Neuronal nitric oxide synthase enzyme activation and calcium channel-dependent relaxation of the internal anal sphincter by Tridax procumbens
Abstract
Objective: To investigate the role of neuronal nitric oxide synthase (nNOS) enzyme activation and calcium channel-dependent mechanisms in mediating the relaxation of the internal anal sphincter (IAS), with specific reference to the pharmacological effects of Tridax procumbens. Data sources: Relevant literature was retrieved from PubMed/MEDLINE, and Google Scholar encompassing published review articles, pharmacological studies, phytochemical investigations, and clinical research related to T. procumbens. Study selection: Published literature describing the phytochemistry, pharmacological activities, therapeutic uses, and formulations of T. procumbens, along with studies on nNOS activation, calcium channel-dependent relaxation, and IAS physiology were included in this review. Only peer-reviewed, English-language articles were considered. Studies with insufficient data, duplicates, and non-peer-reviewed sources were excluded. Summary of contents of the article: Anal fissure results from internal anal sphincter hypertonicity causing ischaemia, spasm, and pain. T. procumbens shows consistent smooth muscle relaxant effects via calcium channel inhibition and nitric oxide release across preclinical studies. A recent randomized controlled trial confirmed its clinical efficacy, matching standard Lignocaine-Nifedipine cream in healing, spasm, and pain relief, with fewer side effects. Conclusion: T. procumbens, acting as a safe chemical sphincterotomy through nitric oxide and calcium-mediated sphincter relaxation, warrants consideration as a first-line treatment for anal fissure.
Keywords: Calcium Channels L-Type, Fissure in ano, Internal Anal Sphincter, Neural Nitric Oxide Synthase, Tridax procumbens
Keywords:
Calcium Channels L-Type, Fissure in ano, Internal Anal Sphincter, Neural Nitric Oxide Synthase, Tridax procumbensDOI
https://doi.org/10.22270/jddt.v16i8.7936References
1. Kumar L, Emmanuel A, “Internal anal sphincter: clinical perspective” The Surgeon, 2017; Aug 1;15(4):211-26. DOI: http://doi.org/10.1016/j.surge.2016.10.003
2. Nothmann Bruce J, Marvin M. Schuster, “Internal anal sphincter derangement with anal fissures” Gastroenterology, 1974; 67, no. 2 216-220. DOI: https://doi.org/10.1016/S0016-5085(19)32882-3
3. Lund JN, “Nitric oxide deficiency in the internal anal sphincter of patients with chronic anal fissure”, International journal of colorectal disease, 2006; Oct;21(7):673-5. DOI: https://doi.org/10.1007/s00384-005-0757-y
4. Lindsey I, Jones OM, Cunningham C, Mortensen NM, “Chronic anal fissure” Journal of British Surgery, 2004; 91(3), 270-9. DOI: https://doi.org/10.1002/bjs.4531
5. Li T, Ye P, He X, Li C, Xi L, Xi Z, “Efficacy and safety of topical vs. oral calcium channel blockers for chronic anal fissures: a systematic review and meta-analysis” Front Pharmacol, 2025; 6:1642347. DOI: https://doi.org/10.3389/fphar.2025.1642347
6. Gorfine SR, Billingham RP, “Treatment of benign anal disease with topical nitroglycerin” Diseases of the colon & rectum, 1995; 38(5):453-7. DOI: https://doi.org/10.1007/BF02148842
7. Lund JN, Scholefield JH, “Aetiology and treatment of anal fissure” Journal of British Surgery, 1996; 83(10), 1335-44. DOI: https://doi.org/10.1002/bjs.1800831006
8. Wang C, Ni J, Xiong Y, Chen J, Li B, Xu L, “The efficacy of diltiazem, glyceryl trinitrate, nifedipine, minoxidil, and lidocaine for the medical management of anal fissure: a systematic review and network meta-analysis of randomized controlled trials” Int J Surg, 2025; 1;111(4):3020-9. DOI: https://doi.org/10.1097/JS9.0000000000002263
