Relaxant Effects of Butylidenephthalide in Isolated Dog Blood Vessels

Abstract

We investigated the reason why butylidenephthalide (Bdph) can have an antianginal effect without changing blood pressure in conscious rats. Isolated dog coronary artery (CA), femoral vein (FV), femoral artery (FA), and mesenteric artery (MA) were used to evaluate the relaxant effects of Bdph. Bdph concentration-dependently relaxed isolated CA, FV, FA, and MA precontracted by KCl (60 mM) and phenylephrine (phe, 5 μM) with the exception that CA was precontracted by prostaglandin F_{2 α} (PGF_{2 α}, 2 μM) instead of phe. The potency order of Bdph to these blood vessels was FV > CA > FA ≥ MA. Bdph also concentration-dependently and non-competitively inhibited cumulative KCl (5 - 120 mM)- and phe (0.1 - 100 μM)-induced contractions in normal, and inhibited cumulative Ca²⁺-induced contractions in depolarized blood vessels. The potency order of Bdph to these blood vessels was FV ≅ CA > FA ≅ MA. Bdph (0.02 - 0.04 mM) concentration-dependently and leftward-shifted the log concentration-response curves in parallel and significantly increased the pD₂ value of forskolin, but not nitroprusside in FV. Bdph (0.1 mM) did both in CA. Bdph (0.225 - 0.45 mM) did the opposite to that of nitroprusside, but not forskolin, in FA. Bdph (0.45 - 0.9 mM) did neither in MA. Bdph (0.1 - 1 mM) significantly inhibited cAMP- but not cGMP-PDE activities in these four blood vessels, suggesting that Bdph more selectively inhibited the former in these tissues. The above results suggest that the higher potencies of Bdph on FV and CA than on FA and MA, may be interpreted as the reason why Bdph is useful in the treatment of angina pectoris without changing blood pressure, after Bdph administration in vivo, because the venoreturn may be reduced and the coronary flow may be increased without affecting the arterioles, such as MA, the main determinant of blood pressure.

Abbreviations

Bdph:butylidenephthalide

Phe:phenylephrine

PGF_2α:prostaglandin F_2α

CA:coronary artery

FV:femoral vein

FA:femoral artery

MA:mesenteric artery

cAMP:adenosine 3′,5′-cyclic monophosphate

cGMP:guanosine 3′,5′-cyclic monophosphate

PDE:phosphodiesterase

Butylidenephthalide - dog blood vessels - Ca²⁺ influx - Ca²⁺ release - cAMP-phosphodiesterase - cGMP-phosphodiesterase - Ligusticum chuaxiong - Umbelliferae

References

• 1 Ko W C, Lin S C, Yeh C Y, Wang Y T. Alkylphthalides isolated from Ligusticum wallichii Franch. and their in vitro inhibitory effects on rat uterine contraction induced by prostaglandin F_{2 α} .  Journal of Formosan Medical Association. 1977;  76 669-77
• 2 Ko W C. A newly isolated antispasmodic - butylidenephthalide.  The Japanese Journal of Pharmacology. 1980;  30 85-91
• 3 Ko W C, Lin L C, Lin S H, Hwang P Y, Hsu C Y, Wang G Y, Chang C W. Effects of alkylidenephthalides on the pituitrin-induced alternations in isolated guinea pig hearts.  Journal of Chinese Medicine. 1992;  2 25-32
• 4 Ko W C, Chang L D, Wang G Y, Lin L C. Pharmacological effects of butylidenephthalide.  Phytotherapy Research. 1994;  8 321-6
• 5 Ko W C, Sheu J R, Tzeng S H, Chen C M. The selective antianginal effect without changing blood pressure of butylidenephthalide in conscious rats.  Planta Medica. 1998;  64 229-32
• 6 Lin L C, Wang C B, Koh V C, Ko W C. Synthesis, properties and molecular structure of alkylidenephthalides.  Bulletin of The Institute of Chemistry, Academia Sinica. 1984;  31 9-15
• 7 Cook S J, Archer K, Martin A, Buchheit K H, Fozard J R, Müller T, Miller A J, Elliott K RF, Foster R W, Small R C. Further analysis of the mechanisms underlying the tracheal relaxant action of SCA40.  British Journal of Pharmacology. 1995;  114 143-51
• 8 Ariëns E J, van Rossum J M. pD_x, pA_x and pD′_x values in the analysis of pharmacodynamics.  Archive Internationales de Pharmacodynamie et de Therapie. 1957;  110 275-97
• 9 Hoffman B B, Lefkowitz R J. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, Molinoff PB, Rubbon RW, Gilman AG, editors Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York; McGraw-Hill 1996: 199-248
• 10 Sabouni M H, Cushing D J, Makujina S R, Mustafa S J. Inhibition of adenylate cyclase attenuates adenosine receptor-mediated relaxation in coronary artery.  Journal of Pharmacology and Experimental Therapeutics. 1991;  254 508-12
• 11 Gruetter C A, Kodowitz P J, Ignarro L. Methylene blue inhibits coronary arterial relaxation and guanylate cyclase activation by nitroglycerine, sodium nitrate and amyl nitrite.  Canadian Journal of Physiology and Pharmacology. 1981;  59 150-6
• 12 Murray M A, Boyle J P, Small R C. Cromakalim-induced relaxation of guinea-pig isolated trachealis: Antagonism by glibenclamide and by phentolamine.  British Journal of Pharmacology. 1989;  98 856-74
• 13 Gimenez-Gallego G, Navia M A, Reuben J P, Katz G M, Kaczorwski G J, Garcia G M. Purification, sequence, and model structure of charybdotoxin, a potent selective inhibitor of calcium-activated potassium channels.  Proceedings of The National Academy of Sciences of The United States of America. 1988;  85 3329-33
• 14 Ignarro L J, Buga G M, Wood K S, Byrns R E, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.  Proceedings of The National Academy of Sciences of The United States of America. 1987;  84 9265-9
• 15 Kanaide H. Calcium transients in primary culture rat aortic smooth muscle cells.  Asia-Pacific Journal of Pharmacology. 1990;  5 177-83
• 16 Chiu A T, Bozarth J M, Timmermans P BMWM. Relationship between phosphatidylinositol turnover and Ca²⁺ mobilization induced by alpha-1 adrenoceptor stimulation in the rat aorta.  Journal of Pharmacology and Experimental Therapeutics. 1987;  240 123-7