cyclic-gmp and Infant--Newborn--Diseases

The appropriate treatment of persistent pulmonary hypertension of the newborn has led to the search for a specific pulmonary vasodilator. Persistent pulmonary hypertension of the newborn is characterized by a high pulmonary vascular resistance resulting in right to left shunting across the fetal channels. The ratio of pulmonary vascular resistance to systemic vascular resistance determines the magnitude of this shunt, and agents which lower both pulmonary and systemic blood pressure do not alleviate the right to left intracardiac shunt. Numerous vasodilator agents,including tolazoline, prostaglandins and nitrovasodilators, have been used but all have been associated with problematic falls in systemic blood pressure. Magnesium, called nature's calcium blocker, antagonizes calcium ion entry into smooth muscle cells, thus promoting vasodilatation. Magnesium is also a non-specific vasodilator,and while potentially lowering pulmonary vascular resistance, has been shown to cause a fall in systemic blood pressure in neonatal models of hypoxic or septic pulmonary hypertension. Case reports and a series of cases have noted beneficial effects in human newborns, which may have been due to other effects of magnesium (eg, sedation, muscle relaxation, bronchodilatation and cardioprotection). There are, however, no reported prospective randomized controlled trials of magnesium sulphate in human newborns with pulmonary hypertension. More recently, the discovery that inhaled nitric oxide acts as a specific pulmonary vasodilator without systemic side effects may reduce enthusiasm for the use of magnesium infusions in neonates with pulmonary hypertension. There appears to be sufficient evidence at present to justify a prospective randomized controlled trial to evaluate the role of magnesium infusion as a specific pulmonary vasodilator for the treatment of pulmonary hypertension in hypoxic human newborns.

Topics: Animals; Blood Coagulation; Calcium Channel Blockers; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Newborn, Diseases; Lung; Magnesium Sulfate; Meconium Aspiration Syndrome; Nifedipine; Nitric Oxide Synthase; Pulmonary Circulation; Respiration, Artificial; Swine; Thromboxane-A Synthase; Vasodilator Agents

Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications.

Topics: Administration, Oral; Animals; Animals, Newborn; Chronic Disease; Cyclic GMP; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Hemodynamics; Humans; Hypertension, Pulmonary; Hypoxia; Infant, Newborn; Infant, Newborn, Diseases; Lung; Piperazines; Pulmonary Artery; Purines; Reference Values; Sildenafil Citrate; Sulfones; Swine; Treatment Outcome; Vasodilator Agents