title: Quantitative analysis of vascular to cardiac selectivity of L- and T-type voltage-operated calcium channel antagonists in human tissues.
abstract: 1. Classical L-type voltage-operated calcium channel (VOCC) antagonists dilate blood vessels, depress myocardial contractility and slow cardiac conduction. 2. We compared four L-type VOCC antagonists and a novel tetralol derivative, mibefradil, reportedly 10-fold more selective for T- (transient) over L-type VOCC in two in vitro assays of human tissue, namely isolated small arteries from the aortic vasa vasorum in a myograph and right atrial trabeculae muscle under isometric force conditions. 3. In arteries contracted with K+ (62 mmol/L), the relaxation pIC50 values for the VOCC antagonists felodipine, nifedipine, amlodipine, verapamil and mibefradil were 8.30, 7.78, 6.64, 6.26 and 6.22, respectively. In atrial trabeculae, the pIC50 values to inhibit the inotropic response to a submaximal concentration of isoprenaline (6 nmol/L) for felodipine, nifedipine, verapamil, amlodipine and mibefradil were 7.21, 6.95, 6.91, 5.94 and 4.61, respectively. 4. Taking the anti-log (pIC50 vessel-pIC50 atrium) the vascular relaxation to cardiac depression potency ratios for mibefradil, felodipine, nifedipine, amlodipine and verapamil were 41, 12, 7, 5 and 0.22, respectively. 5. We conclude that, in human tissue assays, perhaps T- over L-type VOCC selectivity confers the most favourable vascular selectivity on mibefradil. Alternatively, splice variants of L-type VOCC in the vasculature (CaV1.2b) may be more sensitive to mibefradil than the splice variants in the heart (CaV1.2a).
authors: Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia. j.angus@pharmacology.unimelb.edu.au
authors: J A
authors: JA
authors: Angus
authors: D
authors: D
authors: Sarsero
authors: T
authors: T
authors: Fujiwara
authors: P
authors: P
authors: Molenaar
authors: Q
authors: Q
authors: Xi
mesh_terms: D001011:Aorta / Q000187:drug effects / Q000502:physiology; D016275:Atrial Function; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000502:physiology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D014651:Vasa Vasorum / Q000187:drug effects / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type