Biomedical subjects

Z J Bosnjak

Publications and source records attributed to Z J Bosnjak.

At least 19 recordsLinked to original sources

PubMed2001

Nitric oxide activates the sarcolemmal K(ATP) channel in normoxic and chronically hypoxic hearts by a cyclic GMP-dependent mechanism.

Chronic myocardial hypoxia results in elevated nitric oxide (NO) production and increased current through the sarcolemmal K(ATP) channel. We hypothesized these two processes are related and determined whether NO alters the electrophysiology of Purkinje fibers obtained from rabbits (n=12/group) raised in a normoxic (F(I)O2=0.21) or hypoxic (F(I)O2=0.12) environment from birth to 9 days of age. Action potential duration (APD)(90) was shorter (112+/-3 ms v 126+/-3 ms) and maximum diastolic potential (MDP) was more negative (-84+/-2 mV v-80+/-1 mV) in hypoxic hearts compared with normoxic controls. In normoxic hearts the NO donors, S-nitrosoglutathione (GSNO) 50 microM and spermine NONOate (50 microM) shortened APD(90) and increased MDP to levels present in chronically hypoxic hearts. This effect was completely abolished by the K(ATP) channel blocker glibenclamide (3 microM) and by a nitric oxide trap, Carboxy-PTIO (100 microM). The NO carrier glutathione (50 microM) and decomposed spermine NONOate had no effect on APD(90) or MDP. GSNO had no effect in hypoxic hearts; however, when GSNO was combined with glibenclamide APD(90) increased, and MDP decreased to normoxic values. 8-Bromo cGMP (100 microM) shortened APD(90) and increased MDP to levels present in chronically hypoxic hearts. This effect was abolished by glibenclamide. A soluble guanylyl cyclase inhibitor, ODQ (10 microM), had no effect on action potentials in normoxic hearts but in hypoxic hearts resulted in an increase in APD(90) to levels present in normoxic hearts and a decrease in MDP. The effect of ODQ could not be reversed by GSNO. We conclude that NO activates the sarcolemmal K(ATP) channel in normoxic and chronically hypoxic hearts by a cyclic GMP-dependent mechanism.

Action Potentials↗

PubMed2001

Interactions of halothane with isoproterenol and epinephrine on canine epicardial conduction velocity at normal and elevated potassium levels.

BACKGROUND: Halothane is known to potentiate catecholamine-induced depression of conduction velocity in Purkinje fibers but not endocardial muscle fibers. The purpose of this study was to examine the interactions of halothane with epinephrine and isoproterenol on canine epicardial conduction velocity at moderately elevated extracellular potassium concentration ([K]0). METHODS: Epicardial muscle strips (10x10x2 mm) were superfused with Tyrode's solution containing 4 or 8 mM [K]0 in the presence of 5 microM epinephrine or 1 microM isoproterenol with or without 0.8 mM halothane. Conduction velocity in the longitudinal and transverse directions relative to epicardial fiber orientation was recorded during alternate stimulation in each direction. RESULTS: In the presence of halothane, a change from 4 to 8 mM [K]0 decreased (P< or =0.05) longitudinal and transverse conduction velocities by 26% and 21%, respectively. Isoproterenol alone at 4 and 8 mM [K]0 depressed (P<0.05) both longitudinal and transverse conduction velocities. However, the depression of longitudinal conduction velocity by isoproterenol at 4 mM [K]0 was attenuated by halothane. Epinephrine with or without halothane depressed (P<0.05) both longitudinal and transverse conduction velocities at 8 but not at 4 mM [K]0. CONCLUSION: The results do not support a synergistic interaction between halothane and epinephrine on myocardial conduction but do demonstrate depression of conduction by epinephrine at 8 mM [K+]0, a potassium ion concentration comparable to those reported following epinephrine infusions.

Adrenergic beta-Agonists↗

PubMed2001

Mechanisms of isoflurane-mediated hyperpolarization of vascular smooth muscle in chronically hypertensive and normotensive conditions.

