Influence of Antihypertensive and Antidiabetic Drugs on Wound Healing – Essentials of a Systematic In-Vitro Study

AUTHORS

Ewa K. Stuermer

Director, Institute for Translational Wound Research,Centre for Biomedical Education and Research, Witten/Herdecke University

Introduction

Due to the increasing prevalence of so called "life style diseases", such as diabetes, obesity or hypertension, the number of associated vascular and nerve lesions increases. In the lower limbs in particular, bagatelle trauma causes wounds that lead to wound healing disorders and chronic wounds [1]. All these patients are reliant on drugs for the treatment of cardiovascular or diabetic disease. While drugs such as cortisone or non-steroidal anti-inflammatory drugs (NSAIDs) are postulated to have a negative effect on wound healing, it is unknown whether the intake of antihypertensive drugs and antidiabetics, respectively influences wound healing as well. As this is difficult to analyze systematically in clinical investigations, a comparative in-vitro study with human skin cells in 2D and 3D models is performed.

Methods

A systematic literature review on the topic "Wound healing & antihypertensive drugs" and "Wound healing & antidiabetics" was carried out. Based on these findings and according to the latest drug report of a major German health insurance, the effect of the five antihypertensive drugs and four antidiabetics most frequently administered in Germany were analyzed in human fibroblasts and keratinocytes. For the antihypertensive drugs a representative sample of the groups β1-receptor blocker, calcium channel blocker, angiotensin-converting enzyme inhibitors, diuretics and the sartan group was selected. For the antidiabetic drugs representatives of the substance classes biguanides, sulfonylureas, glinides and dipeptidylpeptidase inhibitors (DDPIs) were chosen. In 2D cultures, cell metabolism, cell viability and migration ability were histologically evaluated. In addition, substances were investigated in a 3D wound model according to Timpson [2], regarding epidermal thickness (µm) and fibroblast density (n/µm) at the wound margin and wound bed. Here, cell proliferation, cell migration and apoptosis were immunohistochemically investigated after 12 days of application of antihypertensive drugs and antidiabetics in serum equivalent doses.

Results
There are only few scientific studies investigating the effect of antihypertensive drugs and antidiabetics on wound healing. In addition, their findings are partly contradictory. Among antihypertensive drugs, calcium channel blockers like amlodipine improve the tensile strength, but not the epithelialization of the skin [3, 4, 5]. β-blockers like propranolol or metoprolol have a systemic and locally accelerating effect on wound healing [6, 7]. They activate the keratinocytes, which have a positive effect on wound closure but a negative effect on a possible existing psoriasis [8, 9]. ACE inhibitors like ramipril have a negative effect on cell proliferation and cell migration [10, 11, 12]. This was confirmed by reduced healing processes in the 3D wound model. Ramipril inhibits collagen biosynthesis as well [7]. Among the antidiabetics, metformin belonging to the biguanides impairs wound healing processes qualitatively and quantitatively in-vivo and in-vitro [13, 14]. The negative influence on cell metabolism is particularly noteworthy here. In contrast, the quite new dipeptidyl peptidase inhibitor sitagliptin has a positive effect on the wound and its blood circulation [15, 16]. Sulfonylureas like glibenclamide do not appear to have a positive or negative effect on wound healing [17, 18]. Own results in the in-vitro 3D wound model largely support this above-mentioned effects, with keratinocytes reacting much more sensitive to antihypertensive drugs and antidiabetics. In summary, the negative influence of hydrochlorothiazide and metformin is particularly worth mentioning here.

Discussion
Most patients with chronic wounds also suffer from hypertension and/or diabetes. It is therefore astonishing that "side effects" of drug therapy on wound healing are hardly considered in medical and scientific research. Almost all antidiabetics and antihypertensive drugs have a distinct measurable in-vitro effect on wound healing. There are huge variations among the substance classes: In contrast to systemic application, the application of metformin in serum-equivalent concentration was associated with negative effects on wound healing d in in-vitro analyzes [19]. Repaglinide also tended to have a negative effect on the metabolism of skin cells. In contrast, sitagliptin and glibenclamide had a slightly positive effect. Interestingly, antidiabetics led to an increased rate of apoptosis in the tissue of the wound bed (fibroblasts) when applicated directly. In the case of antihypertensive drugs, β-receptor blockers improve wound healing in in-vivo and in-vitro studies. The results after local application of timolol are particularly noteworthy [4]. Calcium channel blockers showed a positive effect on wound healing. However, the opposite is the case for ACE inhibitors and thiazide diuretics (e.g. HCT): The wound healing in ex-vivo and in-vitro 3D skin model is delayed by HCT in serum equivalent doses [20]. In addition, a possible association between thiazide diuretics and skin cancer should not be neglected. The results presented here should be considered due to their potential relevance for patients with chronic wounds who do not respond to adequate wound therapies. In particular, the negative results of metformin, the first choice therapy for type II diabetes, which does not induce hyperglycemia or weight gain, increases insulin sensitivity and reduces mortality and morbidity, are remarkable and incomprehensible, so that a clinical study is indispensable.

