Diethyl-4,4′-dihydroxy-8,3′-neolign-7,7′-dien-9,9′-dionate exhibits antihypertensive activity in rats through increase in intracellular cGMP level and blockade of calcium channels

We report here the antihypertensive and vasorelaxant potential of some steroidal and non-steroidal compounds identified through a library of compounds. All the novel analogues showed vasorelaxant potential in isolated rat aorta. The most potent lead neolignanl (Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate) produced concentration dependent relaxation with [pD(2) 5.16 +/- 0.05; n=16 and E-max 96.97% +/- 1.12%; n=16]. The neolignanl relaxation is independent of endothelium and is sensitive to ODQ (1H-[1, 2, 4] oxadiazolo [4, 3-a] quinoxalin-1-one; a blocker of soluble guanylyl cyclase (sGC) which synthesizes cGMP (cyclic guanosine monophosphate)). ELISA analysis of treated arterial tissues, showed concentration-dependent increase in cGMP level in treated tissues compared to control (2.03 and 7.16 fold of control at 10 and 30 04 of neolignanl, respectively) and a synergistic increase in cGMP level by 26.66 fold compared to control when used in combination with sildenafil (10 mu M; a known inducer of cGMP level by selectively blocking cGMP specific phosphodiesterase 5). Our present study reports for the first time that neolignans produce,relaxation in isolated rat aorta through increase in intracellular cGMP level. The ODQ resistant relaxation of neolignanl is mediated by blockade of voltage dependent L-type calcium channel (VDCC) as observed in the experiment with CaCl2. Neolignanl upon intravenous administration via tail vein in Spontaneously Hypertensive Rats (SHR) produced significant decrease in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP). The present study concludes that neolignanl exhibited antihypertensive potential in rats through rise in intracellular cGMP and blockade of VDCC.