1 The effects of the novel anti-hypertensive agent BRL 34915, (±) 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl)-2H-benzo [b]pyran-3-ol, have been compared with those of verapamil on rat isolated portal vein. 2 BRL 34915 produced a concentration-dependent reduction in mechanical responses to noradrenaline but had relatively little inhibitory effect on K+-induced contractions. Verapamil reduced the magnitude of both noradrenaline and K+-induced mechanical responses. 3 BRL 34915 delayed the appearance of the reduced noradrenaline contractions, a property not shared by verapamil. 4 BRL 34915 abolished spontaneous electrical and mechanical discharges and hyperpolarized the portal vein cells close to their calculated potassium equilibrium potential. Verapamil inhibited spontaneous electrical and mechanical discharges, effects associated with a small depolarization. 5 BRL 34915 produced a significant increase in the 86Rb efflux rate coefficient whilst verapamil was without effect on this parameter. 6 The inhibitory effects of BRL 34915 were rapid in onset and readily reversible by washing, whilst those of verapamil were slower in onset and only slowly reversible. 7 It is concluded that the inhibitory effects of BRL 34915 in rat portal vein are produced by the opening of potassium channels in the smooth muscle cells. This inhibits spike activity and in sufficient concentration holds the membrane potential at or close to the potassium equilibrium potential, thereby reducing the effects of excitatory agents.

The effects of the antihypertensive agent BRL 34915 on a variety of responses of the aorta and portal vein of the rat have been compared with those of nicorandil. On portal vein, BRL 34915 (0.01–50 × 10−6 M) and nicorandil (0.1–500 × 10−6 M) abolished spontaneous mechanical activity and reduced mechanical responses to noradrenaline (0.1–100 × 10−6 M) and K+ (5–20 × 10−3 M) but had little inhibitory effect on responses to K+ (40–80 × 10−3 M). The onset of the reduced responses to noradrenaline was delayed by both agents. On portal vein, BRL 34915 (0.1–50 × 10−6 M) and nicorandil (0.5–500 × 10−6 M) abolished spontaneous electrical and mechanical activity, hyperpolarized the smooth muscle cells to a value close to their calculated potassium equilibrium potential and increased the 86Rb efflux rate coefficient. On aorta, BRL34915 (0.2‐0.8 × 10−6 M) and nicorandil (8–32 × 10−6 M) reduced mechanical responses to noradrenaline (0.001‐1 × 10−6 M) and K+ (5–20 × 10−3 M) but had little inhibitory effect on responses to K+ (40–80 × 10−3 M). On aorta, BRL 34915 (0.2‐0.8 × 10−6 M) increased the 86Rb efflux rate coefficient whereas nicorandil (8–32 × 10−6 M) was without effect. It is concluded that the inhibitory actions of BRL 34915 on both aorta and portal vein result from the opening of membrane potassium channels. The resulting membrane shunt inhibits the effects of excitatory agents. The inhibitory effects of nicorandil result from a combination of the opening of potassium channels together with an additional, undefined action.

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.

BRL 34915 (4–64 × 10−7 M), isoprenaline (0.5–32 × 10−8 M) and nicorandil (4–64 × 10−6 M) produced a slowly‐developing relaxation of spontaneous tone of the guinea‐pig taenia caeci; with no after‐contraction on washout. These inhibitory responses were unaffected by apamin (10−7 M). Adenosine triphosphate (0.06‐2 × 10−3 M) and noradrenaline (1–16 × 10−7 M) produced a rapid inhibition of spontaneous tone with a prominent after‐contraction, especially on washout. Both the inhibitory effect and the rebound contraction were abolished by apamin (10−7 M). Exposure to both BRL 34915 (64 × 10−7 M) and to nicorandil (64 × 10−6 M) produced an increase in the 86Rb efflux rate coefficient which was unaffected by apamin (10−7 M). Exposure to isoprenaline (32 × 10−8 M) had no effect on the 86Rb efflux rate coefficient. Exposure to noradrenaline (16 × 10−7 M) produced an increase in the 86Rb efflux rate coefficient which was abolished by apamin (10−7 M). The results confirm that both BRL 34915 and nicorandil are capable of opening potassium channels in smooth muscle but show that the channel is not apamin‐sensitive.