Propofol increases contractility during α1a-adrenoreceptor activation in adult rat cardiomyocytes

Abstract

Background: The objective of this study was to identify the extent to which propofol alters intracellular free Ca2+ concentration ([Ca 2+]i), myofilament Ca2+ sensitivity, and contraction of individual cardiomyocytes during activation of α1a adrenoreceptors and to determine the cellular mechanism of action. Methods: Freshly isolated ventricular myocytes were obtained from adult rat hearts. Myocyte shortening and [Ca2+]i were simultaneously monitored in individual cardiomyocytes exposed to phenylephrine after treatment with chloroethylclonidine (α1d-adrenoreceptor antagonist) and BMY 7378 (α1d-adrenoreceptor antagonist). Data are reported as mean ± SD. Results: Phenylephrine increased myocyte shortening by 124 ± 9% (P = 0.002), whereas peak [Ca2+] i only increased by 8 ± 3% (P = 0.110). Inhibition of phospholipase A2 and phospholipase C attenuated the phenylephrine-induced increase in shortening by 84 ± 11% (P = 0.004) and 15 ± 6% (P = 0.010), respectively. Inhibition of protein kinase C (PKC) and Rho kinase attenuated the phenylephrine-induced increase in shortening by 17 ± 8% (P = 0.010) and 74 ± 13% (P = 0.006), respectively. In the presence of phenylephrine, propofol increased shortening by 40 ± 6% (P = 0.002), with no concomitant increase in [Ca2+]i. PKC inhibition prevented the propofol-induced increase in shortening. Selective inhibition of PKCα, PKCδ, PKCε, and PKCζ reduced the propofol-induced increase in shortening by 12 ± 5% (P = 0.011), 36 ± 8% (P = 0.001), 32 ± 9% (P = 0.007), and 19 ± 5% (P = 0.008), respectively. Na+-H+ exchange inhibition reduced the propofol-induced increase in shortening by 56 ± 7% (P = 0.001). Conclusion: Activation of α1a adrenoreceptors increases cardiomyocyte shortening primarily via a phospholipase A2-dependent, Rho kinase-dependent increase in myofilament Ca2+ sensitivity. Propofol further increases myofilament Ca2+ sensitivity and shortening via a PKC-dependent pathway and an increase in Na+-H + exchange activity. © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.