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(Circulation Research. 2001;0:hh1201.092035.)
© 2001 American Heart Association, Inc.

Article

Distinct Pathways of Ca²⁺ Sensitization in Porcine Coronary Artery

Effects of Rho-Related Kinase and Protein Kinase C Inhibition on Force and Intracellular Ca²⁺

Koji Nobe Richard J. Paul

From the Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Correspondence to Dr Richard Paul, Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576. E-mail richard.paul{at}uc.edu

Abstract

Abstract—Alterations of the Ca²⁺ sensitivity of contraction have been reported for porcine coronary artery, but the mechanisms are not clearly understood. We investigated the mechanism(s) of Ca²⁺ sensitization in response to the thromboxane A₂ analogue (U46619). Our hypothesis is that different mechanisms of Ca²⁺ sensitization could be distinguished by their distinct time courses. Therefore, we measured the time course of [Ca²⁺]_i and isometric force simultaneously in an intact artery after a single addition of U46619. The initial transient phase was associated with Ca²⁺ release from the sarcoplasmic reticulum, whereas the maintained phase was associated with Ca²⁺ influx. Two distinct types of Ca²⁺ sensitization characterized these phases with either protein kinase C (PKC)-mediated or Rho-kinase–mediated mechanisms. Their effects were quite distinct on the basis of the time courses over which the sensitization was effective. PKC inhibition (1 µmol/L calphostin C) had a much greater effect in the initial phase, diminishing the size of the transient and prolonging the rise in force and the decline in [Ca²⁺]_i. There were limited effects on the sustained force. Rho-kinase inhibition (10 µmol/L Y27632), in contrast, nearly abolished the sustained force but had a lesser effect on the transient phase. Neither inhibitor had any effect on the force versus [Ca²⁺]_i relations for KCl contractures. Our evidence suggests that both PKC-mediated and Rho-kinase–mediated Ca²⁺ sensitizations are present in coronary arteries, but the latter is dominant in thromboxane A₂ receptor–mediated contraction.

Key Words: coronary arteries • Ca²⁺ sensitization • protein kinase C • Rho-kinase • U46619

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