Metalloproteinase Inhibition Protects against Reductions in Circulating Adrenomedullin during Lead-induced Acute Hypertension

Abstract

Intoxication with lead (Pb) results in increased blood pressure by mechanisms involving matrix metalloproteinases (MMPs). Recent findings have revealed that MMP type two (MMP-2) seems to cleave vasoactive peptides. This study examined whether MMP-2 and MMP-9 levels/activities increase after acute intoxication with low lead concentrations and whether these changes were associated with increases in blood pressure and circulating endothelin-1 or with reductions in circulating adrenomedullin and calcitonin gene-related peptide (CGRP). Here, we expand previous findings and examine whether doxycycline (a MMPs inhibitor) affects these alterations. Wistar rats received intraperitoneally (i.p.) 1st dose 8 μg/100 g of lead (or sodium) acetate, a subsequent dose of 0.1 μg/100 g to cover daily loss and treatment with doxycycline (30 mg/kg/day) or water by gavage for 7 days. Similar whole-blood lead levels (9 μg/dL) were found in lead-exposed rats treated with either doxycycline or water. Lead-induced increases in systolic blood pressure (from 143 ± 2 to 167 ± 3 mmHg) and gelatin zymography of plasma samples showed that lead increased MMP-9 (but not MMP-2) levels. Both lead-induced increased MMP-9 activity and hypertension were blunted by doxycycline. Doxycycline also prevented lead-induced reductions in circulating adrenomedullin. No significant changes in plasma levels of endothelin-1 or CGRP were found. Lead-induced decreases in nitric oxide markers and antioxidant status were not prevented by doxycycline. In conclusion, acute lead exposure increases blood pressure and MMP-9 activity, which were blunted by doxycycline. These findings suggest that MMP-9 may contribute with lead-induced hypertension by cleaving the vasodilatory peptide adrenomedullin, thereby inhibiting adrenomedullin-dependent lowering of blood pressure.