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β-Resorcylidene aminoguanidine (RAG) dilates coronary arteries in an endothelium-independent manner

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Abstract

Background

β-Resorcylidene aminoguanidine (RAG), a highly reactive derivative of aminoguanidine, possesses antithrombotic activity which involves the activation of the vascular COX-2/PGI2 pathway. This endothelium-dependent effect suggests that RAG may demonstrate vasomotor activity in arterial vessels. The aim of the present study was to investigate a possible vasoactive action of RAG in coronary arteries of rat heart.

Methods

Isolated rat hearts were perfused in the Langendorff model. To investigate the dose dependency of the effect of RAG on coronary flow, the hearts were perfused with RAG at increasing concentrations. Mechanisms of RAG-mediated vasodilation were subsequently tested using selective inhibitors of the endothelium-dependent and endothelium-independent mechanisms responsible for regulation of vascular tone.

Results

RAG dilated coronary arteries at concentrations above 10−5 mol/l. Inhibition of the endothelium-dependent mechanism of vasodilation by NG-nitro-l-arginine methyl ester, indomethacin and aminobenzotriazole did not affect RAG-mediated vasodilation. Other compounds also had no impact on the vasodilating effect of RAG: the NO-dependent guanylate cyclase inhibitor – 1H-[1,2,4]oxadiazolo[4,3]quinoxalin-1-one, the cAMP-dependent protein kinase inhibitor – PKAi, and the K+ channel blockers – glibenclamide, tetraethylammonium, charybdotoxin, and apamin.

Conclusions

RAG is a strong vasodilator that exerts its effect via endothelium-independent mechanisms.

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Abbreviations

ABT:

1-aminobenzotriazole

AG:

aminoguanidine

AGE:

advanced glycation endproduct

BAG:

2,5-dihydroxybenzylidene

BK:

bradykinin

CCB:

calcium channel blocker

CF:

coronary flow

cGMP:

cyclic guanosine monophosphate

ChTx:

charybdotoxin

COX-2:

cyclooxygenase

CYP:

cytochrome P450

DEA/NO:

diethylamine NONOate diethylammonium salt

EDHF:

endothelium-derived hyperpolarizing factor

eNOS:

endothelial nitric oxide synthase

GC:

guanylate cyclase

iNOS:

inducible nitric oxide synthase

KATP:

ATP-dependent K+ channel

K-H:

Krebs–Henseleit bicarbonate buffer

L-NAME:

NG-nitro-l-arginine methyl ester

NO:

nitric oxide

ODQ:

1H-[1,2,4]Oxadiazolo[4,3]quinoxalin-1-one

PAG:

pyridoxal aminoguanidine

PGI2:

prostacyclin

PKi:

protein kinase A inhibitor

RAG:

β-resorcylidene aminoguanidine

RAS-on:

resorcylidene semicarbazone

TEA:

tetraethylammonium

VSMCs:

vascular smooth muscle cells

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Authors and Affiliations

  1. Department of Haemostatic Disorders, Medical University of Lodz, Łódź, Poland

    Piotr A. Kazmierczak, Tomasz Przygodzki & Cezary Watala

  2. Department of Cardiosurgery, Polish Mother’s Memorial Hospital – Research Institute, Łódź, Poland

    Piotr A. Kazmierczak

  3. Department of Medicine, Baylor College of Medicine, Houston, USA

    Marcin P. Dobaczewski

  4. Department of Medical Chemistry, Biochemistry and Clinical Biochemistry, Comenius University, Faculty of Medicine, Bratislava, Slovakia

    Marcin P. Dobaczewski & Jozef Carsky

Authors
  1. Piotr A. Kazmierczak
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  2. Marcin P. Dobaczewski
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  3. Tomasz Przygodzki
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  4. Jozef Carsky
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  5. Cezary Watala
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Correspondence to Piotr A. Kazmierczak.

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Kazmierczak, P.A., Dobaczewski, M.P., Przygodzki, T. et al. β-Resorcylidene aminoguanidine (RAG) dilates coronary arteries in an endothelium-independent manner. Pharmacol. Rep 67, 631–635 (2015). https://doi.org/10.1016/j.pharep.2015.01.003

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  • DOI: https://doi.org/10.1016/j.pharep.2015.01.003

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