Smooth muscle and neural mechanisms contributing to the downregulation of neonatal rat spontaneous bladder contractions during postnatal development

Abstract

Spontaneous bladder contractions (SBCs) in the neonatal rat urinary bladder change from a high-amplitude, low-frequency pattern to a low-amplitude, high-frequency pattern during the first 6 wk of life. Understanding the mechanism of this developmental change may provide insights into the causes of bladder overactivity in adults. In vitro whole bladder preparations from Sprague-Dawley rats were used to study the modulation of SBCs by calcium-activated potassium channels (K(Ca)) and electrical field stimulation from 3 days to 6 wk of life. SBCs in 3-day-old bladders were unmasked by treatment with iberiotoxin (100 nM), an inhibitor of large conductance K(Ca) (BK) channels, or apamin (100 nM), an inhibitor of small conductance K(Ca) (SK) channels. Iberiotoxin significantly increased the magnitude of SBCs at 2-3 wk, whereas apamin was only effective at 6 wk. In 1-2 wk bladders, exposure to room temperature Krebs solution decreased SBCs. This decrease was reversed by activating intramural nerves with electrical field stimulation. The effect of electrical field stimulation was inhibited by atropine (1 microM), suramin (10 microM), or pretreatment with tetrodotoxin (1 microM) but was not reversed by tetrodotoxin applied after electrical field stimulation. BK-alpha mRNA increased threefold, and BK-alpha protein increased fivefold from 3 days to 6 wk. These data suggest that BK channels play an important role in the regulation of SBCs in the neonatal bladder and that both increased BK channel activity, as well as changes in smooth muscle sensitivity to locally released neurotransmitters contribute to the downregulation of SBCs during early postnatal development.

Differential Effect of l-Cysteine in Isolated Whole-Bladder Preparations from Neonatal and Adult Rats

“…These findings support the speculation that L-cysteine might have an important role in the modification of thiols on BK Ca channels in neonatal rat bladder. On the other hand, the ineffectiveness of L-cysteine in adult bladder may be caused by BK Ca channels becoming less important in controlling the activity of the bladder in adult rats (Ng et al, 2007).…”

“…Previous experiments de Groat, 1994, 2000;Szell et al, 2003;Kanai et al, 2007;Ng et al, 2007) showed that neonatal and adult bladders have markedly different properties. Neonatal bladders exhibit large-amplitude, lowfrequency rhythmic contractions, whereas adult bladders have low-amplitude, high-frequency contractions.…”

Differential Effects of K<sup>+</sup> Channel Blockers on Phasic Contractility of Transverse and Longitudinal Rat Detrusor Strips

“…In the longitudinal guinea-pig detrusor, phasic activity was increased under IbTx treatment [8]. This was in contrast to the whole rat detrusor where no change in phasic activity was detected [9]. It is possible that phasic activity in individual smooth muscle bundles may not influence intravesical pressure in the whole bladder to a great extent.…”

“…One group of molecular candidates believed to mediate phasic contractions is the K + channels. Several groups have studied the effects of K + channel blockers and reached variable findings attributable to differences between species and experimental conditions [5][6][7][8][9]. Although not as extensively used as other animals, the rat remains a valuable model for studying bladder physiology.…”

Effect of the SK/IK channel modulator 4,5‐dichloro‐1,3‐diethyl‐1,3‐dihydro‐benzoimidazol‐2‐one (NS4591) on contractile force in rat, pig and human detrusor smooth muscle

“…guinea-pigs, rats and mice [8,9]. There seems to be limited information about SK/IK channel properties in detrusor muscles from larger animals and humans.…”