Development of Tachyphylaxis to Aspartyl 1 and Not to Asparginyl 1 Angiotensin II in the Rat

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Abstract
Pressor responses to single increasing doses (0.001 to 10 µg) and constant infusions (0.01 to 5 mg/kg per hr) of synthetic aspartyl1 angiotensin II (Asp1) and asparginyl1 angiotensin II (Aspg1, Hypertensin, CIBA) were measured in normal and nephrectomized rats. Mean blood pressure was recorded directly using strain gauges. Angiotensin tachyphylaxis (decline of maximal response to increasing doses, or return of blood pressure to control levels on constant infusion) was consistently seen with greater than minimal doses of Asp1 while the phenomenon was not observed with Aspg1 at any dose level. The results indicate that in the rat the two octapeptide analogues of angiotensin are not identical in biologic activity as has been previously held, and that the N-terminal amino acid plays an important part in determining the pressor responsiveness especially to higher doses of angiotensin peptides. The pattern of response and development of tachyphylaxis to Asp1 closely resembles that of well known tachyphylaxis to renin. These results lend further support to our earlier findings that Asp1 represents the natural form of angiotensin released in vivo. Renin tachyphylaxis may in its entirety be explained to depend upon the actions of Asp1 released by renin in plasma. Tachyphylaxis to endogenous angiotensin in pathologic as well as certain physiologic conditions may be expected to occur at lower dose levels than is indicated by the available experimental work with Aspg1.

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