Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats

Abstract

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 +/- 3 mmHg in hypoxic controls, 24 +/- 1 mmHg in Batimastat-treated hypoxic rats, and 16 +/- 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.

Recovery from Hypoxic Pulmonary Hypertension in Rats

“…Our previous experiments showed that the first week of hypoxic exposure is crucial for the development of HPH (2,6,10). It seems that the discrepancies in the course of recovery are mainly due to differences in the duration and type of hypoxia (continual or intermittent, normobaric or hypobaric) resulting in the various degree of tissue radical injury and different PAP values at the end of exposure.…”

“…Lungs were filled with formol solution and then the lung sections were stained with the hematoxylin resorcinfuchsin. Percentage of hypertensive double-laminated prealveolar vessels was counted as described previously (6). 73 …”

Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases levels in pediatric patients with congenital heart disease: Relationship to cardiac functions

“…They found an overt increase in matrix metalloproteinase-2 and matrix metalloproteinase-9 activity of the lung in acute pulmonary embolism and then treatment with L-arginine brought relief in pulmonary hypertension and caused reduction of matrix metalloproteinase-2 and matrix metalloproteinase-9 activity. On the same way, batimastat, a specific matrix metalloproteinase inhibitor, were tested by different researchers and batimastat formed a similar beneficial effects in chronically hypoxic rats with pulmonary hypertension (33).…”

“…Finally it is seen that pharmacological inhibitors of matrix metalloproteinases such as doxycycline, zinc chelators and batimastat have been used as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular diseases (32,33). Therefore, the following question comes to mind for our study, wonder if the medications used by patients had impact on the matrix metalloproteinases levels?…”

Hypoxic Pulmonary Arterial Hypertension in the Chicken Model

“…Increased MMP-2 activity in the pulmonary vessels of hypoxic rats was shown to be associated with the severity of PH (Frisdal et al, 2001). In addition, Herget et al (2003) reported that inhibition of MMP activity attenuated pulmonary vascular remodeling as well as hypertension in chronically hypoxic rats, and suggested that the increased MMP activity might represent a substantial factor mediating the effect of hypoxia on the development of PH. Another study by Lepetit et al (2005) demonstrated an imbalance between MMP-3 and TIMP-1 expression and an increase in MMP-2 expression in pulmonary arterial smooth muscle cells from patients with IPAH.…”