Analysis of responses to big endothelin in the hindquarters vascular bed of the cat.

OBJECTIVE

To investigate vascular responses to the endothelin-1 (ET-1) precursor, human big endothelin 1-38 (big ET), in the peripheral vascular bed of the cat.

DESIGN

These studies were designed to investigate the hypothesis that bit ET is converted to an active peptide with properties similar to ET-1.

SETTING

Hindquarters vascular bed of the cat under conditions of controlled bloodflow; changes in perfusion pressure reflect changes in vascular resistance.

ANIMALS

Fifty-four adult mongrel cats.

INTERVENTIONS

Big ET, ET-1, the peptidases chymotrypsin, pepsin and cathepsin-D, and the metalloprotease inhibitor phosphoramidon.

MAIN RESULTS

Intra-arterial injections of big ET induced a slow-developing and sustained increase in hindquarters perfusion pressure which could be blocked by phosphoramidon. ET-1 (0.3 nmol), administered as a slow infusion over a 10-min period, produced a slowly developing increase in hindquarters perfusion pressure in a manner similar to that observed in response to injection of big ET. A bolus injection of ET-1 produced a biphasic response characterized by a transient decrease in pressure followed by an increase which was significantly greater in magnitude and more rapid in onset than the pressor response to big ET (0.3 nmol). After incubation of big ET with chymotrypsin, pepsin and cathepsin-D (each 5% weight/weight) for 30 mins at 37 degrees C, injection of activated big ET produced a biphasic response characteristic of the response to ET-1 with an initial transient decrease in pressure followed by a secondary increase in hindquarters perfusion pressure.

CONCLUSIONS

Big ET produces a phosphoramidon-sensitive pressor response which is similar to that produced by an infusion of ET-1. These data suggest that chymotrypsin, pepsin and cathepsin-D can convert big ET to an active peptide which elicits a biphasic response similar to that produced by ET-1.