Vasodilatory activity and antihypertensive profile mediated by inhibition of phosphodiesterase type 1 induced by a novel sulfonamide compound

Fundamental & Clinical Pharmacology 26 (2012) 690–700.

Luana B. Pontesa, Fernanda Antunesb, Roberto T. Sudoa,c, Juliana M. Raimundoa, Lidia M. Limaa,d, Eliezer J. Barreiroa,d, Gisele Zapata-Sudoa,c

aPrograma de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

bLaboratório de Clínica e Cirurgia Animal, Universidade Estadual Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, RJ, Brazil

cPrograma de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

dPrograma de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

 

Abstract

LASSBio-985 is a sulfonamide compound designed as a simplified structure of a nonselective phosphodiesterase type 4 (PDE-4) inhibitor that promotes vasodilatory activity in vitro. PDE are enzymes responsible for the hydrolysis of cyclic adenosine 3’,5’-monophosphate and cyclic guanosine 3’,5’-monophosphate. Five different isozymes of PDE are found in vascular smooth muscle (PDE1–PDE5). Aortic rings, with or without endothelium, from male normotensive and spontaneously hypertensive rats (SHR) were prepared for isometric tension recording. Blood pressure was measured in Wistar Kyoto (WKY) rats and SHR during intravenous infusion of LASSBio-985 (10 mg/kg/min) during 15 min. LASSBio-985 induced a concentration-dependent vasodilation in aortic rings from normotensive and SHR, which was almost completely inhibited in endothelium-denuded vessels. Vasodilatory activity was also reduced in endothelium-intact aortic rings that had been pretreated with N-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric oxide synthase inhibitor and 1H-[1,2,4]oxadiazolod[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. LASSBio-985-induced vasodilation was also inhibited by sildenafil (100 µM) and SQ 22536, a PDE-5 inhibitor and adenylate cyclase inhibitor, respectively. To evaluate the involvement of some endothelial receptors, atropine, diphenhydramine, HOE 140, naloxone, propranolol, indomethacin, and wortmannin were tested, but none inhibited the effects of LASSBio-985. The residual effect observed on endothelium-denuded aortic rings was abolished by nicardipine, a voltage-sensitive-Ca2+-channel blocker. Intravenous infusion of LASSBio-985 (10 mg/kg/min) significantly reduced systolic and diastolic pressures in both WKY and SHR. LASSBio-985 is a compound with vasodilatory activity, which could be consequent to PDE-1 inhibition and voltage sensitive- Ca2+-channel blockade.

PMID: 22066694

 

Supplement:

Figure 1A shows the tridimensional structure of N-(3,4-dimethoxyphenethyl) methanesulfonamide (LASSBio-985): a novel PDE-1 inhibitor, which induces vasodilator and antihypertensive actions. Figure 1B shows a scheme of the activity of LASSBio-985 in vascular smooth muscle cells. This substance inhibits PDE-1 and increases cyclic GMP (cGMP), which activates cGMP-dependent protein kinase (PKG). PKG activates myosin light chain (MLC) phosphatase and inhibits MLC kinase. In addition, PKG activates potassium channels, reducing membrane potential that leads to the blockade of L-type calcium channels. All these events promote vascular relaxation.

Gisele Zapata Sudo-2

Figure 1: Panel A: Tridimensional structure of LASSBio-985. Panel B: Inhibition of PDE1 by LASSBio-985 in vascular smooth muscle cells. RS: sarcoplasmic reticulum; CaM: calmodulin; GC: guanylate cyclase; cGMP: cyclic guanosine monophosphate; PKG: cGMP-dependent protein kinase; PDE1: phosphodiesterase type 1; Vm: membrane potential; MLC: myosin light chain.

 

Acknowledgements

This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação Universitária Jose Bonifácio (FUJB), Instituto Nacional de Ciência e Tecnologia (INCT), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Programa de Apoio a Núcleos de Excelência (PRONEX).

 

Contact

Dr. Gisele Zapata-Sudo

gsudo@farmco.ufrj.br

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