Distinct Pathways of Ca2+Sensitization in Porcine Coronary Artery

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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 A2analogue (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+]iand 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+]irelations 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 A2receptor–mediated contraction.