[Inhibitory effects of propofol on supraoptic nucleus neurons of rat hypothalamus in vitro].

To investigate the effects of novel intravenous general anesthetic propofol on membrane electrophysiological characteristics and action potential (AP) of the supraoptic nucleus (SON) neurons and possible ionic mechanisms, intracellular recordings were conducted in SON neurons from the coronal hypothalamic slice preparation of adult male Sprague Dawley (SD) rats. The results showed that bath application of 0.1 mmol/L propofol induced a significant decline in resting potential (P < 0.01), and higher concentrations of propofol (0.3 and 1.0 mmol/L) decreased time constant and slope resistance of cell membrane (P < 0.01). Under the hyperpolarizing current pulses exceeding 0.5 nA, an anomalous rectification was induced by hyperpolarization-activated cation channel (I(h) channel) in 11 out of 18 tested SON neurons. Bath of propofol reversibly decreased the anomalous rectification. Moreover, 0.1 mmol/L propofol elevated threshold level (P < 0.01) and decreased Max L. slope (P < 0.05) of the spike potential in SON neurons. Interestingly, 0.3 and 1.0 mmol/L propofol nullified APs in 6% (1/18) and 71% (12/17) tested SON neurons, respectively. In the SON neurons where APs were not nullified, propofol (0.3 mmol/L) decreased the amplitude of spike potential (P < 0.05). The higher concentrations of propofol (0.3 and 1.0 mmol/L) decreased firing frequencies evoked by depolarizing current pulses (0.1-0.7 nA), and shifted the current intensity-firing frequency relation curves downward and to the right. These results suggest that propofol decreases the excitability of SON neurons by inhibiting I(h) and sodium channels.

Lidocaine blocks the hyperpolarization-activated mixed cation current, I(h), in rat thalamocortical neurons.

BACKGROUND: The mechanisms that underlie the supraspinal central nervous system effects of systemic lidocaine are poorly understood and not solely explained by Na(+) channel blockade. Among other potential targets is the hyperpolarization-activated cation current, I(h), which is blocked by lidocaine in peripheral neurons. I(h) is highly expressed in the thalamus, a brain area previously implicated in lidocaine's systemic effects. The authors tested the hypothesis that lidocaine blocks I(h) in rat thalamocortical neurons. METHODS: The authors conducted whole cell voltage- and current-clamp recordings in ventrobasal thalamocortical neurons in rat brain slices in vitro. Drugs were bath-applied. Data were analyzed with Student t tests and ANOVA as appropriate; α = 0.05. RESULTS: Lidocaine voltage-independently blocked I(h), with high efficacy and a half-maximal inhibitory concentration (IC(50)) of 72 µM. Lidocaine did not affect I(h) activation kinetics but delayed deactivation. The I(h) inhibition was accompanied by an increase in input resistance and membrane hyperpolarization (maximum, 8 mV). Lidocaine increased the latency of rebound low-threshold Ca(2+) spike bursts and reduced the number of action potentials in bursts. At depolarized potentials associated with the relay firing mode (>-60 mV), lidocaine at 600 µM concurrently inhibited a K(+) conductance, resulting in depolarization (7-10 mV) and an increase in excitability mediated by Na(+)-independent, high-threshold spikes. CONCLUSIONS: Lidocaine concentration-dependently inhibited I(h) in thalamocortical neurons in vitro, with high efficacy and a potency similar to Na(+) channel blockade. This effect would reduce the neurons' ability to produce intrinsic burst firing and δ rhythms and thereby contribute to the alterations in oscillatory cerebral activity produced by systemic lidocaine in vivo.

Corticospinal-specific HCN expression in mouse motor cortex: I(h)-dependent synaptic integration as a candidate microcircuit mechanism involved in motor control.

