Huina Zhang1, Jinghui Dong2, Chi-Wai Lau3, Yu Huang4. 1. Beijing An Zhen Hospital, Capital Medical University; Key Laboratory of Upper Airway Dysfunction-related Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing, 100029, China. whinnerzhn@126.com. 2. Department of Physiology, Hebei Medical University, Hebei, 050017, China. 3. Shenzhen Research Institute, Heart and Vascular Institute, and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, 999077, China. 4. Shenzhen Research Institute, Heart and Vascular Institute, and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, 999077, China. yu-huang@cuhk.edu.hk.
Abstract
PURPOSE: The aim of this study was to evaluate the effects of berberine on nitroglycerin (NTG) tolerance and explore the underlying mechanism involved. METHODS: NTG tolerance was induced by pre-exposure of Sprague-Dawley rat aortas to NTG in vitro or by pretreating Sprague-Dawley rats with an NTG patch in vivo. The aortas were pre-treated with berberine or PKC inhibitors for different durations of time before induction of NTG tolerance. NTG-induced vasorelaxations was measured on wire myograph. Primary vascular smooth cells (VSMCs) were used to dissect the underlying mechanism of berberine-induced inhibition of NTG tolerance. RESULTS: NTG tolerance induced by either prior exposure of rat aortas to NTG in vitro or pretreatment with an NTG patch in vivo was reversed by co-treatment with berberine, as well as the inhibitors of protein kinase C (PKC) and protein kinase C alpha (PKCα). The mechanistic study revealed that PKCα participated in the development of NTG tolerance as NTG increased the activity of PKCα with enriched PKCα membrane localization and elevated phosphorylation of PKCα in VSMCs, which was reversed by berberine or PKCα inhibitors. CONCLUSION: This study is probably the first demonstration that berberine reverses NTG tolerance through inhibiting PKCα activity in VSMCs and PKCα is an important contributor to the development of NTG tolerance. These new findings suggest that berberine could become a promising drug for prevention of NTG tolerance and that targeting PKCα in VSMCs is likely to be a potential therapeutic strategy for reversal of NTG tolerance in blood vessels.
PURPOSE: The aim of this study was to evaluate the effects of berberine on nitroglycerin (NTG) tolerance and explore the underlying mechanism involved. METHODS: NTG tolerance was induced by pre-exposure of Sprague-Dawley rat aortas to NTG in vitro or by pretreating Sprague-Dawley rats with an NTG patch in vivo. The aortas were pre-treated with berberine or PKC inhibitors for different durations of time before induction of NTG tolerance. NTG-induced vasorelaxations was measured on wire myograph. Primary vascular smooth cells (VSMCs) were used to dissect the underlying mechanism of berberine-induced inhibition of NTG tolerance. RESULTS: NTG tolerance induced by either prior exposure of rat aortas to NTG in vitro or pretreatment with an NTG patch in vivo was reversed by co-treatment with berberine, as well as the inhibitors of protein kinase C (PKC) and protein kinase C alpha (PKCα). The mechanistic study revealed that PKCα participated in the development of NTG tolerance as NTG increased the activity of PKCα with enriched PKCα membrane localization and elevated phosphorylation of PKCα in VSMCs, which was reversed by berberine or PKCα inhibitors. CONCLUSION: This study is probably the first demonstration that berberine reverses NTG tolerance through inhibiting PKCα activity in VSMCs and PKCα is an important contributor to the development of NTG tolerance. These new findings suggest that berberine could become a promising drug for prevention of NTG tolerance and that targeting PKCα in VSMCs is likely to be a potential therapeutic strategy for reversal of NTG tolerance in blood vessels.
Authors: P R Sage; I S de la Lande; I Stafford; C L Bennett; G Phillipov; J Stubberfield; J D Horowitz Journal: Circulation Date: 2000-12-05 Impact factor: 29.690
Authors: Katalin Szöcs; Bernard Lassègue; Philip Wenzel; Maria Wendt; Andreas Daiber; Matthias Oelze; Thomas Meinertz; Thomas Münzel; Stephan Baldus Journal: J Mol Cell Cardiol Date: 2007-03-30 Impact factor: 5.000