PHARMACOLOGICAL PROPERTIES OF THE NATURAL MARINE PRODUCT FUROSPONGIN-1

1. The natural marine product, furospongin-1 (6, 12 and 24.5 mu mol/L) significantly inhibited contractions of segments of guinea-pig ileum induced by submaximal concentrations (0.1 mu mol/L) of acetylcholine ( ACh) and histamine. Furospongin-1 (24.5 and 36.7 mu moI/L) reduced bot h the phasic and tonic components of a contraction induced by 30 mmol/ L K+ solution in the absence and presence of atropine (1 mu mol/L), me pyramine (1 mu mol/L) and phentolamine (1 mu mol/L). Furospongin-1 als o decreased basal tension and the amplitude of spontaneous phasic cont ractions of guinea-pig ileum. 2. The mitochondrial ATP synthase inhibi tor oligomycin (0.3, 1 and 3 mu moI/L) had a similar concentration-dep endent action, reducing basal activity and contractions evoked by hist amine and ACh. Oligomycin also reduced both the phasic and tonic compo nents of a contraction induced by 30 mmol/L K+ solution in the absence and presence of atropine (1 mu mol/L), mepyramine (1 mu mol/L) and ph entolamine (1 mu mol/L). 3. Furospongin-1 (6 and 37.6 mu mol/L) and ol igomycin (3 mu mol/L) had no effect on contractions of chemically skin ned guinea-pig ileum longitudinal muscle segments. In this same tissue , furospongin-1 (6, 12 and 23.5 mu mol/L) and oligomycin (0.3, 1 and 3 mu mol/L) concentration-dependently reduced tissue levels of ATP. 4. In lyzed bovine mitochondria, oligomycin (0.1, 0.3, 1 and 3 mu mol/L) inhibited conversion of AIP to ADP whilst furospongin-1 (6, 12 and 24. 5 mu mol/L) and carbonyl cyanide m-chlorophenylhydrazone (0.5 mmol/L) had no significant effect on ATP breakdown. 5. Furospongin-1 (12 and 2 4.5 mu mol/L) and oligomycin (3 mu mol/L) had no effect on State 4 mit ochondrial respiration of whole bovine mitochondria, but converted Sta te 3 back to State 4 respiration. Carbonyl cyanide m-chlorophenyl-hydr azone (0.5 mmol/L) increased oxygen consumption in both situations. 6. These results suggest that furospongin-1 may inhibit the activity of inner mitochondrial membrane ADP-ATP translocases or other membrane tr ansporters to inhibit ATP synthesis.