Role of Kv7 channels in responses of the pulmonary circulation to hypoxia.

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.

[Pathophysiology of development of pulmonary hypertension after acute pulmonary embolism]. / Patofyziologie vzniku plicní hypertenze po akutní plicní embolii.

Acute pulmonary embolism (PE) is the life-threatening condition with high incidence and mortality where the death is the result of pulmonary hypertension followed by right side heart failure. There are two important mechanisms concerned in the development of pulmonary embolism--induced pulmonary hypertension--mechanic obstruction of pulmonary vessels by the embolus and vasoconstriction. The effect of mechanic obstruction is quite clear, in contrast to the role of vasoconstriction. Activation of endothelial cells, thrombocytes and leucocytes, which release vasoconstricting substances (ET-1, 5-HT etc.) and production of reactive oxygen species (ROS) are the most important factors causing the vasoconstriction after PE. ROS are produced as a result of hypoxia, increased (and decreased) shear stress and are released from activated leukocytes. Vasoconstriction after PE is caused by change of conformation voltage-gated potassium channels, the decrease of vasodilatation effect of NO and activation of matrix metalloproteinases.. Most of the current therapeutic protocols in PE are focused on mechanic obstruction of pulmonary vessels. Thus, the research of the role of vasoconstriction in PE and potentially protective factors in vasocostriction--induced injury represent clinically highly important field.