Stimulation of intestinal sodium and water transport in vivo by angiotensin II and analogs.

Abstract

Studies in pressor and myotropic preparations employing analogs of angiotensin II (A II) demonstrate that the carboxy-terminal amino acid residue, phenylalanine, is essential for the hormonal response. The present study demonstrates that important differences exist between the structural requirements for stimulation of intestinal fluid absorption and those for pressor and myotropic systems. Phenylalanine can be replaced with the aliphatic amino acids, leucine, alanine, or glycine, and by aamino-butyric acid with retention of full agonist activity, but with some variation in the relative potencies of these compounds in stimulating rat intestinal fluid transfer. Certain similarities exist for structural modification of other important residues, as [D-Pya6]A II and [Phe4, Ala8]A II were essentially inactive on all three biological systems. The analogs studied exhibited the following order of potency in stimulating intestinal transport: [Abu8]A II, [Sar1 Leu8]A II > [Sar1, Gly8]A II > [Asp1, lle5]A II > [Asn1, Val5]A II > [Sar1]A II > [Leu8]A II > [Ala8]A II. Thus, the presence of sarcosine as the amino-terminal amino acid residue imparts greater potency to the eight substituted analogs but not to the parent peptide. To determine if A II and two of the most potent eight-substituted analogs were acting via a similar mechanism to stimulate intestinal absorption, two criteriacharacteristic of this response were used, namely whether the response is abolished by pretreatment with cycloheximide and if electroneutral transfer was involved. The stimulation of absorption by A II and the two eight-substituted analogs was abolished by cycloheximide, and all three exhibited electroneutral transfer, providing evidence that these peptides act via a similar mechanism. These data demonstrate the existence of unique receptor interactions for the action of A II in stimulating rat intestinal fluid absorption and have an important implication with respect to the use of angiotensin analogs to define the role of angiotensin in various biological systems.