BACKGROUND: The purpose of this study was to compare the effects of isoflurane on membrane and intracellular mechanisms that regulate vascular smooth muscle (VSM) transmembrane potential (Em; which is related to VSM tone) in the spontaneously hypertensive rat (SHR) model of essential hypertension and its normotensive Wistar-Kyoto (WKY) control. METHODS: Vascular smooth muscle Em values were measured in situ in locally denervated, superfused, intact, small (200-300-microm OD) mesenteric arteries and veins in anesthetized 9-12-week-old SHR and WKY. Effects of 1.0 minimum alveolar concentration (0.60 mM) superfused isoflurane on VSM Em were measured before and during superfusion with specific inhibitors of VSM calcium-activated (KCa) and adenosine triphosphate-regulated (KATP) potassium channels, and with endogenous mediators of vasodilatation (nitric oxide, cyclic guanosine monophosphate, protein kinase G, cyclic adenosine monophosphate, and protein kinase A). RESULTS: Isoflurane significantly hyperpolarized small arteries (5 +/- 3.4 mV) and veins (6 +/- 4.7 mV) (pooled SHR and WKY, mean +/- SD). Inhibition of KCa and KATP channels, cyclic adenosine monophosphate, and protein kinase A, but not nitric oxide, cyclic guanosine monophosphate, and protein kinase G, abolished such hyperpolarization equally in SHR and WKY vessels. CONCLUSIONS: Isoflurane-induced in situ VSM hyperpolarization in denervated, small mesenteric vessels involves a similar activation of KCa and KATP channels and cyclic adenosine monophosphate, but not nitric oxide or cyclic guanosine monophosphate, second messenger pathways in both SHR and WKY. A greater isoflurane-induced VSM hyperpolarization (observed previously in neurally intact SHR vessels) suggests enhanced inhibition of elevated sympathetic neural input as a major mechanism underlying such hyperpolarization (and coupled relaxation) in this neurogenic model of hypertension.

Anesthetics, Inhalation↗

PubMed2001

Differential modulation of the cardiac L- and T-type calcium channel currents by isoflurane.

BACKGROUND: Volatile anesthetics exert their negative chronotropic and inotropic effects, in part by depressing the L- and T-type calcium channels. This study examines and compares the dose-dependent effects of isoflurane on atrial L- and T-type calcium currents (I(Ca,L) and I(Ca,T)) and ventricular I(Ca,L). METHODS: Whole cell I(Ca) was recorded from enzymatically isolated guinea pig cardiomyocytes. Current-voltage relations for atrial and ventricular I(Ca,L) was obtained from holding potentials of -90 and -50 mV to test a potential of +60 mV in 10-mV increments. Atrial I(Ca,T) was determined by subtraction of currents obtained from holding potentials of -50 and -90 mV. Steady state inactivation was determined using standard two-pulse protocols, and data were fitted with the Boltzmann equation. RESULTS: Isoflurane depressed I(Ca) in a dose-dependent manner, with Kd values of 0.23+/-0.03, 0.34+/-0.03, and 0.71+/-0.02 mM of anesthetic for atrial I(Ca,T) and I(Ca,L) and ventricular (ICa,L), respectively, and caused a significant (P < 0.05) hyperpolarizing shift in steady state inactivation. At 1.2 and 1.6 mm, isoflurane caused a significant (P < 0.05) depolarizing shift in the steady state activation in ventricular I(Ca,L) but not in atrial I(Ca,L) or I(Ca,T). In addition to the depression of I(Ca,L), isoflurane also induced a hyperpolarizing shift in the reversal potential of I(Ca) for both atrial and ventricular L-type calcium channels. CONCLUSION: The results show that atrial I(Ca,T) is more sensitive to isoflurane than atrial I(Ca,L), and ventricular I(Ca,L) was the least responsive to the anesthetic. These differential sensitivities of the calcium channels in the atrial and ventricular chambers might reflect phenotypic differences in the calcium channels or differences in modulation by the anesthetic.

Algorithms↗

PubMed2001

Anesthetic effects on mitochondrial ATP-sensitive K channel.

