Vasodilators are used clinically for the treatment of hypertension and heart failure. The effects of some vasodilators seem to be mediated by membrane hyperpolarization. The molecular basis of this hyperpolarization has been investigated by examining the properties of single K+ channels in arterial smooth muscle cells. The presence of adenosine triphosphate (ATP)-sensitive K+ channels in these cells was demonstrated at the single channel level. These channels were opened by the hyperpolarizing vasodilator cromakalim and inhibited by the ATP-sensitive K+ channel blocker glibenclamide. Furthermore, in arterial rings the vasorelaxing actions of the drugs diazoxide, cromakalim, and pinacidil and the hyperpolarizing actions of vasoactive intestinal polypeptide and acetylcholine were blocked by inhibitors of the ATP-sensitive K+ channels, suggesting that all these agents may act through a common pathway in smooth muscle by opening ATP-sensitive K+ channels.

https://science.sciencemag.org/content/sci/245/4914/177.full.pdf

Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle.

Resistance arteries exist in a maintained contracted state from which they can dilate or constrict depending on need. In many cases, these arteries constrict to membrane depolarization and dilate to membrane hyperpolarization and Ca-channel blockers. We discuss recent information on the regulation of arterial smooth muscle voltage-dependent Ca channels by membrane potential and vasoconstrictors and on the regulation of membrane potential and K channels by vasodilators. We show that voltage-dependent Ca channels in the steady state can be open and very sensitive to membrane potential changes in a range that occurs in resistance arteries with tone. Many synthetic and endogenous vasodilators act, at least in part, through membrane hyperpolarization caused by opening K channels. We discuss evidence that these vasodilators act on a common target, the ATP-sensitive K (KATP) channel that is inhibited by sulfonylurea drugs. We propose the following hypotheses that presently explain these findings: 1) arterial smooth muscle tone is regulated by membrane potential primarily through the voltage dependence of Ca channels; 2) many vasoconstrictors act, in part, by opening voltage-dependent Ca channels through membrane depolarization and activation by second messengers; and 3) many vasodilators work, in part, through membrane hyperpolarization caused by KATP channel activation.

Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone

https://www.cell.com/trends/pharmacological-sciences/pdf/0165-6147(88)90238-6.pdf

The pharmacology of potassium channels and their therapeutic potential

The function of the heart depends critically on an adequate oxygen supply through the coronary arteries Coronary arteries dilate when the intravascular oxygen tension decreases Hypoxic vasodilation in isolated, perfused guinea pig hearts can be prevented by glibenclamide, a blocker of adenosine triphosphate (ATP)-sensitive potassium channels, and can be mimicked by cromakalim, which opens ATP-sensitive potassium channels Opening of potassium channels in coronary smooth muscle cells and the subsequent drop in intracellular calcium is probably the major cause of hypoxic and ischemic vasodilation in the mammalian heart

https://science.sciencemag.org/content/sci/247/4948/1341.full.pdf

Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels

Blood flow and blood pressure are determined by an integration of reflex, humoral, and local vascular control mechanisms. Knowledge of these mechanisms has mushroomed over the past 15 years, particularly in the area of local endothelium-dependent vasomotor control. This has stemmed from the pioneering report in 1980 by Robert Furchgott1 demonstrating that the endothelium releases a vasodilator substance in response to acetylcholine. This concept has been expanded with knowledge that the endothelium releases a variety of relaxing and contracting factors that regulate the underlying smooth muscle.2 The most widely known endothelium-derived relaxing factor, nitric oxide, is released from endothelial cells in response to shear stress or stimulation of different receptors for a variety of neurohumoral mediators on the endothelial cell surface.3 The increase in endothelial cell calcium initiated by these stimuli increases the activity of a constitutively expressed enzyme, nitric oxide synthase, which converts l-arginine to nitric oxide and citrulline.4 5 6 7 Nitric oxide thus formed diffuses to and inhibits contraction of the underlying vascular smooth muscle.3 The physiological significance of the production of endothelial nitric oxide is suggested by the vasoconstriction observed in most vascular beds8 9 10 11 12 13 and the increase in systemic arterial blood pressure,14 15 16 which occurs on infusion of inhibitors of nitric oxide synthase. This observation further implies that under normal conditions, endothelial cells are locally liberating nitric oxide which effectively inhibits vasoconstriction arising by other mechanisms. Thus, normal vascular homeostasis depends in the periphery on a balance between neurally and humorally mediated vasoconstriction in skeletal muscle, mesentery, and the kidney, and local endothelium-dependent vasodilatation. In the truly vital areas of the heart, brain, and genitalia, vasodilator neural mechanisms reinforce the vasodilator influence of the endothelium.17 

All is not known regarding the …

Endothelium-Dependent Hyperpolarization Beyond Nitric Oxide and Cyclic GMP

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-b enzo[b]pyran-3-ol, have been compared with those of verapamil on rat isolated portal vein. 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. BRL 34915 delayed the appearance of the reduced noradrenaline contractions, a property not shared by verapamil. 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. BRL 34915 produced a significant increase in the 86Rb efflux rate coefficient whilst verapamil was without effect on this parameter. 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. 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.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1986.tb09476.x

Comparison of the effects of BRL 34915 and verapamil on electrical and mechanical activity in rat portal vein

