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

Abstract

Berdeaux. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol 284: H676-H682, 2003. First published October 24, 2002 10.1152/ajpheart.00564.2002The respective contributions of heart rate (HR) reduction and left ventricular (LV) negative inotropy to the effects of antianginal drugs are debated. Accordingly, eight instrumented dogs were investigated during exercise at spontaneous and paced HR (250 beats/min) after administration of either saline, atenolol, or ivabradine (selective pacemaker current channel blocker). During exercise, atenolol and ivabradine (both 1 mg/kg iv) similarly reduced HR (Ϫ30% from 222 Ϯ 5 beats/ min), and LV mean ejection wall stress was not altered. LV dP/dtmax was reduced by atenolol but not ivabradine. Diastolic time (DT) was increased by atenolol versus saline (195 Ϯ 6 vs. 123 Ϯ 4 ms, respectively) and to a greater extent by ivabradine (233 Ϯ 11 ms). Myocardial oxygen consumption (MV O2) was lower under ivabradine and atenolol versus saline (6.7 Ϯ 0.6 and 4.7 Ϯ 0.4 vs. 8.1 Ϯ 0.6 ml/min, respectively, P Ͻ 0.05). Under pacing, DT and MV O2 were similar between ivabradine and saline but significantly reduced with atenolol. Thus HR reduction and negative inotropy equally contribute to the reduction in MV O2 during exercise in the normal heart. The negative inotropy limits the increase in DT afforded by HR reduction. metabolic demand; chronotropy; inotropy; diastolic time ALTHOUGH IT IS WELL KNOWN that reductions in heart rate and myocardial contractility are both major mechanisms involved in the antianginal effect of ␤-blockers, the relative contributions of these two parameters to the therapeutic properties of these drugs are still debated. 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). 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. Two clinical trials using zatebradine failed to reveal any antianginal activity secondary to the sole reduction in heart rate (8, 9). However, in these studies, reduction in heart rate might have induced changes in other determinants of MV O 2 , e.g., loading conditions. Furthermore, in these studies, the potential beneficial effects of heart rate reduction on diastolic time, i.e., o...

Protective Effects of Ivabradine (Alone and Combined With Atenolol or Enalapril) on Experimentally-Induced Acute Myocardial Infarction in Albino Rats

“…The serum level of NT-proBNP in the ivabradinepretreated group was significantly lower than that of the control MI group. This is consistent with data obtained by Sarullo et al [52] and could be attributed to HR reduction by ivabradine reduces ventricular wall stress during ischemia [47] .…”

“…These results are consistent with that obtained from previous other short-term experimental studies which demonstrated that ivabradine and β-blockers possess complementary and perhaps even additive pharmacological properties linked to their common ability to reduce HR [42,47] . As regard the combined pretreatment with ivabradine and enalapril, the results of the present study demonstrated that ST height and T-wave voltage were not significantly different from either ivabradine or enalapril demonstrating no interaction of the two drugs on these parameters.…”

“…In addition, it decreases myocardial oxygen consumption by reducing HR and ventricular wall stress. Ivabradine does not unmask α-adrenergic coronary vasoconstriction in large epicardial arteries during sympathetic activation which Shireen Sami Mahmoud ; et al… -96-preserves myocardial contractility and coronary vasodilatation during exercise [47,48] . The present work demonstrated that atenolol provides better cardioprotective effects against acute MI than ivabradine regarding values of serum levels of CK-MB hs-CRP and cTnI and infarct size % and these findings are in agreement with that of Colin et al [47] .…”

“…Ivabradine does not unmask α-adrenergic coronary vasoconstriction in large epicardial arteries during sympathetic activation which Shireen Sami Mahmoud ; et al… -96-preserves myocardial contractility and coronary vasodilatation during exercise [47,48] . The present work demonstrated that atenolol provides better cardioprotective effects against acute MI than ivabradine regarding values of serum levels of CK-MB hs-CRP and cTnI and infarct size % and these findings are in agreement with that of Colin et al [47] . This may be attributed to the fact that atenolol produced simultaneous reduction of HR and contractility and thus reducing stroke volume and cardiac output when sympathetic tone increases [48] .…”

Ivabradine: Current and Future Treatment of Heart Failure

“…Furthermore, it seems that the increased length in diastole attained by both drugs only occurs during rest when treated with BAAs, whereas it is present at rest and during exercise in patients treated with ivabradine [32]. Another important aspect is the lowering of blood pressure that is observed with BAAs, whereas ivabradine fails to change blood pressure.…”