Methylflavonolamine hydrochloride inhibits contractions induced by noradrenaline, calcium and potassium in rabbit isolated aortic strips.

1. The effects of methylflavonolamine hydrochloride (4'-methyl-7-(2-hydroxy-3-isopropylamino-propoxy)-flavone hydrochloride, MFA) were investigated and compared with verapamil and papaverine on rabbit isolated aortic strips, which were contracted by noradrenaline, calcium and potassium. 2. Pre-incubation for 25 min with either MFA (0.03 to 0.2 mM) or papaverine (0.03 to 0.2 mM) induced non-parallel and concentration-dependent rightward displacements of the curves to noradrenaline (0.00001 to 0.1 mM) with the maximal response depressed. The calculated pD2' values (mean +/- s.d.) were 3.89 +/- 0.15 for MFA and 3.93 +/- 0.05 for papaverine, respectively. Verapamil (0.03 to 0.2 mM) inhibited the contraction induced by noradrenaline in a competitive manner with a pA2 value of 5.91 +/- 0.83. 3. In depolarized aortic strips of the rabbit, prior exposure to MFA (0.03 to 0.3 mM) and papaverine (0.03 to 0.2 mM) shifted the cumulative curves to Ca2+ (0.003 to 100 mM) parallel to the right with the maximal responses depressed, pD'2 values being 3.88 +/- 0.05 and 3.89 +/- 0.13, respectively. Verapamil produced comparable inhibition of the contraction at much lower concentrations (30 to 300 nM). 4. MFA (0.03 and 0.1 mM) inhibited the contraction elicited by graded depolarization at a constant Ca2+ concentration with a pD'2 value of 4.09 +/- 0.07. 5. The present results show that MFA has some actions consistent with a calcium antagonist. It resembles papaverine more closely than verapamil.

[Effects of methylflavonolamine hydrochloride on physiologic properties of isolated guinea pig atrium].

The effects of methylflavonolamine hydrochloride (MFA) on the contractility, excitability, automaticity and functional refractory period (FRP) were studied in isolated guinea pig atrium. MFA (5 and 75 mumol/L) decreased the contractility, increased the threshold concentration of adrenaline to evoke automaticity of the left atria, depressed the spontaneously beating right atria and lengthened FRP. MFA, at 75 mumol/L but not at 5 mumol/L, and shifted the intensity duration curve to the right. Our results suggest that suppression of the spontaneous and the evoked automaticity and prolongation of FRP may be related to its antiarrhythmic action.

[Effects of methylflavonolamine hydrochloride on tension and cAMP of isolated guinea pig trachea].

Effects of methylflavonolamine (4'-methyl-7-(2-hydroxy-3-isopropylaminopropoxy)-flavone hydrochloride, MFA) on the tension and cAMP content of isolated guinea pig tracheal smooth muscle strips were studied. MFA (0.03-0.6 mmol.L-1) dose-dependently reduced KCl, acetylcholine (ACh) and histamine (Hist)-induced contractions with intracellular increase in cyclic AMP. The reduction in contraction and increase in cAMP were well correlated positively. MFA (0.03 mmol.L-1) showed synergism with isoprenaline (Iso) and aminophylline (Ami) in bronchodilation. The synergism with Iso but not Ami was accompanied by an increase in cAMP levels. It is suggested that the MFA-induced bronchodilation is related to the increase in intracellular cAMP level. The calcium antagonistic effect may be involved in MFA-induced bronchodilation.

[Effects of methylflavonolamine hydrochloride on action potentials of isolated guinea pig papillary muscles].

