title: BK(Ca) channels compensate for loss of NOS-dependent coronary artery relaxation in cardiomyopathy.
abstract: Previously, we showed that development of myocardial necrotic lesions is associated with impaired endothelium-dependent coronary artery relaxation in young cardiomyopathic hamsters. Since active necrosis declines with aging, this study was designed to determine whether coronary artery endothelium-dependent relaxation to ACh is restored and to identify the mechanisms mediating this effect. Intraluminal diameter was recorded in coronary arteries (150-250 micrometer) from control (C, 297 +/- 5 days old) and cardiomyopathic (M, 296 +/- 4 days old) hamsters. Relaxation to ACh (10(-9)-3 x 10(-5) M) was similar in vessels from C and M hamsters. However, mechanisms mediating relaxation to ACh were altered. Inhibition of nitric oxide synthase (NOS) activity with N-nitro-L-arginine (1 mM) had a greater inhibitory effect in vessels from C hamsters, indicating a reduction in NOS-dependent relaxation in vessels from M hamsters. Conversely, inhibition of large Ca(2+)-dependent K(+) (BK(Ca)) channels with charybdotoxin (CTX, 0.1 microM) had a greater inhibitory effect in vessels from M hamsters. In the presence of both N-nitro-L-arginine and CTX, relaxation to ACh was abolished in both groups. CTX (0.1 micrometer) produced a 50 +/- 4 and 30 +/- 3% contraction of vessels from M and C hamsters, respectively, indicating an enhanced role for BK(Ca) channels in regulation of coronary artery tone in M hamsters. Finally, vasodilatory cyclooxygenase products contributed to ACh-induced relaxation in vessels from M, but not C, hamsters. In conclusion, NOS-dependent relaxation of coronary small arteries is reduced in the late stage of cardiomyopathy. An increase in relaxation mediated by BK(Ca) channels and vasodilatory cyclooxygenase products compensates for this effect.
authors.affiliation: Vascular Biology Center and Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Clark
authors.forename: L C
authors.initials: LC
authors.lastname: Fuchs
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000378:metabolism; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D018999:Charybdotoxin / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D003331:Coronary Vessels / Q000201:enzymology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008297:Male; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D009929:Organ Size; D015221:Potassium Channels / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D004791:Enzyme Inhibitors; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D018999:Charybdotoxin; D019335:Nitroarginine; D009569:Nitric Oxide; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine