Stretch-evoked inhibition of spontaneous migrating contractions in a whole mount preparation of the guinea-pig upper urinary tract.

1. The effects of circumferentially-applied stretch on the spontaneous contractility of a whole mount preparation of the guinea-pig upper urinary tract (UUT) (renal pelvis and ureter) were investigated by use of standard isometric tension recording techniques. 2. Simultaneous tension recordings of the proximal and distal portions of the renal pelvis (RP) and ureter revealed that spontaneous contractions, in 79% (n = 66) of preparations, originated in the proximal RP (at a frequency of 4.5 min(-1)) and propagated to the distal RP and ureter at a velocity of 1-3 cm s(-1). Pretreatment with tetrodotoxin (TTX) (3-10 microM) or N(G)-nitro-L-arginine (100 microM) had little effect on the spontaneous contractility of the UUT, motility indexes (MIs) (contraction amplitude x contraction frequency) calculated after 20 min exposure were little affected by TTX or N(G)-nitro-L-arginine (L-NOARG). Omega-conotoxin GVIA (100 nM) significantly reduced MI values in both the proximal RP and ureter. 3. Exposure of the spontaneously-active UUT to capsaicin (10 microM for 15 min) induced a transient increase in UUT contractility, followed by a prolonged negative inotropic effect. The MI values, calculated 60 min after the washout of capsaicin, for the proximal and distal RP and ureter were reduced to 56%, 53% (n = 18) and 61% (n = 16), respectively, of their control values. This capsaicin pretreatment blocked the positive inotropic effects of transmural electrical nerve stimulation on UUT contractility to reveal a small inhibitory effect which was readily blocked by tetrodotoxin (3 microM) (n = 3). The excitatory and inhibitory actions of nerve stimulation were both blocked by TTX (3 microM). 4. A second exposure to capsaicin (10 microM for 15 min), further reduced the MI values (calculated 60 min after washout) in the proximal and distal RP to 41% and 31%, respectively (n = 6; P<0.05), of the initial control values. 5. In 61% (n = 99) of preparations, the application of stretch to the proximal RP (0.5 to 2 mm) evoked a decrease in the amplitude of the contractions recorded in the distal RP, but not in the ureter. Stretch applied to the distal RP or ureter had no effect on the contractions recorded in the other regions of the UUT. 6. In 5 out of 6 preparations, a single application of capsaicin (10 microM for 15 min) had little effect on the change in contractile force of the distal RP evoked upon stretch of the proximal RP. 7. The inhibition of the distal RP upon stretch of the proximal RP was partially reduced (P<0.05) when the UUT was pretreated with the calcitonin gene-related peptide (CGRP) receptor antagonist, hCGRP (8-37) (1 microM). 8. The application of the CGRP receptor agonist, hCGRP (100 nM) inhibited contractility in the UUT in a region dependent manner. The MI of the proximal RP was decreased 32% after 6 min; while the MIs of the distal RP and ureter were reduced 83% and 63%, respectively, within 5 min of the application of hCGRP. 9. Glibenclamide (1 microM) had little effect on the spontaneous contractility of the UUT, but significantly reduced the inhibition of the distal RP evoked upon stretch (0.5 to 2 mm) of the proximal RP. TTX (3-10 microM), L-NOARG (100 microM) or omega-conotoxin GVIA (100 nM) had little effect on the stretch-evoked inhibition of the distal RP. 10. It was concluded that circumferential stretch of the proximal RP inhibits the contractility of the distal RP and that a component of this inhibition involves the activation of a glibenclamide-sensitive mechanism via the release of endogenous CGRP, possibly from the varicosities of intramural sensory nerves.