In vitro Characterization of Parasympathetic and Sympathetic Responses in Cyclophosphamide‐Induced Cystitis in the Rat

Abstract

In cyclophosphamide-induced cystitis in the rat, detrusor function is impaired and the expression and effects of muscarinic receptors altered. Whether or not the neuronal transmission may be affected by cystitis was presently investigated. Responses of urinary strip preparations from control and cyclophosphamide-pretreated rats to electrical field stimulation and to agonists were assessed in the absence and presence of muscarinic, adrenergic and purinergic receptor antagonists. Generally, atropine reduced contractions, but in contrast to controls, it also reduced responses to low electrical field stimulation intensity (1-5 Hz) in inflamed preparations. In both types, purinoceptor desensitization with α , β -methylene adenosine-5'-triphosphate ( α , β -meATP) caused further reductions at low frequencies ( < 10 Hz). The muscarinic receptor antagonists atropine, 4-diphenylacetoxy-N -methylpiperidine (4-DAMP) ('M 1 /M 3 /M 5 -selective'), methoctramine ('M 2 -selective') and pirenzepine ('M 1 -selective') antagonized the tonic component of the electrical field stimulation-evoked contractile response more potently than the phasic component. 4-DAMP inhibited the tonic contractions in controls more potently than methoctramine and pirenzepine. In inflamed preparations, the muscarinic receptor antagonism on the phasic component of the electrical field stimulation-evoked contraction was decreased and the pirenzepine and 4-DAMP antagonism on the tonic component was much less efficient than in controls. In contrast to controls, methoctramine increased -instead of decreased -the tonic responses at high frequencies. While contractions to carbachol and ATP were the same in inflamed and in control strips when related to a reference potassium response, isoprenaline-induced relaxations were smaller in inflamed strips. Thus, in cystitis substantial changes of the efferent functional responses occur. While postjunctional β -adrenoceptor-mediated relaxations are reduced, effects by prejunctional inhibitory muscarinic receptors may be increased.The contraction of the urinary bladder is principally mediated by the parasympathetic stimulation of the muscarinic receptors populating the detrusor [1]. However, a well-known phenomenon in the rat as well as in many other species is that a large part of the parasympathetic contraction of the bladder is resistant to atropine [2,3]. One non-adrenergic, non-cholinergic transmitter candidate in the atropine-resistant contractile response in the rat bladder is adenosine-5'-triphosphate (ATP, [4 -7]), and in this species the purine generates a transient contraction of the bladder by the activation of P 2X purinoceptors, causing depolarization through non-selective cation channels [8][9][10]. Studies show that in the human urinary bladder, the atropine-resistant contractile response is minute or absent [11][12][13][14], but it may appear in the unstable bladder, during interstitial cystitis or due to spinal cord injuries [15][16][17]. Under such pathological conditions of the bladder, cha...

Expressions of Uroplakins in the Mouse Urinary Bladder with Cyclophosphamide-Induced Cystitis

“…However, there have been very few studies that have focused on explaining the interaction between the toxic material and the bladder's barrier. Moreover, previous animal studies with using CP have mainly focused on the neurochemical and electrophysiological properties of the bladder detrusor muscle or the afferent neurons in the bladder wall (5, 17, 18). …”

Muscarinic Receptor Subtypes in the Lower Urinary Tract

“…Upregulation of muscarinic receptors, as well as a parasympathetic sprouting arising in the mucosa, occur during cyclophosphamide-induced cystitis [119] . This may reflect compensatory mechanisms, as the changes in cystitis from prejunctional muscarinic receptor effects might also [120] . In chronic spinal cord injury, a prejunctional change in the muscarinic M 1 , M 2 and M 3 receptor expression may be induced [121] , as well as augmentation of cholinergic-induced release of ATP from the urothelium [122] , and, notably, increases in muscarinic receptor expression at a non-neuronal level occur on suburothelial myofibroblast-like cells during detrusor overactivity and painful bladder syndrome [80] .…”

“…In man, ATP seems to mediate this response also [131,132] , even though other mechanisms have been suggested [133] . In the rat, the bladder contraction consists of a phasic and a tonic component in which ATP and acetylcholine play predominant roles, respectively [120,134,135] . In vivo studies of the rat reveal that both transmitters are important for emptying the bladder [134] .…”

Methylacridinium and its Cholinergic Properties

“…The procedure to measure the actions of muscarinic agents in contracting rat bladder was performed as described previously (Giglio et al 2007). In the current study Sprague-Dawley rats (250-300 g) were used.…”