Kalsner S
Department of Physiology, City University of New York Medical School, New York 10031.
Life Sci. 1994;55(14):1109-21. doi: 10.1016/0024-3205(94)00239-8.
Coronary artery preparations from cattle hearts responded with stable contractions to the thromboxane A2 analogue, U 46619. These contractions were progressively reduced by increasing concentrations of the prototypical potassium channel opener pinacidil (3.8 x 10(-8) to 1.1 x 10(-4) M). Pinacidil-induced relaxations were antagonized significantly by d,l-propranolol (1.2 x 10(-6) to 1.2 x 10(-5) M). Forskolin-induced relaxations of coronary preparations were also antagonized by d,l-propranolol, but those to nitroprusside were not. d-Propranolol also antagonized relaxations to pinacidil but only when used in higher concentrations than the I-isomer. Nadolol and metoprolol, two other beta receptor antagonists with differing profiles of action, also antagonized to some extent the vasodilator action of pinacidil. The known potassium channel antagonist, glibenclamide, shifted the concentration-relaxation curve for pinacidil to the right, but d,l-propranolol produced an additional antagonistic effect in the presence of glibenclamide. Relaxations of contracted tracheal ring preparations of guinea pig by pinacidil, however, were not antagonized by d,l-propranolol, suggesting specificity for vascular tissue. Isoproterenol increased significantly the cyclic AMP levels in coronary tissue, but pinacidil had no such effect, ruling out an adrenergic component to pinacidil action. Pinacidil increased the efflux of 86Rb in isolated coronary preparations, and this effect was blunted by propranolol. It is concluded that beta receptor antagonists inhibit relaxations to a potassium channel opener by a mechanism independent of beta adrenergic receptors and that this effect may have therapeutic implications.
牛心脏的冠状动脉制剂对血栓素A2类似物U 46619产生稳定收缩反应。这些收缩反应随着原型钾通道开放剂吡那地尔（3.8×10⁻⁸至1.1×10⁻⁴ M）浓度增加而逐渐减弱。d,l-普萘洛尔（1.2×10⁻⁶至1.2×10⁻⁵ M）可显著拮抗吡那地尔诱导的舒张。佛司可林诱导的冠状动脉制剂舒张也可被d,l-普萘洛尔拮抗，但硝普钠诱导的舒张则不受影响。d-普萘洛尔也可拮抗吡那地尔引起的舒张，但仅在使用高于其左旋异构体的浓度时才有效。另外两种作用方式不同的β受体拮抗剂纳多洛尔和美托洛尔，在一定程度上也可拮抗吡那地尔的血管舒张作用。已知的钾通道拮抗剂格列本脲可使吡那地尔的浓度-舒张曲线右移，但在格列本脲存在时，d,l-普萘洛尔会产生额外的拮抗作用。然而，d,l-普萘洛尔并不拮抗吡那地尔对豚鼠收缩气管环制剂的舒张作用，提示其对血管组织具有特异性。异丙肾上腺素可显著提高冠状动脉组织中的环磷酸腺苷水平，但吡那地尔无此作用，排除了吡那地尔作用中的肾上腺素能成分。吡那地尔可增加离体冠状动脉制剂中⁸⁶Rb的外流，且这种作用可被普萘洛尔减弱。得出结论：β受体拮抗剂通过一种独立于β肾上腺素能受体的机制抑制对钾通道开放剂的舒张作用，且这种作用可能具有治疗意义。
