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Targeting voltage-gated Ca2+ channels

2001; Elsevier BV; Volume: 357; Issue: 9264 Linguagem: Inglês

10.1016/s0140-6736(00)04440-8

1474-547X

Jörg Striessnig,

Phosphodiesterase function and regulation

In their Oct 14 commentary, James Angus and colleagues1Angus JA Wright CE Xi Q Targeting voltage-gated calcium channels in cardiovascular therapy.Lancet. 2000; 356: 1287-1289Summary Full Text Full Text PDF PubMed Scopus (17) Google Scholar discuss Ca2+ channel subunits and their splice variants as potential targets for new generations of cardiovascular therapeutics. They speculate that selective antagonists to the smooth-muscle Cav1·2b-splice variant would affect vascular tissue and lower total peripheral resistance, while avoiding cardiac depression from blockade of the cardiac splice variant (Cav1·2a). Although these pharmacological actions are expected,2Welling A Ludwig A Zimmer S Klugbauer N Flockerzi V Hofmann F Alternatively spliced IS6 segments of the alpha IC gene determine the tissue-specificity dihydropyridine sensitivity of cardiac and vascular smooth muscle L-type calcium channels.CircRes. 1997; 81: 526-532PubMed Google Scholar it is questionable whether higher vascular selectivity (or specificity) would provide any additional therapeutic benefit for the treatment of hypertension, myocardial ischaemia, or coronary heart failure (CHF). In patients without CHF, rapid lowering of total peripheral resistance by short-acting dihydropyridines can result in reflectory sympathetic activation because these drugs are devoid of direct negative chronotropic action at therapeutic doses in human beings. This effect can increase cardiac oxygen demand and promote cardiac arrhythmias, which is clearly unwanted, especially in patients with coronary artery disease. Reflex tachycardia is not seen with slow-onset, long-acting derivatives (eg, GITS-nifedipine, amlodipine, or extended-release felodipine). These dihydropyridines already have high vascular selectivity. The rationale for the use of extended-release felodipine in the Heart Failure Trial (V-HeFT III)3Cohn JN, Ziesche S, Smith R, et al, and the Vasodilator-Heart Failure Trial (V-HeFT) Study Group Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III.Circulation. 1997; 96: 856-863Crossref PubMed Scopus (310) Google Scholar was its apparent lack of direct negative inotropy at vasodilating doses. The V-Heft III and Praise-1 and 2 trials have shown that felodipine and amlodipine are not beneficial or harmful in patients with CHF when added to standard therapy. For felodipine, no evidence for therapeutically relevant direct negative inotropic actions was obtained in echocardiographic studies of CHF patients.4Platzer J Engel J Schrott-Fischer A et al.Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels.Cell. 2000; 102: 89-97Summary Full Text Full Text PDF PubMed Scopus (687) Google Scholar This lack of evidence for a direct negative inotropic effect argues against the hypothesis that L-type Ca2+ channel blockers with even higher vascular selectivity and less negative inotropic action due to Cav1·2b-specificity would provide any significant additional therapeutic benefit for the treatment of hypertension, myocardial ischaemia, or when added to standard CHF therapy. Unfortunately, Angus and colleagues have not mentioned Cav1·3 L-type Ca2+ channels as potential targets for cardiovascular therapy. The functional role of these channels was believed to be restricted to neuronal and neuroendocrine function. However, gene-knockout experiments in mice have shown that Cav1·3 channels control sinoatrial-node automaticity.5Takimoto K Li D Nerbonne JM Levitan ES Distribution, splicing and glucocorticoid-induced expression of cardiac alpha 1C and alpha 1D voltage-gated calcium channel mRNAs.J Mol Cell Cardiol. 1997; 29: 3035-3042Summary Full Text PDF PubMed Scopus (108) Google Scholar Their absence results in sinus bradycardia and arrhythmia at rest but not during physical activity or sympathetic stimulation. Since these channels cannot contribute to ventricular muscle contraction,5Takimoto K Li D Nerbonne JM Levitan ES Distribution, splicing and glucocorticoid-induced expression of cardiac alpha 1C and alpha 1D voltage-gated calcium channel mRNAs.J Mol Cell Cardiol. 1997; 29: 3035-3042Summary Full Text PDF PubMed Scopus (108) Google Scholar Cav1·3-selective blockers can be predicted to exert bradycardic actions without negative inotropy. Although to what extent Cav1·3 channels contribute to cardiac pacemaker function in human beings is unclear, this channel, together with cardiovascular T-type Ca2+ channels, certainly deserves more attention for further drug discovery than the development of Cav1·2b-specific blockers. Targeting voltage-gated Ca2+ channelsAuthors' reply Full-Text PDF