Ion channels regulating pulmonary vascular tone       

Pulmonary hypertension, or raised blood pressure in the lungs, is a disease with poor prognosis.  It is associated with constriction and remodelling of the small arteries within the lung. 

As the diameter of small arteries is crucial to determining the resistance to blood flow and blood pressure, we are interested in identifying mechanisms that regulate the diameter of pulmonary arteries and can potentially be targetted by drugs acting to lower pulmonary arterial pressure.  

We have a particular interest in the ion channels found in the plasma membranes of pulmonary artery smooth muscle cells.  Our work investigates the physiological roles and pharmacology of specific ion channels in these cells.  We take an interdisciplinary approach to investigating ion channel expression and function, using small-vessel wire myography to investigate constriction in intact vessels, electrophysiology to study the biophysics and pharmacology of ionic currents carried through the channels, fluorescent Ca²⁺ imaging to link channel activity and contraction to the regulation of Ca²⁺ signalling and molecular techniques to study and manipulate the expression of particualr channels. 

Past contributions to the field include the:

• discovery of KATP channels and the two-pore domain channel, TASK-1, as regulators of smooth muscle membrane potential and pulmonary artery tone
• identification of IP₃-induced Ca²⁺ release as the site of action of the vasodilator, hydralazine
• demonstration that potassium channel expression is modulated in pulmonary hypertension and following birth, when the pulmonary circulation begins to function in gas exchange
• identification of mitochondrial Ca²⁺ signalling during agonist activation of vascular myocytes.
• identification and characterisation of store-operated Ca²⁺ channels in pulmonary artery myocytes
• discovery of an oxygen-sensing, non-inactivating K⁺ current that regulates the membrane potential of pulmonary artery smooth muscle
• discovery of potent pulmonary vascular actions of KCNQ (Kv7) potassium channel modulators.