BACKGROUND: Volatile anesthetics show an ischemic preconditioning-like cardioprotective effect, whereas intravenous anesthetics have cardioprotective effects for ischemic-reperfusion injury. Although recent evidence suggests that mitochondrial adenosine triphosphate-regulated potassium (mitoK(ATP)) channels are important in cardiac preconditioning, the effect of anesthetics on mitoK(ATP) is unexplored. Therefore, the authors tested the hypothesis that anesthetics act on the mitoK(ATP) channel and mitochondrial flavoprotein oxidation. METHODS: Myocardial cells were isolated from adult guinea pigs. Endogenous mitochondrial flavoprotein fluorescence, an indicator of mitochondrial flavoprotein oxidation, was monitored with fluorescence microscopy while myocytes were exposed individually for 15 min to isoflurane, sevoflurane, propofol, and pentobarbital. The authors further investigated the effect of 5-hydroxydeanoate, a specific mitoK(ATP) channel antagonist, on isoflurane- and sevoflurane-induced flavoprotein oxidation. Additionally, the effects of propofol and pentobarbital on isoflurane-induced flavoprotein oxidation were measured. RESULTS: Isoflurane and sevoflurane induced dose-dependent increases in flavoprotein oxidation (isoflurane: R2 = 0.71, n = 50; sevoflurane: R2 = 0.86, n = 20). The fluorescence increase produced by both isoflurane and sevoflurane was eliminated by 5-hydroxydeanoate. Although propofol and pentobarbital showed no significant effects on flavoprotein oxidation, they both dose-dependently inhibited isoflurane-induced flavoprotein oxidation. CONCLUSIONS: Inhalational anesthetics induce flavoprotein oxidation through opening of the mitoK(ATP) channel. This may be an important mechanism contributing to anesthetic-induced preconditioning. Cardioprotective effects of intravenous anesthetics may not be dependent on flavoprotein oxidation, but the administration of propofol or pentobarbital may potentially inhibit the cardioprotective effect of inhalational anesthetics.

ATP-Binding Cassette Transporters↗

PubMed2001

Gadolinium prevents stretch-mediated contractile dysfunction in isolated papillary muscles.

We tested the hypothesis that overstretching the myocardium could induce and/or exacerbate contractile dysfunction via stretch-activated (SA) ion channels. Maximum developed tension (T(max)), normalized to a control value, was compared in guinea pig papillary muscles held at one of three resting lengths (physiological stretch, overstretch, and unloaded) for 85 min. Overstretched muscles exhibited decreased contractile force (T(max) = 0.77 +/- 0.03) compared with physiological and unloaded muscles (T(max) = 0.93 +/- 0.05 and 1.03 +/- 0.07, respectively). Gd(3+), an SA channel antagonist, eliminated the adverse effect of overstretching (T(max) = 0.98 +/- 0.06), but nifedipine, a dihydropyridine (DHP) antagonist of L-type calcium channels, did not (T(max) = 0.82 +/- 0.04). Exposure to modified hypoxia-reoxygenation (MHR) during physiological stretch resulted in decreased contractility (T(max) = 0.63 +/- 0.07), an effect that was exacerbated by overstretching (T(max) = 0.44 +/- 0.04). Gd(3+) mitigated the effects of overstretch during MHR (T(max) = 0.64 +/- 0.05), but DHP did not (T(max) = 0.48 +/- 0.04). These data suggest that overstretching of the myocardium contributes to contractile abnormalities via SA channels that are distinct from L-type calcium channels.

Animals↗

PubMed2000

Painful neuropathy decreases membrane calcium current in mammalian primary afferent neurons.

Hyperexcitability of the primary afferent neuron leads to neuropathic pain following injury to peripheral axons. Changes in calcium channel function of sensory neurons following injury have not been directly examined at the channel level, even though calcium is a primary second messenger-regulating neuronal function. We compared calcium currents (I(Ca)) in 101 acutely isolated dorsal root ganglion neurons from 31 rats with neuropathic pain following chronic constriction injury (CCI) of the sciatic nerve, to cells from 25 rats with normal sensory function following sham surgery. Cells projecting to the sciatic nerve were identified with a fluorescent label applied at the CCI site. Membrane function was determined using patch-clamp techniques in current clamp mode, and in voltage-clamp mode using solutions and conditions designed to isolate I(Ca). Somata of peripheral sensory neurons from hyperalgesic rats demonstrated decreased I(Ca). Peak calcium channel current density was diminished by injury from 3.06+/-0.30 pS/pF to 2. 22+/-0.26 pS/pF in medium neurons, and from 3.93+/-0.38 pS/pF to 2. 99+/-0.40 pS/pF in large neurons. Under these voltage and pharmacologic conditions, medium-sized neuropathic cells lacked obvious T-type calcium currents which were present in 25% of medium-sized cells from control animals. Altered Ca(2+) signalling in injured sensory neurons may contribute to hyperexcitability leading to neuropathic pain.

