Top

Published in:

01-06-2019

Vildagliptin, an Anti-diabetic Drug of the DPP-4 Inhibitor, Induces Vasodilation via Kv Channel and SERCA Pump Activation in Aortic Smooth Muscle

Authors: Mi Seon Seo, Hongliang Li, Jin Ryeol An, In Duk Jung, Won-Kyo Jung, Kwon-Soo Ha, Eun-Taek Han, Seok-Ho Hong, Il-Whan Choi, Won Sun Park

Published in: Cardiovascular Toxicology | Issue 3/2019

Abstract

This study investigated vildagliptin-induced vasodilation and its related mechanisms using phenylephrine induced precontracted rabbit aortic rings. Vildagliptin induced vasodilation in a concentration-dependent manner. Pretreatment with the large-conductance Ca²⁺-activated K⁺ channel blocker paxilline, ATP-sensitive K⁺ channel blocker glibenclamide, and inwardly rectifying K⁺ channel blocker Ba²⁺ did not affect the vasodilatory effects of vildagliptin. However, application of the voltage-dependent K⁺ (Kv) channel inhibitor 4-aminopyridine significantly reduced the vasodilatory effects of vildagliptin. In addition, application of either of two sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibitors, thapsigargin or cyclopiazonic acid, effectively inhibited the vasodilatory effects of vildagliptin. These vasodilatory effects were not affected by pretreatment with adenylyl cyclase, protein kinase A (PKA), guanylyl cyclase, or protein kinase G (PKG) inhibitors, or by removal of the endothelium. From these results, we concluded that vildagliptin induced vasodilation via activation of Kv channels and the SERCA pump. However, other K⁺ channels, PKA/PKG-related signaling cascades associated with vascular dilation, and the endothelium were not involved in vildagliptin-induced vasodilation.

Ogurtsova, K., da J. D. Fernandes, Huang, Y., et al. (2017). IDF diabetes atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Research and Clinical Practice, 128, 40–50.CrossRefPubMed

Clemens, K. K., Shariff, S., Liu, K., et al. (2015). Trends in antihyperglycemic medication prescriptions and hypoglycemia in older adults: 2002–2013. PLoS ONE, 10, e0137596.CrossRefPubMedPubMedCentral

McIntosh, C. H., Demuth, H. U., Pospisilik, J. A., et al. (2005). Dipeptidyl peptidase IV inhibitors: How do they work as new antidiabetic agents? Regulatory Peptides, 128, 159–165.CrossRefPubMed

van Poppel, P. C., Netea, M. G., Smits, P., et al. (2011). Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. Diabetes Care, 34, 2072–2077.CrossRefPubMedPubMedCentral

Nelson, M. T., & Quayle, J. M. (1995). Physiological roles and properties of potassium channels in arterial smooth muscle. American Journal of Physiology, 268(4 Pt 1), C799–C822.CrossRefPubMed

Standen, N. B., & Quayle, J. M. (1998). K⁺ channel modulation in arterial smooth muscle. Acta Physiologica Scandinavica, 164, 549–557.CrossRefPubMed

Yuan, X. J. (1995). Voltage-gated K⁺ currents regulate resting membrane potential and [Ca²⁺]_i in pulmonary arterial myocytes. Circulation Research, 77, 370–378.CrossRefPubMed

Ko, E. A., Han, J., Jung, I. D., et al. (2008). Physiological roles of K⁺ channels in vascular smooth muscle cells. Journal of Smooth Muscle Research, 44, 65–81.CrossRefPubMed

Ko, E. A., Park, W. S., Firth, A. L., et al. (2010). Pathophysiology of voltage-gated K⁺ channels in vascular smooth muscle cells: Modulation by protein kinases. Progress in Biophysics & Molecular Biology, 103, 95–101.CrossRef

10.

Wu, K. D., Bungard, D., & Lytton, J. (2001). Regulation of SERCA Ca²⁺ pump expression by cytoplasmic Ca²⁺ in vascular smooth muscle cells. American Journal of Physiology-Cell Physiology, 280, C843–C851.CrossRefPubMed

11.

