Role of Na⁺ and protein kinase C in angiotensin desensitization and tachyphylaxis in the guinea-pig ileum

Summary

Simultaneous recordings of the tension and intracellular Ca²⁺ concentration of guinea-pig ileum longitudinal smooth muscle strips, as well as ²⁴Na⁺ and ⁴⁵Ca²⁺ 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 ⁴⁵Ca²⁺ but not of the ²⁴Na⁺ 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 ²⁴Na⁺ 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.