Propofol increases myofilament Ca2+ sensitivity and intracellular pH via activation of Na+-H+ exchange in rat ventricular myocytes

Background: The objectives were to determine the extent and mechanism of ac tion by which propofol increases myofilament Ca2+ sensitivity and intracell ular pH (pH(i)) in ventricular myocytes. Methods: Freshly isolated adult rat ventricular myocytes were used for the study. Cardiac myofibrils were extracted for assessment of myofibrillar act omyosin adenosine triphosphatase (ATPase) activity, Myocyte shortening (vid eo edge detection) and pH, (2 ' ,7 ' -bis-(2-carboxyethyl)-5(6 ')-carboxyfl uorescein, 500/440 ratio) mere monitored simultaneously in individual cells field-stimulated (0.3 Hz) and superfused with HEPES-buffered solution (pH 7.4, 30 degreesC), Results: Propofol (100 muM) reduced the Ca2+ concentration required for act ivation of myofibrillar actomyosin ATPase from pCa 5.7 +/- 0.01 to 6.6 +/- 0.01. Increasing pH(i) (7.05 +/- 0.03 to 7.39 +/- 0.04) with NH4Cl increase d myocyte shortening by 35 +/- 12%. Washout of NH4Cl decreased pH(i) to 6.8 2 +/- 0.03 and decreased myocyte shortening to 52 +/- 10% of control. Propo fol caused a dose-dependent increase in pHi but reduced myocyte shortening. The propofol-induced increase in pHi was attenuated, whereas the decrease in myocyte shortening was enhanced after pretreatment with ethylisopropyl a miloride, a Na+-H+ exchange inhibitor, or bisindolylmaleimide I, a protein kinase C inhibitor. Propofol also attenuated the NH4Cl-induced intracellula r acidosis, increased the rate of recovery from acidosis, and attenuated th e associated decrease in myocyte shortening. Propofol caused a leftward shi ft in the extracellular Ca2+-shortening relation, and this effect was atten uated by ethylisopropyl amiloride, Conclusions: These results suggest that propofol increases the sensitivity of myofibrillar actomyosin ATPase to Ca2+ (i.e,, increases myofilament Ca2 sensitivity), at least in part by increasing pH, via protein kinase C-depe ndent activation of Na+-H+ exchange.