Action Potentials↗

PubMed2000

Modulation of cardiac inward rectifier K(+)current by halothane and isoflurane.

UNLABELLED: The cellular mechanisms that underlie general anesthetic actions on the inward rectifier K(+) current (IKir), a determinant of the resting potential in myocardium, are not fully understood. Using the whole-cell patch clamp technique, therefore, we investigated the effects of halothane and isoflurane on IKir in guinea pig ventricular myocytes. At membrane potentials negative to the equilibrium potential for potassium both anesthetics decreased amplitude of the steady-state inward IKir in a concentration- and voltage-dependent manner. The slope conductance was reduced, but the activation kinetics of the inward current were not altered. At potentials positive to the equilibrium potential for potassium, the outward current was increased by both anesthetics, which also caused small depolarizing shifts in the activation curve. With high internal magnesium concentration, the outward current increase by isoflurane was abolished, and the inward current block by halothane was attenuated. Spermine prevented the effects of both anesthetics on IKir at all membrane potentials tested. The results show voltage-dependent modulation of cardiac IKir channel by volatile anesthetics. Distinct modification of anesthetic effects by inward rectification gating agents, magnesium and spermine, suggests anesthetic interactions with the IKir channel protein. IMPLICATIONS: Differential modulation of myocardial inward rectifier potassium current by volatile anesthetics under normal and altered rectification may contribute to the mechanism of dysrhythmic actions by these anesthetics.

Anesthetics, Inhalation↗

PubMed2000

Xenon does not alter cardiac function or major cation currents in isolated guinea pig hearts or myocytes.

BACKGROUND: The noble gas xenon (Xe) has been used as an inhalational anesthetic agent in clinical trials with little or no physiologic side effects. Like nitrous oxide, Xe is believed to exert minimal unwanted cardiovascular effects, and like nitrous oxide, the vapor concentration to achieve 1 minimum alveolar concentration (MAC) for Xe in humans is high, i.e., 70-80%. In the current study, concentrations of up to 80% Xe were examined for possible myocardial effects in isolated, erythrocyte-perfused guinea pig hearts and for possible effects on altering major cation currents in isolated guinea pig cardiomyocytes. METHODS: Isolated guinea pigs hearts were perfused at 70 mm Hg via the Langendorff technique initially with a salt solution at 37 degrees C. Hearts were then perfused with fresh filtered (40-microm pore) and washed canine erythrocytes diluted in the salt solution equilibrated with 20% O2 in nitrogen (control), with 20% O2, 40% Xe, and 40% N2, (0.5 MAC), or with 20% O2 and 80% Xe (1 MAC), respectively. Hearts were perfused with 80% Xe for 15 min, and bradykinin was injected into the blood perfusate to test endothelium-dependent vasodilatory responses. Using the whole-cell patch-clamp technique, 80% Xe was tested for effects on the cardiac ion currents, the Na+, the L-type Ca2+, and the inward-rectifier K+ channel, in guinea pig myocytes suffused with a salt solution equilibrated with the same combinations of Xe, oxygen, and nitrogen as above. RESULTS: In isolated hearts, heart rate, atrioventricular conduction time, left ventricular pressure, coronary flow, oxygen extraction, oxygen consumption, cardiac efficiency, and flow responses to bradykinin were not significantly (repeated measures analysis of variance, P>0.05) altered by 40% or 80% Xe compared with controls. In isolated cardiomyocytes, the amplitudes of the Na+, the L-type Ca2+, and the inward-rectifier K+ channel over a range of voltages also were not altered by 80% Xe compared with controls. CONCLUSIONS: Unlike hydrocarbon-based gaseous anesthetics, Xe does not significantly alter any measured electrical, mechanical, or metabolic factors, or the nitric oxide-dependent flow response in isolated hearts, at least partly because Xe does not alter the major cation currents as shown here for cardiac myocytes. The authors' results indicate that Xe, at approximately 1 MAC for humans, has no physiologically important effects on the guinea pig heart.

