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CARDIOVASCULAR

Mesenteric Vasoconstriction and Hindquarters Vasodilatation Accompany the Pressor Actions of Exendin-4 in Conscious Rats

Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom

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 -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 [(±)-1-[2,3-(dihydro-7-methyl-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 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 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.

Address correspondence to: Prof. Sheila M. Gardiner, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK. E-mail: sheila.gardiner{at}nottingham.ac.uk