Motor cortex is a key brain center involved in motor control in rodents and other mammals, but specific intracortical mechanisms at the microcircuit level are largely unknown. Neuronal expression of hyperpolarization-activated current (I(h)) is cell class specific throughout the nervous system, but in neocortex, where pyramidal neurons are classified in various ways, a systematic pattern of expression has not been identified. We tested whether I(h) is differentially expressed among projection classes of pyramidal neurons in mouse motor cortex. I(h) expression was high in corticospinal neurons and low in corticostriatal and corticocortical neurons, a pattern mirrored by mRNA levels for HCN1 and Trip8b subunits. Optical mapping experiments showed that I(h) attenuated glutamatergic responses evoked across the apical and basal dendritic arbors of corticospinal but not corticostriatal neurons. Due to I(h), corticospinal neurons resonated, with a broad peak at ∼4 Hz, and were selectively modulated by α-adrenergic stimulation. I(h) reduced the summation of short trains of artificial excitatory postsynaptic potentials (EPSPs) injected at the soma, and similar effects were observed for short trains of actual EPSPs evoked from layer 2/3 neurons. I(h) narrowed the coincidence detection window for EPSPs arriving from separate layer 2/3 inputs, indicating that the dampening effect of I(h) extended to spatially disperse inputs. To test the role of corticospinal I(h) in transforming EPSPs into action potentials, we transfected layer 2/3 pyramidal neurons with channelrhodopsin-2 and used rapid photostimulation across multiple sites to synaptically drive spiking activity in postsynaptic neurons. Blocking I(h) increased layer 2/3-driven spiking in corticospinal but not corticostriatal neurons. Our results imply that I(h)-dependent synaptic integration in corticospinal neurons constitutes an intracortical control mechanism, regulating the efficacy with which local activity in motor cortex is transferred to downstream circuits in the spinal cord. We speculate that modulation of I(h) in corticospinal neurons could provide a microcircuit-level mechanism involved in translating action planning into action execution.

Review of the If selective channel inhibitor ivabradine in the treatment of chronic stable angina.

Coronary heart disease is the major cause of morbidity and mortality in industrialized countries, and its prevalence is predicted to grow as the population ages. Current drugs for chronic stable angina (such as beta-blockers, calcium-channel blockers, long- and short-acting nitrates, and potassium-channel activators) are often effective, either as monotherapy or in combination, but side effects and contraindications may limit their use. The "I(f)" (for "funny") channel, discovered in 1979, is expressed mainly in the membrane of pacemaker cells present in the sinus node, the atrioventricular node, the ventricular conduction pathways, and ventricular myocytes. By determining the slope of diastolic depolarization, which in turn controls action potential frequency, it is a key determinant of heart rate and so provides a new therapeutic target for controlling angina symptoms. A new antiangina drug, ivabradine, has been developed and licensed for clinical use. It exclusively reduces the heart rate by selectively blocking the I(f) channel of the sino-atrial node. As clinical trials have shown it to be remarkably well-tolerated, ivabradine offers an alternative for patients who cannot take, or are intolerant of, beta blockade. This review provides an insight into this new agent, its historical background, mechanism of action, and pathophysiologic basis, and provides up-to-date evidence-based information on its optimum use in stable angina.

[Clinical efficiency of ivabradine in patients with cardiorespiratory pathology].

Clinical efficiency of If-inhibitor ivabradin (Coraxan, Servier) in 40 patients with cardiorespiratory pathology (CRP) was studied. It was shown, that use of ivabradin in dose of 5 mg two times a day leaded to significant decrease in number of angina attacks in a week, and also in time of painless myocardial ischemia, decrease in heart rate at a day and during physical exercises, increase in 6 minutes walking distance and circadian index, oxygen saturation and partial tension, decrease in average pressure in pulmonary artery, increase in ejection fraction of left ventricle. Thus, ivabradin (Coraxan, Servier) is an effective antianginal drug for CRP patients, it improves life quality and do not has an influence on external respiration function. Ivabradin in dose of 5 mg two times a day can be used for CRP patients and as alternative to beta-adrenoblockers.

Preclinical results with I(f) current inhibition by ivabradine.

Ivabradine, a highly selective I(f) current inhibitor acting directly on the sinoatrial node, induces a rapid, sustained and dose-dependent reduction of heart rate at rest and during exercise, without significant effects on atrioventricular conduction, left ventricular (LV) contraction-relaxation or vascular tissues. These properties, associated with an improvement in LV loading related to bradycardia, resulted in an increase in stroke volume and preservation of cardiac output at rest and during exercise. Reducing myocardial oxygen consumption and improving oxygen supply, ivabradine reduced the severity of ischaemia and associated regional contractile dysfunction of the stunned myocardium. Long-term administration of ivabradine in rats with chronic heart failure improved cardiac haemodynamics associated with a progressive remodelling of LV structure. In dyslipidaemic mice, ivabradine prevented the renal and cerebrovascular endothelial dysfunction associated with atherosclerosis. These preclinical data suggest that long-term reduction in heart rate with ivabradine might interact with multiple a priori unexpected mechanisms involved in cardiac and vascular remodelling processes associated with chronic heart diseases.