Novel Pharmacological Protiles of Dihydropyridines

研究了对L型Ca^<2+>通道以外的离子通道具有阻断活性的二氢吡啶化合物的药理学。T型Ca^<2+>通道阻滞剂作为一种治疗心血管疾病的新方法正受到人们的关注。特异性T型Ca^2+通道阻滞剂尚未建立。我们发现某些二氢吡啶类化合物，如依非地平，对L型和T型Ca^2+通道都具有阻断活性，这可能是它们优异的临床特征，如最小反射性心动过速和肾保护作用的基础。在二氢吡啶环的C5位上的膦酸酯部分或一些庞大的结构对于T型Ca^2+通道阻断活性可能是重要的。AHC-52和PAK 200是二氢吡啶类化合物，可阻断cAMP依赖性氯离子通道，但不阻断L型Ca^2+通道。这些化合物显示出促进缺血再灌注后心肌收缩力的恢复。这种心脏保护的一个显著特点是它不伴有心脏抑制。发现这些化合物通过保护线粒体功能来减弱细胞ATP的减少。因此，对二氢吡啶类化合物进行精确的药理学研究，发现其对L型Ca^2+通道以外的离子通道具有阻断活性，将有助于开发通过新机制发挥作用的心脏保护剂。

Pharmacology of dihydropyridine compounds with blocking activity on ion channels other than the L-type Ca^<2+> channel was studied. T-type Ca^<2+> channel blockade is now receiving attention as a novel therapeutic strategy for various cardiovascular disorders. A specific T-type Ca^<2+> channel blocker has not yet been established. We found that certain dihydropyridine compounds, such as efonidipine, have blocking activity on both L-type and T-type Ca^<2+> channels which possibly underlies their excellent clinical profiles such as minimum reflex tachycardia and renal protection. A phosphonate moiety or some bulky structure at the C5 position of the dihydropyridine ring may be important for the T-type Ca^<2+> channel blocking activity. AHC-52 and PAK200 are dihydropyridine compounds which block the cAMP-dependent chloride channel but not L-type Ca^<2+> channel. These compound were shown to enhance recovery of myocardial contractile force after ishcemia -reperfusion. A remarcable feature of this cardioprotection is that it was not accompanied by cardiosuppression. These compounds were found to attenuate the decrease in cellular ATP through protection of mitochondrial function. Thus, precise pharmacological investigation of dihydropyridine compounds with blocking activity on ion channels other than the L-type Ca^<2+> channel would lead to the development of cardioprotective agents acting through novel mechanisms.