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Open Access Highly Accessed Original investigation

Exenatide induces aortic vasodilation increasing hydrogen sulphide, carbon monoxide and nitric oxide production

Eszter Sélley1, Szilárd Kun1, István András Szijártó2, Boglárka Laczy1, Tibor Kovács1, Ferenc Fülöp3, István Wittmann1* and Gergő A Molnár1

Author Affiliations

1 2nd Department of Medicine and Nephrological Center, University of Pécs, Hungary, 1. Pacsirta St., H-7624 Pécs, Hungary

2 Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum and Experimental and Clinical Research Center (ECRC), Max Delbrück Center for Molecular Medicine, Berlin, Germany

3 Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary

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Cardiovascular Diabetology 2014, 13:69  doi:10.1186/1475-2840-13-69

Published: 2 April 2014

Abstract

Background

It has been reported that GLP-1 agonist exenatide (exendin-4) decreases blood pressure. The dose-dependent vasodilator effect of exendin-4 has previously been demonstrated, although the precise mechanism is not thoroughly described. Here we have aimed to provide in vitro evidence for the hypothesis that exenatide may decrease central (aortic) blood pressure involving three gasotransmitters, namely nitric oxide (NO) carbon monoxide (CO), and hydrogen sulphide (H2S).

Methods

We determined the vasoactive effect of exenatide on isolated thoracic aortic rings of adult rats. Two millimetre-long vessel segments were placed in a wire myograph and preincubated with inhibitors of the enzymes producing the three gasotransmitters, with inhibitors of reactive oxygen species formation, prostaglandin synthesis, inhibitors of protein kinases, potassium channels or with an inhibitor of the Na+/Ca2+-exchanger.

Results

Exenatide caused dose-dependent relaxation of rat thoracic aorta, which was evoked via the GLP-1 receptor and was mediated mainly by H2S but also by NO and CO. Prostaglandins and superoxide free radical also play a part in the relaxation. Inhibition of soluble guanylyl cyclase significantly diminished vasorelaxation. We found that ATP-sensitive-, voltage-gated- and calcium-activated large-conductance potassium channels are also involved in the vasodilation, but that seemingly the inhibition of the KCNQ-type voltage-gated potassium channels resulted in the most remarkable decrease in the rate of vasorelaxation. Inhibition of the Na+/Ca2+-exchanger abolished most of the vasodilation.

Conclusions

Exenatide induces vasodilation in rat thoracic aorta with the contribution of all three gasotransmitters. We provide in vitro evidence for the potential ability of exenatide to lower central (aortic) blood pressure, which could have relevant clinical importance.

Keywords:
Glucagon-like-peptide-1; Exenatide; Vasodilation; Aortic rings; Central blood pressure