Several Animal Models Shed Light on Potential Pulmonary Hypertension Therapies
Pulmonary hypertension (PH) is a rare disorder arising from elevated pulmonary blood pressure, usually due to constriction of the pulmonary vasculature.
At CorDynamics, we address pulmonary hypertension as a complex disorder involving consideration of several physiological systems for its study, diagnosis and treatment. Though no single animal model of PH fully mimics its clinical course, together, the variety of models available has certainly increased our understanding of the disease.
Changes in the cellular structure and function of the pulmonary vasculature occur during the development of PH. Chronic PH creates pressure on the right side of the heart, leading to right ventricular hypertrophy and ultimately, heart failure. Clinically, PH is defined by a mean pulmonary artery pressure of 25 mmHg at rest or 30 mmHg during exercise. There are several classifications of PH based on its origin, however most PH cases can be categorized as either idiopathic, or secondary to an existing pathologic condition such as chronic obstructive pulmonary disease, left-sided heart failure, blood clots, and other various diseases. Currently, there is no cure for PH, and it is often associated with a poor prognosis.
Treatments to alleviate the symptoms of PH remain less than ideal, often requiring constant infusion, or resulting in side effects such as systemic hypotension or liver toxicity. Due to the variety of etiologies leading to PH and the difficulties of exclusively targeting the pulmonary vasculature, PH research remains a challenging endeavor. Several animal models involving both chemical and surgical methods have been developed to study the pathology of PH and investigate potential therapies. In this article we will focus on two of the most common techniques to induce pulmonary hypertension – injection with monocrotaline and exposure to hypoxia.
Monocrotaline-induced PH Models
Monocrotaline is a toxic alkaloid that is activated by the liver and selectively affects the pulmonary vasculature without producing systemic hypertension. Though monocrotaline-induced PH has been most commonly studied in rats, this technique has also been used in dogs and non-human primates. In rats, a single subcutaneous injection of monocrotaline results in the development of PH, with an approximate doubling of pulmonary artery pressure generally occurring within three to four weeks. Accompanying right ventricular hypertrophy and pulmonary edema are apparent by six weeks.
Histologic analysis of lungs from monocrotaline-treated animals exhibit an increase in pulmonary vessel wall medial thickness that correlates with an increase in pulmonary arterial pressure. Using this model, responses to compounds can be evaluated in vivo, as well as on isolated pulmonary arteries.
Hypoxia-induced PH Models
Unlike the systemic arteries, pulmonary arteries constrict in response to hypoxia in order to shunt blood to more ventilated areas of the lungs. This physiologic phenomenon has been exploited in models of PH using exposure to chronic and acute hypoxia. In these models, animals are subjected to either low oxygen conditions (i.e. 10% O2) or reduced atmospheric pressure. Chronic hypoxia leads to remodeling of pulmonary vasculature. Manifestations of PH can revert to pre-hypoxia levels once animals are exposed to normal room air. Studies utilizing hypoxia-induced pulmonary hypertension have been performed in a variety of species ranging from mice to non-human primates, with some species more sensitive to the pulmonary effects of hypoxia (i.e. rats, guinea pigs) than others.
As PH continues to afflict millions around the world, these models will remain valuable instruments in the search for improved PH treatments.
Regards,
Dr. Elaine Tanhehco, CorDynamics Chief Scientific Officer