Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Biochem Pharmacol ; 182: 114263, 2020 12.
Article in English | MEDLINE | ID: mdl-33035505

ABSTRACT

Seventeen compounds, rather selective, direct or indirect inhibitors and activators of PKA, PKG, and PKC, were analysed for effects on vascular CaV1.2 channel current (ICa1.2) by using the patch-clamp technique in single rat tail artery myocytes. The aim was to investigate how PKs regulate ICa1.2 and disclose any unexpected modulation of CaV1.2 channel function by these agents. The cAMP analogues 8-Br-cAMP and 6-Bnz-cAMP partially reduced ICa1.2 in dialysed cells, while weakly increasing it under the perforated configuration. The ß-adrenoceptor agonist isoproterenol and the adenylate cyclase activator forskolin concentration-dependently increased ICa1.2; this effect was reversed by PKA inhibitors H-89 and KT5720, but not by PKI 6-22. The cGMP analogue 8-Br-cGMP, similarly to the NO-donor SNP, moderately reduced ICa1.2, this effect being reversed to a slight stimulation under the perforated configuration. Among PKG inhibitors, Rp-8-Br-PET-cGMPS decreased current amplitude in a concentration-dependent manner while Rp-8-Br-cGMPS was ineffective. The non-specific phosphodiesterase inhibitor IBMX increased ICa1.2, while H-89, KT5720, and PKI 6-22 antagonized this effect. The PKC activator PMA, but not the diacylglycerol analogue OAG, stimulated ICa1.2 in a concentration-dependent manner; conversely, the PKCα inhibitor Gö6976 markedly reduced basal ICa1.2 and, similarly to the PKCδ (rottlerin) and PKCε translocation inhibitors antagonised PMA-induced current stimulation. The ensemble of findings indicates that the stimulation of cAMP/PKA, in spite of the paradoxical effect of both 8-Br-cAMP and 6-Bnz-cAMP, or PKC pathways enhanced, while that of cGMP/PKG weakly inhibited ICa1.2 in rat tail artery myocytes. Since Rp-8-Br-PET-cGMPS and Gö6976 appeared to block directly CaV1.2 channel, their docking to the channel protein was investigated. Both compounds appeared to bind the α1C subunit in a region involved in CaV1.2 channel inactivation, forming an interaction network comparable to that of CaV1.2 channel blockers. Therefore, caution should accompany the use of these agents as pharmacological tools to elucidate the mechanism of action of drugs on vascular preparations.


Subject(s)
Calcium Channels, L-Type/metabolism , Muscle Cells/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Tail/metabolism , Animals , Calcium Channels, L-Type/chemistry , Dose-Response Relationship, Drug , Male , Muscle Cells/drug effects , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Protein Kinases/chemistry , Protein Structure, Secondary , Protein Structure, Tertiary , Rats , Rats, Wistar , Tail/cytology , Tail/drug effects
2.
Pharmacol Res ; 152: 104625, 2020 02.
Article in English | MEDLINE | ID: mdl-31918018

ABSTRACT

Substantial experimental evidences support the hypothesis that dietary flavonoid intake has a favourable impact on cardiovascular diseases such as systemic, arterial hypertension and coronary artery diseases, which represent the leading cause of morbidity and mortality worldwide. The biological effects of flavonoids involve complex biochemical interactions with numerous, specific, cellular and molecular targets. K+ channels, fine modulators of both cardiac action potential and vascular cell membrane potential, represent one of these targets. Overexpression, downregulation or dysfunction of these channel proteins are the cause of many cardiovascular diseases. Therefore, it appears of particular interest a detailed analysis of the flavonoid potential, direct/indirect modulation of cardiovascular K+ channels as these natural compounds ingested with the diet, despite extensive gut metabolism, may accumulate at cellular level in the form of the parent aglycones. The present review will portray their effects on cardiovascular K+ channels. Molecular docking was used to strengthen experimental evidences and describe flavonoid-channel interactions at molecular level.


Subject(s)
Cardiovascular System/drug effects , Flavonoids/pharmacology , Potassium Channels/physiology , Animals , Humans , Molecular Dynamics Simulation
3.
Acta Neurochir Suppl ; 124: 43-47, 2017.
Article in English | MEDLINE | ID: mdl-28120051

ABSTRACT

Vagal nerve stimulation (VNS) is an effective treatment for drug-resistant epilepsy that is not suitable for resective surgery, both in adults and in children. Few reports describe the adverse effects and complications of VNS. The aim of our study was to present a series of 33 pediatric patients who underwent VNS for drug-resistant epilepsy and to discuss the adverse effects and complications through a review of the literature.The adverse effects of VNS are usually transient and are dependent on stimulation of the vagus and its efferent fibers; surgical complications of the procedure may be challenging and patients sometimes require further surgery; generally these complications affect VNS efficacy; in addition, hardware complications also have to be taken into account.In our experience and according to the literature, adverse effects and surgical and hardware complications are uncommon and can usually be managed definitely. Careful selection of patients, particularly from a respiratory and cardiac point of view, has to be done before surgery to limit the incidence of some adverse effects.


