Activation of nitric oxide signaling pathway mediates hypotensive effect of Muntingia calabura L. (Tiliaceae) leaf extract.
The cardiovascular effect of the crude methanol extract from the leaf of Muntingia calabura L. (Tiliaceae) was investigated in the anesthetized rats. The crude methanol extract was sequentially fractionated to obtain the water-soluble extract (WSE). Intravenous administration of the WSE (10, 25, 50, 75 or 100 mg/kg) produced an initial followed by a delayed decrease in systemic arterial pressure (SAP) in a dose-dependent manner. The M. calabura-induced initial hypotension lasted for 10 min and the delayed depressor effect commenced after 90 min and lasted for at least 180 min post-injection. The same treatment, on the other hand, had no appreciable effect on heart rate (HR) or the blood gas/electrolytes concentrations. Both the initial and delayed hypotensive effects of WSE (50 mg/kg, i.v.) were significantly blocked by pre-treatment with a nonselective nitric oxide (NO) synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester ((L)-NAME, 0.325 mg/kg/min for 5 min) or a soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazole[4,3-alpha]quinoxalin-1-one (ODQ, 0.2 mg/kg/min for 5 min). Moreover, whereas the initial depressor effect of WSE was inhibited by pre-treatment with a selective endothelial NOS (eNOS) inhibitor, N5-(1-Iminoethyl)-L-ornithine ((L)-NIO, 1 mg/kg/min for 5 min), the delayed hypotension was attenuated by a selective inducible NOS (iNOS) inhibitor, S-methylisothiourea (SMT, 0.5 mg/kg/min for 5 min). Administration of WSE also produced an elevation in plasma nitrate/nitrite concentration, as well as an increase in the expression of iNOS protein in the heart and thoracic aorta. These results indicate that WSE from the leaf of M. calabura elicited both a transient and delayed hypotensive effect via the production of NO. Furthermore, activation of NO/sGC/cGMP signaling pathway may mediate the M. calabura-induced hypotension.
Shih
Cheng-Dean
CD
Department of Pharmacy and Graduate Institute of Pharmaceutical Technology, Pingtung 907, Taiwan, ROC. cdshih@mail.tajen.edu.tw
Chen
Jih-Jung
JJ
Lee
Hsinn-Hsing
HH
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007275:Injections, Intravenous; D019684:Magnoliopsida / Q000737:chemistry*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D018515:Plant Leaves / Q000737:chemistry*; D010946:Plants, Medicinal / Q000737:chemistry; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000071756:Soluble Guanylyl Cyclase; D029646:Tiliaceae / Q000737:chemistry; D014867:Water / Q000737:chemistry
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010936:Plant Extracts; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D014867:Water; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester