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1-Adrenergic Hypothesis for Pulmonary Hypertension*
* From the Department of Medicine, Southampton General Hospital, Southampton, UK.
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
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
1-adrenergic receptors that are present on the small-
and medium-sized pulmonary arteries have a unique and greatly enhanced
affinity and activity to 1-adrenergic agonists. Under
physiologic conditions, this helps in regulating vascular tone and
maintains an adequate ventilation/perfusion matching. However, the
excessive stimulation of 1-adrenergic receptors produces
not only smooth muscle contraction but also proliferation and growth.
The conditions that produce an increase in
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
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
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.
Key Words: 1-adrenoreceptor • appetite suppressants • hypothesis • hypoxia • norepinephrine • pulmonary hypertension
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