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 neolignan1 (Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate) produced concentration dependent relaxation with [pD25.16±0.05; n=16 and Emax96.97%±1.12%; n=16]. The neolignan1 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 30µM of neolignan1, respectively) and a synergistic increase in cGMP level by 26.66 fold compared to control when used in combination with sildenafil (10µM; 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 neolignan1 is mediated by blockade of voltage dependent L-type calcium channel (VDCC) as observed in the experiment with CaCl2. Neolignan1 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 neolignan1 exhibited antihypertensive potential in rats through rise in intracellular cGMP and blockade of VDCC.
Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
Arjun
A
Singh
Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
B Sathish
BS
Kumar
Molecular and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
Sarfaraz
S
Alam
Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
Hina
H
Iqbal
Division of Pharmacology, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
Mohammad
M
Shafiq
Molecular and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
Feroz
F
Khan
Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
Arvind S
AS
Negi
Division of Pharmacology, CSIR-Central Drug Research Institute, B.S. 10/1, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
Kashif
K
Hanif
Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India. Electronic address: d.chanda@cimap.res.in.
Debabrata
D
Chanda
D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D003373:Coumaric Acids; D006152:Cyclic GMP / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism*; D017705:Lignans / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D062105:Molecular Docking Simulation; D015221:Potassium Channels / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D011918:Rats, Inbred SHR; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003373:Coumaric Acids; D017705:Lignans; D015221:Potassium Channels; C000591907:diethyl 4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate; D006152:Cyclic GMP
Blood pressure; Neolignans; Rat aorta; VDCC; cGMP; sGC