Obstruction-induced changes in urinary bladder smooth muscle contractility: a role for Rho kinase

Abstract

Detrusor smooth muscle (DSM) undergoes hypertrophy after partial bladder outlet obstruction (PBOO) in male rabbits, as it does in men with PBOO induced by benign prostatic hyperplasia. Despite detrusor hypertrophy, some bladders are severely dysfunctional (decompensated). In this study, the rabbit model for PBOO was used to determine the biochemical regulation of the contractile apparatus and force maintenance by the detrusor from decompensated bladders (DB). Bladders from sham-operated rabbits served as a control. On stimulation with 125 mM KCl, the DSM from sham-operated (SB) rabbits showed phasic contractions, whereas the detrusor from DB was tonic, exhibiting slow development of force, a longer duration of force maintenance, and slow relaxation. The Rho kinase (ROK) inhibitor Y-27632 enhanced the relaxation of precontracted DSM strips from DB. The enhancement of relaxation of the KCl-induced contraction of DB by Y-27632 was associated with dephosphorylation of myosin light chain (MLC20). The DSM extract from DB showed low phosphatase activity compared with that from SB. The DB also showed more Ca2+-independent MLC20 phosphorylation, which was partially inhibited by Y-27632. RT-PCR and Western blotting revealed similar expression levels of MLC kinase and ROK-alpha in SB and DB, but ROK-beta was overexpressed in DB. These results suggest that the ROK-mediated pathway is partly responsible for the high degree of force maintenance and slow relaxation in the detrusor from DB.

Comparative pharmacological analysis of Rho-kinase inhibitors and identification of molecular components of Ca2+ sensitization in the rat lower urinary tract

“…This is in agreement with previous work wherein identification of these proteins has also been demonstrated [25,27,30,31,37,45]. In addition, recent reports demonstrate that ROKβ is partly responsible for the high degree of force maintenance in the detrusor smooth muscle in overactive bladders [30][31][32]. Our experiments revealed that both ROKα and ROKβ are expressed at lower levels in the urethra compared to the detrusor and trigone.…”

“…In human, rat, rabbit and guinea pig bladder, the Rho-kinase pathway represents an important regulator of smooth muscle activity and tone [25,[27][28][29][30][31][32]. The prototype Rho-kinase inhibitor Y-27632 has been shown to attenuate contractions of bladder smooth muscle evoked by CCh, through the decrease of Ca 2+ sensitivity of the contractile apparatus [27][28][29].…”

“…The RhoA/Rho-kinase Ca 2+ sensitization pathway is involved in the regulation of bladder smooth muscle contraction and tone in humans [25,26] and animals [27][28][29]. Inhibition of Rho-kinase attenuates bladder hyperactivity in rabbits with partial outlet obstruction [30], diabetic rabbits [31] and hypertensive rats [32].…”

Association of lower urinary tract symptoms and erectile dysfunction: pathophysiological aspects and implications for clinical management

“…39 There is also a possibility that a multisystem dysfunction of Rho kinase exists and leads to both ED and LUTS. 40 Rho kinase has further been shown to have a role in hypertension and its expression correlates to aging, which provides a partial explanation not only for the relationship between LUTS and ED, but also for the connection of LUTS, ED and hypertension. 41 Pelvic atherosclerosis An additional mechanism is diffuse atherosclerosis of blood vessels supplying prostate, penis and bladder.…”

PDE5 inhibitors for LUTS

“…61 Several studies have shown increased Rho-kinase activity in the prostates of hypertensive rats, 62 and the detrusor and corpus cavernosum of rabbits with partial BOO. 63,64 Increased Rho-kinase activity has also been seen in diabetes and vascular smooth muscle in hypertension. 65,66 In addition, Rho-kinase inhibitors have been shown to alleviate ED in rats, with a potentiated effect with concomitant use of PDE5 inhibitors.…”