EFFECT OF EXERCISE AND 2-DEOXYGLUCOSE ON THE K-PIG URETER( CHANNEL OPENER ACTION OF CGRP IN THE GUINEA)

1. In the guinea pig isolated ureter, a maximally effective concentrat ion of calcitonin gene related peptide (CGRP, 0.1 mu M) produced a pro mpt and transient suppression of myogenic phasic contractions (twitche s) evoked by direct excitation (electrical field stimulation, EFS) of the smooth muscle. This suppressant effect is prevented by glibenclami de (1 and 10 mu M), indicating the importance of K+ channel activation in its genesis, In the presence of either 1 or 10 mu M glibenclamide, CGRP produced a partial(about 30%) and delayed inhibition of the evok ed response, but failed to produce a full suppression of twitches. 2. The intensity and duration of the early, glibenclamide sensitive suppr essant effect of CGRP were inversely related to the frequency at which the ureters were driven by EFS. The glibenclamide resistant inhibitor y effect of CGRP was unaffected by changes in the EFS driving frequenc y, and cromakalim (3 mu M) suppressed twitches independently of the EF S driving frequency. 3. Replacement of 80% glucose in the Krebs soluti on with 2-deoxyglucose (2-DOG) reduced the amplitude of the EFS evoked twitches. In the presence of 2-DOG the inhibitory effect of CGRP was enhanced and prolonged when tested in the absence, but not in the pres ence, of glibenclamide. 2-DOG counteracted the inhibitory effect produ ced by increasing the EFS driving frequency on the response to CGRP. 4 . In sucrose gap, both CGRP (0.1 mu M) and cromakalim (3 mu M) produce d prompt hyperpolarization of the membrane. During continued superfusi on for 15 min in unstimulated preparations, the hyperpolarizing effect of cromakalim and CGRP was sustained. When tested within 3 min from t he end of 'exercise', induced by application of EFS at intervals of 15 sec for 30 min, the hyperpolarization by CGRP was reduced and shorten ed but that produced by cromakalim was unaffected. 5. These findings d emonstrate that exercise and metabolic inhibition selectively influenc e, in opposite directions, the K+ channel opener action of CGRP in the guinea pig ureter, indicating that the ability of this neuropeptide t o suppress latent pacemakers in smooth muscle is markedly dependent up on degree/frequency of cell activation. These results suggest that the ability of endogenous CGRP to suppress ureteral motility may be inver sely related to the frequency of ureteral peristalsis, the effect bein g reduced by, for example, increase in diuresis.