Does hypercholesterolemia affect the relaxation of the detrusor smooth muscle in rats? In vitro and in vivo studies

Abstract

To evaluate the effects of hypercholesterolemia on the relaxation function of the urinary bladder, we examined the physiological mechanisms involved in the isoproterenol-induced relaxation in isolated detrusor strips in vitro and voiding behavior in vivo in rats. Adult male Sprague-Dawley rats were fed standard (control, N = 16) or 4 % cholesterol diet (hypercholesterolemia, N = 17) for 4 weeks. Concentration-response curves for isoproterenol-induced relaxations in carbachol-precontracted detrusor muscle strips were recorded. The contributions of β2- and β3-adrenoceptors and ATP-dependent and Ca(2+)-dependent potassium channels to the relaxation response were investigated by using selective adrenergic agonists salbutamol and BRL 37344 and specific potassium channel inhibitors glibenclamide and charybdotoxin, respectively. Cystometrography was performed to assess bladder function. Hypercholesterolemic rats had higher serum cholesterol and low- and high-density lipoprotein levels than the controls with no sign of atherosclerosis. Isoproterenol-induced relaxation was significantly enhanced in the hypercholesterolemia group. Preincubation with the M2 receptor antagonist attenuated the relaxation response in both groups. The relaxation responses to isoproterenol and salbutamol were similar in both groups, while BRL 37344 appeared to produce a greater relaxant effect in the hypercholesterolemic rats. Also, the inhibitory effects of potassium channel inhibitors on relaxation responses were comparable among the groups. The cystometric findings revealed that threshold and basal pressure values were higher in the hypercholesterolemia group compared with controls. We showed that hypercholesterolemia leads to greater relaxation responses to isoproterenol, appears to impair the braking function of M2 cholinergic receptors on adrenoceptor-induced relaxations in the isolated detrusor muscle, and affects the voiding function in rats.

Are blood vessels a target to treat lower urinary tract dysfunction?

“…Similarly, the resistive index of capsular arteries of the prostate has been linked to symptoms of bladder outlet obstruction in men with benign prostatic enlargement (Zhang et al 2012). Bladder hypoperfusion leads to detrusor overactivity in many settings, but severe forms can cause detrusor underactivity A study in this issue of the journal (Bayrak et al 2015) expands our knowledge in two ways. Firstly, this study treated rats with a high-cholesterol diet for 4 weeks during which plasma cholesterol doubled but atherosclerosis as assessed by histological examination of the aorta did not yet develop, i.e., the model represented a very early stage in the development of atherosclerosis.…”

“…Alterations in any of these may at least partly be responsible for detrusor dysfunction and, accordingly, be potential targets for the treatment of bladder dysfunction. As highlighted by an article in this issue of NaunynSchmiedeberg's Archives of Pharmacology (Bayrak et al 2015), there is an additional suspect, the bladder vasculature. This article will discuss the currently available experimental and clinical evidence for a role of the vasculature in causing bladder dysfunction, and how existing and emerging treatments may modulate bladder function by acting on blood vessels.…”

β3‐Adrenoceptors in the normal and diseased urinary bladder—What are the open questions?

“…Blood vessels providing perfusion to the bladder possibly contribute to the regulation of bladder function. In a rat model of bladder hypoperfusion caused by experimental atherosclerosis, the relaxation responses of isolated detrusor strips to isoprenaline and salbutamol remained unchanged whereas those to BRL 37,344 were reported to be increased (Bayrak et al, ). In a different rat model of chronic bladder ischaemia induced by atherosclerosis, chronic treatment with mirabegron prevented bladder hyperactivity and collagen deposition in the bladder wall, suggesting β 3 ‐adrenoceptor agonism may be a potential treatment target for chronic ischaemia‐related bladder dysfunction (Sawada et al, ).…”

Hyperlipidemia impairs uterine β-adrenergic signaling by reducing cAMP in late pregnant rats

“…We noticed that the potencies of both salbutamol and BRL-37344 were significantly reduced in hyperlipidemic animals. In a rat model of hypercholesterolaemia, β-adrenergic response was potentiated in detrusor smooth muscle (Bayrak et al 2015). Acute treatment with simvastatin (a cholesterol synthesis inhibitor) inhibited the relaxant effect of salbutamol in porcine coronary artery (Uhiara et al 2012).…”