PHYSIOLOGICAL-EFFECTS OF A NOVEL BIOACTIVE AGENT

Urinary bladder smooth muscle contraction can be evaluated using field stimulation (neurohumoral transmission), carbachol (muscarinic stimul ation), and KCl (direct membrane depolarization). We recently evaluate d the activity of a novel organic chemical, macrocycle-1, on the contr actile responses of the bladder to field stimulation, carbachol, and K Cl. Isolated strips of rabbit bladder were mounted in individual baths containing 7.5 ml Tyrode's solution. The response to FS (1-32 Hz), ca rbachol (1 mu mol/l), and KCl (120 mmol/l) were determined in the pres ence and absence of 3 different concentrations of macrocycle-1. Maxima l tension, the rate of tension generation, the time to maximal tension , and the rate of decay following maximal tension were determined, The results can be summarized as follows: (1) In the absence of macrocycl e-1, maximal tension and the maximal and mean rate of tension generati on increased with frequency, whereas the time to maximal tension was c onstant. The rate of decay of tension following maximum tension was gr eater for 8, 16 and 32 Hz as compared to 1 or 2 Hz. (2) The maximal re sponse to KCl was lower than either FS or carbachol. The maximal rates of tension generation for carbachol and KCl were lower than that of F S, and the rate of tension generation for KCl was lower than that of c arbachol. The time to maximal stimulation for KCl was greater than tha t of either carbachol or FS. (3) Macrocycle-1 had a greater inhibitory effect on KCl stimulation than on carbachol stimulation: and a greate r inhibitory effect on KCl and carbachol stimulation than on FS. (3) T he rats of tension generation was more sensitive to macrocycle-1 inhib ition than was the maximal tension responses to all methods of stimula tion. Our current hypothesis is that macrocycle-1 is acting as an intr acellular calcium buffer whose affinity constant and association rate does not interfere with rapid intracellular release mechanisms (FS) wh ile it inhibits slow intracellular calcium release mechanisms (carbach ol and KCl).