Use of ionic currents to identify and estimate parameters in models of channel blockade

1990 ◽  
Vol 259 (2) ◽  
pp. H626-H634
Author(s):  
C. F. Starmer ◽  
V. V. Nesterenko ◽  
F. R. Gilliam ◽  
A. O. Grant
Keyword(s):  
Time Course ◽  
Experimental Studies ◽  
Ionic Currents ◽  
Blocking Agent ◽  
Model Parameters ◽  
Protein Conformations ◽  
Channel Blockade ◽  
Channel Blocking ◽  
Individual Contributions ◽  
Modulated Receptor

Models of ion channel blockade are frequently validated with observations of ionic currents resulting from electrical or chemical stimulation. Model parameters for some models (modulated receptor hypothesis) cannot be uniquely determined from ionic currents. The time course of ionic currents reflects the activation (fraction of available channels that conduct in the presence of excitation) and availability of channels (the ability of the protein to make a transition to a conducting conformation and where this conformation is not complexed with a drug). In the presence of a channel blocking agent, the voltage dependence of availability appears modified and has been interpreted as evidence that drug-complexed channels exhibit modified transition rates between channel protein conformations. Because blockade and availability both modify ionic currents, their individual contributions to macroscopic conductance cannot be resolved from ionic currents except when constant affinity binding to a bindable site is assumed. Experimental studies of nimodipine block of calcium channels and lidocaine block of sodium channels illustrate these concepts.

Analysis of responses to kallidin, DABK, and DAK in feline hindlimb vascular bed

1995 ◽  
Vol 269 (6) ◽  
pp. H2057-H2064
Author(s):  
J. A. Santiago ◽  
E. A. Garrison ◽  
H. C. Champion ◽  
R. E. Smith ◽  
O. Del Rio ◽  
...  
Keyword(s):  
Time Course ◽  
Blocking Agent ◽  
Constant Flow ◽  
Flow Conditions ◽  
B1 Receptor ◽  
Vascular Bed ◽  
Channel Blocking ◽  
Kinin B1 Receptor ◽  
B2 Receptors ◽  
Dose Dependent

Responses to kallidin, des-Arg9-bradykinin (DABK), and des-Arg10-kallidin (DAK) were investigated in the hindlimb vascular bed of the cat under constant-flow conditions. Injections of kallidin, DABK, and DAK into the hindlimb perfusion circuit produced dose-dependent vasodilator responses in the hindlimb vascular bed. Vasodilator responses to kallidin and bradykinin (BK) were similar in magnitude and time course, and both peptides were approximately 100-fold more potent than DABK or DAK. Responses to kallidin were decreased by the kinin B2 antagonist, HOE 140, whereas responses to DABK and DAK were reduced by des-Arg9[Leu8]BK, a kinin B1-receptor antagonist. N omega-nitro-L-arginine methyl ester (L-NAME) reduced vasodilator responses to kallidin, DABK, and DAK, whereas meclofenamate, atropine, and U-37883A, a vascular selective ATP-sensitive K+ (K+ATP) channel-blocking agent, did not alter responses to the three peptides. These data suggest that both kinin B1 and B2 receptors are normally present in the hindlimb vascular bed. These data also suggest that kinin B1 and B2 receptor-mediated vasodilator responses are mediated by the release of nitric oxide and that the activation of K+ATP channels or muscarinic receptors, or the release of vasodilator prostaglandins play little if any role in mediating responses to kallidin, DABK, or DAK in the hindlimb vascular bed of the cat.

Modeling ion channel blockade at guarded binding sites: application to tertiary drugs

1986 ◽  
Vol 251 (4) ◽  
pp. H848-H856 ◽  
Author(s):  
C. F. Starmer ◽  
K. R. Courtney
Keyword(s):  
Binding Site ◽  
Sodium Current ◽  
Ph Dependence ◽  
Channel Blockade ◽  
Channel State ◽  
Channel Inactivation ◽  
Excitable Membranes ◽  
Channel Blocking ◽  
Apparent Variation ◽  
Modulated Receptor

