Calcium-channel blockers: possible mechanisms of protective effect on the ischemic myocardium (original) (raw)

~-'1'8ll_v of Cincinnati College u{ 1.\1edicine, Cincinnati. Ohio \'a:-;cular Effects of Cakium-Channt>l Blockers Pre:-<=·tne-fl(>W relationships in the circumflex and left anterior de;;cendinF: eoronar:-arteries CorP nary arterial m·dusion pressures and back now of blood from lT~nplete\y ueduded coronary artt>ries l~t•J.(itllt:JIIlnw rlislrihutit•n actions, actions in ischemia, and finally, a summary of potential mechani:-:;m:;. CALCIUt\1 ANTAGONISTS A.:"JD ISCHEMIC MYOCAHDIL'~, . . t 193 VASCULAR EFFECTS OF CALCIUM·CHANNEL BLOCKERS All the divt:rse chemical agents that are loosely clas:->ified as Ca:!+ antagonists are· p'ut.ent relaxers of vascular smooth muscle and act probably by inhibiting some Ca 1 --dependent event. For example, in porcine coronary artery strips in vitro, nifedipine I> 10_, Ml, verapamil (> w-' M), and diltiazem (> 10-' MJ exert relaxant actions . Coronary flow in dogs is increased by nifedipine (11) and diltiazem (8). Coronary collateral flow to the ischemic myocardium is increased by verapamil (13) and diltiazem (8). Interestingly these agents appear to have different effects depending on whether the vessel is activated by a receptor-mediated pathway or by a voltage-dependent (e.g., KCI) site or sites . The vascular effects of diltiazem and nisoldipine on coronary blood flow can be den10nstrated in dogs with separately controlled and perfused circumflex and left anterior descending coronary arteries (Ftg. 3). Dogs were anesthetized with pentobarbital sodium (30 mg/kg iv), anticoagulated with heparin sodium (5,000 L USP/kg iv), and artificially respired. The chest was opened in the left 5th intercostal space, and a pericardia} cradle was cohstructed to support the hear·t. The left carotid artery was connected to the left circumflex coronary artt>ry, :mel the femoral artery to the left des{'ending coronary artery. Coronal',\' flow in both aneries was kept conswnL and independent. by in-line adjustable fin~er pu111ps. Ml•an l'OI'O!Hll)' perfusion pressureH were made equal to Lht• s.vstemil' systolic arterial blood pres:-;ure. Control coronary flows ranged be· twe!!ll .:to and HO ml/min. Contractile force of the lefl ventricle was recorcil'd from a sLrain ~au~e sulurt~d to the anterior wall close to Lhe apex of the hearL · Hearl ratt•, elertrocardiogram, aortic pressure, coronary pressures, coronary.· flows, contractile force, lefl ventricular pres.-;ure (LVP), and the dP/dt of the LVP were recorded on a Grass P7 polygraph. The flows were measured by Biotronex electromag-netic flowmeters. This permitted us to change flow and; or pressure in one or both of the perfused areas. \Ve cot 1 tld stop anlegrade flow and collect retrograde blood to assess collateral flow during complete coronary t'HL 2. Potential sites of action, of Ca~· anta..:onist. Site I, Pxterior of sar· l'Oh·mma; sill':!. inside sarcolemma (po:>· sihlv via ralmudulin oceupam·.v and/or phospholipids); site :J, on innl'r surfal'e of . .;;arcolemma; site 4, mitoehomirial membrane; site 5, san:oplasmic reticulum; site G, t ruponin, t ropomyu;-;in. actin, and tll,\'osin.