9. Rotholtz NA, Bun M, Mauri MV, Bosio R, Peczan CE, Mezzadri NA, “Long–term assessment of fecal incontinence after lateral internal sphincterotomy” Techniques in coloproctology, 2005; 9, 115-8. DOI: https://doi.org/10.1007/s10151-005-0208-3
10. Gupta GY, Gupta YA, “Comprehensive insights into the adoption of herbal and Ayurvedic medicines in India: a systematic literature review” Int J Ayurvedic Med, 2026; 17(1):55–59. DOI: https://doi.org/10.47552/ijam.v17i1.6321
11. Kanwal A, Ahmad M, Aslam S, Saleem S, Sikandar M, Fatima H, “Phytochemistry and pharmacological aspects of Tridax procumbens (L.): a systematic and comprehensive review” Phytomedicine Plus, 2021; 1(4):100134. DOI: https://doi.org/10.1016/j.phyplu.2021.100134
12. Lund JN, Scholefield JH, “Aetiology and treatment of anal fissure” Br J Surg, 1996; 83(10):1335-44. DOI: https://doi.org/10.1002/bjs.1800831006
13. Nelson RL, Chattopadhyay A, Brooks W, Platt I, Paavana T, Earl S, “Operative procedures for fissure in ano” Cochrane Database Syst Rev, 2011; (11):CD002199. DOI: https://doi.org/10.1002/14651858.CD002199.pub4
14. Stewart DB Sr, Gaertner W, Glasgow S, Migaly J, Feingold D, Steele SR, “Clinical practice guideline for the management of anal fissures” Dis Colon Rectum, 2017; 60(1):7-14. DOI: https://doi.org/10.1097/DCR.0000000000000735
15. Barbeiro S, Atalaia-Martins C, Marcos P, Gonçalves C, Canhoto M, Arroja B, “Long-term outcomes of Botulinum toxin in the treatment of chronic anal fissure: 5 years of follow-up” United European Gastroenterol J, 2017; 5(2):293-7. DOI: https://doi.org/10.1177/2050640616656708
16. Carapeti EA, Kamm MA, Phillips RKS, “Topical diltiazem and bethanechol decrease anal sphincter pressure and heal anal fissures without side effects” Dis Colon Rectum, 2000; 43(10):1359-62. DOI: https://doi.org/10.1007/BF02236630
17. Lund JN, Scholefield JH, “A randomised, prospective, double-blind, placebo-controlled trial of glyceryl trinitrate ointment in treatment of anal fissure” Lancet, 1997; 349(9044):11-4. DOI: https://doi.org/10.1016/S0140-6736(96)06090-4
18. Ghosh P, Biswas S, Biswas M, Dutta A, Sil S, Chatterjee S, “Morphological, Ethno biological and Phytopharmacological Attributes of Tridax procumbens Linn.(Asteraceae): A Review” Int. J. Sci. Res. in Biological Sciences, 2019; 6(2). DOI: https://doi.org/10.26438/ijsrbs/v6i2.182191
19. Verma RK, Gupta MM, “Lipid constituents of Tridax procumbens” Phytochemistry, 1988; Jan 1;27(2):459-63. DOI: https://doi.org/10.1016/0031-9422(88)83120-0
20. Raju TS, Davidson EA, “Structural features of water-soluble novel polysaccharide components from the leaves of Tridax procumbens Linn” Carbohydrate Research, 1994; May 20;258:243-54. DOI: https://doi.org/ 10.1016/0008-6215(94)84090-3
21. Saxena VK, Albert S, “β-Sitosterol-3-O-β-D-xylopyranoside from the flowers of Tridax procumbens Linn” Journal of chemical sciences, 2005; 117(3):263-6. DOI: https://doi.org/10.1007/BF02709296
22. Ali MS, Jahangir M, ul Hussan SS, Choudhary MI, “Inhibition of α-glucosidase by oleanolic acid and its synthetic derivatives” Phytochemistry, 2002; 60(3):295-9. DOI: https://doi.org/10.1016/S0031-9422(02)00104-8
23. Margaret I, Srinivasa RP, Kaiser J, “Antiinflammatory profile of Tridax procumbens in animal and fibroblast cell models” Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives, 1998; 12(4):285-7. DOI: https://doi.org/ 10.1002/(SICI)1099-1573(199806)12:4<285::AID-PTR227>3.0.CO;2-I
