Animal model for angiotensin II effects in the internal anal sphincter smooth muscle: mechanism of action.
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).
Fan
Ya-Ping
YP
Department of Medicine, Division of Gastroenterology and Hepatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Puri
Rajinder N
RN
Rattan
Satish
S
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D001003:Anal Canal; D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004947:Esophagus; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D023421:Models, Animal; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology*; D011224:Prazosin / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000032:analysis; D013779:Tetrodotoxin / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology; D054460:rho-Associated Kinases
D000317:Adrenergic alpha-Antagonists; D057911:Angiotensin Receptor Antagonists; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D020960:omega-Conotoxins; D000804:Angiotensin II; D013779:Tetrodotoxin; D001285:Atropine; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium; D011224:Prazosin