Action Potentials↗

PubMed2000

Multiple agents potentiate alpha1-adrenoceptor-induced conduction depression in canine cardiac purkinje fibers.

BACKGROUND: Halothane more so than isoflurane potentiates an alpha1-adrenoceptor (alpha1-AR)-mediated action of epinephrine that abnormally slows conduction in Purkinje fibers and may facilitate reentrant arrhythmias. This adverse drug interaction was further evaluated by examining conduction responses to epinephrine in combination with thiopental and propofol, which "sensitize" or reduce the dose of epinephrine required to induce arrhythmias in the heart, and with etomidate, which does not, and responses to epinephrine with verapamil, lidocaine, and l-palmitoyl carnitine, a potential ischemic metabolite. METHODS: Action potentials and conduction times were measured in vitro using two microelectrodes in groups of canine Purkinje fibers stimulated at 150 pulses/min. Conduction was evaluated each minute after exposure to 5 microm epinephrine (or phenylephrine) alone or with the test drugs. Changes in the rate of phase 0 depolarization (Vmax) and the electrotonic spread of intracellular current were measured during exposure to epinephrine with octanol to evaluate the role of inhibition of active and passive (intercellular coupling) membrane properties in the transient depression of conduction velocity. RESULTS: Lidocaine (20 microm) and octanol (0.2 mm) potentiated alpha1-AR-induced conduction depression like halothane (0.4 mm), with maximum depression at 3-5 min of agonist exposure, no decrease of Vmax, and little accentuation at a rapid (250 vs. 150 pulses/min) stimulation rate. Thiopental (95 microm), propofol (50 microm), and verapamil (2 microm) similarly potentiated epinephrine responses, whereas etomidate (10 microm) did not. Between groups, the decrease of velocity induced by epinephrine in the presence of (10 microm) l-palmitoyl carnitine (-18%) was significantly greater than that resulting from epinephrine alone (-6%; 0.05 </= P </= 0.10). Current injection experiments were consistent with marked transient inhibition of cell-to-cell coupling correlating with alpha1-AR conduction depression in fibers exposed to octanol. CONCLUSIONS: Anesthetic "sensitization" to the arrhythmogenic effects of catecholamines may be a special case of a more general phenomenon by which not only some anesthetics and antiarrhythmic drugs but also possible ischemic fatty acid metabolites potentiate conduction depression due to acute alpha1-AR-mediated cell-to-cell uncoupling.

Action Potentials↗

PubMed2000

Cannabinoid CB1 receptor-mediated inhibition of prolactin release and signaling mechanisms in GH4C1 cells.

The GH4C1 cell line was used to study the cellular mechanisms of cannabinoid-mediated inhibition of PRL release. Cannabinoid CB1 receptor activation inhibited vasoactive intestinal polypeptide- and TRH-stimulated PRL release, but not its basal secretion. The cannabinoid-mediated inhibition of TRH-stimulated PRL release was reversed by the CB1 receptor-specific antagonist, SR141,716A, and was abolished by pertussis toxin pretreatment, indicating that G alpha subunits belonging to the G(i)alpha and G(o)alpha family were involved in the signaling. Photoaffinity labeling using [alpha-32P] azidoaniline GTP showed that cannabinoid receptor stimulation in cell membranes produced activation of four G alpha subunits (G(i)alpha2, G(i)alpha3, G(o)alpha1, and G(o)alpha2), which was also reversed by SR141,716A. The CB1 receptor agonists, WIN55,212-2 and CP55,940, inhibited cAMP formation and calcium currents in GH4C1 cells. The subtypes of calcium currents inhibited by WIN55,212-2 were characterized using holding potential sensitivity and calcium channel blockers. WIN55,212-2 inhibited the omega-conotoxin GVIA (Conus geographus)- and omega-agatoxin IVA (Aigelenopsis aperta)-sensitive calcium currents, but not the nisoldipine-sensitive calcium currents, suggesting the inhibition of N- and P-type, but not L-type, calcium currents. Taken together, the present findings indicate that CB1 receptors can couple through pertussis toxin-sensitive G alpha subunits to inhibit adenylyl cyclase and calcium currents and suppress PRL release from GH4C1 cells.

