Pehrson Rikard, Ojteg Göran, Ishizuka Osamu, Andersson Karl-Erik
Department of Clinical Pharmacology, Lund University Hospital, 221 85 Lund, Sweden.
Naunyn Schmiedebergs Arch Pharmacol. 2002 Dec;366(6):528-36. doi: 10.1007/s00210-002-0650-y. Epub 2002 Oct 17.
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.
5-羟色胺（5-HT）参与排尿控制。在大鼠中，刺激5-HT（1A）受体可兴奋排尿，而拮抗5-HT（1A）受体则抑制排尿。本研究检测了一种新型、高选择性的5-HT（1A）受体拮抗剂NAD-299对大鼠排尿的影响。并与5-HT（1A）受体特征明确的拮抗剂WAY100635进行了比较。采用雌性Sprague-Dawley大鼠，清醒或麻醉状态，用于膀胱测压研究。植入静脉（i.v.）、动脉内（i.a.）、鞘内（i.t.）或脑室内（i.c.v.）导管用于给药。在体外，大鼠膀胱条带可通过卡巴胆碱或神经电刺激收缩。记录了NAD-299、WAY100635和8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT，一种5-HT（1A）受体激动剂）对膀胱测压参数和膀胱条带收缩的影响。在清醒大鼠中，静脉注射1 μmol kg⁻¹的NAD-299和WAY100635可增加膀胱容量（分别为24±13%和27±19%）并降低排尿压力（分别为16±8%和12±10%）。动脉内注射时，0.25 μmol kg⁻¹的5-HT和0.37 μmol kg⁻¹的8-OH-DPAT可刺激排尿。动脉内注射NAD-299可阻断8-OH-DPAT的作用，但不能阻断5-HT的作用。鞘内或脑室内注射0.03 μmol的8-OH-DPAT可刺激排尿，鞘内或脑室内注射0.1 μmol的WAY100635可阻断该作用。NAD-299或WAY100635（0.1 μmol鞘内注射）无显著作用，但脑室内注射0.1 μmol时，两种药物均可增加膀胱容量（分别为34±12%和22±13%）。高达10⁻⁵ M的NAD-299和WAY100635对大鼠膀胱条带的电刺激或卡巴胆碱诱导的收缩均无影响。静脉注射1 μmol kg⁻¹的NAD-299可抑制氧合血红蛋白诱导的逼尿肌过度活动。结论是，作用于脊髓上部位的NAD-299可抑制大鼠排尿。
