Cyclic GMP‐dependent vasodilatory properties of LASSBio 294 in rat aorta

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Abstract
The effects of LASSBio 294, a new 3,4‐methylenedioxybenzoyl‐2‐thienylhydrazone, on vascular tonus were investigated in isolated rat aortic rings. LASSBio 294 induced a concentration‐dependent relaxation of intact rat aortic rings with an inhibitory concentration (IC50) of 74 μM (95% confidence limits: 59 – 92). The mechanical removal of the endothelium abolished this effect. In aortic rings with intact endothelium the effect of 100 μM LASSBio 294 was not altered by the pharmacological inhibition of NOS and cyclo‐oxygenase pathways with 500 μM L‐NAME and 10 μM indomethacin, respectively. LASSBio 294 (100 μM) was able to relax aortic rings pre‐contracted with high extracellular K+ (KCl 100 mM). The relaxant effect of LASSBio 294 was fully reversed (and prevented) by the addition of 1 μM ODQ (1H‐(1,2,4)oxadiazolo[4,3‐a]quinoxaline‐1‐one), a selective inhibitor of soluble guanylate cyclase. LASSBio 294 (100 μM) had no direct effect on PDE3 and PDE4 activities, however, it increased by 150% cyclic GMP content in aortic rings pre‐treated with 100 μM L‐NAME and 10 μM indomethacin, as did 1 μM zaprinast, a selective PDE5 inhibitor. In conclusion, LASSBio 294 induced relaxation of isolated rat aorta probably by directly increasing cyclic GMP content, possibly as a consequence of PDE5 inhibition. British Journal of Pharmacology (2002) 135, 293–298; doi:10.1038/sj.bjp.0704473

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