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

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 mm Hg), accompanied by substantial falls in mesenteric vascular conductance ( -38 +/- 3% and -047 +/- 3%) and increases in hindquarters vascular conductance ( +82 +/- 14% and +126 +/- 15%). The latter were likely due to adrenaline-mediated activation of beta(2) adrenoceptors since they were abolished by the beta(2) adrenoceptor antagonist, ICI 118551 [( +/-)-1-[ 2,3-( dihydro-7methyl-1H-inden-4-yl) oxy]-3-[( 1-methylethyl) amino]-2-butanol) hydrochloride], or propranolol [( RS)-1-[( 1-methylethyl) amino]-3( 1-naphthalenyloxy)-2-propanol], and absent in adrenaldemedullated rats. In the presence of beta-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 alpha-adrenoceptors. The mesenteric vasoconstrictor effect of exendin-4 was unaffected by antagonism of alpha-adrenoceptors, vasopressin receptors, angiotensin receptors, or GLP- 1 receptors, although antagonism of the latter substantially inhibited the hindquarter 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.