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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Inhibition of Bladder Activity by 5-Hydroxytryptamine₁ Serotonin Receptor Agonists in Cats with Chronic Spinal Cord Injury

Department of Surgery (B.G., K.J.O., K.B.T., P.C.D.), Duke University Medical Center and Veterans Affairs Medical Center, Durham, North Carolina; Dynogen Pharmaceuticals, Durham, North Carolina (K.B.T.); and Institute of Statistics and Decision Sciences, Duke University, Durham, North Carolina (J.P.R.)

The serotonin (5-hydroxytryptamine_1A) 5-HT_1A receptor agonist 8-OH-DPAT [(R)- (+)-8-hydroxy-2-(di-n-propylamino)tetralin] inhibits bladder activity under nociceptive but not innocuous conditions in cats with an intact spinal cord, suggestive of an effect on primary afferent C fibers or their targets. Because C fibers play a key role in reflex micturition in chronic spinal cord injury (SCI), we investigated the effect of 8-OH-DPAT on micturition in SCI cats. We also investigated GR-46611 (3-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide), which has agonist activity predominantly at 5-HT_1B and 5-HT_1D receptors but also at the 5-HT_1A receptor. Chloralose-anesthetized cats were catheterized through the bladder dome for saline-filling cystometry. Dose-response curves for i.v. 8-OH-DPAT (0.3-30 µg/kg) and GR-46611 (0.03-300 µg/kg) were followed in three cases each by 5-HT_1A antagonist WAY-100635 [N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide] at 300 µg/kg. Threshold volume, capacity, residual volume, micturition volume, and arterial pressure were measured. Intact cats showed few significant changes in cystometric variables. SCI cats responded to both 8-OH-DPAT and GR-46611 with dose-dependent increases in threshold volume, capacity, and residual volume, significant at 10 µg/kg for 8-OH-DPAT and at 3 µg/kg for GR-46611. Effects of 8-OH-DPAT but not GR-46611 were largely reversed by WAY-100635. Both 5-HT_1A and 5-HT_1B/1D agonists may offer a promising means of reducing bladder hyperactivity and increasing bladder capacity in patients with chronic SCI.

Address correspondence to: Dr. Paul C. Dolber, Division of Urology, Box 3453, Department of Surgery, Duke University Medical Center, Durham, NC 27710. E-mail dolber{at}acpub.duke.edu

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