Animal model for angiotensin II effects in the internal anal sphincter smooth muscle: mechanism of action

Abstract

Effect of ANG II was investigated in in vitro smooth muscle strips and in isolated smooth muscle cells (SMC). Among different species, rat internal and sphincter (IAS) smooth muscle showed significant and reproducible contraction that remained unmodified by different neurohumoral inhibitors. The AT(1) antagonist losartan but not AT(2) antagonist PD-123319 antagonized ANG II-induced contraction of the IAS smooth muscle and SMC. ANG II-induced contraction of rat IAS smooth muscle and SMC was attenuated by tyrosine kinase inhibitors genistein and tyrphostin, protein kinase C (PKC) inhibitor H-7, Ca(2+) channel blocker nicardipine, Rho kinase inhibitor Y-27632 or p(44/42) mitogen-activating protein kinase (MAPK(44/42)) inhibitor PD-98059. Combinations of nicardipine and H-7, Y-27632, and PD-98059 caused further attenuation of the ANG II effects. Western blot analyses revealed the presence of both AT(1) and AT(2) receptors. We conclude that ANG II causes contraction of rat IAS smooth muscle by the activation of AT(1) receptors at the SMC and involves multiple intracellular pathways, influx of Ca(2+), and activation of PKC, Rho kinase, and MAPK(44/42).

Role ofpp60c-srcandp44/42MAPK in ANG II-induced contraction of rat tonic gastrointestinal smooth muscles

“…ANG II-induced contraction of LES and IAS circular smooth muscles is inhibited specifically by the AT 1 antagonist losartan. This observation combined with the presence of AT 1 receptors in the LES and IAS smooth muscles suggests a specific role for AT 1 receptors in the mediation of ANG II-induced contraction in these tissues (16).…”

The Effects of Some Neuropeptides on Motor Activity of Smooth Muscle Organs in Abdominal and Pelvic Cavities

“…Most of the effects of Ang II concerning the smooth muscle contractile activity of GIT are associated with AT1 receptors (Fändriks, 2010;Fan et al, 2002;Hawcock & Barnes, 1993;Rattan et al, 2003). AT2 receptors are also described in GIT (Fändriks, 2010;Fan et al, 2002;Hawcock & Barnes, 1993;Ewert et al, 2003;Leung et al, 1993;De Godoy et al, 2002).…”

“…AT2 receptors are also described in GIT (Fändriks, 2010;Fan et al, 2002;Hawcock & Barnes, 1993;Ewert et al, 2003;Leung et al, 1993;De Godoy et al, 2002). Although different signaling pathways have been assumed, for example activation of various phosphatases, cGMP -NO system etc.…”

“…Dosedependent curves, which are commonly used as a method for studying the provoked smooth muscle contractions (Fändriks, 2010;Fan et al, 2002;Hawcock & Barnes, 1993;Leung et al, 1993;Park et al, 1973), could give information about the effective doses and maximal responses, but not a data for other important characteristics of the smooth muscle contractions. The different phases of the contraction in the various segments of the GIT, were not clarified and analyzed by application of a time-parameter analysis, as it was made in the study of the skeletal muscle contraction (Raikova & Aladjov, 2004).…”

“…It had been demonstrated that only AT1 receptors are relevant for the maximum response in ANG-induced contractions (Hawcock & Barnes, 1993;Fändriks, 2010;Fan et al, 2002;Rattan et al, 2003;Ewert et al, 2006;Fändriks, 2010). Despite the existing assumptions that stimulation of AT2 receptors may have the opposite effect than that of AT1 (Gallinat et al, 2000), the role of AT2 receptors for the relaxation phase of the SMC in GIT is not examined.…”