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 Ϫ1 i.v., exendin-4 had little effect, but doses of 250 and 2500 ng kg Ϫ1 had significant tachycardic effects (ϩ66 Ϯ 9 and ϩ95 Ϯ 16 beats min Ϫ1 at 5 min, respectively) and pressor actions (ϩ10 Ϯ 2 and ϩ12 Ϯ 1 mm Hg), accompanied by substantial falls in mesenteric vascular conductance (Ϫ38 Ϯ 3% and Ϫ47 Ϯ 3%) and increases in hindquarters vascular conductance (ϩ82 Ϯ 14% and ϩ126 Ϯ 15%). The latter were likely due to adrenaline-mediated activation of ␤ 2 adrenoceptors since they were abolished by the ␤ 2 adrenoceptor antagonist, ICI 118551, and absent in adrenaldemedullated 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.Members of the superfamily of glucagon-related peptides include glucagon, glucagon-like peptide (GLP)-1, GLP-2, secretin, pituitary adenylate cyclase-activating polypeptide-27, and vasoactive intestinal polypeptide (for review, see Kieffer and Habener, 1999). It is now known that these peptide hormones are produced not only in the gastrointestinal tract but also in the peripheral and central nervous systems (for review, see Kieffer and Habener, 1999) and that, in addition to metabolic effects, they have significant cardiovascular actions, although these vary between the peptides (e.g., Gardiner et al., 1994).GLP-1 receptors are found not only in the pancreas but also in the stomach, lung, kidney, heart, and in several regions of the brain, many of which are intimately involved in cardiovascular regulation (for review, see Kieffer and Habener, 1999). Because of their beneficial effects on glucose metabolism, GLP-1 and other "incretin mimetics" are promising therapeutic agents for the treatment of type 2 diabetes (Drucker, 2001;Knudsen, 2004), but their potential cardiovascular actions and any underlying mechanisms have not been fully elucidated. Barragá n et al. (1994, 1996, 1999) performed a series of experiments concerned with the cardiovascular actions of the full-length GLP-1-(1-37), truncated GLP-1-(7-36) amide, and the structurally related pept...

Exendin-4 increases blood glucose levels acutely in rats by activation of the sympathetic nervous system

“…However, the role of brain GLP-1R signaling on glucose metabolism is complex since chronic central administration of a GLP-1R antagonist seems to have beneficial effects in mice fed a high-fat diet (22). Ex-4 activates the SNS when given peripherally or centrally to mice (40,41) and causes pressor and tachycardic responses in rats also through SNS activation (4,5,13,14). Our results are consistent with these earlier findings in that an increase in SNS activity of sufficient magnitude to raise blood pressure could also increase blood glucose likely through enhanced hepatic glucose production.…”

Insulin Inhibits and Oral Sucrose Increases Neointimal Growth after Arterial Injury in Rats

“…Glucose intake orally stimulates gastrointestinal hormones, such as glucagon-like peptide-1 and gastric inhibitory peptide, whose receptors are present in vascular cells. Glucagon-like peptide-1 has been reported to induce vasodilation [12,13] and improve endothelial function [14], whereas in dogs gastric inhibitory peptide was found to affect splanchnic hemodynamics [15]. Thus these hormones can have vascular actions, although their effect on neointimal growth has not been investigated.…”

Exenatide Improves Hypertension in a Rat Model of the Metabolic Syndrome

“…After a total of 7 days of exenatide treatment, hypertension was reduced hypertension in animals and humans 27 while glucocorticoid receptor blockade or adrenal insuffi ciency reduces blood pressure. 16,28 Furthermore, abdominal obesity and the metabolic syndrome associated with hypertension are affi liated with increased glucocorticoid activity. [29][30][31] Our results are consistent with a previous report showing in human diabetic subjects that 82 weeks of exenatide treatment resulted in clinically meaningful reductions in systolic and diastolic blood pressure in those subjects who had elevated blood pressures at baseline (>140 mmHg and…”

“…13 The GLP-1 receptor agonist exendin-4 is also reported to have direct cardiac and vasodilator effects. 16 However, previous reports have demonstrated increases in blood pressure and heart rate after acute systemic or intracerebroventricular administration of exendin-4 or GLP-1 in the rat. 17,18 This acute pressor effect appears to be species dependent and transient, 19 and may depend on the animal's physiological state, study conditions, or dosing regimen.…”

“…9 Long-term exenatide treatment improves blood pressure and cardiovascular risk factors in humans with type 2 diabetes, 10 a signifi cant observation given that these patients have a four-fold increased risk of cardiovascular comorbidities such as stroke or heart attack. 11 In parallel with its actions to improve insulin secretion and glucose use, GLP-1 has cardioprotective effects, [12][13][14] is associated with diuresis, 15 has direct cardiac and vasodilator effects, 12,16 and reduces peripheral vascular resistance in animals. 13 The GLP-1 receptor agonist exendin-4 is also reported to have direct cardiac and vasodilator effects.…”