Effect of Perhexiline and Oxfenicine on Myocardial Function and Metabolism During Low-Flow Ischemia/Reperfusion in the Isolated Rat Heart

Abstract

Perhexiline is a potent prophylactic anti-anginal agent that has been shown to inhibit myocardial utilization of long-chain fatty acids and to inhibit the mitochondrial enzyme carnitine palmitoyltransferase (CPT)-1. We compared the hemodynamic and biochemical effects of perhexiline (0.5 and 2.0 microM) and of another CPT-1 inhibitor, oxfenicine (0.5 mM), in Langendorff-perfused rat hearts subjected to 60 min of low-flow ischemia (95% flow reduction) followed by 30 min of reperfusion. Both perhexiline (2 microM only) and oxfenicine attenuated (p < 0.003, p < 0.0002, respectively) increases in diastolic tension during ischemia, without significant effects on developed tension, or on cardiac function during reperfusion. Myocardial concentrations of long-chain acylcarnitines (LCAC), products of CPT-1 action, were decreased (p < 0.05) by oxfenicine, unaffected by 2 microM perhexiline, and increased slightly by 0.5 microM perhexiline. Perhexiline, but not the active metabolite of oxfenicine, also inhibited cardiac CPT-2 with similar IC50 and Emax, although lower Hill slope, compared with CPT-1. Oxfenicine, but not perhexiline, reduced concentrations of the endogenous CPT-1 inhibitor, malonyl-CoA. Perhexiline, but not oxfenicine, inhibited myocardial release of lactate during normal flow. We conclude that (a) perhexiline protects against diastolic dysfunction during ischemia in this model, independent of major changes in LCAC accumulation and (b) this may result from simultaneous effects of perhexiline on myocardial CPT-1 and CPT-2.

Cardiac metabolism — A promising therapeutic target for heart failure

“…However, this study found no change in cardiac substrate utilization despite these clear beneficial effects on energetic status, suggesting an alternative mechanism of action rather than CPT1 inhibition, at least with short term administration. Similarly, in the isolated rat heart models by Kennedy et al (2000) and Unger et al (2005), perhexiline perfusion did not alter FA oxidation or CPT1 activity (Kennedy, et al, 2000;Unger, et al, 2005), despite markedly increasing LV mechanical efficiency.…”

“…Kennedy and colleagues also revealed that oxfenicine attenuated the rise in LVEDP following low-flow ischemia in a rat HF model (Kennedy, et al, 2000). Both of these studies highlight the beneficial effects of oxfenicine-induced FA oxidation inhibition within the myocardium under ischemic conditions.…”

Metabolic Modulation With Perhexiline in Chronic Heart Failure

“…31 Initial studies suggested that perhexiline had calcium channel-blocking properties, 32,33 but subsequent studies showed that this was only observed at very high plasma concentrations. 33,34 In a non-heart failure population, no effect was observed on systemic vascular resistance at therapeutic plasma concentrations. 17 We, however, cannot exclude an effect on systemic vascular resistance in this study.…”

“…12,13 This may be due to the observation that activation of the peroxisome proliferator-activated receptor-␣ by FAs upregulates mitochondrial uncoupling protein expression. 14 Perhexiline maleate is an antianginal drug that potently inhibits the mitochondrial FFA uptake enzymes carnitine palmitoyl transferase-1 (CPT-1) and CPT-2, 15 thereby shifting muscle substrate utilization from FFAs toward glucose. 16 It is not negatively inotropic and does not alter systemic vascular resistance at therapeutic plasma levels.…”

Modulation of Myocardial Energetics

“…7 In addition to reducing angina, perhexiline has been shown to attenuate the increase in diastolic tension associated with myocardial ischemia 8 and to improve myocardial efficiency 9 in animal models. Despite these potential favorable actions, the direct myocardial and hemodynamic effects of perhexiline in patients with heart failure are unknown.…”