EFFECT OF AMLODIPINE AND ENALAPRIL ON WOUND HEALING IN DIABETIC WISTAR ALBINO RATS
Keywords:
Antihypertensive drugs, Diabetic ulcers, Re-epithelization, StreptozotocinAbstract
Objective: A number of structural and functional mechanisms have been identified in the pathogenesis of impaired wound healing in diabetes. Diabetes promotes endothelial dysfunction as evidenced by decreased nitric oxide (NO) production. NO deficiency and resultant impaired angiogenesis have been implicated in impaired wound healing in diabetes. The objective of this study was to evaluate the effects of amlodipine and enalapril on wound healing in streptozotocin induced diabetic rats based on previous observations that amlodipine increases NO bioavailability and enalapril promote angiogenesis.
Methods: Four groups for each wound model (n=6 in each group; total 8 groups) were used and served as diabetic control, active control (glibenclamide), amlodipine, and enalapril groups. Wound closure rate and re-epithelialization were studied in the excision wounds. Incision wounds were studied for wound breaking strength while dead space wounds were studied for granulation tissue weight, hydroxyproline content, and histological changes in granulation tissue.
Results: Amlodipine and enalapril significantly (P<0.05) increased re-epithelialization in excision wound model. Amlodipine significantly improved incision wound breaking strength while enalapril increased granulation tissue formation. None of the study agents had a significant effect on wound granulation tissue histology.
Conclusion: Amlodipine and enalapril enhance the re-epithelialization in the diabetic wound. Choosing amlodipine or enalapril as antihypertensive in diabetic patients may help to improve impaired wound healing in these patients. Further human trials are needed to demonstrate similar benefits in diabetic patients with wounds.
Keywords:Antihypertensive drugs, Diabetic ulcers, Re-epithelization, StreptozotocinÂ
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Singer AJ, Clark RAF. Cutaneous wound healing. N Engl J Med 1999;341:738-46.
Ramsey SD, Newton K, Blough D, McCulloch DK, Sandhu N, Reiber GE, et al. Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care 1999;22:382-7.
Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005;366:1736-43.
Anderson TJ. Nitric oxide, atherosclerosis and the clinical relevance of endothelial dysfunction. Heart Failure Rev 2003;8:71-86.
Traub O, Bibber VR. Role of nitric oxide in insulin-dependent diabetes mellitus related vascular complication. West J Med 1995;162:439-45.
Schaffer MR, Tantry U, Efron PA, Ahrendt GM, Thornton FJ, Barbul A. Diabetes-impaired healing and reduced wound nitric oxide synthesis: a possible pathophysiologic correlation. Surgery 1997;121:513-9.
Ghori V, Mandavia DR, Patel TK, Tripathi CB. Effect of topical nitric oxide donor (0.2 % glyceryl trinitrate) on wound healing in diabetic Wistar rats. Int J Diabetes Dev Countries 2014;34:45-9.
Berkels R, Taubert D, Bartels H, Breitenbach T, Klaus W, Roesen R. Amlodipine increases endothelial nitric oxide by dual mechanisms. Pharmacology 2004;70:39-45.
Silvestre JS, Lévy BI. Molecular basis of angiopathy in diabetes mellitus. Circ Res 2006;98:4-6.
Isner JM. Method of using angiotensin-converting enzyme inhibitor to stimulate angiogenesis. U. S. Patent No. 6,191,144; 2001.
Fabre JE, Rivard A, Magner M, Silver M, Isner JM. Tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo. Circulation 1999;99:3043-9.
Fallahzadeh AR, Khazaei M, Sharifi MR. Restoration of angiogenesis by enalapril in diabetic hindlimb ischemic rats. Biomed Papers 2011;155:137–42.
Bhaskar HN, Udupa SL, Udupa AL. Effect of Nifedipine and amlodipine on wound healing in rats. Indian J Physiol Pharmacol 2004;48:111–4.
Bhaskar HN, Udupa SL, Udupa AL. Effect of nifedipine and amlodipine on dead space wound healing in rats. Indian J Exp Biol 2005;43:294-6.
Torgal SS, Hiremath SV, Majagi SI, Gouripur VV, Patil PA, Hogade AP. Evaluation of wound healing activity of angiotensin converting enzyme inhibitors in wistar rats. Recent Res Sci Technol 2010;2:76-80.
Morton JJP, Malone MH. Evaluation of vulneray activity by an open wound procedure in rats. Arch Int Pharmacodyn Ther 1972;196:117-26.
Ehrlich HP, Hunt TK. The effects of cortisone and anabolic steroids on the tensile strength of healing wounds. Ann Surg 1969;170:203-6.
