A metabolic control mechanism for calcium ion influx that may protect the ventricular myocardial cell

Abstract

Calcium ion influx into the myocardial cell during the action potential initiates and controls the degree of contraction. The Ca ++ influx leads to an increase of the myoplasmic free Ca ++ concentration to about 10 −5 molar for activation of the myofibrils; Ca ++ may also be released from the sarcoplasmic reticulum by the entering Ca ++ or by voltage change across its membrane. The inward Ca ++ current during the action potential plateau traverses the sarcolemma through a separate set of slow cation channels that have some peculiar properties compared to fast sodium ion channels: Slow channels are not sensitive to tetrodotoxin, have lower activation and inactivation potentials and are kinetically slow (slow activation, inactivation and recovery processes). Slow Ca ++ channels require metabolic energy and are blocked by verapamil, manganese ion, lanthanum ion and acidosis. When the fast Na ++ channels are blocked by tetrodotoxin or voltage inactivated by 27 millimolar potassium ion, excitability is lost but can be restored by catecholamines and methylxanthines: Propagating slowly rising electrical responses (accompanied by contractions) occur that resemble the plateau of the normal action potential. Positive inotropic agents such as norepinephrine, theophylline and histamine appear to act by elevating cyclic adenosine monophosphate (AMP) levels and increasing the number of Ca ++ channels available for voltage activation. Increased cyclic AMP could lead to phosphorylation of a membrane protein constituent of the slow channels by means of a cyclic AMP-dependent protein kinase and adenosine triphosphate (ATP). Thus, the myocardial cell exercises control over the number of available slow channels and, hence, the Ca ++ influx per impulse. This control mechanism could serve to protect the myocardial cell during periods of regional ischemia by acting to conserve ATP through reduced Ca ++ influx and contraction, and thus preventing the affected cells from working themselves to death. The Ca ++ channels in ischemic cells could be made inoperative by decreased ATP, decreased pH or accumulation of some other metabolite.