Stereoselective handling of perhexiline:Implications regarding accumulation within the human myocardium

Purpose: Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of perhexiline within myocardium. Method: Patients (n = 129) from the active arm of a randomised controlled trial of preoperative perhexiline in cardiac surgery were treated with oral perhexiline for a median of 9 days. Correlates of atrial and ventricular concentrations of enantiomers were sought via univariate followed by multivariate analyses. Results: Myocardial uptake of both (+) and (−) perhexiline was greater in ventricles than in atria, and there was more rapid clearance of (−) than (+) perhexiline. The main determinants of atrial uptake of both (+) and (−) perhexiline were the plasma concentrations [(+) perhexiline: β = −0.256, p = 0.015; (−) perhexiline: β = −0.347, p = 0.001] and patients’ age [(+) perhexiline: β = 0.300, p = 0.004; (−) perhexiline: β = 0.288, p = 0.005]. Atrial uptake of (+) enantiomer also varied directly with duration of therapy (β = 0.228, p = 0.025), while atrial uptake of (−) perhexiline varied inversely with simultaneous heart rate (β = −0.240, p = 0.015). Conclusion: (1) Uptake of both perhexiline enantiomers into atrium is greater with advanced age and displays evidence of both saturability and minor stereoselectivity. (2) Atrial uptake of (−) perhexiline may selectively modulate heart rate reduction

Hydralazine does not ameliorate nitric oxide resistance in chronic heart failure

Purpose: The A-HeFT trial demonstrated incremental survival with hydralazine/isosorbide dinitrate combination in African–American patients with chronic heart failure (CHF). It has been suggested that hydralazine might enhance nitric oxide (NO)—mediated effects of organic nitrates by decreasing superoxide (O2−) formation, one of the factors inducing NO resistance. We evaluated whether hydralazine therapy potentiates nitrate-induced vasodilation and inhibition of platelet aggregation by ameliorating NO resistance. Methods: Patients (n  = 14) with NYHA class II-III CHF were studied in a randomised, double-blind, placebo-controlled, crossover study of the effects of hydralazine therapy (25 mg b.d., for 1 week) on physiological responsiveness to glyceryl trinitrate (GTN). Vascular response to GTN was assessed via applanation tonometry, as change in augmentation index (AIx) over time. Platelet responsiveness to GTN and sodium nitroprusside (SNP) was determined, as inhibition of ADP-induced platelet aggregation. O2− release was evaluated during aggregation via lucigenin-derived chemiluminescence. Results: Platelet responsiveness to the NO donors GTN and SNP was impaired, denoting the presence of severe NO resistance. Hydralazine therapy decreased systolic blood pressure by 6.8 ± 10.5 (S.D.) mmHg (p = 0.02), and caused a reduction in AIx by 15 ± 24% (p = 0.03). However, there were no significant changes in platelet aggregability and associated O2− release, or in platelet or vascular responses to NO donor. Conclusion: The results of the present study do not support the assumption that hydralazine could be viewed as a “NO enhancer”; there is no evidence of attenuation of NO resistance by hydralazine treatment.Yuliy Y. Chirkov, Michele De Sciscio, Aaron L. Sverdlov, Sue Leslie, Peter R. Sage and John D. Horowit