Autonomic nervous system-dependent and -independent cardiovascular effects of exendin-4 infusion in conscious rats

Background and purpose: Glucagon-like peptide-1 (GLP) receptor agonists are promising therapeutic agents for the treatment of type II diabetes, but effects other than those on glucoregulation need assessing. Cardiovascular actions of bolus doses of the GLP receptor agonist exendin-4 have been reported, but to date the effects of continuous infusions have not been described. Experimental approach: The regional haemodynamic effects and possible underlying mechanisms of 6 h infusions of exendin-4 were measured in conscious, chronically instrumented rats. Key results: A 6 h infusion of exendin-4 (up to 6 pmol kg(-1) min(-1)) only modestly influenced blood pressure, but caused substantial, opposing, regionally selective vascular effects and tachycardia. A major involvement of beta-adrenoceptors in the vasodilator and cardiac effects was identified, with little or no direct contribution from alpha-adrenoceptors to the vasoconstriction seen. Under conditions where alpha-and alpha-adrenoceptors were antagonized, or when ganglionic transmission was blocked, a marked vasoconstrictor effect of exendin-4 was revealed in the mesenteric and hindquarters vascular beds (about 50% fall in vascular conductances). No role for endogenous angiotensin II, vasopressin, endothelin, neuropeptide Y or prostanoids could be shown in these vasoconstrictor actions of exendin-4. Conclusions and implications: The results show not only an important involvement of the autonomic nervous system in the cardiovascular actions of exendin-4 infusion but also an underlying non-autonomically mediated vasoconstrictor action, the mechanism of which remains to be identified.