Mibefradil Hydrochloride

Ischemia/reperfusion (I/R) injury is a pathological condition that arises from the complex interplay of multifaceted mechanisms such as calcium imbalance, oxidative stress, mitochondrial dysfunction, and inflammatory processes. Voltage-gated calcium channels (VGCCs) play a critical role in this pathogenesis by regulating calcium influx into the cell, thereby initiating a cascade of detrimental intracellular events. During the ischemic phase, depletion of ATP reserves leads to the dysfunction of calcium transport systems; in the reperfusion phase, the stimulation of VGCCs by reactive oxygen species (ROS) intensifies intracellular calcium overload. This accumulation triggers the opening of mitochondrial permeability transition pores, amplifies ROS production, and activates cell death pathways such as apoptosis, necrosis, and ferroptosis. This comprehensive review explores the structural subtypes and physiological functions of VGCCs in detail while broadly investigating their behavior under I/R conditions across various organ systems, including the cardiovascular, neurological, renal, and reproductive systems. The review focuses on the distinct roles of L-, T-, N-, and R-type VGCCs and examines current findings on tissue- and isoform-specific pharmacological blockade strategies. Experimental studies demonstrating the protective effects of VGCC inhibitors-such as nimodipine, mibefradil, and SNX-111-are critically evaluated along with their translational limitations. By integrating up-to-date mechanistic insights with preclinical and early clinical data, this review highlights VGCCs as promising molecular targets for preventing I/R injury. Future therapeutic strategies should focus on isoform-specific targeting, time-dependent administration, and organ-directed formulations to enhance efficacy and safety.

Internal mammary artery (IMA) is the most commonly used graft in coronary artery bypass grafting (CABG). Spasm of the IMA is a long‐recognized problem with the reported prevalence of 0.43% in all CABG surgery. This study explored the antispastic effect and the mechanism of a new generation of dihydropyridine calcium channel blocker efondipine in the IMA.

Discarded distal IMA taken from 54 patients undergoing CABG were collected. The concentration–relaxation curves of efonidipine (−12 to −4.5 log M) in the IMA precontracted with KCl or U46619 were constructed, and the effect was compared to a T‐type calcium channel blocker, mibefradil. The pretreatment effect of efonidipine on the contraction of vasoconstrictors was also studied. The Cav1.2 and Cav3.1 protein expression was detected by Western blot.

Efonidipine‐induced dose‐dependent relaxation in the IMA precontracted with KCl or U46619 ( p  < 0.05). Pretreatment with −6.5 log M of efonidipine significantly inhibited the vasoconstriction by KCl ( p  < 0.01) or U46619 ( p  = 0.04). Cav1.2 and Cav3.1 protein expression levels were significantly decreased by efonidipine. The relaxation effect of efonidipine was significantly greater than that of mibefradil.

The present study revealed a significant antispastic effect of efonidipine in the human IMA due to its effect on the expression of L‐type (Cav1.2) and T‐type (Cav3.1) proteins. The dual effect of efonidipine on both L‐ and T‐type calcium channels is significantly greater than that of T‐type calcium channel blockers. These findings suggest that efonidipine is an effective drug to prevent and treat vasospasm of the IMA during CABG surgery.