Protein kinase C modulators enhance angiotensin II desensitization of guinea pig ileum via maxi-K+ channels.

We investigated the role of protein kinase C in the desensitization of the angiotensin II-induced contraction of guinea pig ileum. In contrast to their antagonistic effects on enzymatic activity, both activator and blockers accelerated the dissipation of the 10(-7) M angiotensin II isometric contractile response. These agents indirectly activated maxi-K+ channels in cell-attached membrane patches from freshly dispersed myocytes bathed in high-K+ solution and clamped at -40 mV. In parallel with the contractile responses, fura 2-loaded myocytes bathed in Tyrode solution showed additive increases in [Ca2+]i in response to both angiotensin II and phorbol dibutyrate (PDB). The PDB-promoted increase of the rate of angiotensin II desensitization was completely abolished by pretreatment of the tissue strips with 93 nM iberiotoxin or 8 mM KCl. Thus, we conclude that protein kinase C modulators promote faster angiotensin II desensitization by recruiting maxi-K+ channels and inducing membrane repolarization rather than by affecting the protein kinase C activity.