Role of 5-HT1A receptors in control of lower urinary tract function in anesthetized rats

Abstract

The role of 5-hydroxytryptamine (5-HT) 1A (5-HT1A) receptors in lower urinary tract function was examined in urethane-anesthetized female Sprague-Dawley rats. Bladder pressure and the external urethral sphincter electromyogram (EUS EMG) activity were recorded during continuous-infusion transvesical cystometrograms (TV-CMGs) to allow voiding and during transurethral-CMGs (TU-CMGs) which prevented voiding and allowed recording of isovolumetric bladder contractions. 8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, decreased volume threshold (VT) for initiating voiding and increased contraction amplitude (CA) during TU-CMGs but decreased CA during TV-CMGs. 8-OH-DPAT prolonged EUS bursting as well as the intrabursting silent periods (SP) during voiding. N-[2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamine trihydrochloride (WAY-100635), a 5-HT1A antagonist, increased VT, increased residual volume, markedly decreased voiding efficiency, decreased the amplitude of micturition contractions recorded under isovolumetric conditions, and decreased the SP of EUS bursting. These results indicate that activation of 5-HT1A receptors by endogenous 5-HT lowers the threshold for initiating reflex voiding and promotes voiding function by enhancing the duration of EUS relaxation, which should reduce urethral outlet resistance.

Fig. 1.

Effect of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT; 0.3 mg/kg iv) and WAY-100635 (0.1 mg/kg iv) on bladder (top traces) and external urethral sphincter electromyogram (EUS EMG) activity (bottom traces) during a continuous-infusion (0.123 ml/min) transvesical cystometrogram (CMG) in an anesthetized rat with urethral outlet open and bladder able to empty. iv, Intravenous drug administration; Inf, start of saline infusion to the bladder. A: CMG pattern after vehicle administration showing large-amplitude EUS EMG activity occurring at the onset and during reflex bladder contractions. B: 8-OH-DPAT reduced the volume threshold (VT) for inducing a reflex bladder contraction and activated EUS EMG activity during the filling phase and bladder contractions. C: in the same rat, 1 h after administration of 8-OH-DPAT, WAY-100635 increased VT and suppressed EUS EMG activity during the filling phase and bladder contractions. Vertical calibration, intravesical pressure (in cmH₂O); horizontal calibration, time (in minutes). Asterisks indicate voiding responses shown on an expanded scale in Fig. 3.

Fig. 2.

Bladder (top traces) and EUS EMG activity (bottom traces) recorded during a continuous-transvesical infusion CMG in an anesthetized rat. A: intravesical pressure and EUS EMG activity were relatively stable during the filling phase. A reflex bladder contraction, indicated by an abrupt, large increase in bladder pressure, was accompanied by large-amplitude EUS EMG activity. B: same recording indicated by asterisk in A shown at faster time scale. The bracket in B indicates the recording period in C, and the bracket in C indicates the recording period in D at a faster time scale. Note the decline in intravesical pressure during EUS EMG bursting in B and C, which indicates the period of voiding. C: tonic EUS EMG activity precedes the large rise in intravesical pressure and shifts to a bursting pattern at the peak of bladder contraction before the onset of voiding. Small oscillations in intravesical pressure coincide with each burst of EMG activity. D: recordings in C shown at very fast time scale showing individual EUS EMG bursts composed of active (AP) and silent periods (SP; brackets) and the small fluctuations in intravesical pressure accompanying each burst. Vertical calibration, intravesical pressure (in cmH₂O); horizontal calibration, time (in minutes or seconds); Inf, start of saline infusion.

Fig. 3.

Bladder (top traces) and EUS EMG activity (bottom traces) during bladder contractions after sequential administration in the same rat shown in Fig. 1 of vehicle (A), 8-OH-DPAT (0.3 mg/kg iv; B), and WAY-100635 (0.1 mg/kg iv) 1 h after 8-OH-DPAT (C). Recordings of the intravesical pressure and EUS EMG activity depicted in Fig. 1 at increasing time scales showing the interval of silent and active period during bursting period. Vertical calibration, intravesical pressure (in cmH₂O); horizontal calibration, time (in seconds).

Fig. 4.

Effect of sequential intravenous administration of vehicle (A), 8-OH-DPAT (0.3 mg/kg iv; B), and WAY-100635 (0.1 mg/kg iv; C) on rhythmic isovolumetric contractions evoked by bladder distension in the same rat. Vertical and horizontal calibrations correspond to intravesical pressure (in cmH₂O) and time (in minutes), respectively. ICI, intercontraction interval.