Regional haemodynamic effects of exendin-4 in conscious rats

T Bennett, J E March, P AKemp & S M Gardiner, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK.

The glucagon-like peptide (GLP) -1 receptor agonist, exendin-4, has pressor and tachycardic effects, likely due to sympathoadrenal activation (Yamamoto et al., 2002), although the associated haemodynamic changes have not been described. Therefore, we assessed the regional haemodynamic effects of exendin-4 in conscious, male Sprague-Dawley rats (350-450g).

Animals underwent a two-stage procedure for the implantation of pulsed Doppler flow probes (renal (R), mesenteric (M), hindquarters (H)) and, subsequently, intravascular catheters (jugular vein, distal aorta via caudal artery). All surgery was under general anaesthesia (fentanyl and medetomidine, 300 µg kg-1 of each i.p.) with post-operative anaesthetic reversal and analgesia provided by atipamezole and nalbuphine (1 mg kg-1 of each s.c.). At least 24h after catheter implantation, heart rate (HR), mean blood pressure (BP) and regional vascular conductances (VC) were measured with animals conscious and unrestrained, with free access to food and water. On Day 1, animals (n=8) were given 3 i.v. doses of exendin-4 (6, 60 and 600 pmol kg-1) in ascending order, with 1h between the first and second dose, and 3h between the second and third dose. On Days 2, 3 and 4, exendin-4 (60 pmol kg-1) was given in the presence of the β2-adrenoceptor antagonist, ICI 118551 (0.2 mg kg-1, 0.1 mg kg-1 h-1), propranolol (1 mg kg-1, 0.5 mg kg-1 h-1), and propranolol (dose as above) together with phentolamine (1 mg kg-1, 1 mg kg-1 h-1), respectively. Before intervention, resting cardiovascular variables (mean ± s.e. mean) were:- HR 324 ± 7 beats min-1, BP 106 ± 2 mmHg, RVC 70 ± 8, MVC 76 ± 6, HVC 44 ± 4 (kHz mmHg-1)103. Table 1 summarises some results.

Table 1. Changes in cardiovascular variables following administration of exendin-4 (60 pmol kg-1) in the absence (C) and presence of propranolol (Prop) and propranolol plus phentolamine (Prop + Phent). VC = vascular conductance. Values are mean ± s.e. mean. * P<0.05 vs baseline (Friedman’s test).

At 60 and 600 pmol kg-1, exendin-4 caused dose-related pressor and tachycardic effects, accompanied by hindquarters vasodilatation and renal and mesenteric vasoconstriction. Propranolol blocked the tachycardic and hindquarters vasodilator effects of exendin-4, and enhanced its pressor and renal and mesenteric vasoconstrictor actions (P<0.05 at 10 min (Friedman’s test)). Furthermore, in the presence of α- and β-adrenoceptor antagonism, exendin-4 still caused significant pressor and renal and mesenteric vasoconstrictor effects, which are likely due to mechanisms other than straightforward sympathoadrenal activation.

Yamamoto, H. et al. (2002). J. Clin. Invest., 110, 43-52.