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...
Tissue kallikrein (TK), a major kinin-forming enzyme, is synthesized in the heart and arteries. We tested the hypothesis that TK plays a protective role in myocardial ischemia by performing ischemia-reperfusion (IR) injury, with and without ischemic preconditioning (IPC) or ACE inhibitor (ramiprilat) pretreatment, in vivo in littermate wild-type (WT) or TK-deficient (TK-/-) mice. IR induced similar infarcts in WT and TK-/-. IPC reduced infarct size by 65% in WT, and by 40% in TK-/- (P<0.05, TK-/- vs WT). Ramiprilat also reduced infarct size by 29% in WT, but in TK-/- its effect was completely suppressed. Pretreatment of WT with a B2, but not a B1, kinin receptor antagonist reproduced the effects of TK deficiency. However, B2 receptor-deficient mice (B2-/-) unexpectedly responded to IPC or ramiprilat like WT mice. But pretreatment of the B2-/- mice with a B1 antagonist suppressed the cardioprotective effects of IPC and ramiprilat. In B2-/-, B1 receptor gene expression was constitutively high. In WT and TK-/- mice, both B2 and B1 mRNA levels increased several fold during IR, and even more during IPC+IR. Thus TK and the B2 receptor play a critical role in the cardioprotection afforded by two experimental maneuvers of potential clinical relevance, IPC and ACE inhibition, during ischemia.
Selective heart rate reduction not only provides an anti-ischaemic effect but also per se improves contractility of the stunned myocardium. Additional negative inotropism is protective against ischaemia but deleterious during stunning.
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