Effect of Bay K 8644 and ryanodine on the refractory period, action potential and mechanical response of the guinea-pig ureter to electrical stimulation.

We have investigated the effect of the dihydropyridine calcium channel agonist, Bay K 8644, and of the plant alkaloid blocker of calcium-induced calcium release (CICR) from the sarcoplasmic reticulum, ryanodine, on the refractory period, action potential and mechanical response of the guinea-pig isolated ureter to electrical stimulation. All experiments were performed in ureters pre-exposed to 10 microM capsaicin to eliminate the inhibitory influence exerted by local release of sensory neuropeptides on ureteral excitability and contraction. In organ bath experiments, electrical field stimulation with parameters which produce direct excitation of ureteral smooth muscle (train of pulses at 10 Hz, 5 ms pulse width, 60 V for 1 s) produced tetrodotoxin- (1 microM) resistant phasic contractions. The response to EFS was abolished by nifedipine (1 nM-3 microM) and was enhanced by Bay K 8644 (1 nM-3 microM). In the presence of Bay K 8644 (1 microM), nifedipine (30 microM) abolished the evoked contractions. Ryanodine (10-100 microM) had no significant effect on the amplitude of evoked contraction. The response of the guinea-pig ureter to direct electrical stimulation of smooth muscle is characterized by a refractory period: at least 40 s interstimulus interval was required to produce a second response in all preparations tested. Bay K 8644 (1 microM) markedly reduced the refractory period of the ureter and a similar effect was observed with ryanodine (100 microM). To further analyze the effect of Bay K 8644 and ryanodine on the refractory period, the response of the ureter was investigated over a 10 s period of stimulation (other parameters as above). In control ureters, continuous stimulation for 10 s produced only one phasic contraction just after the beginning of the train of stimuli. In the presence of Bay K 8644 or ryanodine, more than one phasic contraction developed during a 10 s stimulation, i.e. the refractory period became shorter than the train duration. When both Bay K 8644 and ryanodine were tested on the same preparations, an additive excitatory effect was observed on the mechanical response to electrical stimulation. A slight elevation of KCl concentration (5-10 mM) reduced the refractory period of the ureter as observed with ryanodine or Bay K 8644. Application of KCl (80 mM) produced a biphasic contractile response of the ureter: a series of phasic contractions occurred first, which were then replaced by a slowly developing tonic response. Bay K 8644 (1 microM) enhanced both components of the response to KCl. Ryanodine (10 and 100 microM) markedly prolonged the duration of phasic contractions evoked by KCl and, at 100 microM, slightly (about 25%) reduced the amplitude of tonic contraction.(ABSTRACT TRUNCATED AT 400 WORDS)