BIG ENDOTHELIN-1 AND BIG ENDOTHELIN-3 ARE CONSTRICTOR AGENTS IN THE MICROVASCULATURE - EVIDENCE FOR THE LOCAL PHOSPHORAMIDON-SENSITIVE CONVERSION OF BIG ENDOTHELIN-1

The effect of local administration of big endothelin-1 (1-38, big ET-1) has been investigated on blood flow in the skin of anaesthetised rats, measured by Xe-133 clearance. The local effects of big ET-1 and big endothelin-3 (1-41, big ET-3) have also been determined on microvessel diameter by intravital microscopy of the cheek pouch of anaesthetised hamsters. Big ET-1 (i.d.) caused a dose-dependent decrease in skin blood flow and was 10 times less potent than endothelin-1 (ET-1). Phosphoramidon (30 nmol/site i.d.) did not effect blood flow but when coinjected selectively attenuated the effect of big ET-1 (1 and 3 pmol/site, P < 0.05). In the cheek pouch big ET-1 (100 pmol) induced an intense and long-lasting arteriolar constriction. Phosphoramidon (100 nmol) abolished constriction to big ET-1 (100 pmol) but not to ET-1 (10 pmol). The modest constriction induced by big ET-3 (300 pmol) was not inhibited by phosphoramidon (100 nmol). Results suggest that a phosphoramidon-sensitive endothelin-converting enzyme situated close to microvascular vessels is important in the conversion of big ET-1. The mechanism for activity of big ET-3 in the microcirculation is unclear.