Received for publication July 22, 2005.
Revised October 10, 2005.
Accepted for publication October 11, 2005.

Mesenteric vasoconstriction and hindquarters vasodilatation accompany the pressor actions of exendin-4 in conscious rats

Abstract

The hemodynamic effects of the glucagon-like peptide-1 (GLP-1) receptor agonist, exendin-4, and putative underlying mechanisms, were assessed in conscious male Sprague-Dawley rats. At a dose of 25 ng kg^-1 i.v., exendin-4 had little effect but doses of 250 and 2500 ng kg^-1 had significant tachycardic effects (+66 ± 9 and + 95 ± 16 beats min^-1 at 5 min, respectively) and pressor actions (+10 ± 2 and +12 ± 1 mmHg), accompanied by substantial falls in mesenteric vascular conductance (-38 ± 3 and -47 ± 3 %) and increases in hindquarters vascular conductance (+82 ± 14 and +126 ± 15%). The latter were likely due to adrenaline-mediated activation of ₂ adrenoceptors since they were abolished by the ₂ adrenoceptor antagonist, ICI 118551 (or propranolol), and absent in adrenal-demedullated rats. In the presence of -adrenoceptor antagonism, the tachycardic effects of exendin-4 were suppressed, but the pressor action was enhanced. Enhancement of the pressor action of exendin-4 was not seen in adrenal-demedullated rats, or in animals given phentolamine in addition to propranolol, consistent with a component of the pressor action of exendin-4 being due to an adrenaline-mediated positive inotropic effect mediated by -adrenoceptors. The mesenteric vasoconstrictor effect of exendin-4 was unaffected by antagonism of -adrenoceptors, vasopressin (V₁) receptors, angiotensin (AT₁) receptors or GLP-1 receptors, although the latter substantially inhibited the hindquarters vasodilator effects of exendin-4. These results are consistent with exendin-4 having cardiovascular effects through GLP-1 receptor-dependent and -independent mechanisms, some of which involve sympathoadrenal activation.

Key words: adrenal medulla, exendin-4, glucagon-like peptide, hemodynamics, vasoconstriction, vasodilatation