Mechanisms of improved ischemic regional dysfunction by bradycardia. Studies on UL-FS 49 in swine.

Abstract

In anesthetized swine, the left anterior descending coronary artery was cannulated and perfused at constant blood flow levels during two grades of ischemia. In one group (n = 10), moderate ischemia reduced percent systolic wall thickening (by sonomicrometry) from 25+±7% to 6±2%, whereas in the other group (n =7), severe ischemia reduced percent wall thickening from 24+6% to -0.5+4%. Heart rate was paced in both groups at 91 beats/min. After reperfusion and complete return to control conditions, administration of the bradycardic agent UL-FS 49 (0.37 mg/kg i.v.) decreased the heart rate to 55±5 beats/min. During subsequent ischemia at the same coronary inflow as before bradycardia, percent wall thickening in the ischemic zone during moderate ischemia was increased from 6+2% to 25 ±6% (p<0.01) (not significantly different from control without ischemia), and during severe ischemia, percent wall thickening increased from -0.5±4% to 13 ±7% (p <0.01). During moderate ischemia, bradycardia caused an increase in the subendocardial blood flow from 0.24+±0.60 to 0.42+±0.17 (ml/min)/g (p<0.009) and during severe ischemia, bradycardia caused an increase from 0.14±0.08 to 0.2+0.1 (ml/min)/g (p<0.001). At each level of ischemia, a more marked improvement occurred in subendocardial blood flow per beat ([(ml/min)/g]/heart rate). The relation between myocardial blood flow and wall function at a heart rate of 55 beats/min (n = 14) was plotted and compared with that studied at a heart rate of 122 beats/min in another group of pigs (n = 14). The increase in subendocardial blood flow per minute during bradycardia was not sufflicient to explain the striking increase in function; thus, an independent relation (p<0.05) between blood flow per minute and contractile function (percent wall thickening) was found for each heart rate. In contrast, when myocardial blood flow was normalized for heart rate and expressed per beat, data from both heart rate groups could be described by a single relation. Thus, the subendocardial blood flow per beat predicted wall function independently of heart rate and accounted for changes in both oxygen supply and demand. (Circulation 1989;80:983-993) I ncreased heart rate aggravates myocardial ischemia,1-4 and pharmacologic reduction of heart rate by ,B-adrenergic blockade has been an important form of therapy in patients with coronary artery disease. Mechanisms involved in the

Heart rate and force-frequency effects on diastolic function of the left ventricle in exercising dogs.

“…11 A possible direct effect of the specific bradycardiac drug UL-FS 49 on diastolic events cannot be excluded. However, the action of the drug to selectively suppress the sinus node rate, and other data demonstrating no direct effect on myocardial contractility and systolic events, [16][17][18][19] suggest that UL-FS 49 may not have important direct effects on diastolic properties.…”

Contributions of heart rate and contractility to myocardial oxygen balance during exercise

“…Accordingly, Guth et al (13) abolished the anti-ischemic effect of atenolol through atrial pacing during exercise-induced ischemia, suggesting that the negative inotropic effect of this ␤-blocker was negligible in this setting. Furthermore, zatebradine and ivabradine, two selective heart rate-reducing agents devoid of any negative inotropic effect, afforded significant anti-ischemic effects during exercise-induced ischemia in conscious dogs (12,18) and pigs (16). In contrast, Buck et al (2) reported only a partial attenuation of the beneficial effects of ␤-blockade on myocardial blood flow distribution and dynamic severity of a proximal coronary artery stenosis after atrial pacing.…”

Effects of Tachycardia on Regional Wall Motion in Acute Ischemic Canine Heart

“…In all dogs, after coronary occlusion, systolic bulging appeared in the ischemic region. Ten minutes after coronary occlusion, UL-FS 49 (Karl Thomae, Biberach, the Federal Republic of Germany ([FRG]), 8 mg of a selective bradycardic agent (Kobinger and Lillie 1984;Dammgen et al 1985;Guth et al 1987;Indolfi et al 1989) were administered intravenously, and an additional dose of the drug (2 mg/each) was infused until the heart rate decreased to under 90 beats/minute (total dose: 8~14 mg), if necessary. About ten minutes later, the hemodynamic and segment lengths were stable.…”