Angiotensin II receptor type I-regulated anion secretion in cystic fibrosis pancreatic duct cells.

• The beta-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 (ISC) technique. An increase in ISC could be induced in CFPAC-1 cells by basolateral or apical application of AII in a concentration-dependent manner (EC50 at 3 microm 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 microm) could completely inhibit the AII-induced ISC, whereas, PD123177 exerted insignificant effect on the ISC, 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 ISC. Treatment of the monolayers with a Cl- channel blocker, DIDS, markedly reduced the ISC, indicating that a large portion of the AII-activated ISC was Cl--dependent. AII-induced ISC was also observed in monolayers whose basolateral membranes had been permeabilized by nystatin, suggesting that the ISC 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

Nyckelord

4

4'-Diisothiocyanostilbene-2

2'-Disulfonic Acid

pharmacology

Angiotensin II

pharmacology

Antiporters

metabolism

Bicarbonates

metabolism

Biological Transport

Active

drug effects

Biphenyl Compounds

pharmacology

Calcium

physiology

Cell Polarity

Cells

Cultured

Chloride-Bicarbonate Antiporters

Chlorides

metabolism

Cystic Fibrosis

metabolism

pathology

Cystic Fibrosis Transmembrane Conductance Regulator

deficiency

Humans

Imidazoles

pharmacology

Intracellular Fluid

metabolism

Ion Transport

drug effects

Losartan

Microscopy

Confocal

Nystatin

pharmacology

Pancreatic Ducts

drug effects

pathology

secretion

Pyridines

pharmacology

Receptor

Angiotensin

Type 1

Receptor

Angiotensin

Type 2

Receptors

Angiotensin

agonists

antagonists & inhibitors

physiology

Secretory Rate

drug effects

Tetrazoles

pharmacology

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)