Combined Inotropic and Bradycardic Effects of a Sodium Channel Enhancer in Conscious Dogs with Heart Failure: A Mechanism for Improved Myocardial Efficiency Compared with Dobutamine

Abstract

We compared the cardiac inotropic, chronotropic, and myocardial O 2 consumption (MVO 2 ) responses to the sodium (Na ϩ ) channel enhancer, LY341311 [(S)-4-[3-[[1-(diphenylmethyl)-3-azetidinyl]oxy]-2-hydroxypropoxy]-1H-indole-2-carbonitrile monohydrate], with the ␤-receptor agonist dobutamine in conscious dogs with heart failure. Heart failure was induced in chronically instrumented dogs by right ventricular pacing at 240 beats per minute for 3 to 4 weeks. LY341311 (10 -100 g/kg/min i.v.) dose dependently increased cardiac contractile function as reflected, at the highest dose, by increases in left ventricular dP/dt max (55 Ϯ 7%), and fractional shortening (62 Ϯ 9%), accompanied by increases in cardiac stroke work (111 Ϯ 18%) and minute work (34 Ϯ 10%) and decreases in heart rate (33 Ϯ 4%). Dobutamine (2-15 g/kg/min i.v.) increased contractile responses to a similar degree but also increased heart rate (15 Ϯ 5%) at the highest dose. Complete ganglionic blockade with hexamethonium and atropine or with hexamethonium alone abolished the bradycardic effect but not the inotropic response to LY341311. At similar levels of inotropic response, dobutamine (10 g/kg/min) increased MVO 2 by 23 Ϯ 7% (P Ͻ 0.05), whereas LY341311 (100 g/kg/min) had no effect. In the presence of left atrial pacing at a constant heart rate and at matched contractile work, MVO 2 was increased by LY341311 to the same extent as dobutamine. These data indicate that autonomically mediated bradycardia produced by LY341311 contributes to a favorable net metabolic effect on myocardial O 2 utilization in the failing heart while providing inotropic support comparable to a ␤-receptor-mediated agonist.A variety of therapeutic strategies have been applied to augment the depressed left ventricular function of heart failure, particularly during periods of acute decompensation (Packer, 1988;Rahimtoola, 1989;Shipley and Hess, 1995). Current clinically available inotropic agents that act via elevation of cyclic AMP, such as dobutamine and phosphodiesterase inhibitors; are associated with tachycardia, significant changes in preload or afterload or increases in myocardial O 2 consumption (MVO 2 ), and decreases in myocardial mechanical efficiency (Katz, 1986;Simaan et al., 1988). Recently, there has been interest in agents that either increase myofibrillar Ca 2ϩ availability or directly sensitize myocardial cells to Ca 2ϩ without the participation of cAMP (Ruegg, 1986;Doggrell et al., 1994;Mathew and Katz, 1998). One strategy has been the development of Na ϩ channel enhancers that prolong the open state of Na ϩ channels, increasing net Na ϩ influx and the activity of reverse mode Na ϩ /Ca 2ϩ exchange (for review, see Steinberg et al., 1998). This leads to a decrease in net Ca 2ϩ efflux and increases in intracellular free Ca 2ϩ (Romey et al., 1987;Scholtysik, 1989). Sodium channel enhancers have been shown to elicit positive inotropic effects in isolated cardiac tissues from experimental animals and from human papillary muscles obtained from normal as well as...

Computationally Managed Bradycardia Improved Cardiac Energetics While Restoring Normal Hemodynamics in Heart Failure

“…Shen et al 25 compared the inotropic/chronotropic effects and MVO 2 in response to the sodium channel enhancer LY341311 with those in response to dobutamine in dogs with heart failure. LY341311 increased LV dP/dt max and decreased HR.…”

“…16,25 Single drug or two-drug combinations were used and infusions were titrated manually. However, HR reduction inevitably induced changes in AP, CO, or P LA in these studies.…”

KB130015, A New Amiodarone Derivative with Multiple Effects on Cardiac Ion Channels

“…Whereas the cardiac glycosides increase [Na + ] i by inhibiting the Na + -K + -ATPase, such an increase can also be achieved by raising Na + influx. It has been pointed out that the positive inotropic action of cAMPincreasing agents tend to be limited in failing myocardium, while that of drugs that alter Na + channel function is preserved (57,58,76). Figure 6A illustrates recordings of cell shortening in pig ventricular myocytes superfused with normal Tyrode at 37°C.…”

Exhaustion of the Frank–Starling mechanism in conscious dogs with heart failure induced by chronic coronary microembolization

“…Left ventricular function in these dogs was also assessed using echocardiogram in the conscious state. To determine the cardiac systolic functional response to β-adrenergic stimulation: all experimental dogs (n = 9) were studied with a dobutamine challenge in control and heart failure, in which dobutamine was administrated in 5-min graded intravenous infusion of 2, 5, 10, and 15 μg/kg/min (Shen et al, 2002).…”

“…LV end-systolic elastance (Ees) was calculated as the slope of the end-systolic pressure-dimension relation, and LV lateral wall (posterior) end-systolic elastance (wall Ees) was calculated as the slope of the end-systolic pressure-wall thickening relation. Left ventricular stroke work was measured as the integral area of the pressure-dimension loops, and cardiac work (per minute) was calculated as the product of LV stroke work and heart rate (Shen et al, 2002;Stewart et al, 1992).…”