24. Nia R, Essien EE, Oladimeji OH, Iyadi KC, Franz G, “Investigation into in-vitro radical scavenging and in-vivo anti-inflammatory potential of Tridax procumbens” Nigerian Journal of Physiological Sciences, 18(1), 39–43. DOI: https://doi.org/10.4314/njps.v18i1.32617
25. Tiwari U, Rastogi B, Singh P, Saraf DK, Vyas SP, “Immunomodulatory effects of aqueous extract of Tridax procumbens in experimental animals” Journal of ethnopharmacology, 2004; May 1;92(1):113-9. DOI: https://doi.org/ 10.1016/j.jep.2004.02.001
26. Ravikumar V, Shivashangari KS, Devaki T, “Effect of Tridax procumbens on liver antioxidant defense system during lipopolysaccharide-induced hepatitis in D-galactosamine sensitised rats” Molecular and cellular biochemistry, 2005; Jan;269(1):131-6. DOI: https://doi.org/10.1007/s11010-005-3443-z
27. Bhagwat DA, Killedar SG, Adnaik RS, “Anti-diabetic activity of leaf extract of Tridax procumbens” International Journal of Green Pharmacy (IJGP), 2008; 2(2). DOI: https://doi.org/10.22377/ijgp.v2i2.46
28. Salahdeen HM, Yemitan OK, Alada AR, “Effect of aqueous leaf extract of Tridax procumbens on blood pressure and heart rate in rats” African Journal of Biomedical Research, 2004; 7(1). DOI: https://doi.org/10.4314/ajbr.v7i1.54062
29. Jain DK, Patel NS, Nagar H, Patel A, Chandel HS, “Anti-arthritic activity of Tridax procumbens ethanolic extract of leaves” RGUHS J. Pharm. Sci., 2012; Oct;2(4):80-6. DOI: https://doi.org/10.4103/0974-8490.110541
30. Martín-Quintal Z, Moo-Puc R, González-Salazar F, Chan-Bacab MJ, Torres-Tapia LW, Peraza-Sánchez SR, “In vitro activity of Tridax procumbens against promastigotes of Leishmania Mexicana” Journal of Ethnopharmacology, 2009; Apr 21;122(3):463-7. DOI: https://doi.org/10.1016/j.jep.2009.01.037
31. Chinnappan BA, Krishnaswamy M, Bal T, Rajora AD, “In vitro-in vivo wound healing efficacy of Tridax Procumbens extract loaded Carboxymethylcellulose film” International Journal of Biological Macromolecules, 2023; Dec 31;253:126695. DOI: https://doi.org/10.1016/j.ijbiomac.2023.126695
32. Pareek H, Sharma S, Khajja BS, Jain K, Jain GC, “Evaluation of hypoglycemic and anti-hyperglycemic potential of Tridax procumbens (Linn.)” BMC complementary and alternative medicine, 2009; Nov 29;9(1):48. DOI: https://doi.org/10.1186/1472-6882-9-48
33. Fenner DE, Kriegshauser JS, Lee HH, Beart RW, Weaver A, Cornella JL, “Anatomic and physiologic measurements of the internal and external anal sphincters in normal females” Obstetrics & Gynecology, 1998; 91, 369-374. DOI: https://doi.org/10.1016/S0029-7844(97)00678-9
34. Keef KD, Cobine CA, “Control of Motility in the Internal Anal Sphincter” Journal of Neurogastroenterology and Motility, 2019; 25, 189-204. DOI: https://doi.org/10.5056/jnm18172
35. Kumar L, Emmanuel A, “Internal anal sphincter: clinical perspective” The Surgeon, 2017; 15, 211-226. DOI: https://doi.org/10.1016/j.surge.2016.10.003
36. Schouten WR, Briel JW, Auwerda JJ, “Relationship between anal pressure and anodermal blood flow the vascular pathogenesis of anal fissures” Diseases of the Colon & Rectum, 1994; 37, 664-669. DOI: https://doi.org/10.1007/BF02054409
37. Duthie HL, Gairns FW, “Sensory nerve-endings and sensation in the anal region of man” British Journal of Surgery, 1960; 47, 585-595. DOI: https://doi.org/10.1002/bjs.18004720602
38. Schouten WR, Briel JW, Auwerda JJ, “Relationship between anal pressure and anodermal blood flow The vascular pathogenesis of anal fissures” Diseases of the Colon & Rectum, 1994; Jul;37(7):664–669. DOI: https://doi.org/10.1007/BF02054409
