 mM) and these relaxations were well-maintained. 4 SNP was a relatively effective inhibitor of contractions produced by KCl (80mM). ACh was relatively ineffective and cromakalim was without effect against such contractions. 5 Membrane potential and cyclic GMP concentrations were higher in tissues with an intact endothelium whereas rubbed tissues had a higher 86Rb efflux rate coefficient. 6 ACh and cromakalim produced a transient and long-lasting hyperpolarization, respectively. These changes were accompanied by increases in the 86Rb efflux rate coefficient with a time course comparable to that of the electrical changes. 7 Tissue cyclic GMP concentrations were significantly increased in the presence of ACh or SNP, whereas cromakalim had no effect. 8 Transmission electron microscopy showed the presence of endothelial cells on intact tissues. On rubbed preparations, such cells were absent and some damage to the underlying smooth muscle cells was detected. 9 It is concluded that at least two inhibitory substances are released from the endothelial cells by ACh. One of these increases tissue cyclic GMP concentrations and produces an electrically-silent relaxation. The other produces a transient hyperpolarization associated with the opening of 86Rb-permeable K-channels. This event may serve to initiate relaxation processes and to close any open voltage-dependent Ca-channels.

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1 The effects of pinacidil have been compared with those of glyceryl trinitrate (GTN) using the aorta and portal vein of the rat and the trachealis and taenia caeci of the guinea-pig. 6 In portal veins loaded with 86Rb as a K+-marker, pinacidil significantly increased the 16Rb efflux rate coefficient whilst GTN had no effect on 'Rb exchange.7 In taenia caeci, both pinacidil and GTN inhibited the spontaneous tone of the preparation. These inhibitory effects were not antagonized by apamin. 8 It is concluded that pinacidil and GTN do not share a common relaxant mechanism. Evidence has been obtained that pinacidil exerts its inhibitory effects by the opening of apamin-insensitive, 86Rb-permeable K+ channels.

In rat aorta and rat portal vein, (-)- and (+)-pinacidil each produced a concentration-dependent inhibition of tension development. Although the (-) isomer was the more potent, concentration effect curves for each isomer were steep with similar slopes. In rat portal vein, tetraethylammonium and procaine antagonised the relaxant effect of (+/-)-pinacidil, whereas 3,4-diamino-pyridine was without effect. Intracellular microelectrode recording in rat portal vein showed that low concentrations of (+/-)-pinacidil reduced the duration of multispike electrical complexes. In both rat aorta and rat portal vein, higher concentrations of (+/-)-pinacidil hyperpolarised the membrane towards the potassium equilibrium potential. (+/-)-Pinacidil increased 86Rb efflux from rat aorta and rat portal vein in a concentration dependent manner. In a separate study, (+/-)-pinacidil increased 42K efflux from rat portal vein. (+/-)-Pinacidil had no effect on cyclic GMP or cyclic AMP levels in rat aorta. It is concluded that pinacidil opens 86Rb-permeable potassium channels in rat aorta and rat portal vein. This mechanism is independent of cyclic nucleotide changes and may be responsible for the antihypertensive effect of pinacidil.

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