VENTRICULAR PERFORMANCE Elimination of exercise - induced regional myocardial dysfunction by a bradycardiac agent in dogs with chronic coronary stenosis

We have previously demonstrated that the beneficial effect of cardioselective 13-blockade on exercise-induced ischemia is due entirely to negative chronotropism. Therefore we studied the effect of a new bradycardiac agent (UL-FS 49) in 10 dogs with chronic coronary artery stenosis produced by an ameroid constrictor. Regional myocardial function (sonomicrometers, wall thickness) and blood flow (microspheres) were measured during a control treadmill exercise bout and an identical run 3 hr later after the administration of UL-FS 49 (1.0 mg/kg iv). In the control run, heart rate increased from 114 ± 20 to 230 ± 19 beats/min and systolic wall thickening (%WT) in the poststenotic myocardium decreased from 23.3 ± 5.2% at rest to 9.3 ± 5.0%, a 60% reduction. Subendocardial blood flow in the ischemic area decreased from 1.04 ± 0.30 to 0.55 0.40 ml/min/g, blood flow per beat decreased from 9.1 x 10-3 to 2.5 x 10-3 m1/g, and mean transmural flow failed to increase (1.06 + 0.30 vs 1.08 ± 0.39 ml/min/g). During exercise with UL-FS 49, heart rate increased from 89 10 to only 139 ± 10 beats/min. End-diastolic left ventricular pressure was increased compared with that during the control run (35.7 ± 3.0 vs 28.9 ± 5.5 mm Hg) but left ventricular peak systolic pressure and dP/dt were unchanged. %WT in the ischemic zone did not change significantly during exercise with UL-FS 49 (23.3 ± 7.9% at rest, 21.5 ± 8.4% during the run), and in the nonischemic zone it increased to the same extent as during the control run. Absolute subendocardial blood flow (0.75 + 0.32 mllmin/g) and flow per beat (5.3 + 2.0 x 10-3 m1/g) were significantly increased compared with those during the control run (p < .05), and transmural blood flow per beat increased to 9.8 ± 1.7 x 10-3 m1/g (p < .01). These data demonstrate that UL-FS 49 is an effective bradycardiac agent that can markedly attenuate exercise-induced ischemic dysfunction and improve regional perfusion without compromising contractile function of nonischemic areas or global left ventricular contractility. Circulation 75, No. 3, 661-669, 1987. CARDIOSELECTIVE /8-adrenergic blockade with atenolol was shown by this laboratory to reduce exercise-induced regional myocardial ischemia and wall dysfunction in dogs with chronic, single-vessel coronary artery stenosis. l More recently, we used the same experimental preparation to demonstrate that the beneficial effect of atenolol is dependent on the reduction of From the Seaweed Canyon Laboratory, Division of Cardiology, Department of Medicine, University of California School of Medicine, San Diego. Supported by a Specialized Center for Research on Ischemic Heart Disease (HL-17682) from the NHLBI. Address for correspondence: Brian D. Guth, Ph.D., Division of Cardiology, Department of Medicine, A-011, University of California San Diego, La Jolla, CA 92093. Received July 14, 1986; revision accepted Nov. 21, 1986. *Current address: Physiologisches Institut, Universitaet Duesseldorf, Moorenstr. 5, 4000 Duesseldorf, Federal Republic of Germany. **Current address: II. Chir. Univ. Clinic, Spitalgasse 23, 1180 Vienna, Austria. Vol. 75, No. 3, March 1987 heart rate during exercise. Atrial pacing during exercise to prevent the bradycardiac effect of atenolol eliminated all of the improvements observed at the reduced heart rate.2 These findings stress the importance of heart rate control for reducing stress-induced myocardial ischemia and suggest the use of a specific bradycardiac agent for reducing exercise-induced ischemia and wall dysfunction to avoid the negative inotropic effect associated with ,3-blockade during exercise.1 Specific bradycardiac agents are a chemically diverse group of compounds, but all are characterized by the production of sinus bradycardia at dosages that result in minimal secondary cardiovascular effects such as negative inotropism, membrane depressant antiarrhythmic effects, or hypotension.' One such agent, UL-FS 49, has been shown to effectively reduce heart rate in conscious dogs without changes in blood pressure4 and was shown to increase ischemic myocardial 661 by gest on A ril 3, 2017 http://ciajournals.org/ D ow nladed from