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Calcium Blockers Inhibit Cyclosporine A-Induced Hyperreactivity of Vascular Smooth Muscle Cells

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Calcium Blockers Inhibit Cyclosporine A-Induced Hyperreactivity of Vascular Smooth Muscle Cells MOLECULAR MEDICINE REPORTS 5: 1469-1474, 2012 Calcium blockers inhibit cyclosporine A-induced hyperreactivity of vascular smooth muscle cells GRZEGORZ GRZEŚK1, MICHAŁ WICIŃSKI1, BARTOSZ MALINOWSKI2, ELŻBIETA GRZEŚK3, SŁAWOMIR MANYSIAK2, GRAŻYNA ODROWĄŻ-SYPNIEWSKA2, NASSER DARVISH1 and MACIEJ BIERWAGEN4 Departments of 1Pharmacology and Therapeutics, 2Laboratory Medicine, 3Pediatrics, Hematology and Oncology, and 4Neurosurgery and Neurotraumatology, Collegium Medicum, Nicolaus Copernicus University, 85-094 Bydgoszcz, Poland Received December 19, 2011; Accepted March 12, 2012 DOI: 10.3892/mmr.2012.847 Abstract. Cyclosporine belongs to the group of the most increase in the receptor reserve. The analysis of the reactivity commonly used immunosuppressants. Hypertension occurs in of vascular smooth muscle showed that CsA increased the approximately 30% of patients treated with this drug. However, influx of calcium ions from the extracellular to the intracel- the pathogenesis of this occurrence has not been explained to lular area. No difference was found between the contraction date. The purpose of our study was to clarify the mechanisms triggered by Bay-K8644 in the presence of CsA and the control leading to the evolution of hypertension induced by cyclospo- probe. The increase in perfusion pressure induced by CsA was rine A (CsA). We examined the changes in transmission within blocked by L-type calcium channel blockers (nifidipine and receptors and around the receptors. We also aimed to elucidate diltiazem). The results from our experiments show that CsA the mechanisms responsible for averting arterial hyperrespon- increases the reactivity of vessels to the effect of catechol- siveness induced by the drug. Experiments were performed amines. CsA also enhances signal transmission between on isolated and perfused tail arteries of Wistar rats. Tissues G-protein coupled receptors (GPCRs) and calcium channels. surrounding the artery were removed and the proximal segment The activation of protein kinase C also plays a significant role (length of 2-3 cm) was used for cannulation. Cannulated arteries in this process. Our results suggest that the best choice for the were placed in a 20-ml glass chamber (vertical position). The pharmacotherapy of hypertension induced by CsA would be contraction force in our model was measured by an increased calcium channel antagonists. degree of perfusion pressure with a constant flow rate (approxi- mately 1 ml/min). The results showed that in the presence of Introduction CsA, the concentration-response curves/phenylephrine (PHE) curve shifted to the left. Cyclosporine increased the reactivity Cyclosporine A (CsA) is the most commonly used drug in of the arteries to PHE. This effect was directly linked to the immunosuppressive therapy after kidneys, liver, heart or bone marrow transplantation (1). The first polypeptide was isolated from the fungus Tolypocladium inflatum. CsA was introduced into clinical practice as a new generation of immu- nosuppresants in the 1980's. It is widely used to prevent the Correspondence to: Dr Grzegorz Grześk, Department of Pharmacology and Therapeutics, Collegium Medicum, Nicolaus rejection of transplanted organs. However, the drug also has Copernicus University, 9 Skłodowskiej-Curie Street, 85-094 Bydgoszcz, toxic effects. The spectrum of the usage of CsA is not limited Poland only to transplantology; it has also been used to treat patients E-mail: [email protected] with uveitis - the first effective therapy was documented in 1979 (2,3). CsA has also been used in other cases where Abbreviations: AVP, arginine vasopressin; CRCs, concentration conventional treatment has not been effective (4,5). response curves; CsA, cyclosporine A; DAG, diacyloglicerole; CsA inhibits the activity of lymphocytes, especially ER, endoplasmic reticulum; GPCRs, G-protein coupled receptors; Th and Tc, decreasing the production of pro-inflammatory IP3, inositol 1,4,5-trisphosphate; IP3R, inositol 1,4,5-trisphosphate interleukin (IL)-2. This effect is based on the binding of CsA receptor; NF-AT, nuclear factor of activated T lymphocytes; PHE, to the cytosolic protein, cyclophilin of lymphocytes. The phenylephrine; PIP , phosphatidylinositol 4,5-bisphosphate; PKC, 2 complex form of CsA and cyclophilin binds to the calcium protein kinase C; ROC, receptor-operated channel; RyR, rynodine receptor; SMOC, second messanger-operated channel; VOC, ions, calmodulin and calcineurin (CN). The inhibition of CN voltage-operated channel; VSMCs, vascular smooth muscle cells phosphatase activity, which leads to the dephosphorylation of the nuclear factor of activated T lymphocytes (NF-AT), Key