Interactions of exendin-(9–39) with the effects of glucagon-like peptide-1-(7–36) amide and of exendin-4 on arterial blood pressure and heart rate in rats

Abstract

This study was designed to determine the interactions of peptide exendin-(9–39) with the effect of glucagon-like peptide-1-(7–36) (GLP-1 (7–36)) amide and of exendin-4 on arterial blood pressure and heart rate in the rat. Both GLP-1 (7–36) amide and exendin-4 produced a dose-dependent increase in systolic, diastolic and mean arterial blood pressure, as well as in heart rate, although the effect of exendin-4 was more prolonged. These data indicate a longer functional half-life in vivo for exendin-4 as compared to GLP-1 (7–36) amide, which may have therapeutical applications. The antagonist effect of exendin-(9–39) on these cardiovascular parameters was also tested with 3000 ng of exendin-(9–39) intravenously administered 5 min before i.v. injection of 10 ng of either GLP-1 (7–36) amide or exendin-4. Under these experimental conditions the effect of the latter two peptides on arterial blood pressure and heart rate was blocked. By contrast, single administration of exendin-(9–39) did not modify cardiovascular parameters. These findings indicate that exendin-4 is an agonist and that exendin-(9–39) is an antagonist of the action of GLP-1 (7–36) amide on arterial blood pressure and heart rate. Therefore, the action of GLP-1 (7–36) amide on these parameters seems to be mediated through its own receptors.

Introduction

Glucagon-like peptide ((GLP)-1) (7–36) amide is derived from the post-translational processing of proglucagon in intestinal L-cells [1]and in discrete areas of rat brain 2, 3and is considered to be the member of the family of glucagon and related peptides with the highest biological activity. Thus, GLP-1 (7–36) amide is a powerful stimulus for glucose-dependent insulin secretion by pancreatic B-cells [4]and for the inhibition of pentagastrin-stimulated gastric acid secretion [5], while in the central nervous system it induces a selective release of glutamine and glutamic acid by the caudate-putamen of the conscious rat [6]. GLP-1 (7–36) amide binding sites have been characterized in rat insulinoma cells [7], rat gastric glands [8]and lung [9], adipocyte [10]and brain 11, 12rat membranes.

Although glucagon and glucagon-like peptides have structural similarities, they behave in different ways as regards cardiovascular parameters. Glucagon has positive inotropic and chronotropic effects [13]; it also produces a slight but significant increase in arterial blood pressure in normal individuals [14]and affects regional blood circulation [15]. GLP-1 (1–37) produces a moderate but significant increase in both systolic and diastolic blood pressure while GLP-2 has no effect on these parameters [16]. In contrast, GLP-1-(7–36) amide induces a concentration-dependent increase in systolic and diastolic blood pressure and heart rate, at both physiological and pharmacological doses [16].

Descriptions of exendin-4 and exendin-(9–39) as agonists and antagonists, respectively of GLP-1 (7–36) amide provide a good tool for the characterization, both in vivo and in vitro, the physiological effects of the latter peptide. Exendin-4 is a 39-amino-acid peptide that has been purified from H. suspectum venom [17]and its shares 53% structure homology with GLP-1 (7–36) amide. Both exendin-4 and GLP-1 (7–36) amide compete specifically with the GLP-1 receptor from different cell-types [7]. Like GLP-1 (7–36) amide, exendin-4 has a pronounced effect on the production of cyclic AMP and stimulates glucose-induced insulin secretion by pancreatic rat islets [7]. These effects are significantly reduced by exendin-(9–39) [7].

Taking the above into consideration, we investigated the effects of GLP-1 (7–36) amide, exendin-4 and exendin-(9–39) on arterial blood pressure and heart rate, observing that exendin-4 is an agonist and exendin-(9–39) is an antagonist of the action of GLP-1 (7–36) amide on both cardiovascular parameters.