Endothelin receptor blockade has an oxygen-saving effect in Dahl salt-sensitive rats with heart failure

Abstract

. Endothelin receptor blockade has an oxygen-saving effect in Dahl salt-sensitive rats with heart failure. Am J Physiol Heart Circ Physiol 285: H1428-H1434, 2003. First published June 5, 2003 10.1152/ ajpheart.00731.2002The effects of endothelin (ET) receptor blockade on energy utilization in heart failure (HF) are unknown. We administered ET type A (ET A), ET type B (ET B), and ETA/ETB antagonists to isolated hearts from Dahl salt-sensitive (DS) rats with HF and controls. Contractile efficiency was assessed as slope Ϫ1 of myocardial O2 consumption (V O2)-pressure-volume area relation. In HF, ETA and ETA/ETB but not ETB blockade decreased the contractility index (Emax) (Ϫ15 Ϯ 3% and Ϫ17 Ϯ 2%, P Ͻ 0.05), excitationcontraction (E-C) coupling V O2 (Ϫ39 Ϯ 4% and Ϫ37 Ϯ 5%, P Ͻ 0.01), and efficiency (Ϫ15 Ϯ 4% and Ϫ17 Ϯ 2%, P Ͻ 0.05). Despite decreased efficiency, ETA and ETA/ETB blockade decreased total V O2 (Ϫ24 Ϯ 3% and Ϫ22 Ϯ 2%, P Ͻ 0.05). Na ϩ /H ϩ exchanger inhibition decreased Emax and E-C coupling V O2 similar to ETA and ETA/ETB blockade, but did not alter efficiency. In HF, endogenous ET-1 maintains contractility at expense of increased V O2 through ETA receptor activation, likely mediated by Na ϩ /H ϩ exchange.oxygen consumption ACUTELY ADMINISTERED ENDOTHELIN (ET)-1 has positive inotropic effects in normal myocardium (22,27). In contrast, chronic ET-1 inhibition improves cardiac function and prognosis in animal models of heart failure (HF) (23,29,33). Recently, Takeuchi et al. (35) reported that in addition to positive inotropic effects acutely administered exogenous ET-1 increases left ventricular (LV) chemomechanical energy conversion efficiency through ET type A (ET A ) receptor activation in normal rats. The role of endogenous ET-1 in energy utilization in HF, where chronic activation is present, has not been assessed in vitro. Moreover, there are no reports comparing ET A and ET B receptors in this setting.To clarify these issues, we used the myocardial O 2 consumption (V O 2 )-pressure-volume area (PVA) framework to delineate effects of acute ET-1 blockade on mechanoenergetics in isolated, crystalloid-perfused hearts from Dahl salt-sensitive (DS) rats, which develop pressure and volume overload when fed a highsalt (HS) diet (4). The V O 2 -PVA relationship allows quantification of energy conversion efficiency of the contractile machinery (contractile efficiency) and energy use for excitation-contraction (E-C) coupling and basal metabolism (6, 34). We found that blockade of endogenous ET-1 in HF produces complex effects on V O 2 through ET A receptor inhibition. E-C coupling energy saving effects compensate for the energy-wasting effects on the contractile machinery, resulting in net reduction in energy consumption. METHODS Animal ModelAll protocols were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Vermont.Sixty 6-wk-old male DS rats (Taconic Farms, Germantown, NY) were divided into groups receiving a HS (8% NaCl) or low-salt (LS) diet (0.3% NaCl). Com...

Functional Consequences of Sarcomeric Protein Abnormalities in Failing Myocardium

“…A similar finding was reported in chronic tachycardia heart failure in dogs [70]. Economy and efficiency are also increased in Dahl salt sensitive rats with chronic left ventricular dilatation and reduced shortening fraction due to severe, salt-induced hypertension [16].…”

“…However, the mechanism(s) is uncertain. In Dahl rats, we have shown that the mechanoenergetic alterations of the contractile machinery are largely reversible with acute endothelin A but not B receptor blockade [70]. This suggests a role for PKC signaling, since the latter is a key downstream effector of endothelin receptor activation.…”

“…In myothermal studies performed in isometrically contracting, excitable myocardial strips [15,65,68] and in O2 consumption (VO2) studies performed in the isolated, perfused heart preparation [16,18,41,69,70], it is possible to partition energy input or consumption into components used for basal metabolism, excitation-contraction coupling (mainly calcium re-uptake by the sarcoplasmic reticulum)) and crossbridge cycling by the contractile machinery contained within the myofilament. In strips, this has been accomplished by measuring heat production (a direct measure of ATP consumption) before and after selective inhibition of crossbridge cycling [15,65,68].…”

“…In the ventricle, pressure-volume area (PVA), as first proposed and studied by Suga [69], has proven useful for assessment of the mechanoenergetic behavior of the contractile machinery [16,18,41,70]. Briefly, as shown in Figure 1(A), based on the time varying elastance model of contraction, PVA is defined as the area contained within the pressure-volume loop of a contraction (its external work) plus the area bounded by the left side of the pressure-volume loop and the endsystolic and end-diastolic elastance relations (a measure of the potential energy of the contraction), and is theoretically equal to the total mechanical energy of left ventricular contraction.…”

“…Briefly, as shown in Figure 1(A), based on the time varying elastance model of contraction, PVA is defined as the area contained within the pressure-volume loop of a contraction (its external work) plus the area bounded by the left side of the pressure-volume loop and the endsystolic and end-diastolic elastance relations (a measure of the potential energy of the contraction), and is theoretically equal to the total mechanical energy of left ventricular contraction. For an isovolumic contraction (as typically employed in balloon in ventricle isolated heart preparations) [16,18,41,70], there is no external work, i.e., all mechanical output is generated as potential energy. Under a variety of conditions, the relation between total VO2 and PVA is highly linear (Fig.…”