Adenylyl Cyclases↗

PubMed1999

The effects of the new antiarrhythmic E 047/1 on postoperative ischemia-induced arrhythmias in dogs.

UNLABELLED: Perioperative malignant ventricular tachyarrhythmias pose an imminent clinical danger by potentially precipitating myocardial ischemia and severely compromising hemodynamics. Thus, immediate and effective therapy is required, which is not always provided by currently recommended IV drug regimens, indicating a need for more effective drugs. We examined antiarrhythmic effects of the new benzofurane compound E 047/1 on spontaneous ventricular tachyarrhythmia in a conscious dog model. One day after experimental myocardial infarction, 40 dogs exhibiting tachyarrhythmia randomly received (bolus plus 1-h infusion) E 047/1 6 mg/kg plus 6 mg x kg(-1) x h(-1), lidocaine 1 mg/kg plus 4.8 mg x kg(-1) x h(-1), flecainide 1 mg/kg plus 0.05 mg x kg(-1) x h(-1), amiodarone 10 mg/kg plus 1.8 mg x kg(-1) x h(-1), or bretylium 10 mg/kg plus 20 mg x kg(-1) x h(-1). Electrocardiogram was evaluated for number of premature ventricular contractions (PVC), normally conducted beats originating from the sinoatrial node, and episodes of ventricular tachycardia. Immediately after the bolus, E 047/1 reduced PVCs by 46% and increased sinoatrial beats from 4 to 61 bpm. The ratio of PVCs to total beats decreased from 98% to 58%. Amiodarone and flecainide exhibited antiarrhythmic effects with delayed onset. Lidocaine did not suppress PVCs significantly, and bretylium was proarrhythmic. The antiarrhythmic E 047/1 has desirable features, suppressing ischemia-induced ventricular tachyarrhythmia quickly and efficiently, and may be a useful addition to current therapeutic regimens. IMPLICATIONS: Life-threatening arrhythmias of the heart after myocardial infarction or ischemia may be treated quickly and efficiently by the new drug E 047/1.

Animals↗

PubMed1999

Potassium channel-mediated hyperpolarization of mesenteric vascular smooth muscle by isoflurane.

BACKGROUND: A primary source of calcium (Ca2+) necessary for excitation contraction in vascular smooth muscle (VSM) is influx via voltage-dependent Ca2+ channels. Thus, force generation in VSM is coupled closely to resting transmembrane potential, which itself is primarily a function of potassium conductance. Previously, the authors reported that volatile anesthetics hyperpolarize VSM of small mesenteric resistance arteries and capacitance veins. The current study was designed to determine whether isoflurane-mediated hyperpolarization is the result of specific effects on one or more of four types of potassium channels known to exist in VSM. METHODS: Transmembrane potentials (Em) were recorded from in situ mesenteric capacitance and resistance vessels in Sprague-Dawley rats weighing 250-300 g. In separate experiments, selective inhibitors of each of four types of potassium channels known to exist in VSM were administered in the superfusate of the vessel preparations to assess their effects on isoflurane-mediated hyperpolarization. RESULTS: Resting VSM Em ranged from -38 to -43 mV after local sympathetic denervation. Isoflurane produced a significant hyperpolarization (2.7-4.3 mV), whereas each potassium channel inhibitor significantly depolarized (2.8-8.5 mV) the VSM. Both 100 nM iberiotoxin (inhibitor of high conductance calcium-activated potassium channels) and 1 microM glybenclamide (inhibitor of adenosine triphosphatase-sensitive potassium channels) significantly inhibited VSM hyperpolarization induced by 1 MAC (minimum alveolar concentration) levels of inhaled isoflurane (0.1-0.9 mV Em change, which was not significant). In contrast, isoflurane hyperpolarized the VSM significantly despite the presence of 3 mM 4 aminopyridine (inhibitor of voltage-dependent potassium channels) or 10 microM barium chloride (an inhibitor of inward rectifier potassium channels) (3.7-8.2 mV change in VSM Em). CONCLUSIONS: These results suggest that isoflurane-mediated hyperpolarization (and associated relaxation) of VSM can be attributed in part to an enhanced (or maintained) opening of calcium-activated and adenosine triphosphate-sensitive potassium channels but not voltage-dependent or inward rectifier potassium channels.