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 X 10(-6) M) and nicorandil (0.1-500 X 10(-6) M) abolished spontaneous mechanical activity and reduced mechanical responses to noradrenaline (0.1-100 X 10(-6) M) and K+ (5-20 X 10(-3) M) but had little inhibitory effect on responses to K+ (40-80 X 10(-3) M). The onset of the reduced responses to noradrenaline was delayed by both agents. On portal vein, BRL 34915 (0.1-50 X 10(-6) M) and nicorandil (0.5-500 X 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, BRL 34915 (0.2-0.8 X 10(-6) M) and nicorandil (8-32 X 10(-6) M) reduced mechanical responses to noradrenaline (0.001-1 X 10(-6) M) and K+ (5-20 X 10(-3) M) but had little inhibitory effect on responses to K+ (40-80 X 10(-3) M). On aorta, BRL 34915 (0.2-0.8 X 10(-6) M) increased the 86Rb efflux rate coefficient whereas nicorandil (8-32 X 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.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of BRL 34915 and nicorandil on electrical and mechanical activity and on 86Rb efflux in rat blood vessels.

BRL 34915 (4-64 X 10(-7) M), isoprenaline (0.5-32 X 10(-8) M) and nicorandil (4-64 X 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 X 10(-3) M) and noradrenaline (1-16 X 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 X 10(-7) M) and to nicorandil (64 X 10(-6) M) produced an increase in the 86Rb efflux rate coefficient which was unaffected by apamin (10(-7) M). Exposure to isoprenaline (32 X 10(-8) M) had no effect on the 86Rb efflux rate coefficient. Exposure to noradrenaline (16 X 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.

/pdf/effect-of-apamin-on-responses-to-brl-34915-nicorandil-and-674qi4iyzi.pdf

Effect of apamin on responses to BRL 34915, nicorandil and other relaxants in the guinea-pig taenia caeci

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. In aorta, both pinacidil and GTN inhibited responses to noradrenaline and showed some selective inhibition of contractions to 20 mM K+. Responses to 80 mM K+ were little affected. In trachealis, both pinacidil and GTN inhibited spontaneous tone and selectively relaxed spasms to 20 mM K+. Responses to 80 mM K+ were unaffected. In portal vein, pinacidil completely inhibited spontaneous electrical and mechanical activity. GTN reduced the amplitude of tension waves and extracellularly-recorded discharges, but increased the frequency of spontaneous electrical and mechanical activity. In portal vein, pinacidil inhibited contractions to noradrenaline and selectively inhibited responses to 20 mM K+. GTN had little inhibitory effect on responses to either noradrenaline or K+. In portal veins loaded with 86Rb as a K+-marker, pinacidil significantly increased the 86Rb efflux rate coefficient whilst GTN had no effect on 86Rb exchange. In taenia caeci, both pinacidil and GTN inhibited the spontaneous tone of the preparation. These inhibitory effects were not antagonized by apamin. 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.

Evidence that the mechanism of the inhibitory action of pinacidil in rat and guinea-pig smooth muscle differs from that of glyceryl trinitrate.

1. Contractile responses of rabbit aortic rings elicited by KCl-depolarization, angiotensin II (AII), 5-hydroxytryptamine (5-HT) and noradrenaline (NA) have been investigated in the presence of cromakalim (BRL 34915) and isradipine (PN 200-110). 2. Above 10(-6)M, cromakalim inhibited contractile responses to low (less than or equal to 32 mM) but not to higher KCl concentrations. The 5-HT and AII concentration-response curves were antagonized noncompetitively by cromakalim (10(-7)-10(-5)M) and the maximal responses were inhibited by 40 and 55%, respectively. 3. Isradipine caused less inhibition of AII and 5-HT contractile responses than cromakalim, and in the presence of isradipine (10(-7)M), cromakalim was still able to antagonize further the contractions to AII in this vessel. 4. NA-induced contractions were relatively insensitive to inhibition by cromakalim and isradipine, both drugs causing a small rightward shift of the NA concentration-response curve. This result suggests that NA utilizes different Ca2+ pools from those involved in AII- and 5-HT-induced contractions of this vessel. 5. The sustained (tonic) part of the NA response was inhibited in a concentration-dependent manner by cromakalim (10(-7)-10(-5)M), but not by isradipine. 6. In aortic rings partially depolarized with 3.5 x 10(-2)M KCl, the ability of cromakalim, but not of sodium nitroprusside, atriopeptin III or hydralazine, to inhibit AII- and tonic NA-induced contractions was abolished. 7. Antivasoconstrictor activity of cromakalim on the rabbit aorta appears to involve factors in addition to an indirect inhibition of Ca2+ entry through dihydropyridine-sensitive Ca2+ channels. 8. The ability of cromakalim to open K+ channels and thereby modify the membrane potential would appear to underlie these antivasoconstrictor effects. This mechanism of action of cromakalim clearly differs from that of other vasodilators such as sodium nitroprusside and hydralazine.

Sheila W. Weir

Papers

Comparison of the effects of BRL 34915 and verapamil on electrical and mechanical activity in rat portal vein

The effects of BRL 34915 and nicorandil on electrical and mechanical activity and on 86Rb efflux in rat blood vessels.

Effect of apamin on responses to BRL 34915, nicorandil and other relaxants in the guinea-pig taenia caeci

Evidence that the mechanism of the inhibitory action of pinacidil in rat and guinea-pig smooth muscle differs from that of glyceryl trinitrate.

Anti‐vasoconstrictor effects of the K+ channel opener cromakalim on the rabbit aorta—comparison with the calcium antagonist isradipine