Cyclic GMP-dependent vasodilatory properties of LASSBio 294 in rat aorta.
. The effects of LASSBio 294, a new 3,4-methylenedioxybenzoyl-2-thienylhydrazone, on vascular tonus were investigated in isolated rat aortic rings. 2. LASSBio 294 induced a concentration-dependent relaxation of intact rat aortic rings with an inhibitory concentration (IC(50)) of 74 microM (95% confidence limits: 59 - 92). The mechanical removal of the endothelium abolished this effect. 3. In aortic rings with intact endothelium the effect of 100 microM LASSBio 294 was not altered by the pharmacological inhibition of NOS and cyclo-oxygenase pathways with 500 microM L-NAME and 10 microM indomethacin, respectively. 4. LASSBio 294 (100 microM) was able to relax aortic rings pre-contracted with high extracellular K(+) (KCl 100 mM). 5. The relaxant effect of LASSBio 294 was fully reversed (and prevented) by the addition of 1 microM ODQ (1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one), a selective inhibitor of soluble guanylate cyclase. 6. LASSBio 294 (100 microM) had no direct effect on PDE3 and PDE4 activities, however, it increased by 150% cyclic GMP content in aortic rings pre-treated with 100 microM L-NAME and 10 microM indomethacin, as did 1 microM zaprinast, a selective PDE5 inhibitor. 7. In conclusion, LASSBio 294 induced relaxation of isolated rat aorta probably by directly increasing cyclic GMP content, possibly as a consequence of PDE5 inhibition.
Silva
C L M
CL
Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Faculdade de Farmácia, Federal University of Rio de Janeiro, 21941-590, Brazil.
Noël
F
F
Barreiro
E J
EJ
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D006835:Hydrazones; C439284:LASSBio 294; D010069:Oxadiazoles; D011810:Quinoxalines; D013876:Thiophenes; D014665:Vasodilator Agents; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin