Novel options for the pharmacological treatment of chronic anal fissure--role of botulin toxin.
A chronic anal fissure (CAF) is commonly referred to as an ischemic ulcer. For many years it was thought that sphincteroctomy produces anal sphincter relaxation, enhances microcirculation and promotes CAF healing. The latest studies have shown that fissure healing does not appear to be dependent on reduction in mean resting anal pressure. Our description of the process of CAF healing is based on understanding the balance between nitric oxide (NO) concentration and a level of oxidative and nitroxidative stress in wounds, which is responsible for contraction of smooth muscles (also anal sphincters), endothelial/skeletal muscle cell remodelling and proliferation. Pharmacological sphincterotomy with botulinum toxin (BTX) has an effect on motor endplate but it also has an influence on nitric oxide synthase (NOS) and other agents. Hypoxia in contracted anal sphincters induces vasoconstriction, in part, by decreasing endothelial NOS expression. Clostridium botulinum C3 exoenzyme - Rho-kinase inhibitor reverses this vasoconstriction. CAF is a site where the haemostatic mechanisms are activated. Rho inactivator C3-transferase from Clostridium botulinum abolished thrombin - stimulated endothelial cell contraction. Attenuated biotransformation of Glyceryl trinitrate (GTN) by mitochondrial aldehyde dehydrogenase and suppression of cGMP-dependent protein kinase expression may play a key role in understanding the problem of synergistic action of BTX and GTN. BTX and GTN are different forms of pharmacological sphincterectomies. This mechanism could explain the potentiate effect of BTX action after NO donors application for CAF. The application of BTX releases the blockage in GTN bioactivation in smooth muscle cells and suppresses basal continuous sympathetic activity, causing modulation of anal sphincters. It is responsible for CAF healing.
Madalinski
Mariusz
M
Department of Gastroenterology, Royal Infirmary of Edinburgh, Edinburgh, UK.
Kalinowski
Leszek
L
D000287:Administration, Topical; D001905:Botulinum Toxins / Q000494:pharmacology / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D002908:Chronic Disease; D005401:Fissure in Ano / Q000188:drug therapy*; D006801:Humans; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014945:Wound Healing / Q000187:drug effects
D002121:Calcium Channel Blockers; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D001905:Botulinum Toxins