Subject(s)
Anticonvulsants/therapeutic use , Drug Resistant Epilepsy/therapy , Prosthesis Implantation , Vagus Nerve Stimulation/methods , Adolescent , Child , Child, Preschool , Cough/etiology , Female , Humans , Infant , Keloid/epidemiology , Male , Nausea/etiology , Postoperative Complications/epidemiology , Thoracic Duct/injuries , Vagus Nerve Stimulation/adverse effects , Vomiting/etiology
4.
Naunyn Schmiedebergs Arch Pharmacol ; 389(9): 1033-43, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27351883

ABSTRACT

Asymmetrical N,N-bis(alkanol)amine aryl esters (FRA77, GDE6, and GDE19) are potent multidrug resistance (MDR) reversers. Their structures loosely remind that of the Ca(2+) antagonist verapamil. Therefore, the aim of this study was to investigate their vascular activity in vitro. Their effects on the mechanical activity of fresh and cultured rat aorta rings on Cav1.2 channel current (I Ca1.2) of A7r5 cells and their cytotoxicity on A7r5 and EA.hy926 cells were analyzed. Docking at the rat α1C subunit of the Cav1.2 channel was simulated in silico. Compounds tested were cytotoxic at concentrations >1 µM (FRA77, GDE6, GDE19) and >10 µM (verapamil) in EA.hy926 cells, or >10 µM (FRA77, GDE6, GDE19) and at 100 µM (verapamil) in A7r5 cells. In fresh rings, the three compounds partly antagonized phenylephrine and 60 mM K(+) (K60)-induced contraction at concentrations ≥1 and ≥3 µM, respectively. On the contrary, verapamil fully relaxed rings pre-contracted with both agents. In cultured rings, 10 µM GDE6, GDE19, FRA77, and verapamil significantly reduced the contractile response to both phenylephrine and K60. Similarly to verapamil, the three compounds docked at the α1C subunit, interacting with the same amino acids residues. FRA77, GDE6, and GDE19 inhibited I Ca1.2 with IC50 values 1 order of magnitude higher than that of verapamil. FRA77-, GDE6-, and GDE19-induced vascular effects occurred at concentrations that are at least 1 order of magnitude higher than those effectively reverting MDR. Though an unambiguous divergence between MDR reverting and vascular activity is of overwhelming importance, these findings consistently contribute to the design and synthesis of novel and potent chemosensitizers.


Subject(s)
Amines/pharmacology , Calcium Channel Blockers/pharmacology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Endothelial Cells/drug effects , Esters/pharmacology , Molecular Docking Simulation , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Amines/chemistry , Amines/metabolism , Animals , Binding Sites , Calcium Channel Blockers/metabolism , Calcium Channels, L-Type/chemistry , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/metabolism , Cell Line , Dose-Response Relationship, Drug , Endothelial Cells/metabolism , Esters/chemistry , Esters/metabolism , Humans , Male , Membrane Potentials , Molecular Structure , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Protein Binding , Rats , Rats, Wistar , Structure-Activity Relationship , Tissue Culture Techniques , Vasodilator Agents/chemistry , Vasodilator Agents/metabolism , Verapamil/metabolism , Verapamil/pharmacology
5.
Eur J Neurol ; 23(1): 190-5, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26498428

ABSTRACT

BACKGROUND AND PURPOSE: For many years deep brain stimulation (DBS) devices relied only on voltage-controlled stimulation (CV), but recently current-controlled devices have been developed and approved for new implants as well as for replacement of CV devices after battery drain. Constant-current (CC) stimulation has been demonstrated to be effective in new implanted parkinsonian and dystonic patients, but the effect of switching to CC therapy in patients chronically stimulated with CV implantable pulse generators (IPGs) has not been assessed. This report shows the results of a consecutive retrospective data collection performed at five Italian centers before and after replacement of constant-voltage with constant-current DBS devices, in order to verify the clinical efficacy and safety of this procedure. METHODS: Nineteen patients with Parkinson's disease or dystonic syndrome underwent DBS IPG CV/CC replacement. Clinical features and therapy satisfaction were assessed before surgery, 1 week after and 3 and 6 months after replacement. Programming settings and impedances were recorded before removing the CV device and when the CC IPGs were switched on. RESULTS: The clinical outcome of CC stimulation was similar to that obtained with CV devices and remained stable at 3 and 6 months of follow-up. Impedance values recorded for CV and CC IPGs were similar. Ninety-five percent of patients and physicians were satisfied with mixed implants. No adverse events occurred after IPG replacement. CONCLUSION: Replacing CV with CC IPGs is a safe and effective procedure. Longer follow-up is necessary to better clarify the impact of CC stimulation on clinical outcome after chronic stimulation in CV mode.


Subject(s)
Deep Brain Stimulation/methods , Dystonic Disorders/therapy , Electricity , Parkinson Disease/therapy , Electrodes, Implanted , Follow-Up Studies , Humans , Retrospective Studies , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL
...