Effects of [Sar1] Angiotensin II on Proenkephalin Gene Expression and Secretion of [Met5]Enkephalin in Bovine Adrenal Medullary Chromaffin Cells

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Abstract
We have studied the effect of [Sar1]angiotensin II [S1-AII; a degradation-resistant analogue of angiotensin II (All)] on the release of [Met5]enkephalin (ME) and proenkephalin A (proENK) gene expression. Short-term (15-min to 1-h) stimulation of bovine adrenal medullary chromaffin (BAMC) cells with S1-AII at concentrations from 0.1 to 100 nM had no significant effect on secretion of ME, whereas high concentrations of S1-AII (3 to 100 μM) produced a concentration-dependent increase in the concentration of ME in the incubation media. In contrast, long-term (3- to 24-h) stimulation with low concentrations (0.1 nM-1μM) of S1-AII increased the secretion of ME in a concentration-dependent manner (EC50= 1 nM). The intracellular level of ME was not changed by long-term treatment with S1-AII (100 nM). In addition to increased ME secretion, long-term (24-h) stimulation with S1-AII increased the expression of proENK mRNA in a concentration-dependent manner (EC50= 4 nM). Losartan (2-n-butyl-4 chloro-5-hydroxy-methyl-l-[(2′-(l H-tetrazol-5-yl)biphenyl-4-yl)-meth-yl]imidazole potassium salt, a type 1 All receptor antagonist inhibited these effects, whereas PD123319 (50 μM, a type 2 All receptor antagonist) was inactive. Our results suggest that All in BAMC cells exerts a major effect on the long-term regulation of expression of proENK mRNA and secretion of ME. These effects appear to be mediated by type 1-like All receptors.