TY - JOUR
T1 - Competitive effects of verapamil and calcium ion as regulators of myocardial enzyme leakage
AU - Cohen, Louis
AU - Gilula, Zvi
AU - Meier, Paul
AU - Lazaron, Betsy
AU - Herbstman, David
PY - 1981
Y1 - 1981
N2 - Verapamil (Vp) has been found to augment the creatine kinase (CK) and lactate dehydrogenase (LDH) leakage from isolated mouse heart incubated in vitro at 25°C. This leakage was concentration-dependent, and in the second hour followed the Henri-Michaelis-Menten kinetics model. Least-squares estimates obtained with this model for the Km values of verapamil were 0.38 ± 0.16 mM (CK leakage) and 0.51 ± 0.21 mM (LDH leakage). Calcium ion inhibited this effect of verapamil, completely abolishing it when the [Ca2+]:[Vp] ≤ 2. At lower [Ca2-], the effect of verapamil also followed hyperbolic kinetics; the Km of verapamil was increased, but the asymptotic leakage rate at high [Vp] was not changed significantly. These features indicate that the calcium ion is a competitive inhibitor of verapamil-augmented enzyme leakage. These observations suggest that there may exist a common calcium ion and verapamil binding site, or two allosterically related binding sites, which represent a prime determinant of myocardial leakage. The concept of a vulnerable site that binds calcium ions and verapamil competitively and initiates or vitiates processes that influence myocardial enzyme leakage is attractive because it suggests new approaches to the problem of myocardial preservation. As verapamil is thought not to enter the cell, the site of the competitive inhibition may be the sarcolemmal coat.
AB - Verapamil (Vp) has been found to augment the creatine kinase (CK) and lactate dehydrogenase (LDH) leakage from isolated mouse heart incubated in vitro at 25°C. This leakage was concentration-dependent, and in the second hour followed the Henri-Michaelis-Menten kinetics model. Least-squares estimates obtained with this model for the Km values of verapamil were 0.38 ± 0.16 mM (CK leakage) and 0.51 ± 0.21 mM (LDH leakage). Calcium ion inhibited this effect of verapamil, completely abolishing it when the [Ca2+]:[Vp] ≤ 2. At lower [Ca2-], the effect of verapamil also followed hyperbolic kinetics; the Km of verapamil was increased, but the asymptotic leakage rate at high [Vp] was not changed significantly. These features indicate that the calcium ion is a competitive inhibitor of verapamil-augmented enzyme leakage. These observations suggest that there may exist a common calcium ion and verapamil binding site, or two allosterically related binding sites, which represent a prime determinant of myocardial leakage. The concept of a vulnerable site that binds calcium ions and verapamil competitively and initiates or vitiates processes that influence myocardial enzyme leakage is attractive because it suggests new approaches to the problem of myocardial preservation. As verapamil is thought not to enter the cell, the site of the competitive inhibition may be the sarcolemmal coat.
KW - Calcium
KW - Creatine kinase
KW - Enzyme leakage
KW - Kinetics
KW - Statistical modification
KW - Verapamil
UR - http://www.scopus.com/inward/record.url?scp=0019474817&partnerID=8YFLogxK
U2 - 10.1097/00005344-198105000-00017
DO - 10.1097/00005344-198105000-00017
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C2 - 6168839
AN - SCOPUS:0019474817
SN - 0160-2446
VL - 3
SP - 581
EP - 597
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
IS - 3
ER -