(Hypertension. 1996;27:859-866.)
© 1996 American Heart Association, Inc.
Articles |
Phorbol Ester Activation of the Rat Vascular Myocyte Na+-H+ Exchanger Isoform 1
From the Department of Medicine and Therapeutics, Leicester (UK) Royal Infirmary.
Correspondence to Dr Martin Siczkowski, Division of Clinical Pharmacology, Department of Medicine and Therapeutics, Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK.
Abstract Vascular myocytes from the spontaneously hypertensive rat (SHR) demonstrate elevated Na+-H+ exchanger activity associated with increased cell proliferation and hyperresponsiveness to agonists such as phorbol esters. Since the Na+-H+ exchanger isoform 1 (NHE-1) is stimulated by protein kinase C, we have investigated the effects of phorbol esters on NHE-1 activity and its phosphorylation in vascular myocytes of these rats. SHR cells demonstrated a larger alkalinization response to 12-O-tetradecanoylphorbol 13-acetate than Wistar-Kyoto rat (WKY) cells. Kinetic analyses indicated that whereas 12-O-tetradecanoylphorbol 13-acetate increased the maximal transport capacity of NHE-1 in both cell types, affinity for H+ was increased in WKY cells and cooperativity for H+ at the internal modifier site was reduced in SHR cells. In neither cell type was the subcellular distribution of NHE-1 altered by phorbol ester stimulation. NHE-1 phosphorylation was markedly reduced in WKY cells stimulated by the phorbol ester, an effect abolished by inhibition of protein kinase C. In contrast, NHE-1 phosphorylation in quiescent SHR cells was approximately double that of WKY cells and was reduced after phorbol ester treatment. Inhibition of protein kinase C in SHR cells led to a marked elevation of NHE-1 phosphorylation that was not associated with a change in exchanger activity, but WKY cells exhibited a small, insignificant rise in NHE-1 phosphorylation. Thus, the kinetic responses of NHE-1 to phorbol esters in vascular myocytes of these rat strains are different, the changes in exchanger kinetics of SHR resembling those described in human hypertension. NHE-1 phosphorylation has an inverse relationship with protein kinase C activity. However, modulation of NHE-1 phosphorylation may not be associated with concurrent alterations in activity, indicating a role for non–phosphorylation-dependent mechanisms.
Key Words: Na+-H+ exchanger • vascular myocytes • phorbol esters • phosphorylation
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