Pulmonary hypertension is a syndrome of elevated pulmonary arterial pressure, pulmonary vascular resistance, or both. It complicates about 10% of cases of chronic lung diseases, or can have unknown cause (so called primary pulmonary hypertension). It is associated with a significant mortality and morbidity. Factors most important in the pathogenesis of pulmonary hypertension inlude pulmonary vasoconstriction and proliferation of vascular smooth muscle and connective tissue. Currently, there is no reliable and effective therapy available, especially because pharmacotherapy with vasodilators causes an undesirable and dangerous systemic hypotension. In a search for effective selective therapy, we tried several substances known to inhibit vasoconstriction and vascular smooth muscle proliferation, including hirudin, angiopeptin, nitric oxide (NO) solution infusion, and inhalation of aerosolized NO-releasing compound. Only the latter proved effective.

Inhalation of nitric oxide (NO) gas is used quite successfully to treat several forms of pulmonary hypertension, especially when the duration of treatment does not need to be long. However, some forms of pulmonary hypertension, such as that complicating some chronic lung diseases, require long-term treatment for which inhaled NO gas is technically less suitable. We hypothesized that long-term infusion of NO solution into the central venous circulation, not suffering from this drawback, might reduce chronic pulmonary hypertension. However, we found that infusion of saturated NO solution from implantable minipumps (from Alza), while technically feasible, did not reduce pulmonary hypertension in rats.

I used this study to test a recently developed, nonlinear, distensible vessel model for pressure-flow curve analysis (Linehan et al., J Appl Physiol 73: 987-994; 1992) in the conditions of pulmonary hypertension. The model fit with the data was very good (Figure), and the result, increased near-zero pressure resistance (R₀) in chronic hypoxia, is in accord with previously known facts about chronic hypoxic pulmonary hypertension. Thus, this model is useful for studies of pulmonary hypertension.

Evaluation of the pressure-flow relationship in isolated lungs of rats with pulmonary hypertension. Isolated rat lungs were perfused in zone III with Krebs-albumin solution. Individual data points are shown along with the best model fits (curves).

Because infused NO solution does not work as a substitution for inhalated NO in treating chronic pulmonary hypertension (see previous study), we looked for other alternatives. We hypothesized that when aerosolized solution of an NO-generating substance will be repeatedly inhaled, it will adhere to the walls of the airways for some time, and NO produced during this time will reduce pulmonary hypertension. Indeed, daily inhalations of one such substance, diethylenetriamine NO adduct (DETA/NO), significantly reduced pulmonary hypertension in rats (Figue A). Systemic vasodilation, which complicates and more or less prevents the use of other vasodilators for reducing pulmonary hypertension, did not occurr to any significant degree (Figure B).

A

B

Repeated, daily inhalations of aerosolized DETA/NO reduce monocrotaline (MCT)-induced chronic pulmonary hypertension (A) with no significant change in systemic vascular resistance (B). NS = P>0.05

Heparin reduces pulmonary hypertension. Thrombin contracts vascular smooth muscle and stimulates its proliferation. Using a specific thrombin inhibitor, hirudin, we studied whether thrombin contributes to the development of pulmonary hypertension. Hirudin was infused intravenously (0.2 mg/h/kg) by minipumps in rats during a 3-week exposure to hypoxia. Although hirudin slightly reduced mean pulmonary arterial pressure, there were no significant changes in other indices of pulmonary hypertension, such as the perfusion pressure-flow relationship in isolated lungs (Figure). Thus hirudin, in a dose sufficient to reduce thrombin's catalytic effect on fibrinogen, does not significantly prevent the development of chronic hypoxic pulmonary hypertension.

Pulmonary vascular pressure-flow relationship, shifted towards higher pressures by chronic hypoxia (hypoxic control), is not significantly affected by hirudin. Isolated rat lungs were perfused with Krabs-albumin solution. *P<0.05 hypoxic groups differ from the normoxic control group.

Angiopeptin is an analog of somatostatin-14, which has been found to inhibit cellular proliferation in several models of systemic vascular injury. As proliferation plays a major role in pulmonary hypertension, we examined the hypothesis that angiopeptin (infused intravenously by minipumps at 90-100 µg/kg/day) would inhibit the development of chronic hypoxic pulmonary hypertension in the rat. However, pulmonary hypertension was not significantly altered by this regime of angiopeptin infusion.