Effect of exercise and 2-deoxyglucose on the K+ channel opener action of CGRP in the guinea pig ureter.
1. In the guinea pig isolated ureter, a maximally effective concentration of calcitonin gene-related peptide (CGRP, 0.1 microM) produced a prompt and transient suppression of myogenic phasic contractions (twitches) evoked by direct excitation (electrical field stimulation, EFS) of the smooth muscle. This suppressant effect is prevented by glibenclamide (1 and 10 microM), indicating the importance of K+ channel activation in its genesis. In the presence of either 1 or 10 microM glibenclamide, CGRP produced a partial (about 30%) and delayed inhibition of the evoked response, but failed to produce a full suppression of twitches. 2. The intensity and duration of the early, glibenclamide-sensitive suppressant effect of CGRP were inversely related to the frequency at which the ureters were driven by EFS. The glibenclamide-resistant inhibitory effect of CGRP was unaffected by changes in the EFS driving frequency, and cromakalim (3 microM) suppressed twitches independently of the EFS driving frequency. 3. Replacement of 80% glucose in the Krebs solution 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 presence, of glibenclamide. 2-DOG counteracted the inhibitory effect produced by increasing the EFS driving frequency on the response to CGRP. 4. In sucrose gap, both CGRP (0.1 microM) and cromakalim (3 microM) produced prompt hyperpolarization of the membrane. During continued superfusion for 15 min in unstimulated preparations, the hyperpolarizing effect of cromakalim and CGRP was sustained. When tested within 3 min from the end of 'exercise', induced by application of EFS at intervals of 15 sec for 30 min, the hyperpolarization by CGRP was reduced and shortened but that produced by cromakalim was unaffected. 5. These findings demonstrate that exercise and metabolic inhibition selectively influence, in opposite directions, the K+ channel opener action of CGRP in the guinea pig ureter, indicating that the ability of this neuropeptide to suppress latent pacemakers in smooth muscle is markedly dependent upon degree/frequency of cell activation. These results suggest that the ability of endogenous CGRP to suppress ureteral motility may be inversely related to the frequency of ureteral peristalsis, the effect being reduced by, for example, increase in diuresis.
Maggi
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Pharmacology Department, A. Menarini Pharmaceuticals, Florence Italy.
Santicioli
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Giuliani
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D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology*; D005905:Glyburide / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D007004:Hypoglycemic Agents / Q000037:antagonists & inhibitors; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010805:Physical Conditioning, Animal; D015221:Potassium Channels / Q000187:drug effects*; D014513:Ureter / Q000187:drug effects*
D000963:Antimetabolites; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D003847:Deoxyglucose; D015740:Calcitonin Gene-Related Peptide; D005905:Glyburide