Stott, J. B., Povstyan, O. V., Carr, G., et al. (2015). G-protein βγ subunits are positive regulators of Kv7. 4 and native vascular Kv7 channel activity. Proceedings of the National Academy of Sciences United States of America, 112, 6497–6502.CrossRef

12.

Morrish, N. J., Wang, S. L., Stevens, L. K., et al. (2001). Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia, 44, S14–S21.CrossRef

13.

Sowers, J. R., Epstein, M., & Frohlich, E. D. (2001). Diabetes, hypertension, and cardiovascular disease: An update. Hypertension, 37, 1053–1059.CrossRefPubMed

14.

Nissen, S. E., & Wolski, K. (2007). Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New England Journal of Medicine, 356, 2457–2471.CrossRefPubMed

15.

Hernandez, A. V., Usmani, A., Rajamanickam, A., et al. (2011). Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: A meta-analysis and meta-regression analysis of placebo-controlled randomized clinical trials. American Journal of Cardiovascular Drugs, 11, 115–128.CrossRefPubMed

16.

Zimmerman, B. R. (1997). Sulfonylureas. Endocrinology and Metabolism Clinics of North America, 26, 511–522.CrossRefPubMed

17.

Black, C., Donnelly, P., McIntyre, L., et al. (2007). Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews, 18, CD004654.

18.

McInnes, G., Evans, M., Del Prato, S., et al. (2015). Cardiovascular and heart failure safety profile of vildagliptin: A meta-analysis of 17 000 patients. Diabetes, Obesity and Metabolism, 17, 1085–1092.CrossRefPubMed

19.

Foley, J. E., & Jordan, J. (2010). Weight neutrality with the DPP-4 inhibitor, vildagliptin: Mechanistic basis and clinical experience. Vascular Health and Risk Management, 6, 541–548.CrossRefPubMedPubMedCentral

20.

Dejager, S., Razac, S., Foley, J. E., et al. (2007). Vildagliptin in drug-naive patients with type 2 diabetes: A 24-week, double-blind, randomized, placebo-controlled, multiple-dose study. Hormone and Metabolic Research, 39, 218–223.CrossRefPubMed

21.

Mathieu, C., & Degrande, E. (2008). Vildagliptin: A new oral treatment for type 2 diabetes mellitus. Vascular Health and Risk Management, 4, 1349–1360.CrossRefPubMedPubMedCentral

22.

Ahrén, B., Schweizer, A., Dejager, S., et al. (2009). Vildagliptin enhances islet responsiveness to both hyper-and hypoglycemia in patients with type 2 diabetes. Journal Of Clinical Endocrinology And Metabolism, 94, 1236–1243.CrossRefPubMed

23.

Jackson, W. F. (2018). Kv channels and the regulation of vascular smooth muscle tone. Microcirculation. 25. https://doi.org/10.1111/micc.12421.

24.

Xu, C., Lu, Y., Tang, G., et al. (1999). Expression of voltage-dependent K⁺ channel genes in mesenteric artery smooth muscle cells. American Journal of Physiology, 277(5 Pt 1), G1055–G1063.PubMed

25.

Yuan, X. J., Wang, J., Juhaszova, M., et al. (1998). Molecular basis and function of voltage-gated K⁺ channels in pulmonary arterial smooth muscle cells. American Journal of Physiology, 274(4 Pt 1), L621–L635.PubMed

26.

Belevych, A. E., Beck, R., Tammaro, P., et al. (2002). Developmental changes in the functional characteristics and expression of voltage-gated K⁺ channel currents in rat aortic myocytes. Cardiovascular Research, 54, 152–161.CrossRefPubMed

27.

Zhou, P., Fu, L., Pan, Z., et al. (2008). Testosterone deprivation by castration impairs expression of voltage-dependent potassium channels in rat aorta. European Journal of Pharmacology, 593, 87–91.CrossRefPubMed

28.