Lee KH. Studies on the mechanism of action of salicylate. II. Retardation of wound healing by aspirin. J Pharm Sci 1968;57:1042-3.
Woessner Jr JF. The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch Biochem Biophys 1961;93:440-7.
Dipasquale G, Meli A. Effect of body weight changes on the formation of cotton pellet-induced granuloma. J Pharm Pharmacol 1965;17:379-82.
Abramov Y, Golden B, Sullivan M, Botros SM, Miller JJR, Alshahrour A, et al. Histologic characterization of vaginal vs. abdominal surgical wound healing in a rabbit model. Wound Repair Regeneration 2007;15:80-6.
Ziche M, Morbidelli L, Masini E, Amerini S, Granger HJ, Maggi CA, et al. Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 1994;94:2036–44.
Sumi Y, Ishihara M, Kishimoto S, Takikawa M, Hattori H, Takikawa M, et al. Effective wound healing in streptozotocin-induced diabetic rats by adipose-derived stromal cell transplantation in plasma-gel containing fragmin/protamine microparticles. Ann Plast Surg 2014;72:113-20.
Luo, JD, Wang YY, Fu WL, Wu J, Chen AF. Gene therapy of endothelial nitric oxide synthase and manganese superoxide dismutase restores delayed wound healing in type 1 diabetic mice. Circulation 2004;110:2484–93.
Teixeira AS, Caliari MV, Rocha OA, Machado RDP, Andrade SP. Aminoguanidine prevents impaired healing and deficient angiogenesis in diabetic rats. Inflammation 1999;23:569-81.
McMurry JF Jr. Wound healing with diabetes mellitus. Better glucose control for better wound healing in diabetes. The Surg Clin North Am 1984;64:769-78.
Zhu H, Ka B, Murad F. Nitric oxide accelerates the recovery from burn wounds. World J Surg 2007;31:624-31.
Stallmeyer B, Anhold M, Wetzler C, Kahlina K, Pfeilschifter J, Frank S. Regulation of eNOS in normal and diabetes-impaired skin repair: implications for tissue regeneration. Nitric Oxide 2002;6:168-77.
Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest 2000;117:1162-72.
Werner S, Peters KG, Longaker MT, Fueller-Pace F, Banda MJ, Williams LT. Large induction of keratinocyte growth factor expression in dermis during wound healing. Proc Natl Acad Sci USA 1992;89:6896-900.
Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res 2009;153:347-58.
Ondrick K, Samojla BG. Angiogenesis. Clin Podiatric Med Surgery 1992;9:185-202.
Galiano RD, Tepper OM, Pelo CR, Bhatt KA, Callaghan M, Bastidas N, et al. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. Am J Pathol 2004;164:1935–47.
Seymour RA, Ellis JS, Thomson JM, Monkman S, Idle JR. Amlodipine-induced gingival overgrowth. J Clin Periodontol 1994;21:281-3.
Joshi S, Bansal S. A rare case report of amlodipine-induced gingival enlargement and review of its pathogenesis. Case Reports Dentistry 2013. Doi.org/10.1155/2013/138248. [Article in Press]
Brown RS, Sein P, Corio R, Bottomley WK. Nitrendipine-induced gingival hyperplasia. First case report. Oral Surg Oral Med Oral Pathol 1990;70:593-6.
Eickelberg O, Roth M, Block LH. Effects of amlodipine on gene expression and extracellular matrix formation in human vascular smooth muscle cells and fibroblasts: implications for vascular protection. Int J Cardiol 1997;62:S31–7.
Martelli-Junior H, Cotrim P, Graner E, Sauk JJ, Coletta RD. Effect of transforming growth factor-β1, interleukin-6, and interferon-γ on the expression of type i collagen, heat shock protein 47, matrix metalloproteinase (MMP)-1 and MMP-2 by fibroblasts from normal gingiva and hereditary gingival fibromatosis. J Periodontol 2003;74:296-306.
Robertson WV. Metabolism of collagen in mammalian tissues. Biophys J 1964;4;93-106.
Madden JW, Peacock EE Jr. Studies on the biology of collagen during wound healing: rate of collagen synthesis and deposition is cutaneous wounds in rats. Surg 1968;64:288-94.
Keeley FW, Elmoselhi A, Leenen FH. Enalapril suppresses normal accumulation of elastin and collagen in cardiovascular tissues of growing rats. Am J Physiol 1992;262:H1013-21.
McGrath MH, Emery III JM. The effect of inhibition of angiogenesis in granulation tissue on wound healing and the fibroblast. Ann Plast Surg 1985;15:105-22.