References

1.Sen CK, Gordillo GM, Roy S, Robert K ,Lynn L et al. (2009) Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen 17(6):763-771.

2.Timpson P, McGhee EJ, Erami Z,  Max N Jean A.Q et al. (2011) Organotypic collagen I assay: a malleable platform to assess cell behaviour in a 3-dimensional context. J Vis Exp. 13:e3089.

3. Lee RC, Ping JA.(1990) Calcium antagonists retard extracellular matrix production in connective tissue equivalent. J Surg Res.49(5):463-466.

4. Uchino Y, Matsumoto J, Watanabe T, Masato H, Takashi T et al. (2015) Nifedipine prevents sodium caprate-induced barrier dysfunction in human epidermal keratinocyte cultures. Biol Pharm Bull.38(6):926-999.

5. Sato N, Matsumoto H, Akimoto Y, Fujii A (2005) The effect of IL-1alpha and nifedipine on cell proliferation and DNA synthesis in cultured human gingival fibroblasts. J Oral Sci47(2):105-110.

6. Ali A, Herndon DN, Mamachen A, Hasan S, Andersen CR et al (2015) Propranolol attenuates hemorrhage and accelerates wound healing in severely burned adults. Critical Care.4:217-223.

7. Braun LR, Lamel SA, Richmond NA,  et al. (2013) Topical timolol for recalcitrant wounds. JAMA Dermatol.;149(12):1400-1402.

8. Armstrong AW. (2014) Psoriasis provoked or exacerbated by medications: identifying culprit drugs. JAMA Dermatol 150(9):963.

9. Kim GK, Del Rosso JQ. (2010) Drug-provoked psoriasis: is it drug induced or drug aggravated?: understanding pathophysiology and clinical relevance. J Clin Aesthet Dermatol3(1):32-38.

10. Baroni A, Buommino E, Ruocco E, Marcella P,Anna DF,et al. (2011 Captopril modulates acetylcholinesterase in human keratinocytes. Arch Dermatol Res. 303(7):491-497.

11 Karna E, Szoka L, Palka JA. (2010) Captopril-dependent inhibition of collagen biosynthesis in cultured fibroblasts. Pharmazie.65(8):614-617.

12. Zeeli T, Langberg M, Rotem C,  David M, Koren R et al. (2011) Vitamin D inhibits captopril-induced cell detachment and apoptosis in keratinocytes. Br J Dermatol.164(1):62-67.

13. Li W, Ma W, Zhong H, et al. (2014) Metformin inhibits proliferation of human keratinocytes through a mechanism associated with activation of the MAPK signaling pathway. Exp Ther Med. 7(2):389-392.

14. Ochoa-Gonzalez F, Cervantes-Villagrana AR, Fernandez-Ruiz JC, Hilda S. Nava-R,Adriana C. H et al. (2016) Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients. PLoS One. 2016;11(3):e0150900.

15. Saboo A, Rathnayake A, Vangaveti VN, Usman H.M (2016) Wound healing effects of dipeptidyl peptidase-4 inhibitors: An emerging concept in management of diabetic foot ulcer-A review. Diabetes Metab Syndr10(2):113-119.

16. Schuermann C, Linke A, Engelmann-Pilger K,  Cornelia S, Michael M et al. (2012) The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob/ob mice. J Pharmacol Exp Ther 342(1):71-80.

17. Papapetropoulos A, Pyriochou A, Altaany Z,  Guangdong Y, Antonia M et al.(2009) Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc Natl Acad Sci U S A. 22 106(51):1972-1977.

18. Bodiga VL, Eda SR, Chavali S, et al. (2014) In vitro biological evaluation of glyburide as potential inhibitor of collagenases. Int J Biol Macromol 70:187-192.

19. Stuermer EK, Besser M, Terberger N, Koester V, Bachmann HS. et al (2019) Side effects of frequently used oral antidiabetics on wound healing in vitro. Naunyn Schmiedebergs Arch Pharmacol.392:371-380.

20. Stuermer EK, Besser M, Terberger N, Koester V, Bachmann HS, et al (2019) Side effects of frequently used antihypertensive drugs at wound healing in-vitro. Skin Pharmacol Physiol  [accepted]