The effects of Ins2(Akita) diabetes and chronic angiotensin II infusion on cystometric properties in mice

Abstract

Aims Diabetes is associated with both dysfunction of the lower urinary tract (LUT) and overactivity of the renin-angiotensin system (RAS). Although it is well known that the RAS affects normal LUT function, very little is known about RAS effects on the diabetic LUT. Accordingly, we investigated the effects of chronic angiotensin II (AngII) treatment on the LUT in a model of type 1 diabetes. Methods Ins2(Akita) diabetic mice (20 wk old) and their age-matched background controls underwent conscious cystometric evaluation after 4 wk of chronic AngII treatment (700 ng/kg/min by osmotic pump) or vehicle (saline). Results Diabetic mice had compensated LUT function with bladder hypertrophy. Specifically, micturition volume, residual volume and bladder capacity were all increased, while voiding efficiency and pressure generation were unchanged as bladder mass, contraction duration, and phasic urethral function were increased. AngII significantly increased voiding efficiency and peak voiding pressure and decreased phasic frequency irrespective of diabetic state and, in diabetic but not normoglycemic control mice, significantly decreased residual volume and increased contraction duration and nonphasic contraction duration. Conclusions The Ins2(Akita) diabetic mice had compensated LUT function at 20 wk of age. Even under these conditions, AngII had beneficial effects on LUT function, resulting in increased voiding efficiency. Future studies should therefore be conducted to determine whether AngII can rescue the decompensated LUT function occurring in end-stage diabetic uropathy.

A systematic review of urinary bladder hypertrophy in experimental diabetes: Part 2. Comparison of animal models and functional consequences

“…Acute administration of the α 1A ‐adrenoceptor antagonist silodosin did not markedly alter these three parameters, and the acetylcholinesterase inhibitor distigmine had inconclusive effects; combination of silodosin and distigmine, however, reduced BC and PVR and increased voiding efficiency. Akita mice also exhibited an elevated BC and PVR, irrespective whether they had undergone extended infusion with angiotensin II . db/db mice also exhibited the increase in BC and bladder compliance consistently observed in STZ‐injected rats .…”

“…About half of all 129/SvEv mice, also known as Akita mice, have a tyrosine for cysteine mutation in the Ins2 gene encoding insulin two leading to hypoinsulinemia and, consequently, hyperglycemia. Such mice had a BW of 155% of control and a BBW of 164% of control at an age of 20 weeks (Figure , Supplementary Table S1) . Thus, hereditary rat and mouse models of T1DM also exhibit bladder hypertrophy, although based on a limited number of studies to a lesser extent than the rat STZ model.…”

Evaluation of voiding assays in mice: impact of genetic strains and sex

“…It is tempting to speculate that the rate of infusion may alter mechanosensation and thus the volume at which micturition is initiated, but subsequent studies performed at the University of Wisconsin using female C57BL/6J mice demonstrated that adjusting the infusion rate incrementally from 0.8 to 1.5 or from 1.5 to 0.8 ml/h caused a concomitant decrease or increase in ICI (data not shown). A recent study in which the infusion rate was modulated in an attempt to stimulate an average of 10 voiding cycles within 10 min in diabetic or control mice that either did or did not receive angiotensin II resulted in infusion rates that varied from 0.45 to 5.0 ml/h (8). It should be noted that bladder capacity varied among animals in that study, but these results also suggest that the mechanical response to bladder distention may vary among individual mice.…”

“…However, there currently is little consensus on how various parameters, such as threshold pressure (the intravesical pressure thought to initiate a voiding contraction), are determined. For example, a nonvoiding contraction has been variously defined as an increase from 1 (10) to 6.8 (6) cmH 2 O not associated with voiding of urine, but there is no general agreement as to how to define nonvoiding bladder contraction (8). Again, the method of analysis of results of cystometry used in the current study was chosen to allow direct comparison with results of a previous study (31).…”

“…Rates of fluid infusion during performance of cystometry in mice have ranged from 0.6 to 6 ml/h (6,14,28). Infusion rates were adjusted to obtain 10 voiding cycles within 10 min in mice, and it was found that infusion rates required to achieve this objective varied from 0.45 to 5.0 ml/h (8). When cystometry is performed in awake mice, movement or increases in intra-abdominal pressure by muscle contraction can significantly affect intravesical pressure, and it has been recommended that intra-abdominal pressure be measured by placement of a balloon-tipped catheter within the abdominal cavity or placement of a similar catheter within the colon (13,17).…”