Anesthetics, Inhalation↗

PubMed1999

Effects of halothane and isoflurane on fast and slow inactivation of human heart hH1a sodium channels.

BACKGROUND: Cloning and heterologous expression of ion channels allow biophysical and molecular studies of the mechanisms of volatile anesthetic interactions with human heart sodium channels. Volatile anesthetics may influence the development of arrhythmias arising from cardiac sodium channel dysfunction. For that reason, understanding the mechanisms of interactions between these anesthetics and cardiac sodium channels is important. This study evaluated the mechanisms of volatile anesthetic actions on the cloned human cardiac sodium channel (hH1a) alpha subunit. METHODS: Inward sodium currents were recorded from human embryonic kidney (HEK293) cells stably expressing hH1a channels. The effects of halothane and isoflurane on current and channel properties were evaluated using the whole cell voltage-clamp technique. RESULTS: Halothane at 0.47 and 1.1 mM and isoflurane at 0.54 and 1.13 mM suppressed the sodium current in a dose- and voltage-dependent manner. Steady state activation was not affected, but current decay was accelerated. The voltage dependence of steady state fast and slow inactivations was shifted toward more hyperpolarized potentials. The slope factor of slow but not fast inactivation curves was reduced significantly. Halothane increased the time constant of recovery from fast inactivation. The recovery from slow inactivation was not affected significantly by either anesthetic. CONCLUSIONS: In a heterologous expression system, halothane and isoflurane interact with the hH1a channels and suppress the sodium current. The mechanisms involve acceleration of the transition from the open to the inactivated state, stabilization of the fast and slow inactivated states, and prolongation of the inactivated state by delayed recovery from the fast inactivated to the resting state.

Anesthetics, Inhalation↗

PubMed1999

Effect of isoflurane on in situ vascular smooth muscle transmembrane potential in spontaneous hypertension.

BACKGROUND: Administration of general anesthetics to patients with chronic hypertension often causes hemodynamic instability that has been attributed in part to a poorly understood increased loss of control of peripheral vascular smooth muscle tone. The purpose of the current study was to determine if such an increased loss occurs in the spontaneously hypertensive (SH) rat neurogenic model of chronic hypertension, as reflected by a greater volatile anesthetic-induced in situ vascular smooth muscle hyperpolarization compared with normotensive Wistar-Kyoto (WKY) rat controls. METHODS: Vascular smooth muscle transmembrane potentials (E(m)s) were measured in situ using glass microelectrodes in externalized small mesenteric resistance- and capacitance-regulating blood vessels in 10- to 12-week-old SH and WKY rats before, during and after administration of 1 minimum alveolar concentration levels (1.5%) of inhaled or 0.60 mM superfused isoflurane. Vascular smooth muscle E(m)s were also measured in vessels after local sympathetic denervation with superfused 6-hydroxydopamine. RESULTS: Local sympathetic denervation caused a significant hyperpolarization of arterial and venous vascular smooth muscle in SH but not WKY rats. Hyperpolarization induced by either inhaled or superfused isoflurane was significantly greater in innervated than in denervated arterial and venous vascular smooth muscle, particularly in SH rats. In addition, for innervated (but not denervated) arterial and venous vascular smooth muscle, hyperpolarization induced by inhaled (but not superfused) isoflurane was significantly greater in SH than in WKY rats. CONCLUSIONS: In the neurogenic SH rat model of human hypertension, a primary mechanism underlying elevated isoflurane-induced vascular smooth muscle hyperpolarization (and reduced vascular smooth muscle tone) in both resistance- and capacitance-regulating blood vessels is a central neural inhibition of excitatory sympathetic input. Peripheral neural and nonneurally mediated hyperpolarization by isoflurane is similar in SH and WKY rat vascular smooth muscles.

