Enhancement of the vasorelaxant potency of nicorandil by metabolic inhibition and adenosine in the pig coronary artery

Davie, Christina; Standen, N B

doi:10.1016/s0008-6363(97)00262-9

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…Evidence that this is the case for levcromakalim has been obtained by Randall & Gri th (1993) and Randall et al (1994), who showed that hypoxia, inhibition of oxidative phosphorylation, or adenosine increased the potency of the drug in causing vasorelaxation in the rabbit ear artery, though the potency of pinacidil was una ected. In porcine coronary arteries, we have recently shown that nicorandil relaxations were enhanced by metabolic inhibition, decreased pH, or adenosine receptor activation, so in this respect the K + channel opening action of nicorandil appears to resemble that of levcromakalim rather than pinacidil (Davie & Standen, 1998). Our present results suggest that this is also so in rat small mesenteric arteries, since both inhibition of oxidative phosphorylation with CCCP and removal of glucose potentiated nicorandil-induced relaxations.…”

Section: The E Ect Of Metabolic Inhibition On Vasorelaxation By Nicorsupporting

confidence: 67%

Potassium channel activation and relaxation by nicorandil in rat small mesenteric arteries

Davie

Kubo

Standen

1998

British J Pharmacology

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1 We used whole-cell patch clamp to investigate the currents activated by nicorandil in smooth muscle cells isolated from rat small mesenteric arteries, and studied the relaxant e ect of nicorandil using myography. 2 Nicorandil (300 mM) activated currents with near-linear current-voltage relationships and reversal potentials near to the equilibrium potential for K + . 3 The nicorandil-activated current was blocked by glibenclamide (10 mM), but una ected by iberiotoxin (100 nM) and the guanylyl cyclase inhibitor LY 83583 (1 mM). During current activation by nicorandil, openings of channels with a unitary conductance of 31 pS were detected. 4 One hundred mM nicorandil had no e ect on currents through Ca 2+ channels recorded in response to depolarizing voltage steps using 10 mM Ba 2+ as a charge carrier. A small reduction in current amplitude was seen in 300 mM nicorandil, though this was not statistically signi®cant. 5 In arterial rings contracted with 20 mM K + Krebs solution containing 200 nM BAYK 8644, nicorandil produced a concentration-dependent relaxation with mean pD 2 =4.77+0.06. Glibenclamide (10 mM) shifted the curve to the right (pD 2 =4.32+0.05), as did 60 mM K + . LY 83583 caused a dosedependent inhibition of the relaxant e ect of nicorandil, while LY 83583 and glibenclamide together produced greater inhibition than either alone. 6 Metabolic inhibition with carbonyl cyanide m-chlorophenyl hydrazone (30 nM), or by reduction of extracellular glucose to 0.5 mM, increased the potency of nicorandil. 7 We conclude that nicorandil activates K ATP channels in these vessels and also acts through guanylyl cyclase to cause vasorelaxation, and that the potency of nicorandil is increased during metabolic inhibition.

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Section: The E Ect Of Metabolic Inhibition On Vasorelaxation By Nicorsupporting

confidence: 67%

Potassium channel activation and relaxation by nicorandil in rat small mesenteric arteries

Davie

Kubo

Standen

1998

British J Pharmacology

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“…The exact mechanisms of these effects have not been clearly identified. A recent study, however, indicated that metabolic inhibition significantly increased the potency of nicorandil on pig coronary artery relaxation (20). These results suggest that MgADP may enhance nicorandil induced KATP channel activities.…”

Section: Discussionmentioning

confidence: 88%

Effects of ketamine on nicorandil induced ATP-sensitive potassium channel activity in cell line derived from rat aortic smooth muscle

et al. 2010

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“…Its effectiveness as an anti-anginal may be increased by a synergistic action with the intrinsic metabolic sensitivity of the K ATP channel, so that it preferentially activates channels in ischaemic tissue. In vitro studies on coronary arteries suggest that it may have such a self-targeting action [171]. A further incentive to consider K ATP channel openers as anti-anginal drugs may be an added benefit of a cardiprotective effect that is probably mediated by cardiac rather than vascular channels [169,170].…”

Section: Vascular Effects Of Potassium Channel Openersmentioning

confidence: 99%

ATP-Sensitive Potassium Channels

Rodrigo

Standen²

2005

CPD

105

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ATP-sensitive potassium (K(ATP)) channels link membrane excitability to metabolism. They are regulated by intracellular nucleotides and by other factors including membrane phospholipids, protein kinases and phosphatases. K(ATP) channels comprise octamers of four Kir6 pore-forming subunits associated with four sulphonylurea receptor subunits. The exact subunit composition differs between the tissues in which the channels are expressed, which include pancreas, cardiac, smooth and skeletal muscle and brain. K(ATP) channels are targets for antidiabetic sulphonylurea blockers, and for channel opening drugs that are used as antianginals and antihypertensives. This review focuses on non-pancreatic K(ATP) channels. In vascular smooth muscle, K(ATP) channels are extensively regulated by signalling pathways and cause vasodilation, contributing both to resting blood flow and vasodilator-induced increases in flow. Similarly, K(ATP) channel activation relaxes smooth muscle of the bladder, gastrointestinal tract and airways. In cardiac muscle, sarcolemmal K(ATP) channels open to protect cells under stress conditions such as ischaemia or exercise, and appear central to the protection induced by ischaemic preconditioning (IPC). Mitochondrial K(ATP) channels are also strongly implicated in IPC, but clarification of their exact role awaits information on their molecular structure. Skeletal muscle K(ATP) channels play roles in fatigue and recovery, K+ efflux, and glucose uptake, while neuronal channels may provide ischaemic protection and underlie the glucose-responsiveness of hypothalamic neurones. Current therapeutic considerations include the use of K(ATP) openers to protect cardiac muscle, attempts to develop openers selective for airway or bladder, and the question of whether block of extra-pancreatic K(ATP) channels may cause adverse cardiovascular side-effects of sulphonylureas.

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Enhancement of the vasorelaxant potency of nicorandil by metabolic inhibition and adenosine in the pig coronary artery

Cited by 4 publications

References 25 publications

Potassium channel activation and relaxation by nicorandil in rat small mesenteric arteries

Potassium channel activation and relaxation by nicorandil in rat small mesenteric arteries

Effects of ketamine on nicorandil induced ATP-sensitive potassium channel activity in cell line derived from rat aortic smooth muscle

ATP-Sensitive Potassium Channels

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