The paradoxical vascular interactions between endothelin-1 and calcitonin gene-related peptide in the rat gastric...

1. The interactions between local intra-arterial infusion of endothelin-1 (ET-1) and rat alpha-calcitonin gene-related peptide (alpha-CGRP) on gastric mucosal damage and blood flow have been investigated in the pentobarbitone-anaesthetized rat. 2. Close-arterial infusion of ET-1 (2-200 pmol kg-1 min-1) induced a significant and dose-dependent increase in gastric mucosal haemorrhagic injury. 3. Close-arterial infusion of the higher doses of ET-1 (100 and 200 pmol kg-1 min-1) resulted in a biphasic effect on mucosal blood flow, as determined by laser Doppler flowmetry (LDF). This consisted of an initial transient increase followed by a pronounced and sustained fall in LDF. 4. Local microvascular constriction may thus contribute to the mechanisms underlying the gastric injury induced by these higher doses of ET-1. 5. However, close-arterial infusion of lower doses of ET-1 (2-50 pmol kg-1 min-1), that also provoked substantial mucosal damage, induced only a sustained and significant mucosal hyperaemia, which may be secondary to microvascular injury. 6. Concurrent dose-arterial administration of rat alpha-CGRP (50 pmol kg-1 min-1) significantly inhibited the extent of gastric mucosal injury induced by ET-1 (5 pmol kg-1 min-1). 7. Furthermore, concurrent close-arterial infusion of this dose of alpha-CGRP, which itself increased mucosal LDF, significantly inhibited the hyperaemic response induced by close-arterial infusion of ET-1 (5 pmol kg-1 min-1). 8. These results indicate a damaging action on the gastric mucosa by low doses of ET-1 which is independent of local vasoconstriction, that may involve a direct injury of the microvascular endothelium. The protective action of alpha-CGRP thus seems unlikely to be due to a local vasodilator effect but may reflect protective actions on the microvascular endothelium