MYORELAXANT ACTIVITY OF 2-T-BUTYL-4-METHOXYPHENOL (BHA) IN GUINEA-PIGGASTRIC FUNDUS

This study investigates the mechanism whereby the antioxidant 2-t-buty l-4-methoxyphenol (BHA) relaxes guinea pig gastric fundus smooth muscl e. In circular smooth muscle strips, 10 mu M cyclopiazonic acid, a spe cific inhibitor of sarcoplasmic reticulum Ca2+-ATPase, induced a prolo nged rise in tension which depended on the presence of extracellular C a2+. BHA (pIC(50) = 5.83), sodium nitroprusside (6.85), isoproterenol (7.69) and nifedipine (8.02), but not 2,6-di-t-butyl-4-methoxyphenol ( DTBHA) (up to 30 mu M), relaxed muscle strips contracted with cyclopia zonic acid. 4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate (Bay K 8644) (1 mu M) antagonised the nifedipine- but not the BHA-induced rel axation. Nifedipine and isoproterenol(10 mu M) caused a decrease in sp ontaneous tone, but did not counteract the subsequent rise in tension elicited by 10 mu M cyclopiazonic acid. Conversely, 100 mu M BHA and 1 00 mu M sodium nitroprusside not only significantly reduced spontaneou s tone but also markedly impaired the response of the muscles to cyclo piazonic acid. DTBHA failed to show either effect. When added to prepa rations completely relaxed by 100 mu M BHA, 10 mM tetraethylammonium s till elicited nifedipine-sensitive tonic and phasic contractions in th e presence or absence of 10 mu M cyclopiazonic acid. BHA and DTBHA inh ibited, in a concentration-dependent manner, the Ca2+-promoted contrac tion of strips depolarised by 10 mM tetraethylammonium. The BHA antago nism showed a non-competitive profile while that of DTBHA was competit ive. In muscle strips at rest, 10 mu M BHA caused a significant increa se in tissue cAMP concentration, leaving cGMP unmodified. To conclude, the myorelaxant action of BHA on gastric fundus smooth muscle appears to be mediated partly by an increase in cAMP levels and partly by inh ibition of Ca2+ influx from the extracellular space. (C) 1998 Elsevier Science B.V. All rights reserved.