Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs.

Abstract

We examined the importance of decreased heart rate in the beneficial effect of beta-adrenergic blockade on exercise-induced regional myocardial ischemia and contractile dysfunction in conscious dogs with single vessel coronary stenosis (ameroid constrictor). Studies were performed during control treadmill exercise, which produced regional myocardial ischemia (blood flow measured with microspheres) and wall dysfunction (measured using sonomicrometers). A second run was performed after the administration of atenolol (0.3-1.0 mg/kg i.v.), and the reduced heart rate caused by atenolol during early steady-state running was then prevented by atrial pacing during the latter portion of the run. Atenolol reduced the exercise heart rate from 217 +/- 25 beats per minute (SD, n = 9) to 166 +/- 15, and ischemic zone wall thickening during systole improved from 27 +/- 22% of the resting value in the control run to 50 +/- 25% of the resting value in the atenolol run (p less than 0.01). Atrial pacing then increased heart rate to 217 +/- 23 beats per minute, and regional wall thickening deteriorated to 15 +/- 25% of the resting value. Regional subendocardial blood flow in the ischemic zone during atrial pacing with atenolol was slightly less than that observed in the control run, in both ischemic and control zones, indicating no remaining beneficial effect of atenolol when heart rate reduction was eliminated. We conclude that the only significant mechanism for the improvement in exercise-induced ischemia and wall motion produced by atenolol is a reduction in the exercise heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

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

“…Extrapolation of these quantifications to other situations than exercise should be cautious because we did not observe such responses at rest after administration of either atenolol or ivabradine, i.e., when sympathetic tone is low. In addition, these results obtained in the normal heart might partly explain the deleterious effects on regional myocardial blood flows observed by Guth et al (13) during exercise-induced ischemia under atenolol when heart rate reduction was prevented by atrial pacing. The lack of stroke volume measurement might represent a limitation of these results as stroke work is an important correlate of MV O 2 (19).…”

“…Heart rate reduction is indeed critical to reduce exercise-induced ischemia by increasing subendocardial myocardial blood flows and diastolic perfusion time (12) and by decreasing myocardial oxygen consumption (MV O 2 ). 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).…”

Inhibitory actions of ZENECA ZD7288 on whole‐cell hyperpolarization activated inward current (If) in guinea‐pig dissociated sinoatrial node cells

“…The use of P-adrenoceptor antagonists in coronary angina is based on their ability to attenuate increases in heart rate by reducing the effects of sympathetic activity (Guth et al, 1987b). However, the non-cardiac actions of these agents have disadvantages, and drugs have been identified recently which have the ability to reduce heart rate while allowing the occurrence of responses to exercise, without the non-cardiac side effects of P-adrenoceptor blockade.…”

Myocardial Ischemia

“…11 In the absence of heart rate reduction (atrial pacing), β-blockade is not beneficial at all, but reduces regional myocardial blood flow and contractile function in the ischemic region. 19 Apparently, β-blockade does not reduce the oxygen demand of ischemic myocardium but even permits an increase in its oxygen consumption secondary to an increase in blood flow. Thus, β-blockade does not reduce the virtual oxygen demand of the ischemic myocardium, but the real oxygen consumption of the nonischemic adjacent myocardium, resulting in a beneficial redistribution of blood flow from the nonischemic toward the ischemic myocardium.…”