ROLE OF NA-KINASE-C IN ANGIOTENSIN DESENSITIZATION AND TACHYPHYLAXIS IN THE GUINEA-PIG ILEUM( AND PROTEIN)

Simultaneous recordings of the tension and intracellular Ca2+ concentr ation of guinea-pig ileum longitudinal smooth muscle strips, as well a s Na-24+ and Ca-45(2+) influx measurements in cultured myocytes from t he same tissue, were used to investigate the mechanisms underlying ang iotensin-induced desensitization and tachyphylaxis. Angiotensin II and [2-lysine]-angiotensin II (Lys2All), incubated for prolonged periods (10 min) with muscle strips, induced fading of the contractile respons e (desensitization) and reappearance of the intracellular Ca2+ concent ration oscillations, which were inhibited during the initial increase in cytosolic Ca2+. The desensitization was paralleled, in cultured myo cytes, by inhibition of the Ca-45(2+) but not of the Na-24+ influxes w hich were initially stimulated by the peptides. On the other hand, rep eated administrations of angiotensin II (but not of LyS2All) caused gr adual reduction of the contractile response and of the Na-24+ influx s timulation evoked by the agonist (tachyphylaxis). Treatment with phorb ol 12-13 dibutyrate accelerated the desensitization induced by both an giotensin II and by Lys2All and aggravated the tachyphylaxis to angiot ensin II. The results support the hypothesis that activation of protei n kinase C is responsible for the desensitization and that tachyphylax is is due to the slow dissociation of angiotensin II from a postulated Na+-dependent regulatory site on the receptor.