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 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 β2 adrenoceptors since they were abolished by the β2 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 β-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 α-adrenoceptors. The mesenteric vasoconstrictor effect of exendin-4 was unaffected by antagonism of α-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.
Footnotes
-
Some of these results have been presented to the British Pharmacological Society Meeting, July 2005, Cambridge, UK.
-
doi:10.1124/jpet.105.093104.
-
ABBREVIATIONS: GLP, glucagon-like peptide; propranolol, (RS)-1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-2-propanol; HDAS, hemodynamic data acquisition system; ICI 118551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol) hydrochloride; V1, vasopressin; AVP, arginine vasopressin; losartan, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl] imidazoline, potassium salt; BP, mean arterial blood pressure; phentolamine mesylate, (2-[N-(m-hydroxyphenyl)-p-toluidinomethyl]-imidazoline) methanesulfonate.
- Received July 22, 2005.
- Accepted October 11, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|