Effects of felodipine on the ischemic heart: Insight into the mechanism of cytoprotection

Abstract

To assess whether the administration of felodipine protects the myocardium in a dose-dependent manner against ischemia and reperfusion, isolated rabbit hearts were infused with three different concentrations of felodipine: 10(-10), 10(-9), and 10(-8) M. Diastolic and developed pressures were monitored; coronary effluent was collected and assayed for CPK activity and for noradrenaline concentration; mitochondria were harvested and assayed for respiratory activity; and ATP production and calcium content and tissue concentration of ATP, creatine phosphate (CP), and calcium were determined. The occurrence of oxidative stress during ischemia and reperfusion was also monitored in terms of tissue content and release of reduced (GSH) and oxidized (GSSG) glutathione. Treatment with felodipine at 10(-10) and 10(-9) M had no effect on the hearts when perfused under aerobic conditions, whilst the higher dose reduced developed pressure from 57.7 +/- 2.6 to 30.0 +/- 2.6 mmHg (p < 0.01). On reperfusion treated hearts recovered better than the untreated hearts with respect to left ventricular performance, replenishment of ATP and CP stores, and mitochondrial function. Recovery of developed pressure was 100% at 10(-8) M, 55% at 10(-9) M, and 46% at 10(-10) M. The reperfusion-induced tissue and mitochondrial calcium overload, release of CPK and noradrenaline, and oxidative stress were also significantly reduced. The effects of felodipine were dose dependent. Felodipine inhibited the initial rate of ATP-driven calcium uptake but failed to affect the initial rate of mitochondrial calcium transport. It is concluded that felodipine infusion provides dose-dependent protection of the heart against ischemia and reperfusion. Because this protection also occurred at 10(-9) M and 10(-10) M in the absence of a negative inotropic effect during normoxia and of a coronary dilatory effect during ischaemia, it cannot be attributed to an energy-sparing effect or to improvement in oxygen delivery. From our data we can envisage two other major mechanisms-(1) membrane protection and (2) reduction in oxygen toxicity. The ATP-sparing effect occurring at 10(-8) M is likely to be responsible for the further protection.

Protein Kinase C in Normal and Pathologic Myocardial States

“…In this regard, many stress stimuli (i.e., ischemia, LPS, heat shock) result in myocardial preconditioning [53], and although they themselves are not protective, induce myocardial protection (preconditioning). Similarly, inhibition of Ca 2ϩ has been determined to inhibit myocardial preconditioning [68] while inhibition of Ca 2ϩ entry during long ischemia has proven protective [122][123][124][125]. Thus, stimuli that are deleterious to cardiac function can at times confer protection, without themselves being protective.…”

The Effect of Captopril on Membrane Bound Enzymes in Ischemia—Reperfusion Injury

“…In previous studies angiotensin converting enzyme (ACE) inhibitors were found to reduce ischemiareperfusion injury [5][6][7]. Several investigators have reported that captopril, a sulfhydryl containing ACE inhibitor, may be beneficial at preventing ischemiareperfusion injury [8].…”

Evaluation of First-Pass Cytochrome P4503A (CYP3A) and P-glycoprotein Activities Using Felodipine and Hesperetin in Combination in Wistar Rats and Everted Rat Gut Sacs in Vitro

“…Felodipine has greater selectivity for vascular smooth muscle relative to myocardial muscle than does other 1, 4-DHPs. Felodipine also has cardio protective (Ferrari et al, 1996) and antioxidant (Hishikawa and Lüscher, 1998) activities.…”