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Received August 16, 2006
Revised September 12, 2006
Accepted after revision September 12, 2006
1 St George's, University of London
* To whom correspondence should be addressed. E-mail: aalbert{at}sghms.ac.uk.
Angiotensin II (Ang II) is a potent vasoconstrictor with an important role in controlling blood pressure but there is little information on cellular mechanisms underlying Ang II-evoked vasoconstrictor responses. The present study investigates the effect of Ang II on cation conductances in freshly dispersed rabbit mesenteric artery myocytes at the single channel level using patch clamp techniques. In cell-attached patches bath application of low concentrations of Ang II (1 nM) activated cation channel currents (Icat1) with conductances states of about 15 pS, 30 pS and 45 pS. At relatively high concentrations Ang II (100 nM) inhibited Icat1 but evoked another cation channel with a conductance of approximately 2 pS, Icat2. Ang II-evoked Icat1 and Icat2 were inhibited by the AT1 receptor antagonist losartan and the phospholipase C (PLC) inhibitor U73122. The diacylgycerol (DAG) lipase inhibitor RHC80267 initially induced Icat1 which was subsequently inhibited to reveal Icat2. The DAG analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG, 1 µM) activated Icat1 and Icat2 but inositol 1,4,5-trisphosphate (IP3) did not evoked either conductance. The protein kinase C (PKC) inhibitor chelerythrine (3 µM) potentiated Ang II-evoked Icat1 and inhibited Icat2 whereas the PKC activator phorbol-12,13-dibutyrate (PDBu, 1 µM) reduced Ang II-induced Icat1 but activated Icat2. Moreover in cell-attached patches pretreated with chelerythrine application of 100 nM Ang II now activated Icat1 and these data indicate that PKC inhibits Icat1 but stimulates Icat2. Agents that deplete intracellular Ca2+ stores also activated cation channel currents with similar properties to Icat2. Bath application of anti-TRPC6 and anti-TRPC1 antibodies to inside-out patches inhibited Icat1 and Icat2 respectively. Also flufenamic acid (FFA) and zero external Ca2+ concentration respectively potentiated and reduced Ang II-evoked Icat1. Immunocytochemical studies showed TRPC6 and TRPC1 expression with TRPC6 preferentially distributed in the plasma membrane and TRPC1 expression located throughout the myocyte. These results indicate that Ang II activates two distinct cation conductances in mesenteric artery myocytes by stimulation of AT1 receptors linked to PLC. Icat1 is activated by DAG via a PKC-independent mechanism whereas Icat2 involves DAG acting via a PKC-dependent pathway. Higher concentrations of Ang II inhibit Icat1 by activating an inhibitory effect of PKC. It is proposed that TRPC6 and TRPC1 channel proteins are important components of Ang II-induced Icat1 and Icat2 respectively.
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