The β-adrenergic (cAMP-dependent) regulation of Cl− conductance is defective in cystic fibrosis (CF). The present study explored alternative regulation of anion secretion in CF pancreatic ductal cells (CFPAC-1) by angiotensin II (AII) using the short-circuit current (I SC ) technique. An increase in I SC could be induced in CFPAC-1 cells by basolateral or apical application of AII in a concentration-dependent manner (EC50 at 3 μm and 100 nm, respectively). Angiotensin receptor subtypes were identified using specific antagonists, losartan and PD123177, for AT1 and AT2 receptors, respectively. It was found that losartan (1 μm) could completely inhibit the AII-induced I SC , whereas, PD123177 exerted insignificant effect on the I SC , indicating predominant involvement of AT1 receptors. The presence of AT1 receptors in CFPAC-1 cells was also demonstrated by immunohistochemical studies using specific antibodies against AT1 receptors. Confocal microscopic study demonstrated a rise in intracellular Ca2+ upon stimulation by AII indicating a role of intracellular Ca2+ in mediating the AII response. Depletion of intracellular but not extracellular pool of Ca2+ diminished the AII-induced I SC . Treatment of the monolayers with a Cl− channel blocker, DIDS, markedly reduced the I SC , indicating that a large portion of the AII-activated I SC was Cl−-dependent. AII-induced I SC was also observed in monolayers whose basolateral membranes had been permeabilized by nystatin, suggesting that the I SC was mediated by apical Cl− channels. Our study indicates an AT1-mediated Ca2+-dependent regulatory mechanism for anion secretion in CF pancreatic duct cells which may be important for the physiology and pathophysiology of the pancreas.
The Journal of Membrane Biology – Springer Journals
Published: Apr 1, 1997
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