Cholinergic and purinergic contribution to the micturition reflex in conscious rats with long‐term bladder outlet obstruction

Abstract

The urethra of female Wistar rats was partially obstructed for 15 weeks. The effects of atropine (1 mg/kg i.v.), suramin (100 mg/kg i.v.), and a combination of atropine and suramin on the peak micturition pressure (MP) were compared during cystometry in conscious rats controls or subjected to outlet obstruction. On the isolated bladder dome, we studied the inhibitory effect of 1 micromol/L atropine, 1 mmol/L suramin, and the combination of the two drugs on contractions induced by electrical field stimulation (EFS). We studied also the contractile response to 80 mmol/L KCl and the concentration-response curves to noradrenaline, phenylephrine, and carbachol on the bladder dome and bladder neck and alpha, beta-methylene adenosine triphosphate on the bladder dome. In conscious rats, the MP, bladder capacity, and micturition volume were significantly higher in obstructed rats than in controls. Suramin induced the same inhibition in the two groups of animals (-30.7 +/- 13.3% in controls and -29.2 +/- 8.5% in obstructed rats). Atropine decreased the MP, but this effect was twofold greater in obstructed animals (-28.1 +/- 3.1% and -65.1 +/- 6.9% in control and obstructed animals, respectively). However, the combined effect of atropine and suramin was additive in controls but not in obstructed (-56.7 +/- 5.4% and -55.9 +/- 9.4%, respectively). Similar results were obtained in vitro using 1 micromol/L atropine and 1 mmol/L suramin. In the obstructed bladder dome and bladder neck, we found a great reduction in KCl- and carbachol-induced contractility but no difference in the response to EFS. Responses to noradrenaline and phenylephrine were moderately reduced in the bladder neck only, whereas responses to alpha, beta-methylene adenosine triphosphate in the bladder dome were not reduced except at the concentration of 300 micromol/L. We conclude that long-term obstruction in rats could induce cholinergic nerve fiber proliferation as suggested by the decrease in M(3) muscarinic receptor contractility (desensitization) and by a greater sensitivity of the MP to atropine.

Ca 2+ Regulation in Detrusor Smooth Muscle From Ovine Fetal Bladder After In Utero Bladder Outflow Obstruction

“…Apart from alterations to receptors per se, abnormalities "downstream" from the receptors may also be responsible, which has been suggested for impaired 11 responsiveness to adrenergic stimulation. 13 As such, impaired downstream coupling to the SR Ca 2+ release (see later) has been shown in the present study, which would additionally contribute to the reduced efficacy and sensitivity of muscarinic receptors.…”

“…However, reduced receptor responses to neurotransmitters have been documented in hypertrophic muscle in adult hollow organs following obstruction or increased afterload. Impaired muscarinic as well as purinergic responses have been observed in hypertrophied human bladders and in adult models of severe bladder hypertrophy [12][13][14][15] . A reduction in -adrenergic receptor responsiveness and subsequent altered myocardial contractile function has also been observed with pressure overload-induced cardiac hypertrophy.…”

“…10 A crucial question yet to be answered is whether intracellular Ca 2+ regulation, a determinant of smooth muscle contraction, is altered due to obstruction. Of particular interest is whether alterations to cholinergic and purinergic pathways in detrusor muscle occur, such 4 as observed in both adult animal models of BOO and human neurogenic bladders [12][13][14][15] when purinergic mechanisms assume a greater importance. We therefore tested the hypothesis that changes to intracellular Ca 2+ regulation contribute to impaired contractility of smooth muscle from obstructed fetal bladders.…”

The effect of hypercholesterolemia on the contractions of detrusor strips in response to neural stimulation in rats

“…In our study the duration of the high cholesterol diet was sufficient to increase plasma cholesterol and LDL without causing atherosclerosis. The contribution of the cholinergic component in rat detrusor smooth muscle strips was reported as 42% (19), 47% (28), and 33% (27) (14) reported no difference in response to EFS; however, they found a diminished proportion of the cholinergic component stimulated by EFS (50 Hz) in hyperlipidemic rats. We did not observe any difference in the atropine-sensitive nerve-mediated contractions between the groups in this study.…”

“…Under physiological conditions, the cholinergic component that can be eliminated by atropine has the largest share in detrusor smooth muscle contractions, and the purinergic component, although negligible in healthy human bladders, has a considerable impact in rats (19,27,28). The studies about the effect of hypercholesterolemia on detrusor smooth muscle contractility are limited and conflicting.…”