words: cyclosporine A, vascular smooth muscle cells, receptors prevents its activation. In this case, the promoter for IL-2 is reserve, calcium signals, protein kinase C, BayK-8644 blocked (6,7). The application of CsA is associated with many side-effects, such as hypertension, renal failure, hepatotoxicity, neurological disorders or cancers, which cannot be eliminated 1470 GRZEŚK et al: CYCLOSPORINE A-INDUCED HYPERREACTIVITY OF VASCULAR SMOOTH MUSCLE CELLS to date (8). One of the main reasons for restricting the usage of The aim of the study was to investigate whether calcium CsA in certain situations is nephrotoxicity and hypertension blockers inhibit CsA-induced hyperactivity of vascular smooth in approximately 30% of patients. However, the mechanism of muscle cells (VSMCs). this action remains unknown (9). Hypertension caused by immunosuppressants is one of Materials and methods the main risk factors of cardiovascular diseases. High blood pressure persisting for long periods of time may lead to organ Animals. Experiments were performed on isolated, perfused complications, atherogenesis, renal failure, heart failure or Wistar rat tail arteries. Animals were housed under a 12/12-h stroke. Decisions regarding the treatment of hypertension light/dark cycle and had unlimited access to food and water. should be based on clinical investigations that include clas- Male rats weighing 250-270 g were narcotized by intraperito- sification of hypertension, presence of organ complication, neal injection of 120 mg urethane per 1 kg of body mass. Rats additional risk factors (intercurrent diseases) and age (9). Due were sacrificed by stunning and cervical dislocation. CsA was to the similar effectiveness of drugs from five basic groups, applied intraperitoneally. The study protocol was approved by the European Society of Hypertension, European Society of the local ethics committee. All experiments were carried out Cardiology and Polish Society of Hypertension do not recom- in accordance with the United States NIH guidelines [Guide mend a specific class of hypertension drugs. The effectiveness for the Care and Use of Laboratory Animals (1985), DHEW of treatment depends on the choice of appropriate therapy Publication No. (NIH) 8523: Office of Science and Health (mono- or polytherapy), drug dose, interactions between drugs Reports, DRR/NIH, Bethesda, MD, USA]. and the tolerance of drug by the patient (10,11). Drugs and solutions. CsA (1 and 10 nM, or accordingly, Role of calcium ions in vascular smooth muscle tone. The 121.6 and 1,216 ng/ml) dissolved in ethanol solution (70%). contraction of vascular smooth muscle is upregulated by Krebs solution contained NaCl (71.8 mM/l), KCl (4.7 mM/l), membrane G-protein coupled receptors (GPCRs), which CaCl2 (1.7 mM/l), NaHCO3 (28.4 mM/l), MgSO4 (2.4 mM/l), increase phospholipase C (PLC) activity. Vascular receptors KH2PO4 (1.2 mM/l) and glucose (11.1 mM/l). All reagents which demonstrate pressor effect are as follows: α1, V1, ETA and were purchased from the Sigma-Aldrich Chemical Company AT1. The complex agonist/receptor leads to Gq protein activa- (Poznan, Poland). tion (first order relay). Through the subunit of Gq protein, PLC is activated. PLC catalyzes the hydrolysis of phosphatidylino- Study design and performance. After dissection from sitol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate surrounding tissues, a 2-3 cm long segment of rat tail artery (IP3) and diacyloglicerole (DAG) (12,13). was cannulated and connected to a perfusion device. The The activation of protein kinase C (PKC) is significant distal part was weighed with a 500-mg weight and the tail in off-receptor signal regulation induced by DAG. There was placed in a 20-ml container filled with oxygenated Krebs are many isolated izoenzymes of PKC which demonstrate solution at 37˚C. The perfusion pressure was continuously tissue specificity. PKC enhances the contraction of vascular measured. We gradually increased the perfusion solution smooth muscle by L-type calcium channel phosporylation. flow using a peristaltic pump up to 0.25-1 ml/min. Vessel The importance of PKC activation is proven by the fact that contractions induced by phenylephrine (PHE) [an adrenergic phorbol esters, a group of synthetic PKC activators, induce the α-1 receptor, arginine vasopressin (AVP)] and vasopressin contraction of vascular smooth muscle (14-18). (non-selective agonist α-1 receptor, V1, V2) were measured as Calcium ion homeostasis is upregulated by their passive an increase in perfusion pressure. transport to the intracellular space of the myocyte and through active transport to the endoplasmic reticulum (ER) and extra- Data analysis and statistical procedures. Perfusion pres- cellular area in cooperation with ion exchangers. sure was measured on Nyketron 1675 and TZ-21S devices. Ca2+ ion concentration inside the myocyte is ~10-7 M, Concentration
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