ABSTRACT
Because adrenergic contractions can contribute to the development of life-threatening spasm of coronary artery bypass graft, this study was performed to investigate the effect of adenosine 3-phosphate (ATP)-sensitive K channel (KATP) opener P1075 on contractions of isolated human saphenous vein (HSV) and human internal mammary artery (HIMA). Phasic contractions were evoked by electric field stimulation (20 Hz) and noradrenaline. The sustained contractions were evoked by phenylephrine. The presence of pore-forming Kir6.1 and Kir6.2 subunits of the KATP channels in the HIMA and only Kir6.2 in the HSV was confirmed immunomorphologically. P1075 inhibited in the HSV only, the electrical field stimulation contractions more strongly than noradrenaline contractions. In addition, the phenylephrine contractions of HSV were more sensitive to P1075 in comparison to those of HIMA. Glibenclamide, a KATP channel blocker antagonized the vasodilatation produced by P1075 in both grafts differently, because its effect was more prominent on the P1075-induced inhibition of contractions of HSV than of HIMA. We conclude that P1075 has a vasorelaxant effect and inhibited adrenergic contractions of the tested grafts. This effect is graft and vasoconstrictor selective and seems to be mediated by Kir6.1- and/or Kir6.2-containing KATP channels. Thus, P1075 can be considered as a potential drug in the prevention of graft spasm.
Subject(s)
Guanidines/pharmacology , KATP Channels/agonists , Mammary Arteries/drug effects , Pyridines/pharmacology , Saphenous Vein/drug effects , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Aged , Electric Stimulation , Glyburide/pharmacology , Guanidines/antagonists & inhibitors , Humans , KATP Channels/metabolism , Male , Mammary Arteries/cytology , Mammary Arteries/metabolism , Middle Aged , Organ Culture Techniques , Organ Specificity , Osmolar Concentration , Potassium Channel Blockers/pharmacology , Potassium Channels, Inwardly Rectifying/metabolism , Protein Subunits/metabolism , Pyridines/antagonists & inhibitors , Saphenous Vein/cytology , Saphenous Vein/metabolism , Vasoconstriction/drug effects , Vasodilator Agents/antagonists & inhibitorsABSTRACT
Resveratrol, a stilbene polyphenol found in grapes and red wine, produces vasorelaxation in both endothelium-dependent and endothelium-independent manners. The mechanisms by which resveratrol causes vasodilatation are uncertain. The aim of this study was to investigate the mechanism(s) of endothelium-independent resveratrol-induced vasorelaxation in human internal mammary artery (HIMA) obtained from male patients undergoing coronary artery bypass surgery and to clarify the contribution of different K+ channel subtypes in resveratrol action in this blood vessel. HIMA rings without endothelium were precontracted with phenylephrine. Resveratrol induced a concentration-dependent relaxation of the HIMA. A highly selective blocker of ATP-sensitive K+ channels, glibenclamide, as well as nonselective blockers of Ca2+-sensitive K+ channels, tetraethylammonium and charybdotoxin, did not block resveratrol induced relaxation of HIMA rings. 4-Aminopyridine (4-AP), non selective blocker of voltage gated K+ (KV) channels, and margatoxin that inhibits KV1.2, KV1.3, and KV1.6 channels abolished relaxation of HIMA rings induced by resveratrol. In conclusion, we have shown that resveratrol potently relaxed HIMA rings with denuded endothelium. It seems that 4-AP- and margatoxin-sensitive K+ channels located in smooth muscle of HIMA mediated this relaxation.
Subject(s)
Mammary Arteries/drug effects , Muscle, Smooth, Vascular/drug effects , Stilbenes/pharmacology , Vasodilator Agents/pharmacology , Wine , 4-Aminopyridine/pharmacology , Anti-Arrhythmia Agents/pharmacology , Charybdotoxin/pharmacology , Coronary Artery Bypass , Coronary Disease/surgery , Glyburide/pharmacology , Humans , Male , Mammary Arteries/metabolism , Middle Aged , Muscle Relaxation/drug effects , Muscle, Smooth, Vascular/metabolism , Neurotoxins/pharmacology , Potassium Channel Blockers/pharmacology , Potassium Channels/metabolism , Resveratrol , Scorpion Venoms/pharmacology , Tetraethylammonium/pharmacology , Vasodilation/drug effectsABSTRACT
It is well established that spasm of an arterial and venous graft conduit may occur during harvesting or after coronary artery bypass grafting (CABG). The antivasoconstrictor effect of levcromakalim and rilmakalim, K(+) channel openers (KCOs), was studied in isolated human internal mammary artery (HIMA) and human saphenous vein (HSV) prepared for CABG. HIMA and HSV rings were contracted by electrical field stimulation (EFS, 20 Hz ) or with exogenous noradrenaline (NA). Levcromakalim induced a concentration-dependent and equipotent inhibition of contraction of HIMA and HSV preconstricted by EFS and exogenoulsy applied NA, while rilmakalim produced a stronger inhibition of EFS- than NA-evoked contractions. Glibenclamide, a selective ATP-sensitive K(+) channel (K(ATP) channel) blocker, significantly antagonized levcromakalim-induced inhibition of EFS- and NA-evoked contractions, as well as rilmakalim-induced inhibiton of EFS-evoked contractions on HIMA and HSV. However, glibenclamide failed to antagonize rilmakalim-induced inhibition of NA-evoked contractions. The results suggest that the antivasoconstrictor effect of levcromakalim occurs postsynapticaly by the opening K(ATP) channels in the vascular smooth muscle cells. They also suggest that the effect of rilmakalim on EFS-evoked contractions involves K(ATP) channels located pre-synaptically. However, the mechanism by which rilmakalim inhibits NA-evoked contraction seems to be K(ATP) channel independent and warrants further elucidation.
