Effects of verapamil and propranolol on changes in extracellular K+, pH, and local activation during graded coronary flow in the pig.

Abstract

The ,3-adrenergic and calcium channel blocking agents are known to reduce heart rate and alter myocardial contractility. More recent evidence suggests that both agents affect the metabolic consequences of ischemia, independent of their effects on heart rate and contractility. We used a low-flow model of ischemia in swine with heart rate held constant by atrial pacing. Blood was shunted from the carotid artery to the left anterior descending coronary artery through a controlled-flow roller pump to assess the threshold flow for the rise in extracellular potassium ([K4Ie) and fall in extracellular pH (pHe) associated with ischemia during control situations and after the administration of either propranolol or verapamil. We also measured the changes in activation delay and contractility associated with graded flow reductions in the presence and absence of these drugs. We found that when heart rate is held constant, 1) verapamil shifts the threshold flow for [K4Ie and pH, to lower levels, but propranolol does not; 2) verapamil lessens activation delay, while propranolol aggravates the delay; and 3) verapamil reduces afterload and selectively depresses contractility in the reperfused ischemic zone. We conclude that the calcium channel blockers and the f-adrenergic-blocking agents have different effects and possibly different modes of action and should not be considered interchangeable when evaluating therapeutic options for patients with ischemic heart disease. (Circulation 1989;79: 939-947) T he ,3-adrenergic-blocking agents and the calcium channel blocking agents are both used in the treatment of patients with effortinduced ischemial2 due to coronary artery disease. The beneficial effects of these agents are attributed to their ability to reduce heart rate and contractility, thereby lessening the myocardial oxygen requirement. In addition, there is evidence to suggest that both the 8-adrenergic-and the calcium channel blocking agents may alter the metabolic consequences of reduced coronary blood flow independently of changes in heart rate or contractility.3,4 after the complete interruption of coronary blood flow5-8 been attributed to this mechanism. These effects would be expected to allow the myocardium to tolerate lower levels of coronary blood flow without becoming ischemic.Our recent studies9 have shown that the changes in extracellular potassium concentration ([K']e) and extracellular pH (pHe) are the most sensitive markers of ischemia when coronary blood flow is progressively reduced. As such, they provide a means for assessing the effects of physiologic and pharmacologic interventions on the coronary blood flow associated with the onset of ischemia. The present experiments were conducted to determine if propranolol or verapamil or both were capable of altering the coronary flow associated with the first change in[K4]e and pHe when heart rate was held constant. We also studied the effects of these drugs on myocardial activation during the progressive reduction of coronary blood flow because it is known th...

Continuous Coronary Venous K<SUP>+</SUP> Monitoring During Myocardial Ischemia in Swine Hearts

“…25,37) Aother calcium channel blocker, nisoldipine also demonstrated to protection against myocardial ischemia assessed by valinomycin K + -sensitive mi cro electrodes. 38) We also showed that ATP-sensitive K + c h a n n e l o p e n e r, p i n a c i d i l d e c r e a s e s t h e rise in [K + ] e during no-flow ischemia.…”

“…24,25) Eleven domestic swine of either sex and weighing 20-30 kg were anesthetized with sodium pentobarbital (25 mg/kg), and this was followed by α-chloralose, as needed. Mechanical ventilation and oxygen supplementation were provided via an endotracheal tube attached to a Harvard respirator.…”

“…A carotid artery-to-LAD shunt was created, as previously described. 24,25) Placement of the shunt in the LAD took approximately 2-3 minutes, but the LAD flow was stopped for 5 minutes because successive occlusions produced similar metabolic and electrical changes.…”

“…In 4 of the 11 hearts, verapamil was administered intravenously at a loading dose of 0.2 mg/kg followed by 6.5 μ/kg/min after the first reduction in coronary flow, and in 3 other hearts, propranolol was administered intravenously at a loading dose of 0.4 mg/kg followed by 3 μ/kg/min after the first reduction in coronary flow. 25) …”

“…22 24) We also examined the effects of calcium channel blocker and β-adrenergic-blocking agent on these variables. 25) However, these variables cannot be measured clinically. Therefore, in the study described herein, we measured mid-myocardial [ …”