Methylflavonolamine hydrochloride (4'-methyl-7-(2-hydroxy-3-isopropylamino-propoxy)-flavone hydrochloride, MFA) is a new compound synthesized by Shanghai Institute of Pharmaceutical Industry in China. Its effects on the fast and evoked slow response action potentials of isolated guinea pig papillary muscles have been studied by intracellular microelectrode techniques. The data were automatically analysed by a microcomputer system. At concentrations of 5-75 mumol/L, MFA caused a significant decrease in the duration required for 30, 50, 90% repolarization and a shift in the plateau to more negative transmembrane potentials. MFA 5 mumol/L had no effect on the maximal upstroke velocity during phase 0 (Vmax) but decreased it at 75 mumol/L. MFA had no significant effects on other AP parameters. It significantly inhibited the slow AP induced by isoprenaline or histamine (1 mumol/L) after myocardial cells were depolarized in high K+ (25 mmol/L) solution. The results suggest that MFA inhibits the inward Ca2+ current and at high concentration inhibits also the Na+ current.

[Anti-arrhythmia and anti-lipid peroxidation effects of methylflavonolamine].

Effects of methylflavonolamine (MFA) on arrhythmias induced by myocardial reperfusion were studied with rat hearts in situ and in vitro. In pentobarbital-anesthetized rats, MFA (20 mg.kg-1, i.v.) pretreatment reduced the incidence of reperfusion-induced ventricular fibrillation after left descending coronary artery ligation (15 min) and reperfusion (3 min) (28.6% vs 85.7% in control, P less than 0.05). Malondialdehyde (MDA) production (85 +/- 9 nmol/g wet wt) was inhibited in myocardium from the reperfused area in comparison with control (133 +/- 15 nmol/g wet wt). In isolated rat hearts with local ischemia (15 min) and reperfusion (1 min), MFA 5 mumol.L-1 (perfused 10 min prior to coronary artery ligation) prevented reperfusion-induced arrhythmias (0% vs 85.7% in control, P less than 0.01). In myocardium from the reperfused area, superoxide dismutase (SOD) and catalase (Cat) activity was increased and xanthine oxidase (XOD) activity, MDA production and nonesterified fatty acids (NEFA) contents were decreased. The results show that MFA prevents reperfusion-induced arrhythmia by inhibiting lipid peroxidation and regulating the metabolism of NEFA.

Methylflavonolamine protects aorta from atherosclerosis in cholesterol-fed rabbits.

The effect of methylflavonolamine [4'-methyl-7-(2-hydroxy-3-isopropylamino-propoxy)-flavone hydrochloride, MFA], synthesized recently by the Shanghai Institute of Pharmaceutical Industry, on the development of atherosclerosis was studied in male New Zealand white rabbits fed cholesterol for 10 wk. MFA, 7 mg.kg-1 daily ip, did not significantly alter the serum total cholesterol, HDL, and triglyceride levels, but significantly lowered the aortic cholesterol and calcium contents. Atheromatous lesions covered 53.3 +/- 11.8% of the intimal surface of the aorta in the saline group and 11.3 +/- 2.3% in the MFA group (P < 0.01). We conclude that MFA suppresses cholesterol-induced atherosclerosis.

[Effects of methylflavonolamine hydrochloride on contractility of isolated rabbit ileum].

Methylflavonolamine hydrochloride (MFA), verapamil (Ver), and trifluoperazine (Tri) inhibited the contractions induced by submaximal concentrations of acetylcholine (ACh) and serotonin (5-HT). IC50 values (mumol.L-1) were 33.2 +/- 0.7, 0.276 +/- 0.018, 3.83 +/- 0.23, and 15.31 +/- 0.10, 0.233 +/- 0.017, 2.33 +/- 0.20, respectively. MFA, Ver, and Tri inhibited the contractions induced by CaCl2 and pD'2 values were 4.3 +/- 0.3, 6.23 +/- 0.22, 4.99 +/- 0.24, respectively. MFA 3 mumol.L-1, Ver 0.03 mumol.L-1, and Tri 3 mumol.L-1 inhibited the contractions induced by ACh in Ca(2+)-free medium, while MFA 60 mumol.L-1, Tri 30 mumol.L-1, but not Ver 0.6 mumol.L-1, had pronounced inhibitions on extracellular calcium-dependent contractions induced by ACh. These results suggest that MFA has a calcium antagonistic effect and that MFA is similar to Tri, but not Ver, in mechanism.