Excitable membranes exposed to sodium channel blocking agents (D; local anesthetics and antiarrhythmic drugs) show a progressive reduction of peak sodium current when repetitively depolarized (use dependence). Thus, with repetitive excitation, use dependence reflects a net rightward shift in the balance between unblocked channels (U) and blocked channels (B): U + D in equilibrium with B. The modulated receptor hypothesis (a 7-parameter model) has been proposed to account for this shift and is based on a channel lumen binding site whose affinity varies with channel state and where drug-complexed channels exhibit modified inactivation gate kinetics. Alternatively, we consider use-dependent binding as the result of transient access to a constant-affinity binding site. In this setting, the channel gate conformation is viewed as controlling the flux of drug as it diffuses between drug pools and the binding site. Apparent variation in binding rates is therefore considered the result of variations in the fraction of accessible sites. This guarded receptor hypothesis, with three fewer parameters, is able to predict apparent changes in channel binding and apparent shifts in channel inactivation without incorporating modified gating parameters in drug-complexed channels. Furthermore, with this model one is able to characterize both relaxation kinetics and channel blockade associated with tertiary amines as well as hydrophobic and hydrophilic agents. The pH dependence of repriming rates is utilized to estimate several of the important parameters associated with this simplified hypothesis.

A mathematical model of cardiovascular dynamics for the diagnosis and prognosis of hemorrhagic shock

2021 ◽  
Author(s):  
Laura D’Orsi ◽  
Luciano Curcio ◽  
Fabio Cibella ◽  
Alessandro Borri ◽  
Lilach Gavish ◽  
...  
Keyword(s):  
Heart Rate ◽  
Cardiac Output ◽  
Arterial Pressure ◽  
Hemorrhagic Shock ◽  
Time Course ◽  
Differential Algebraic Equations ◽  
Model Parameters ◽  
Algebraic Equations ◽  
Cardiovascular Dynamics ◽  
Compensation Mechanisms

Abstract A variety of mathematical models of the cardiovascular system have been suggested over several years in order to describe the time-course of a series of physiological variables (i.e. heart rate, cardiac output, arterial pressure) relevant for the compensation mechanisms to perturbations, such as severe haemorrhage. The current study provides a simple but realistic mathematical description of cardiovascular dynamics that may be useful in the assessment and prognosis of hemorrhagic shock. The present work proposes a first version of a differential-algebraic equations model, the model dynamical ODE model for haemorrhage (dODEg). The model consists of 10 differential and 14 algebraic equations, incorporating 61 model parameters. This model is capable of replicating the changes in heart rate, mean arterial pressure and cardiac output after the onset of bleeding observed in four experimental animal preparations and fits well to the experimental data. By predicting the time-course of the physiological response after haemorrhage, the dODEg model presented here may be of significant value for the quantitative assessment of conventional or novel therapeutic regimens. The model may be applied to the prediction of survivability and to the determination of the urgency of evacuation towards definitive surgical treatment in the operational setting.

Mechanosensitive afferents of femoral-saphenous vein

1987 ◽  
Vol 252 (2) ◽  
pp. R367-R370 ◽  
Author(s):  
P. W. Davenport ◽  
F. J. Thompson
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Contractile Response ◽  
Blocking Agent ◽  
Urotensin Ii ◽  
Dibutyryl Cyclic Amp ◽  
Maximal Contraction ◽  
Channel Blocking ◽  
Apparent Concentration ◽  
Small Contraction

Urotensin II (U II) caused marked concentration-dependent contractions of helical strips from several major arteries of the rat. The thoracic aorta was most sensitive; the apparent concentration of U II producing half-maximal contraction was 6.8 X 10(-10) M. Papaverine, dibutyryl cyclic AMP, forskolin, and nitroprusside antagonized the contractile responses to U II at the apparent concentrations producing 50% inhibition (IC50) of 7.6 X 10(-6), 2.1 X 10(-4), 2.5 X 10(-6), and 1.5 X 10(-8) M, respectively. Verapamil, a calcium channel-blocking agent, partially inhibited the contractile response to U II at IC50 = 6.5 X 10(-6) M. Maximal relaxation, i.e., a complete inhibition, could not be obtained even at a concentration of 3 X 10(-5) M verapamil. Cyproheptadine reduced the U II-induced contraction at higher concentrations. Phentolamine (10(-5) M), propranolol (10(-5) M), atropine (10(-4) M), tetrodotoxin (10(-6) M), burimamide (10(-5) M), and indomethacin (10(-5) M) did not change the U II-induced contraction. At higher concentration, U II (10(-8) M) induced a small contraction of aortic strips in Ca2+-free Krebs Henseleit solution similar to that of norepinephrine, but the U II-induced contraction was not inhibited by phentolamine or propranolol. The action of U II did not require the presence of endothelial cells. It is concluded that U II acts on vascular smooth muscle and induces the contraction partly through intracellular Ca2+ mobilization but mainly by stimulating the influx of extracellular Ca2+ via potential dependent and potential independent calcium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil in Bipolar Illness

