α1-adrenergic hypothesis for pulmonary hypertension

Pulmonary hypertension (PH) is a chronic and disabling condition that affects the pulmonary vasculature. Once PH is diagnosed, the prognosis is generally poor with a rapid downhill course. PH management is largely empirical because the underlying pathophysiologic mechanisms that are responsible for the excessive vasoconstrictor and vascular smooth muscle proliferative responses are poorly understood. Based on new information concerning the role of adrenergic receptors in regulating various cellular functions, a new perspective on the genesis of PH has emerged, along with a unifying hypothesis for the role of alpha(1)-adrenergic receptors present in the pulmonary vasculature as the major contributor to the pathophysiologic changes associated with PH. Adrenergic receptors that are present on vascular smooth muscle cells regulate vascular tone and growth. The alpha(1)-adrenergic receptors that are present on the small- and medium-sized pulmonary arteries have a unique and greatly enhanced affinity and activity to alpha(1)-adrenergic agonists. Under physiologic conditions, this helps in regulating vascular tone and maintains an adequate ventilation/perfusion matching. However, the excessive stimulation of alpha(1)-adrenergic receptors produces not only smooth muscle contraction but also proliferation and growth. The conditions that produce an increase in alpha(1)-adrenoreceptor gene synthesis, density, and activity (such as hypoxia or changes in vessel wall pressure) or increase the levels of its agonists (such as norepinephrine, appetite suppressants, or cocaine) greatly enhance pulmonary vascular smooth muscle contractile and proliferative responses and lead to the development of PH. An understanding of the role played by these receptors in the pathophysiology of PH would not only help to avoid the use of alpha(1)-agonists for appetite suppression and other disease states, but also would help in developing new drugs to block these receptors. A further understanding of the alpha(1)-adrenoreceptor subtypes present in the pulmonary vasculature, the factors that regulate their expression, and their intracellular signaling pathways would help researchers to devise newer therapeutic strategies and, hopefully, to find a cure for this crippling condition.