Angiotensin II activates two cation conductances with distinct TRPC1 and TRPC6 channel properties in rabbit mesenteric artery myocytes

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Abstract
Angiotensin II (Ang II) is a potent vasoconstrictor with an important role in controlling blood pressure; however, there is little information on cellular mechanisms underlying Ang II‐evoked vasoconstrictor responses. The aim of the present study is to investigate 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, 30 and 45 pS. At relatively high concentrations, Ang II (100 nm) inhibitedIcat1but evoked another cation channel (Icat2) with a conductance of approximately 2 pS. Ang II‐evokedIcat1andIcat2were inhibited by the AT1receptor antagonist losartan and the phospholipase C (PLC) inhibitor U73122. The diacylglycerol (DAG) lipase inhibitor RHC80267 initially inducedIcat1which was subsequently inhibited to revealIcat2. The DAG analogue 1‐oleoyl‐2‐acetyl‐sn‐glycerol (1 μm) activatedIcat1andIcat2but inositol 1,4,5‐trisphosphate did not evoke either conductance. The protein kinase C (PKC) inhibitor chelerythrine (3 μm) potentiated Ang II‐evokedIcat1and inhibitedIcat2whereas the PKC activator phorbol‐12,13‐dibutyrate (1 μm) reduced Ang II‐inducedIcat1but activatedIcat2. Moreover in cell‐attached patches pretreated with chelerythrine, application of 100 nmAng II activatedIcat1. These data indicate that PKC inhibitsIcat1but stimulatesIcat2. Agents that deplete intracellular Ca2+stores also activated cation channel currents with similar properties toIcat2. Bath application of anti‐TRPC6 and anti‐TRPC1 antibodies to inside‐out patches inhibitedIcat1andIcat2, respectively. Also flufenamic acid and zero external Ca2+concentration, respectively, potentiated and reduced Ang II‐evokedIcat1. 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 AT1receptors linked to PLC.Icat1is activated by DAG via a PKC‐independent mechanism whereasIcat2involves DAG acting via a PKC‐dependent pathway. Higher concentrations of Ang II inhibitIcat1by activating an inhibitory effect of PKC. It is proposed that TRPC6 and TRPC1 channel proteins are important components of Ang II‐inducedIcat1andIcat2, respectively.

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