Effect of the combination of diltiazem and atenolol on exercise-induced regional myocardial ischemia in conscious dogs.

Abstract

The effect of combination therapy with diltiazem and atenolol on the regional myocardial blood flow-function relationship was studied in eight conscious dogs with chronic coronary artery stenosis. An ameroid constrictor and hydraulic occluder were placed around the left circumflex coronary artery, sonomicrometers were implanted for measuring wall thickness in control and ischemic regions, and regional myocardial blood flow was measured with the microsphere method. Eighteen days (average) after surgery, resting regional myocardial function and blood flow were normal, but treadmill exercise induced severe regional myocardial dysfunction in the posterior wall (wall thickening during systole reduced from 25.5% to 2.7%, a 90% reduction). Subendocardial blood flow decreased by 68% from the control standing value, while subepicardial flow increased. An identical exercise bout was performed 3 hr after administration of atenolol (1.0 mg/kg orally) and 15 min after administration of diltiazem (0.3 mg/kg iv). Heart rate during running was significantly lower as were left ventricular peak systolic pressure, end-diastolic pressure, and peak dP/dt. Wall thickening in the control region was not augmented during exercise after atenolol and diltiazem. There was less dysfuncion in the ischemic region (35% reduction) and the improved performance was accompanied by a substantial increase in subendocardial perfusion (0.31 + 0.14 vs 0.61 + 0.30 ml/min/g, a 36% reduction from rest). Epicardial flow was unchanged, and the endocardial/epicardial ratio increased (0.27 + 0.13 vs 0.62 + 0.29). Recovery time for regional wall thickening also improved. The beneficial effects of the combination of atenolol and diltiazem in a preparation of single-vessel chronic coronary stenosis were shown to be significantly greater than those of either drug alone. Circulation 72, No. 1, 233-243, 1985. ,8-ADRENERGIC BLOCKADE is effective in improving exercise tolerance in patients with angina pectoris but sometimes optimum results are not achieved when the drugs are used alone.'`A second drug is therefore sometimes added to therapy, such as a longacting nitrate,4 a calcium blocker,5 ' or occasionally digitalis.8 Calcium channel-blocking drugs, which inhibit the influx of calcium ions during cell depolarization in both smooth and cardiac muscle, are highly effective in the therapy of vasospastic myocardial ischemia and stable angina pectoris.

Calcium channel antagonism and beta blockade in combination—A therapeutic alternative in cardiovascular disorders. A review

“…Bush and coworkers [19] found that in dogs with temporary occlusion of the LAD, propranolol and diltiazem significantly decreased the extent of histological necrosis, as well as the macrohistochemically determined infarct. Results similar to these have also been presented by Matsuzaki et al [20]. In some studies, beta-blocking agents have also been shown to inhibit the reflex tachycardia occurring in some patients given calcium-channel antagonists.…”

Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents

“…Nevertheless, when normalizing blood flow to a single cardiac cycle and thus considering heart rate, the relationships at two different heart rates are superimposable (Figure 7) ( Indolfi et al , 1989 ). In a series of studies, all pharmacological agents that attenuate exercise‐induced myocardial ischaemia (β‐blockers, calcium antagonists, nitrates and their combinations) were demonstrated to operate along such consistent flow–function relationship, further strengthening the concept of perfusion–contraction matching ( Matsuzaki et al , 1984a , 1984b , 1985 ; Guth et al , 1986 ).…”

Pharmacological mechanisms to attenuate sympathetically induced myocardial ischemia

“…However, when the heart rate reduction caused by beta-adrenoceptor blockade with atenolol was prevented by atrial pacing, regional myocardial blood flow of the ischemic area was even reduced compared to the untreated situation. In recent experiments in conscious dogs, combined administration of atenolol and diltiazem increased regional blood flow and function during exercise-induced poststenotic myocardial ischemia to a greater extent than administration of either drug alone [77] (Figure 8). The aggravation of myocardial ischemia was possibly due to an unmasking of alpha-adrenergic constriction in the ischemic coronary microcirculation.…”