Anesthetics, Inhalation↗

PubMed1999

Contribution of carotid chemoreceptors to mesenteric venoconstriction during acute hypercapnia in rabbits.

The contribution of carotid chemoreceptors to hypercapnia-induced mesenteric venoconstriction was examined in 12 alpha-chloralose-anesthetized rabbits (1.0-1.6 kg). Surgical preparation consisted of a tracheotomy, femoral arterial and venous cannulation, and a midline laparotomy through which a 13-cm loop of ileum was exteriorized and superfused with physiological salt solution. Mesenteric vein diameter and intravenous pressure (using a servo-null measurement system) were measured in 500- to 1,000-micron mesenteric veins during 40-s periods of 15%, 20%, and 25% CO2 inhalation. Measurements were then repeated following bilateral ablation of the carotid chemoreceptors. Before denervation, mesenteric vein diameter constricted 6.5 +/- 1.1%, 11.9 +/- 1.1%, and 17.9 +/- 2.2% during the 15%, 20%, and 25% CO2 inhalation, respectively. After denervation, these values were reduced to 5.0 +/- 0.9%, 6.9 +/- 1.2%, and 8.4 +/- 1.3%, respectively. We conclude that activation of the carotid chemoreceptors by hypercapnia induces active mesenteric venoconstriction. After denervation of the carotid baroreceptors and chemoreceptors, there was also a small decrease in venule diameter proportional to the level of inspired CO2. We further conclude that noncarotid body chemoreceptor activation contributes to mesenteric venular constriction.

Animals↗

PubMed1998

Effects of the optical isomers of verapamil on electrophysiological properties of the heart in conscious dogs.

We compared the cumulative dose-response relations of verapamil (0.1, 0.2 and 0.4 mg kg(-1)) in different R/S enantiomer ratios (100/0, 90/10, 80/20, 50/50 and 20/80) on the electrophysiological and hemodynamic characteristics of the heart using the conscious dogs. A reduction of mean arterial pressure occurred with 20R/80S producing a 3-times greater decrease than 100R/0S, but an increase in heart rate occurred with 20R/80S producing a 9-times greater increase than 100R/0S. Increased heart rate was concurrent with decreased mean arterial pressure most prevalent with a higher ratio of S-isomer that produced a greater reduction in mean arterial pressure and increase in heart rate at lower overall verapamil doses. Atrio-ventricular conduction time increased 3-5 min after each infusion, with 20R/80S producing a 4-times greater effect than 100R/0S. These results indicate that the peripheral and cardiac electrophysiologic properties of various nonracemic verapamil mixtures are mainly attributable to the concentration of S-isomer.

Animals↗

PubMed1998

Cardiovascular effects of verapamil enantiomer combinations in conscious dogs.

We examined the systemic and coronary hemodynamic effects of five combinations of R- and S-verapamil enantiomers (R/S; 100/0, 90/10, 80/20, 50/50, and 20/80%, respectively) in conscious dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dt, subendocardial segment length, coronary blood flow velocity, and aortic blood flow. Dogs received escalating doses (0.1, 0.2, and 0.4 mg kg(-1)) of each verapamil combination over 2 min at 30 min intervals on different experimental days and peak changes in hemodynamics were recorded 2 min after each dose. All verapamil combinations increased heart rate, mean aortic blood flow, and coronary blood flow velocity and decreased calculated systemic and coronary vascular resistance. Alterations in coronary hemodynamics were most pronounced with 20/80 R/S verapamil. Racemic and 20/80 R/S verapamil decreased mean arterial and left ventricular systolic pressure, in contrast to combinations with greater concentrations of the R enantiomer. Left ventricular function was unchanged during administration of 100/0, 90/10, and 80/20 R/S verapamil. Direct negative inotropic and lusitropic effects occurred with 50/50 and 20/80 R/S verapamil. The high dose of 20/80 R/S verapamil also increased left ventricular end-diastolic pressure and the regional chamber stiffness constant, consistent with diastolic dysfunction. The results indicate that combinations of R- and S-verapamil produce differential hemodynamic and left ventricular functional effects in conscious, unsedated dogs that are dependent on the relative ratio of these enantiomers.

Animals↗