Altered ureteral contractility with ageing: Role of the rho-kinase pathway

Abstract

This study investigated the role of calcium sensitisation in the regulation of ureteral contractility with ageing. Isolated ureteral strips from young (6-month old) and older (3-year old) pigs were mounted in Krebs bicarbonate solution and contractility induced by the α1-adrenoceptor agonist phenylephrine (30 and 300 μM) and 5-HT (10 and 100 μM), recorded in the absence and presence of the rho-kinase inhibitors Y-27632 (10 μM) and fasudil (30 μM). Ureteral strips developed bursts of contractile activity which was measured as area under the curve (AUC) and frequency. Maximum contraction to phenylephrine was significantly enhanced in tissues from older animals compared to younger animals (p < 0.001) while maximum contraction to 5-HT was greater in tissues from younger animals (p < 0.001). Both inhibitors significantly depressed AUC and frequency responses to both agonists in ureters from both age groups (p < 0.05). Inhibition by Y-27632 of phenylephrine (300 μM)- and 5-HT(100 μM)-induced contractions was greater in tissues from older animals than young (p < 0.05). Rho-kinase activity was also assayed in ureteral tissues, and basal activity was similar in ureters from both age groups. Neither phenylephrine nor 5-HT increased rho-kinase activity over basal levels. These data demonstrate the significant role rho-kinase plays in ureteral contractility and possible alterations with age.

A porcine model of ureteral contractile activity: Influences of age, tissue orientation, region, urothelium, COX and NO

“…We have previously reported that there are differences in contractions of the ureter in response to both α 1-adrenoceptor and 5-HT receptor stimulation (Lim, Chess-Williams, & Sellers, 2018b). The present results show that ureteral contraction in response to muscarinic receptor stimulation also differs in tissues from the two age groups.…”

The enhancing effect of 5-HT on phasic contractions of human isolated distal ureter and possible mediating mechanisms

“…5-HT-induced increase in the tension of isolated porcine intravesical ureters was reduced by 5-HT 2 and 5-HT 2A receptor antagonists, ritanserine and spiperone (Hernandez et al, 2003). The 5-HT 2 agonist, α-methyl-5HT, increased phasic contractions and overall contractile activity in isolated porcine distal ureter, which could be inhibited by the 5-HT 2 receptor antagonist, ketanserin (Lim, Chess-Williams & Sellers, 2018b). However, in human ureters, the role of 5-HT 2 has not been confirmed.…”

“…The vital role of 5-HT in the regulation of ureteral contraction has been revealed in ureteral preparations from different species. Enhanced ureteral contractions induced by 5-HT presented as increase in the frequency or elevated tension of phasic contractions have been observed in ureters from pigs (Hauser et al, 2002;Hernandez et al, 2003;Lim, Chess-Williams & Sellers, 2018b;Lim, Chess-Williams & Sellers, 2020) and humans (Gidener, Gumustekin & Kirkali, 1999;Gidener, Kirkali & Guven, 1995;Kuwahara, 1983;Long & Nergardh, 1978). However, no effects of 5-HT have been observed in canine and rabbit ureters (Borgstedt, Emmel & Benjamin, 1966;Yalcin et al, 2013), and no effects or dose-dependent effects (high doses inhibit and low doses excite) have been reported in rat ureters (Ancill, Jackson & Redfern, 1972).…”

“…5-HT 3 subtypes are the ligand-gated cation channels. 5-HT 2 receptors, particularly the 5-HT 2A subtype, which are located on smooth muscles, have been shown to be the predominant receptor for 5-HT-induced ureteral contractions in porcine ureters (Hauser et al, 2002;Hernandez et al, 2003;Lim, Chess-Williams & Sellers, 2018b). Intravenous and topical application of the 5-HT 2A agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), increased the frequency of pig ureteral contractions in vivo , which were reduced by the 5-HT 2 receptor antagonist, ketanserin or methysergide (Hauser et al, 2002).…”

17β-estradiol and ureteral contractility: A role for the G protein-coupled estrogen receptor

“…Our previous studies on the porcine distal ureter have shown that it is not possible to obtain reproducible concentration-response curves due to tachyphylaxis (Lim et al, 2018(Lim et al, , 2020.…”