title: Phosphodiesterase inhibitors cause relaxation of the internal anal sphincter in vitro.
abstract: OBJECTIVE
  Pharmacologic treatments are gaining widespread acceptance as first-line therapy for anal fissure. However, existing treatments have limited clinical usefulness because of side effects and incomplete healing rates.
  
  
  METHODS
  Fresh human surgical resection specimens containing internal anal sphincter and rectal circular muscle were collected. Strips of smooth muscle were cut from each muscle group and mounted in a superfusion organ bath. The effects of increasing concentrations of phosphodiesterase inhibitors were evaluated.
  
  
  RESULTS
  All phosphodiesterase inhibitors tested caused a dose-dependent reduction in the tone of the internal anal sphincter, with potencies as follows: vinpocentine (phosphodiesterase-1 inhibitor; 50 percent maximum inhibition concentration = 0.87 +/- 0.10 microM), erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (phosphodiesterase-2 inhibitor; 32 +/- 4.8 microM), trequinsin (phosphodiesterase-3 inhibitor; 0.28 +/- 0.041 microM), rolipram (phosphodiesterase-4 inhibitor; 63 +/- 9 microM), zaprinast (phosphodiesterase-1,5,6,9,11 inhibitor; 3 +/- 0.69 microM), and dipyridamole (phosphodiesterase-5,6,8,10,11 inhibitor; 5.5 +/- 2 microM). Although all inhibitors were also effective on rectal circular muscle strips, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride, trequinsin, and rolipram were at least an order of magnitude more potent in this tissue than in the internal anal sphincter.
  
  
  CONCLUSIONS
  There are several functionally important phosphodiesterases in the internal anal sphincter and rectal circular muscle. Both adenosine 3', 5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate appear to be important in the myogenic tone of the internal anal sphincter, and this study provides further evidence of the sphincteric specialization of this tissue. Phosphodiesterase inhibitors might represent a new therapy for the treatment of anal fissure.
authors: University Department of Pharmacology, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Oliver M
authors: OM
authors: Jones
authors: Alison F
authors: AF
authors: Brading
authors: Neil J
authors: NJ
authors: McC Mortensen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D001003:Anal Canal / Q000187:drug effects*; D004176:Dipyridamole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D012007:Rectum / Q000187:drug effects; D020889:Rolipram / Q000494:pharmacology; D044005:Tetrahydroisoquinolines; D014748:Vinca Alkaloids / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011688:Purinones; D044005:Tetrahydroisoquinolines; D014748:Vinca Alkaloids; C013983:vinpocetine; C010192:9-(2-hydroxy-3-nonyl)adenine; D004176:Dipyridamole; C035964:trequinsin; C011145:zaprinast; D000225:Adenine; D020889:Rolipram