ANGIOTENSIN-II TACHYPHYLAXIS IN THE GUINEA-PIG ILEUM AND ITS PREVENTION - A PHARMACOLOGICAL AND BIOCHEMICAL-STUDY

Angiotensin II (All) tachyphylaxis occurs in the guinea pig ileum, but is not induced by analogs lacking the N-terminal amino group or the A rg(2) guanidino group. Both All and Lys(2)AII increased cell inositol trisphoshate content in cultured intestinal smooth muscle cells. Prote in kinase C inhibition by staurosporine or downregulation by prolonged incubation with phorbol reverted tachyphylaxis of the inositol trisph oshate response, but not that of the Na+ uptake response, indicating t hat the uncoupling of the phosphoinositide signal system by protein ki nase C did not involve all processes distal to receptor activation. Ta chyphylaxis of the Na+ uptake response was prevented when receptor int ernalization was blocked by reduction of the temperature (4 degrees C) or by pretreatment of the cells with phenylarsine oxide. Acid washing s, which prevented tachyphylaxis of the Na-24(+) influx response, also prevented tachyphylaxis of the contractile response of the guinea pig ileum to AII. Although these findings suggest that sequestration or i nternalization of the AII receptor might be involved in AII tachyphyla xis, binding of [I-125]AII and of [I-125]Lys(2)AII to the cells was eq ually unaffected by repeated administrations of the peptides. The resu lts suggest that conformational change of the AII-receptor complex wit hin the plasma membrane, but not internalization, is the most importan t factor responsible for tachyphylaxis.