Grant: Operating Grant - PA: Regional Partnership Program : Manitoba

The newborn lung is very sensitive to low levels of oxygen. In infants who do not receive enough oxygen at birth, the low oxygen level causes lung blood vessels to go into spasm. Then blood cannot flow through the lung for gas exchange. This causes the heart to fail. This deadly disease, persistent pulmonary hypertension of the newborn (PPHN) accounts for 10% of all admissions to newborn intensive care. Heart muscle and lung blood vessel muscles have opposite jobs at birth. The heart needs to contract harder, and lung blood vessels need to relax. These opposite events happen through a single system of signals inside the cell, called the adenylyl cyclase pathway. We studied the effects of low oxygen levels on the function of the heart, and on muscle lining the blood vessels of the newborn lung. In low oxygen, muscles in the heart and blood vessels do not respond properly to medications. We now find that the adenylyl cyclase pathway does not work in low oxygen. Prostacyclin is a powerful molecule produced during labour and delivery, which uses the adenylyl cyclase signal system. In healthy newborns, prostacyclin protects blood vessels from excessive contraction. However in low oxygen, the signals that connect prostacyclin to blood vessel relaxation are lost. Prostacyclin cannot do its protective job. Other important drugs use the adenylyl cyclase signal system, including those we use in the ICU to make a baby's heart pump better. These drugs also stop working in low oxygen. We plan to study the adenylyl cyclase signal system in muscle from lung blood vessels and in heart muscle from PPHN animals, to see why low oxygen stops it from working. We will look at the mechanisms for switching adenylyl cyclase on and off, and see how they are affected by low oxygen. Finally we will try to reactivate adenylyl cyclase in the heart and lung blood vessels of PPHN animals, using new selective drugs. These reactivating drugs may help us treat babies with PPHN.