Potassium channels are central to the regulation of pulmonary vascular tone. The smooth muscle cells of pulmonary artery display a background K ϩ conductance with biophysical properties resembling those of KCNQ (K V 7) potassium channels. Therefore, we investigated the expression and functional role of KCNQ channels in pulmonary artery. The effects of selective KCNQ channel modulators were investigated on K ϩ current and membrane potential in isolated pulmonary artery smooth muscle cells (PASMCs), on the tension developed by intact pulmonary arteries, and on pulmonary arterial pressure in isolated perfused lungs and in vivo. The KCNQ channel blockers, linopirdine and XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone], inhibited the noninactivating background K ϩ conductance in PASMCs and caused depolarization, vasoconstriction, and raised pulmonary arterial pressure without constricting several systemic arteries or raising systemic pressure. The KCNQ channel openers, retigabine and flupirtine, had the opposite effects. PASMCs were found to express KCNQ4 mRNA, at higher levels than mesenteric artery, along with smaller amounts of KCNQ1 and 5. It is concluded that KCNQ channels, most probably KCNQ4, make an important contribution to the regulation of pulmonary vascular tone, with a greater contribution in pulmonary compared with systemic vessels. The pulmonary vasoconstrictor effect of KCNQ blockers is a potentially serious side effect, but the pulmonary vasodilator effect of the openers may be useful in the treatment of pulmonary hypertension.

Hypoxic pulmonary vasoconstriction (HPV) is a beneficial mechanism that diverts blood from hypoxic alveoli to better ventilated areas of the lung, but breathing hypoxic air causes the pulmonary circulation to become hypertensive. Responses to airway hypoxia are associated with depolarization of smooth muscle cells in the pulmonary arteries and reduced activity of K+ channels. As Kv7 channels have been proposed to play a key role in regulating the smooth muscle membrane potential, we investigated their involvement in the development of HPV and hypoxia-induced pulmonary hypertension. Vascular effects of the selective Kv7 blocker, linopirdine, and Kv7 activator, flupirtine, were investigated in isolated, saline-perfused lungs from rats maintained for 3–5 days in an isobaric hypoxic chamber (FiO2 = 0.1) or room air. Linopirdine increased vascular resistance in lungs from normoxic, but not hypoxic rats. This effect was associated with reduced mRNA expression of the Kv7.4 channel α-subunit in hypoxic arteries, whereas Kv7.1 and Kv7.5 were unaffected. Flupirtine had no effect in normoxic lungs but reduced vascular resistance in hypoxic lungs. Moreover, oral dosing with flupirtine (30 mg/kg/day) prevented short-term in vivo hypoxia from increasing pulmonary vascular resistance and sensitizing the arteries to acute hypoxia. These findings suggest a protective role for Kv7.4 channels in the pulmonary circulation, limiting its reactivity to pressor agents and preventing hypoxia-induced pulmonary hypertension. They also provide further support for the therapeutic potential of Kv7 activators in pulmonary vascular disease.

The effect of three-day fasting on cardiac ischemic tolerance was investigated in adult male Wistar rats. Anesthetized open-chest animals (pentobarbitone 60 mg/kg, i.p.) were subjected to 20-min left anterior descending coronary artery occlusion and 3-h reperfusion for infarct size determination. Ventricular arrhythmias were monitored during ischemia and at the beginning (3 min) of reperfusion. Myocardial concentrations of beta-hydroxybutyrate and acetoacetate were measured to assess mitochondrial redox state. Short-term fasting limited the infarct size (48.5±3.3 % of the area at risk) compared to controls (74.3±2.2 %) and reduced the total number of premature ventricular complexes (12.5±5.8) compared to controls (194.9±21.9) as well as the duration of ventricular tachycardia (0.6±0.4 s vs. 18.8±2.5 s) occurring at early reperfusion. Additionally, fasting increased the concentration of beta-hydroxybutyrate and beta-hydroxybutyrate/acetoacetate ratio (87.8±27.0) compared to controls (7.9±1.7), reflecting altered mitochondrial redox state. It is concluded that three-day fasting effectively protected rat hearts against major endpoints of acute I/R injury. Further studies are needed to find out whether these beneficial effects can be linked to altered mitochondrial redox state resulting from increased ketogenesis.

Reduced coronary perfusion in acute coronary syndrome causes myocardial ischemia. Also the effect of reactive oxygen species (ROS) induced ischemia‐reperfusion injury contributes to myocardial lesion. ROS generation in hypoxia is modulated by the redox state. Fasting before exposure to ischemia should increase ketogenesis that consumes reduced coenzymes and consequently reduces free radical damage.We investigated whether the 3‐day fasting affects production of ROS, incidence of ventricular arrhythmias during ischemia/reperfusion and myocardial infarction size.We analyzed production of the lipid peroxidation end products (LFP) in the heart tissue. Open‐chest rats were subjected to 20‐min LAD coronary artery occlusion followed by reperfusion. A single‐lead ECG was recorded and arrhythmias were assessed. The infarction size in excised hearts was determined by triphenyltetrazolium chloride staining and it was normalized to area at risk (IS/AR).Three day fasting reduced LFP production in heart tissue. During early reperfusion the number of premature ventricular complexes was reduced in fasting rats compared to controls, as well as ventricular tachycardia duration. In fasting rats the IS/AR reached 48.5 ± 3.3 % while in controls it was 74.3 ± 2.2 %, p<0.005.Acute caloric restriction limits free radical damage in heart, reperfusion ventricular arrhythmias and myocardial infarction size in rats.Supported by GAUK 60009/2009 and MSMT 1M 0510.

Hypoxic stress at birth is linked with increased susceptibility to various diseases in adulthood. Perinatal hypoxia causes irreversible changes of the pulmonary vascular bed, some of which are more expressed in females. KCNQ (subgroup of voltage gated K+) channels have been suggested to play a role in pulmonary vascular reactivity. We hypothesized that perinatal hypoxia alters KCNQ channel activity in adulthood.Rats of the perinatal hypoxic group (PH) were born in a normobaric hypoxic chamber (FiO2 0.12; one week before the delivery) and kept in the chamber for one week after birth. Then they were raised in atmospheric air. Normoxic controls (N) were born and kept in room air. Both groups were divided according to gender and studied at the age of 20 weeks. We measured changes in perfusion pressure in isolated, saline‐perfused lungs. Dose‐response to a specific KCNQ channel inhibitor linopiridine (0.5–16 μM) was tested.In contrast to males, PH females have increased basal perfusion pressure and increased reactivity to K+ than N females. PH rats of both sexes are more sensitive to linopirdine. The increase in perfusion pressure in response to the highest linopiridine dose was 10.2 ± 1.6 mmHg in the PH group and only 5.0 ± 0.8 mmHg in the N group.Exposure to hypoxia in perinatal period increases KCNQ channel activity in adult rats.Supported by Cardiovascular Research Center MSMT 1M 0510 and Czech Science Foundation 305/08/0108.