Effects of NAD-299, a new, highly selective 5-HT 1A receptor antagonist, on bladder function in rats

Abstract

5-HT is involved in micturition control. In the rat, stimulation of the 5-HT(1A) receptor excites, whereas 5-HT(1A) receptor antagonism inhibits micturition. The present study examined the effects of a new, highly selective, 5-HT(1A) receptor antagonist, NAD-299, on micturition in rats. Comparisons were made with WAY100635, a well-characterised antagonist at the 5-HT(1A) receptor. Female Sprague-Dawley rats, conscious or anaesthetised, were used for cystometric studies. Intravenous (i.v.), intraarterial (i.a.), intrathecal (i.t.) or intracerebroventricular (i.c.v.) catheters were implanted for drug administration. In vitro, rat bladder strips were contracted by carbachol or electrical stimulation of nerves. The effects of NAD-299, WAY100635 and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT(1A) receptor agonist) on cystometric parameters and contraction of bladder strips were recorded. In conscious rats, i.v. NAD-299 and WAY100635 at 1 micro mol kg(-1) increased bladder capacity (24+/-13% and 27+/-19% respectively) and decreased micturition pressure (16+/-8% and 12+/-10% respectively). Given i.a., 5-HT 0.25 micro mol kg(-1) and 8-OH-DPAT 0.37 micro mol kg(-1) stimulated micturition. The effect of 8-OH-DPAT, but not those of 5-HT, was blocked by i.a. NAD-299. 8-OH-DPAT 0.03 micro mol given i.t. or i.c.v. stimulated micturition, an effect blocked by WAY100635 0.1 micro mol, given i.t or i.c.v. NAD-299 or WAY100635 (0.1 micro mol i.t.) were without significant effects, but given i.c.v. at 0.1 micro mol both drugs increased bladder capacity (34+/-12% and 22+/-13% respectively). Neither NAD-299 nor WAY100635 up to 10(-5) M had effects on electrically- or carbachol-induced contractions of rat bladder strips. NAD-299 1 micro mol kg(-1) i.v. suppressed oxyhaemoglobin-induced detrusor over-activity. It is concluded that NAD-299, acting at a supraspinal site, can inhibit micturition in the rat.

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

“…Based on these and further studies, Testa et al (1999Testa et al ( , 2001 concluded that neutral 5-HT 1A receptor antagonists have favorable effects on the bladder, inducing an increase in bladder capacity with no derangement of bladder contractility. This conclusion has been supported by the results of other investigators (Kakizaki et al, 2001;Pehrson et al, 2002b). Kakizaki et al (2001) showed that rhythmic isovolumetric bladder contractions, evoked by bladder distension, were abolished by i.t.…”

The Selective 5-Hydroxytryptamine 1A Antagonist, AZD7371 [3(R)-(N,N-Dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (R,R)-tartrate Monohydrate] (Robalzotan Tartrate Monohydrate), Inhibits Visceral Pain-Related Visceromotor, but Not Autonomic Cardiovascular, Responses to Colorectal Distension in Rats

“…Hjorth, unpublished observations). In addition, in the present experiments, intracerebroventricular AZD7371 was effective at inhibiting micturition, a well characterized, 5-HT 1A -and centrally mediated effect of AZD7371 (Pehrson et al, 2002;Yoshiyama et al, 2003), thus indicating that the lack of effects of intracerebroventricular AZD7371 on pseudoaffective VMRs is likely not due to an ineffective blockade of central 5-HT 1A receptors. Moreover, the lack of effects of AZD7371 on CRD responses after intracerebroventricular administration reported here reinforces the view that inhibitory effects of the compound on VMRs are exerted, probably at a spinal location, and are independent of any effect at supraspinal sites.…”

Neural Control of the Lower Urinary Tract

“…The inhibition is antagonized by pretreatment with mesulergine, a 5-HT 2 receptor antagonist, indicating that 5-HT 2 receptors are involved in descending raphe/spinal inhibitory mechanisms (629). Similar inhibitory effects of another 5-HT 1A receptor antagonist, NAD-299, on the micturition reflex have been reported in rats (502).…”