PATHOPHYSIOLOGY OF PULMONARY HYPERTENSION
Table 1: The Physiologic Factors That Affect Pulmonary Arterial Tone and Platelet Function*
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Pulmonary hypertension develops when there is an imbalance among the factors that control pulmonary arterial vasoconstriction,
vasodilation, platelet activation, and smooth muscle cell proliferation (Table 1).3 By understanding these factors, practitioners are better able to choose the therapy or combination of medications that is
most likely to help reduce pulmonary arterial pressure. For instance, by understanding the roles that prostaglandins, endothelin,
and nitric oxide play in pulmonary vessel constriction and dilation, you can choose the best therapy for your patient.
Alveolar hypoxia
Alveolar hypoxia elicits pulmonary vessel vasoconstriction, a response unique to the pulmonary system. Vasoconstriction allows
deoxygenated blood to be shunted to areas of the lung that are better ventilated and improves ventilation-perfusion matching,
which is thought to be a beneficial physiologic response in acute instances but, in chronic conditions, may lead to pulmonary
hypertension.
Pulmonary vasculature tone is controlled by potassium, calcium, and chloride channels. The activity of these channels is affected
by local oxygen tension. Poor oxygen tension, or hypoxia, leads to vasoconstriction mainly in small pulmonary arteries and
arterioles, leading to increased pulmonary vascular resistance.2 If oxygen tension remains poor over a long period, pulmonary vasoconstriction results in increased pulmonary arterial pressure
and pulmonary hypertension.
Alveolar hypoxia also induces growth factors, such as platelet-derived growth factors A and B, vascular endothelial growth
factor, endothelin, and serotonin. These factors are associated with endothelial cell proliferation and vascular remodeling,
as seen in Figure 2.2
Adrenergic control
Pulmonary arterial vasoconstriction occurs in response to the stimulation of alpha-adrenergic receptors. Alpha-adrenergic
receptors found in the pulmonary arteries have a high affinity for their agonists, such as norepinephrine, and, when excessively
stimulated, may also cause pulmonary arterial remodeling.2 Pulmonary arterial vasodilation occurs in response to the stimulation of beta-adrenergic receptors.
Eicosanoids: prostaglandins and thromboxane
Prostaglandins are hormone-like substances that are actively synthesized, metabolized, and released by the lungs. Prostacyclin
and prostaglandin E1 cause vasodilation and vascular hypertrophy and remodeling and inhibit platelet aggregation. On the other hand, prostaglandin
F2α and prostaglandin A2 cause vasoconstriction.2,8
Thromboxane, a substance derived from prostaglandins, is synthesized by and stored in platelets. Thromboxane is associated
with vasoconstriction and platelet activation. In people with pulmonary hypertension, there is a documented prostacyclin-thromboxane
imbalance with associated pulmonary artery vasoconstriction, thrombosis, and proliferation.9
Nitric oxide
3. A schematic demonstrating the actions of nitric oxide in pulmonary vascular endothelial and smooth muscle cells (NO = nitric
oxide; NOS = nitric oxide synthase; GTP = guanosine triphosphate; GC = guanylate cyclase; cGMP = cyclic guanosine monophosphate;
PDE5 = phosphodiesterase 5; GMP = guanosine monophosphate).
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Nitric oxide is synthesized in endothelial cells from L-arginine and oxygen by the enzyme nitric oxide synthase. Once produced,
nitric oxide is released by the vascular endothelium and travels to smooth muscle cells. There, nitric oxide stimulates the
enzyme guanylate cyclase, which catalyzes guanosine triphosphate conversion to cyclic guanosine monophosphate (cGMP), leading
to an increase in cGMP concentrations. cGMP inhibits calcium release from the endoplasmic reticulum and causes pulmonary vasodilation
(Figure 3). Vasodilation is limited by phosphodiesterase 5 inactivation of cGMP.1 Nitric oxide also inhibits platelet activation and smooth muscle cell hypertrophy.10
Endothelin-1
Endothelin-1 is a peptide released by the vascular endothelium in response to changes in blood flow, vascular stretch, oxygenation,
and thrombin concentrations. Once released, endothelin-1 causes vasoconstriction, stimulates growth factors and smooth muscle
cell proliferation, and promotes vascular remodeling.8 Production of endothelin-1 is inhibited by prostacyclin and nitric oxide.2
Endothelin-1 is considered a potent vasoconstrictor and has been well-studied in human medicine. Circulating endothelin-1
concentrations are elevated in people with pulmonary hypertension, and there is a correlation between endothelin-1 concentrations
and the severity of pulmonary hypertension and the prognosis for people with pulmonary hypertension.11 Veterinary studies have also confirmed that endothelin-1 concentrations are elevated in dogs with pulmonary hypertension.12
Serotonin
Serotonin is produced by the gastrointestinal tract from tryptophan.5 Once produced, serotonin is released into circulation and taken up by platelets. Platelets then release serotonin in response
to blood vessel wall damage so that serotonin causes local vasoconstriction. As mentioned above, serotonin can act as a growth
factor and also causes smooth muscle cell hypertrophy and vascular remodeling.8
Angiotensin II
Angiotensin II is a peptide produced by the actions of the angiotensin-converting enzyme (ACE) on angiotensin I. In animal
models of pulmonary hypertension, pulmonary hypertension is associated with an increase in ACE expression and activity.2 Angiotensin II causes vasoconstriction and vascular remodeling.2
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