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

Simultaneous recordings of the tension and intracellular Ca2+ concentration of guinea-pig ileum longitudinal smooth muscle strips, as well as Na-24+ and Ca-45(2+) influx measurements in cultured myocytes from the same tissue, were used to investigate the mechanisms underlying angiotensin-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 response (desensitization) and reappearance of the intracellular Ca2+ concentration oscillations, which were inhibited during the initial increase in cytosolic Ca2+. The desensitization was paralleled, in cultured myocytes, by inhibition of the Ca-45(2+) but not of the Na-24+ influxes which were initially stimulated by the peptides. On the other hand, repeated administrations of angiotensin II (but not of LyS2All) caused gradual reduction of the contractile response and of the Na-24+ influx stimulation evoked by the agonist (tachyphylaxis). Treatment with phorbol 12-13 dibutyrate accelerated the desensitization induced by both angiotensin II and by Lys2All and aggravated the tachyphylaxis to angiotensin II. The results support the hypothesis that activation of protein kinase C is responsible for the desensitization and that tachyphylaxis is due to the slow dissociation of angiotensin II from a postulated Na+-dependent regulatory site on the receptor.