39. Nelson RL, Thomas K, Morgan J, Jones A, “Non surgical therapy for anal fissure” Cochrane Database of Systematic Reviews, 2012; Feb 15;(2):CD003431. DOI: https://doi.org/10.1002/14651858.CD003431.pub3
40. Salahdeen HM, Murtala BA, “Vasorelaxant effects of aqueous leaf extract of Tridax procumbens on aortic smooth muscle isolated from the rat” Journal of Smooth Muscle Research, 2012; 48(2_3):37-45. DOI: https://doi.org/10.1540/jsmr.48.37
41. Salahdeen HM, Idowu GO, Yemitan OK, Murtala BA, Alada AR, “Calcium-dependent mechanisms mediate the vasorelaxant effects of Tridax procumbens aqueous leaf extract in rat aortic ring” Journal of Basic and Clinical Physiology and Pharmacology, 2014; Apr;25(2):161–166. DOI: https://doi.org/10.1515/jbcpp-2013-0030
42. Salahdeen HM, Idowu GO, Yemitan OK, Murtala BA, Alada AR, “The relaxant actions of ethanolic extract of Tridax procumbens (Linn.) on rat corpus cavernosum smooth muscle contraction” Journal of Basic and Clinical Physiology and Pharmacology, 2015; Apr;26(2):211–216. DOI: https://doi.org/10.1515/jbcpp-2013-0032
43. Salahdeen HM, Idowu GO, Salami SA, Murtala BA, Alada AA, “Mechanism of vasorelaxation induced by Tridax procumbens extract in rat thoracic aorta” Journal of Intercultural Ethnopharmacology, 2016; 5(2):174. DOI: https://doi.org/10.5455/jice.20160329030307
44. Salahdeen HM, Salami SA, Paul CO, Murtala BA, Alada AA, “Biochemical parameters as indicators of antihypertensive efficacy of leaf aqueous extract of Tridax procumbens (Linn.) in L-NAME-induced hypertensive rats” Journal of Molecular Pathophysiology, 2017; Jul;6(2):30–38. DOI: https://doi.org/10.5455/jmp.20170721110820
45. Salami SA, Salahdeen HM, Rahman OC, Murtala BA, Raji Y, “Oral administration of Tridax procumbens aqueous leaf extract attenuates reproductive function impairments in L-NAME-induced hypertensive male rats” Middle East Fertility Society Journal, 2017; Sep;22(3):219–225. DOI: https://doi.org/10.1016/j.mefs.2017.03.001
46. Salami SA, Salahdeen HM, Ugbebor EC, Murtala BA, Raji Y, “Effects of aqueous leaf extract of Tridax procumbens on contractile activity of corpus cavernosum in N-nitro-l-arginine methyl ester-induced hypertensive male rats” Journal of integrative medicine, 2018; Jan 1;16(1):51-6. DOI: https://doi.org/10.1016/j.joim.2017.11.001
47. Omedine K, Loetitia M, Ismael H, Alphonse S, “Hypotensive activity of Tridax procumbens hydroethanolic extract: Roles of sodium and potassium transport in Wistar rats” American Journal of PharmTech Research, 2018; Feb;8(1):289–302. DOI: https://doi.org/10.46624/ajptr.2018.v8.i1.020
48. Salami SA, Salahdeen HM, Idowu GO, Murtala BA, Alada ARA, “Tridax procumbens leaf extract elicits relaxation of rat mesenteric artery by activation of Na+ -K+ ATPase / Na+ - Ca2+ exchanger” National Journal of Physiology, Pharmacy and Pharmacology, 2021; Jun;11(6):638–644. DOI: https://doi.org/10.5455/njppp.2021.11.12351202113042021
49. Salami SA, Salahdeen HM, Anidu BS, Murtala BA, Alada AA, “Preliminary mechanistic study on the trachea smooth muscle relaxant activity of aqueous leaf extract of Tridax procumbens in male Wistar rats” Journal of Pharmacopuncture, 2022; Sep;25(3):209–217. DOI: https://doi.org/10.3831/KPI.2022.25.3.20
50. Bobade S, Asutkar S, “Comparative Evaluation of the Healing Effect of Topical Jayanti (Tridax procumbens) Cream versus Topical Lignocaine and Nifedipine Cream in Parikartika (Acute Fissure in Ano): A Randomised Controlled Trial” J Clin Diagn Res, 2025; Nov;19(11):JC07-JC13. DOI: https://doi.org/10.7860/JCDR/2025/77107.21991
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