Possible involvement of GLP‐1(9–36) in the regional haemodynamic effects of GLP‐1(7–36) in conscious rats

Abstract

The incretin hormone, glucagon-like peptide (GLP)-1(7-36), is rapidly cleaved by dipeptidyl peptidase 4 (DPP-4) into GLP-1(9-36), and although it is agreed that most, if not all, of the metabolic effects are attributable to the intact peptide, the degree to which the cardiovascular effects are due to the cleavage product is unclear. The purpose of this study was to measure the regional haemodynamic effects of GLP-1(7-36), and determine the extent to which the cardiovascular effects of GLP-1(7-36) were influenced by DPP-4 inhibition and reproduced by GLP-1(9-36). Additional experiments investigated the involvement of autonomic mechanisms in the cardiovascular effects of GLP-1(7-36). EXPERIMENTAL APPROACHRegional haemodynamic effects of bolus doses and 4 h infusions of GLP-1(7-36) amide and GLP-1(9-36) amide were measured in conscious, chronically instrumented rats; the influence of DPP-4 inhibition and autonomic blockade on responses to GLP-1(7-36) were also assessed. KEY RESULTSGlucagon-like peptide-1(7-36) had clear regional haemodynamic effects comprising tachycardia, a rise in blood pressure, renal and mesenteric vasoconstriction and hindquarters vasodilatation, whereas GLP-1(9-36) was devoid of any cardiovascular actions. The effects of GLP-1(7-36) were enhanced by DPP-4 inhibition, and the tachycardia and hindquarters vasodilatation were b-adrenoceptor-mediated. CONCLUSIONS AND IMPLICATIONSIn conscious rats, the cardiovascular effects of GLP-1(7-36) resemble those of the GLP analogue, exendin-4, and are attributable to the intact peptide rather than the cleavage product, GLP-1(9-36).

Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow

“…Whether the observed increase in blood pressure is due to an increased cardiac output or to an increase in peripheral resistance cannot be determined from the present results. Blood pressure increases after acute intravenous infusion of GLP-1 or exendin-4 have been observed in both conscious (13) and anesthetized normotensive rats (3,4,44). In healthy humans, GLP-1 transiently increases HR (41) or both HR and MAP (11).…”

“…In our study, GLP-1 (9 -36)amide did not affect RBF or RVR in vivo, which could be due to differences between the investigated vascular beds. Gardiner et al (13) found no vascular effects of GLP-1 (9 -36)amide in conscious rats in an investigation of the renal and mesenteric circulation. However, they did report vasoconstriction in response to GLP-1 in the renal and mesenteric circulation, which may relate to the experiments being performed in conscious rather than anesthetized rats.…”

“…In normotensive animals, GLP-1 increases blood pressure and HR (4,13), whereas in hypertensive models, GLP-1 receptor activation reduces arterial blood pressure (23,26,30). In a clinical study (28) where patients with type 2 diabetes mellitus were treated with GLP-1 receptor agonists, blood pressure was generally reduced.…”

Effects of exogenous glucagon-like peptide-1 on blood pressure, heart rate, gastric emptying, mesenteric blood flow and glycaemic responses to oral glucose in older individuals with normal glucose tolerance or type 2 diabetes

“…GLP-1 and GLP-1 receptor (GLP-1R) agonists induce a sustained elevation of BP in rodents [2,3,27], attributable to central and peripheral mechanisms, but not in largeranimal models [28] or apparently humans [29,30]. However, in a recent study, a modest (~5 mmHg) increase in systolic (but not diastolic) BP, associated with an increase in cardiac output attributable to rises in stroke volume as well as HR, was evident in healthy middle-aged men in response to an i.v.…”

DPP 4 (dipeptidylpeptidase-4) inhibitors: beyond glycemic control

“…Thus long-term DPP-4 inhibition may have clinical benefits and/or consequences including cardioprotective actions. Effects on contractility, blood pressure, cardiac output and cardioprotection appear to be independent of diabetes [12][13][14][15][16][17][18][19] . A few studies have been published on cardioprotective effect of GLP-1 analogues and DPP 4 inhibitors.…”