ABSTRACT
Myograph recording from ring segments of pig small coronary arteries was used to investigate the effects of adenosine receptor activation on the vasorelaxant potency of ATP-sensitive K(+) channel opening drugs. Receptor activation with 2-chloroadenosine (2-CA, 300 nM) increased the potency of both nicorandil and levcromakalim, shifting the pEC(50)s from 4.68+/-0.03 to 5.05+/-0.04 and from 6.34+/-0.06 to 6.72+/-0.06, respectively (P<0.05 in each case). Experiments with selective adenosine receptor agonists (2-chloro-N(6)-cyclopentyladenosine (CCPA), 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680)) and antagonists (8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), 4-(2-[7-amino-2-(2-furyl)[1,2, 4]triazolo[2,3-a] [1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385)) suggest that both A(1) and A(2a) receptors can increase the potency of nicorandil, while that of levcromakalim is increased only by A(2) receptors. Adenosine receptor activation did not affect the potency of pinacidil. Thus, adenosine receptor activation can increase the potency of some K(+) channel opening drugs to relax coronary arteries, but the details of the interaction with adenosine receptors depend on the particular drug.
Subject(s)
Coronary Vessels/drug effects , Potassium Channels/agonists , Purinergic P1 Receptor Agonists , Purinergic P1 Receptor Antagonists , Vasodilator Agents/pharmacology , ATP-Binding Cassette Transporters , Adenosine/analogs & derivatives , Adenosine/pharmacology , Animals , Cromakalim/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , In Vitro Techniques , KATP Channels , Nicorandil/pharmacology , Phenethylamines/pharmacology , Pinacidil/pharmacology , Potassium Channels, Inwardly Rectifying , Swine , Triazines/pharmacology , Triazoles/pharmacology , Xanthines/pharmacologyABSTRACT
OBJECTIVE: Nicorandil is used clinically to treat angina and acts in part by opening ATP-sensitive K+ channels whose opening is also enhanced by metabolic compromise. We have therefore investigated whether treatments that mimic conditions in ischaemia can increase the potency of nicorandil to dilate coronary arteries. METHODS: Ring segments from pig small coronary arteries were mounted on a myograph, contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 6844, and relaxations to cumulative doses of nicorandil were measured. RESULTS AND CONCLUSIONS: Nicorandil produced a dose-dependent relaxation with a mean pEC50 (-log EC50, M) of 4.76 +/- 0.02. Inhibition of metabolism with carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 100 nM) or by removal of extracellular glucose significantly increased the potency of nicorandil (pEC50s of 5.11 +/- 0.08 and 5.08 +/- 0.06, p < 0.05 in each case). The adenosine analogue 2-chloroadenosine (2-CA, 300 nM) had a similar effect (pEC50 = 5.17 +/- 0.06, p < 0.05). Reducing extracellular pH to 6.8 also significantly increased the potency of nicorandil, but to a smaller extent. Glibenclamide reduced the potency of nicorandil (pEC50 = 3.81 +/- 0.01, n = 7), and abolished its enhancement by CCCP, zero glucose, 2-CA or pH 6.8 solution. 2-CA did not affect the potency of nicorandil in relaxing contractions to 80 mM K+ or the potency of glyceryl trinitrate. We conclude that the potency of nicorandil to cause coronary vasorelaxation is increased under conditions of metabolic inhibition. This effect appears to result from the K+ channel opening action of the drug, and may have significant consequences for its therapeutic effectiveness.
Subject(s)
Coronary Vessels/metabolism , Niacinamide/analogs & derivatives , Potassium Channels/drug effects , Vasodilator Agents/pharmacology , 2-Chloroadenosine/pharmacology , Animals , Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology , Coronary Vessels/drug effects , Glucose/metabolism , Glyburide/pharmacology , Hydrogen-Ion Concentration , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Ionophores/pharmacology , Niacinamide/pharmacology , Nicorandil , SwineABSTRACT
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 effect of nicorandil using myography. 2. Nicorandil (300 microM) 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 microM), but unaffected by iberiotoxin (100 nM) and the guanylyl cyclase inhibitor LY 83583 (1 microM). During current activation by nicorandil, openings of channels with a unitary conductance of 31 pS were detected. 4. One hundred microM nicorandil had no effect on currents through Ca2+ channels recorded in response to depolarizing voltage steps using 10 mM Ba2+ as a charge carrier. A small reduction in current amplitude was seen in 300 microM nicorandil, though this was not statistically significant. 5. In arterial rings contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 8644, nicorandil produced a concentration-dependent relaxation with mean pD2 = 4.77+/-0.06. Glibenclamide (10 microM) shifted the curve to the right (pD2 = 4.32+/-0.05), as did 60 mM K+. LY 83583 caused a dose-dependent inhibition of the relaxant effect 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 KATP channels in these vessels and also acts through guanylyl cyclase to cause vasorelaxation, and that the potency of nicorandil is increased during metabolic inhibition.