1986 ◽  
Vol 31 (5) ◽  
pp. 442-444 ◽  
Author(s):  
Leigh Solomon ◽  
Peter Williamson
Keyword(s):  
Calcium Channel ◽  
Affective Disorder ◽  
Bipolar Affective Disorder ◽  
Blocking Agent ◽  
Bipolar Illness ◽  
The Past ◽  
First Case ◽  
Treatment Of Depression ◽  
Channel Blocking ◽  
Successful Control

The authors report two cases of Bipolar Affective Disorder which were responsive to Lithium therapy in the past, but could no longer be treated with Lithium due to hyperparathyroidism in the first case and noncompliance in the second. In both cases, successful control of hypomania was achieved with Verapamil, but treatment of depression required the addition of Trazodone. The rationale for employing a calcium channel blocking agent, such as Verapamil, in bipolar illness is reviewed.

scholarly journals Plasma Hepcidin Correlates Positively With Interleukin-6 in Patients Undergoing Pulmonary Endarterectomy

2011 ◽  
pp. 493-502 ◽  
Author(s):  
P. MARUNA ◽  
M. VOKURKA ◽  
J. LINDNER
Keyword(s):  
Acute Phase ◽  
Iron Metabolism ◽  
Time Course ◽  
Acute Phase Proteins ◽  
Human Subjects ◽  
Circulatory Arrest ◽  
Experimental Studies ◽  
Acute Phase Reactant ◽  
Deep Hypothermic Circulatory Arrest ◽  
Pulmonary Endarterectomy

Hepcidin, a recently discovered antimicrobial peptide synthesized in the liver, was identified to be the key mediator of iron metabolism and distribution. Despite our knowledge of hepcidin increased in recent years, there are only limited data on hepcidin regulation during systemic inflammatory response in human subjects. In a prospective study, the time course of plasma hepcidin was analyzed in relations to six inflammatory parameters – plasma cytokines and acute-phase proteins in patients undergoing uncomplicated pulmonary endarterectomy. Twenty-four patients (males, aged 52.6±10.2 years, treated with pulmonary endarterectomy in a deep hypothermic circulatory arrest) were enrolled into study. Hepcidin, interleukin (IL)-6, IL-8, tumor necrosis factor-α, C-reactive protein, α1-antitrypsin and ceruloplasmin arterial concentrations were measured before surgery and repeatedly within 120 h post-operatively. Hemodynamic parameters, hematocrit and markers of iron metabolism were followed up. In a postoperative period, hepcidin increased from preoperative level 8.9 ng/ml (6.2-10.7) (median and interquartile range) to maximum 16.4 ng/ml (14.1-18.7) measured 72 h after the end of surgery. Maximum post-operative concentrations of hepcidin correlated positively with maximum IL-6 levels. Both hepcidin and IL-6 maximum concentrations correlated positively with extracorporeal circulation time. In conclusions, the study demonstrated that plasma hepcidin is a positive acute-phase reactant in relation to an uncomplicated large cardiac surgery. Hepcidin increase was related to IL-6 concentrations and to the duration of surgical procedure. Our clinical findings are in conformity with recent experimental studies defining hepcidin as a type II acute-phase protein.

scholarly journals CARDIO NEUROLOGICAL SYMPTOMS CAUSED BY AN ACUTE POISONING WITH SLOW CALCIUM CHANNEL BLOCKING AGENT (VERAPAMIL)

2020 ◽  
Vol 26 (4) ◽  
pp. 34-39
Author(s):  
Boris Borisovich Yatsinyuk ◽  
◽  
Pavel Pavlovich Gavrikov ◽  
Yulia Vasilyevna Lobur
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Blocking Agent ◽  
Acute Poisoning ◽  
Frequency Of Occurrence ◽  
Hemodynamic Parameters ◽  
Hemodynamic Effects ◽  
Channel Blocking ◽  
Consciousness Disorder ◽  
Calcium Channels Blockers

The research of an analysis of the cardiac hemodynamic effects of an acute chemical trauma with slow calcium channels blockers (verapamil) shows that the depth of disorder of cardiac hemodynamic parameters and the level and frequency of occurrence of consciousness disorder were determined in 46 patients within the period of 2007–2017 in this nosological form of acute poisoning.

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