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Endothelin-1 and PKC Induce Positive Inotropy Without Affecting pH_i in Ventricular Myocytes

Department of Physiology, Molecular and Cellular Pharmacology Training Program, University of Wisconsin, Madison, Wisconsin 53706

To whom requests for reprints should be addressed at ¹ Department of Physiology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706. E-mail: jwalker{at}physiology.wisc.edu

Abstract

It has been proposed that intracellular alkalinization underlies the enhanced contractility of ventricular myocytes exposed to endothelin (ET)-1. The effects of ET-1 on the contractility and intracellular pH (pH_i) were examined here in cultured adult rat ventricular myocytes by employing the pH-sensitive fluorescent dye SNARF-1. Variable pH_i changes were observed on ET-1 stimulation. Most myocytes (n = 20 of 32) did not alkalinize, but showed an approximate 60% increase in twitch amplitude in response to ET-1. In the remaining myocytes (12 of 32), ET-1 induced an increase in pH_i by 0.05 ± 0.02 pH units with a similar approximate 60% increase in twitch amplitude. Therefore, there was no strong correlation between ET-1–mediated positive inotropy (enhanced contractility) and intracellular alkalinization. To determine whether ET-1 contractile and pH_i responses were mediated by protein kinase C (PKC), yellow fluorescent protein (YFP)–fused dominant negative (dn) PKC constructs were used as isoform specific inhibitors. In dn-PKC--YFP–expressing myocytes, the ET-1–mediated positive inotropic response was greatly diminished to 13 ± 15%, but alkalinization was still observed. Expression of dn-PKC--YFP also did not block alkalinization, but in this case the positive inotropic response was still observed. In a previous study, we showed that expression of PKC- and PKC- caused a strong positive inotropy on stimulation with phorbol 12,13-dibutyrate (PDBu). Using this system, PDBu failed to affect pH_i in the majority of PKC expressing myocytes despite increases in twitch amplitudes of >60%. Overall, the poor correlation of positive inotropic responses and alkalinization was observed for ET-1 with and without dn-PKC constructs and for PDBu with and without wild-type PKC constructs. These results suggest that ET-1 produces positive inotropy via PKC- by mechanisms other than intracellular alkalinization.

Key Words: endothelin-1 • positive inotropy • protein kinase C • alkalinization

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