Inhibitory Effect of N(G)-Nitro-L-arginine Methyl Ester on the Anti-Adrenergic Response Elicited by Ayanin in the Pithed Rat

Abstract

In this study we evaluated the anti-adrenergic response elicited by ayanin, a flavonoid compound isolated from Croton schiedeanus Schlecht, in the pithed rat, and the inhibitory effect of NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), and its acute toxicity profile in mice. In pithed rats ayanin (5 - 50 mg/kg i. v.) caused a dose-dependent decrease in the pressor and chronotropic responses induced by intravenous noradrenaline administration (0.25 μg/kg). This anti-adrenergic response was completely abolished by prior treatment with L-NAME (10 mg/kg i.v ) and the inhibitory effect of L-NAME was reversed after intravenous administration of L-arginine (100 mg/kg, i. v.). No lethal or major toxic effects were observed in mice receiving i. p. administration of ayanin up to a dose of 500 mg/kg. Our findings confirm that ayanin exerts protective cardiovascular effects against the increase in blood pressure and heart rate mainly through a mechanism that depends on the NO/cyclic guanosine monophosphate (cGMP) pathway without acute toxic effects. These results suggest that extracts of Croton schiedeanus, the native south American plant from which ayanin was isolated, might be beneficial in cardiovascular disease.

Key words

Nitric oxide - Ayanin - pithed rat - acute toxicity - flavonoids

References

• 1 Guerrero M F, Carrón R, Martín M L, San Román L, Reguero M T. Antihypertensive and vasorelaxant effects of aqueous extract from Croton schiedeanus Schlecht in rats.  Journal of Ethnopharmacology. 2001;  75 33-6
• 2 Panza J, Quyyumi A, Brush J, Epstein S. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension.  New England Journal of Medicine. 1990;  323 22-7
• 3 Cooke J P, Andon N A, Girerd X J, Hirsch A T, Creager M A. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta.  Circulation. 1991;  83 1057-62
• 4 Forstermann U, Mugge A, Alheid U, Haverch A, Frolich J C. Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries.  Circulation Research. 1988;  62 185-90
• 5 Aleixandre A, López-Miranda V, Ortega A. Alpha-vascular responses after short-term and long-term inhibition of nitric oxide synthesis.  Journal of Cardiovascular Pharmacology. 2001;  37 133-42
• 6 Malan E, Roux D G. Flavonoids from Distemonanathus benthamianus Baillon. Methoxylated flavones and inter-relationships of benthamianin, [2]benzopyrano[4,3-b][1]benzopyran. Journal of Chemical Society Perkin Translation I 1979: 2696-703
• 7 Agraval P K. Carbon-13 NMR of flavonoids. Amsterdam; Elsevier 1989
• 8 Gillespie J S, Muir J C. A method of stimulating the complete sympathetic outflow from the spinal cord to blood vessel in the pithed rat.  Brithis Journal of Pharmacology and Chemotherapy. 1967;  30 78
• 9 Schuldt E Z, Ckless K, Sima E, Farias M R, Ribeiro R M. Butanolic fraction from Cuphea carthagenensis Jacq McBride relaxes rat thoracic aorta through endothelium-dependent and endothelium-independent mechanisms.  Journal of Cardiovascular Pharmacology. 2000;  35 234-9
• 10 Fitzpatrick D F, Hirschfield S L, Ricci T, Jantzen P, Coffey R G. Endothelium-dependent vasorelaxation caused by various plant extracts.  Journal of Cardiovascular Pharmacology. 1995;  26 90-5
• 11 Correa J, Bernal H. Especies Vegetales Promisorias de los Países del Convenio Andrés Bello. Santafe de Bogotá,Colombia; 1992 7: 314-22
• 12 García H. Flora Medicinal de Colombia. Santafe de Bogotá, Colombia; 1975 2: 87-91
• 13 García L, Guarín D, Tovar M. Obtención de ayanina de las hojas de Croton glabellus .  Revista Colombiana de Ciencias Químico Farmacéuticas. 1986;  15 95-8
• 14 Yeh J, Liou S, Liang J, Huang Y, Chaing L, Wu J, Lin Y, Chen I. Vanidipinedilol: a vanilloid-based B-adrenoceptor blocker displaying calcium entry blocking and vasorelaxant activities.  Journal of Cardiovascular Pharmacology. 2000;  35 51-63
• 15 Boucher J L, Moali C, Tenu J P. Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization.  Cellular and Mollecular Life Sicences. 1999;  55 1015-28