Lipskaia, L., Hulot, J. S., & Lompré, A. M. (2009). Role of sarco/endoplasmic reticulum calcium content and calcium ATPase activity in the control of cell growth and proliferation. Pflügers Archiv: European Journal of Physiology, 457, 673–685.CrossRefPubMed

29.

Lim, J. J., Liu, Y. H., Khin, E. S., et al. (2008). Vasoconstrictive effect of hydrogen sulfide involves downregulation of cAMP in vascular smooth muscle cells. American Journal Of Physiology-Cell Physiology, 295, C1261–C1270.CrossRefPubMed

30.

Lincoln, T. M., Dey, N., & Sellak, H. (1985). Invited review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: From the regulation of tone to gene expression. Journal of Applied Physiology, 91, 1421–1430.CrossRef

31.

Koivumäki, J. T., Takalo, J., Korhonen, T., et al. (2009). Modelling sarcoplasmic reticulum calcium ATPase and its regulation in cardiac myocytes. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 367, 2181–2202.CrossRef

32.

Lüscher, T. F., Bock, H. A., Yang, Z. H., et al. (1991). Endothelium-derived relaxing and contracting factors: Perspectives in nephrology. Kidney International, 39, 575–590.CrossRefPubMed

33.

Yetik-Anacak, G., & Catravas, J. D. (2006). Nitric oxide and the endothelium: History and impact on cardiovascular disease. Vascular Pharmacology, 45, 268–276.CrossRefPubMed

34.

Croxtall, J. D., & Keam, S. J. (2008). Vildagliptin: A review of its use in the management of type 2 diabetes mellitus. Drugs, 68, 2387–2409.CrossRefPubMed

35.

Rosenstock, J., & Fitchet, M. (2008). Vildagliptin: Clinical trials programme in monotherapy and combination therapy for type 2 diabetes. International Journal of Clinical Practice, 159, 15–23.CrossRef

36.

Baetta, R., & Corsini, A. (2001). Pharmacology of dipeptidyl peptidase-4 inhibitors: Similarities and differences. Drugs, 71, 1441–1467.CrossRef

37.

He, Y. L., Wang, Y., Bullock, J. M., et al. (2007). Pharmacodynamics of vildagliptin in patients with type 2 diabetes during OGTT. Journal of Clinical Pharmacology, 47, 633–641.CrossRefPubMed

Title: Vildagliptin, an Anti-diabetic Drug of the DPP-4 Inhibitor, Induces Vasodilation via Kv Channel and SERCA Pump Activation in Aortic Smooth Muscle
Authors: Mi Seon Seo
Hongliang Li
Jin Ryeol An
In Duk Jung
Won-Kyo Jung
Kwon-Soo Ha
Eun-Taek Han
Seok-Ho Hong
Il-Whan Choi
Won Sun Park
Publication date: 01-06-2019
Publisher: Springer US
Published in: Cardiovascular Toxicology / Issue 3/2019
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI: https://doi.org/10.1007/s12012-018-9496-5

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Vildagliptin, an Anti-diabetic Drug of the DPP-4 Inhibitor, Induces Vasodilation via Kv Channel and SERCA Pump Activation in Aortic Smooth Muscle

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2019

Cobalt Administration Causes Reduced Contractility with Parallel Increases in TRPC6 and TRPM7 Transporter Protein Expression in Adult Rat Hearts

Digitalis Promotes Ventricular Arrhythmias in Flecainide- and Ranolazine-Pretreated Hearts

Limb Blood Flow Restriction Plus Mild Aerobic Exercise Training Protects the Heart Against Isoproterenol-Induced Cardiac Injury in Old Rats: Role of GSK-3β

Late Cardiac Complications of Sulfur Mustard Poisoning in 38 Iranian Veterans

MiR-15b-5p is Involved in Doxorubicin-Induced Cardiotoxicity via Inhibiting Bmpr1a Signal in H9c2 Cardiomyocyte

Synthetic Cannabinoids and Cardiac Arrhythmia Risk: Review of the Literature

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page