The antispasmodic effects of 3-t-butyl-4-hydroxyanisole (BHA) and some structurally related compounds were investigated in endothelium-intact rat aorta rings. Nordihydroguaieretic acid (NDGA), BHA, 3,5-di-t-butyl-4-hydroxyanisole (DTBHA), 2,6-di-isopropyl phenol (propofol) and 2,2'-dihydroxy-3,3'-di-t-butyl-5, 5'-dimethoxydiphenyl (DIBHA) did not cause relaxation when added at the plateau of phenylephrine-evoked contraction, nor did they affect the concentration-relaxation curve for acetylcholine in precontracted rings. In rings depolarised with physiological salt solution (PSS) containing 40 mM K(+), NDGA, BHA, DTBHA, 2, 5-di-t-butyl-1,4-benzohydroquinone (BHQ), propofol and nifedipine, but not DIBHA, inhibited the contraction induced by cumulative addition of Ca(2+) (0.05-10 mM) in a concentration-dependent manner; this inhibition was inversely related to the Ca(2+) concentration. In 40 mM K(+) PSS, 25 nM nifedipine blocked the 1 mM Ca(2+)-induced contraction, whereas 50 microM DTBHA, NDGA, BHA, BHQ and propofol significantly antagonised it by 84.4%, 73.0%, 52.8%, 45.6% and 35.7%, respectively. In the presence of 1 microM methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate (Bay K 8644), the response to Ca(2+) did not differ from control values with nifedipine and BHQ, was partially restored with DTBHA and NDGA, and was not affected with BHA and propofol. Nifedipine markedly inhibited (85.2%) the Ba(2+)-induced contraction and this effect was totally reversed by Bay K 8644. BHA and DTBHA showed antispasmodic activity (45.3% and 43.1%, respectively) which was partly reversed by Bay K 8644. In contrast, Bay K 8644 did not affect the inhibition exerted by BHQ, NDGA and propofol (69.5%, 53. 3% and 46.1%, respectively). Nifedipine, BHA, DTBHA, propofol and NDGA inhibited the contractile response to 1 mM Ca(2+) of aorta rings depolarised with 40 or 80 mM K(+) PSS to a similar extent. Cromakalim inhibited the Ca(2+)-evoked contraction only in 30 mM K(+) PSS and BHQ only in 80 mM K(+) PSS. DIBHA had no effect on this model. Cromakalim, but not BHA, stimulated 86Rb(+) efflux from ring preparations. In 80 mM K(+) PSS containing 1 microM nifedipine, only papaverine affected the phenylephrine-induced contraction. Moreover, when the rings were preincubated with 1 mM Ni(2+), the response to phenylephrine in the presence of BHQ was significantly reduced. In conclusion, we propose that BHA may non-specifically inhibit Ca(2+) influx at the plasmalemma level rather than affect the function of K(+) channels, Ca(2+) release from intracellular stores or endothelium-dependent relaxation.

Fusi, F., Marazova, K., Pessina, F., Gorelli, B., Valoti, M., Frosini, M., et al. (2000). On the mechanisms of the antispasmodic action of some hindered phenols in rat aorta rings. EUROPEAN JOURNAL OF PHARMACOLOGY, 394(1), 109-115 [10.1016/S0014-2999(00)00152-7].

On the mechanisms of the antispasmodic action of some hindered phenols in rat aorta rings

FUSI, FABIO;PESSINA, FEDERICA;GORELLI, BEATRICE;VALOTI, MASSIMO;FROSINI, MARIA;SGARAGLI, GIAN PIETRO
2000-01-01

Abstract

The antispasmodic effects of 3-t-butyl-4-hydroxyanisole (BHA) and some structurally related compounds were investigated in endothelium-intact rat aorta rings. Nordihydroguaieretic acid (NDGA), BHA, 3,5-di-t-butyl-4-hydroxyanisole (DTBHA), 2,6-di-isopropyl phenol (propofol) and 2,2'-dihydroxy-3,3'-di-t-butyl-5, 5'-dimethoxydiphenyl (DIBHA) did not cause relaxation when added at the plateau of phenylephrine-evoked contraction, nor did they affect the concentration-relaxation curve for acetylcholine in precontracted rings. In rings depolarised with physiological salt solution (PSS) containing 40 mM K(+), NDGA, BHA, DTBHA, 2, 5-di-t-butyl-1,4-benzohydroquinone (BHQ), propofol and nifedipine, but not DIBHA, inhibited the contraction induced by cumulative addition of Ca(2+) (0.05-10 mM) in a concentration-dependent manner; this inhibition was inversely related to the Ca(2+) concentration. In 40 mM K(+) PSS, 25 nM nifedipine blocked the 1 mM Ca(2+)-induced contraction, whereas 50 microM DTBHA, NDGA, BHA, BHQ and propofol significantly antagonised it by 84.4%, 73.0%, 52.8%, 45.6% and 35.7%, respectively. In the presence of 1 microM methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate (Bay K 8644), the response to Ca(2+) did not differ from control values with nifedipine and BHQ, was partially restored with DTBHA and NDGA, and was not affected with BHA and propofol. Nifedipine markedly inhibited (85.2%) the Ba(2+)-induced contraction and this effect was totally reversed by Bay K 8644. BHA and DTBHA showed antispasmodic activity (45.3% and 43.1%, respectively) which was partly reversed by Bay K 8644. In contrast, Bay K 8644 did not affect the inhibition exerted by BHQ, NDGA and propofol (69.5%, 53. 3% and 46.1%, respectively). Nifedipine, BHA, DTBHA, propofol and NDGA inhibited the contractile response to 1 mM Ca(2+) of aorta rings depolarised with 40 or 80 mM K(+) PSS to a similar extent. Cromakalim inhibited the Ca(2+)-evoked contraction only in 30 mM K(+) PSS and BHQ only in 80 mM K(+) PSS. DIBHA had no effect on this model. Cromakalim, but not BHA, stimulated 86Rb(+) efflux from ring preparations. In 80 mM K(+) PSS containing 1 microM nifedipine, only papaverine affected the phenylephrine-induced contraction. Moreover, when the rings were preincubated with 1 mM Ni(2+), the response to phenylephrine in the presence of BHQ was significantly reduced. In conclusion, we propose that BHA may non-specifically inhibit Ca(2+) influx at the plasmalemma level rather than affect the function of K(+) channels, Ca(2+) release from intracellular stores or endothelium-dependent relaxation.
2000
Fusi, F., Marazova, K., Pessina, F., Gorelli, B., Valoti, M., Frosini, M., et al. (2000). On the mechanisms of the antispasmodic action of some hindered phenols in rat aorta rings. EUROPEAN JOURNAL OF PHARMACOLOGY, 394(1), 109-115 [10.1016/S0014-2999(00)00152-7].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/2405