tram-34 and Hyperemia

The purpose of this investigation was to elucidate the contribution of intermediate conductance calcium-activated potassium channels (IK(Ca)) to the regulation of coronary blood flow in vivo. We hypothesized that IK(Ca) channels modulate coronary arteriolar resistance at rest and contribute to vasomotor responses to changes in coronary perfusion pressure and/or in response to cardiac ischemia. Experiments were conducted in open-chest anesthetized dogs in the absence and presence of IK(Ca) channel inhibitor, TRAM-34 (1 μg/min, intracoronary), and the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine-methyl ester (L-NAME) (150 μg/min, intracoronary). We found that administration of the potent SK(Ca) and IK(Ca) channel agonist NS309 dose-dependently increased coronary blood flow and that inhibition of IK(Ca) channels with TRAM-34 attenuated this response by ∼90%. The increase in coronary blood flow to NS309 was also decreased ∼100% by the inhibition of NO production with L-NAME. Multiple linear regression analysis demonstrated that TRAM-34 diminished the autoregulatory capability of the coronary circulation at coronary pressures ranging from 60 to 120 mmHg. However, inhibition of IK(Ca) channels did not affect coronary vasodilation in response to a transient 15 s coronary artery occlusion (i.e. reactive hyperemia). Our data reveal that IK(Ca) channels are functionally expressed in the coronary circulation and that activation of these channels produces marked coronary vasodilation in vivo, primarily via increases in endothelial NO production. In addition, IK(Ca) channels modestly contribute to changes in coronary vascular resistance in response to alterations in coronary perfusion pressure but do not contribute to the reactive hyperemic response following a brief coronary artery occlusion.

Topics: Acetylcholine; Anesthesia; Animals; Coronary Circulation; Dogs; Endothelium; Hemodynamics; Homeostasis; Hyperemia; Indoles; Intermediate-Conductance Calcium-Activated Potassium Channels; Oximes; Pressure; Pyrazoles; Small-Conductance Calcium-Activated Potassium Channels; Vasodilation