title: 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.
authors.affiliation: Department of Pharmacology, Biosciences Institute of Botucatu, Sao Paulo State University - UNESP, Botucatu, SP, Brazil.
authors.forename: Regina A
authors.initials: RA
authors.lastname: Nascimento
authors.forename: Gabryella
authors.initials: G
authors.lastname: Mendes
authors.forename: Jose S
authors.initials: JS
authors.lastname: Possomato-Vieira
authors.forename: Victor Hugo
authors.initials: VH
authors.lastname: Gonçalves-Rizzi
authors.forename: Hélio
authors.initials: H
authors.lastname: Kushima
authors.forename: Flavia K
authors.initials: FK
authors.lastname: Delella
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Dias-Junior
mesh_terms: D053607:Adrenomedullin / Q000097:blood*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000097:blood; D004318:Doxycycline / Q000494:pharmacology; D019332:Endothelin-1 / Q000097:blood; D006973:Hypertension / Q000097:blood* / Q000139:chemically induced / Q000188:drug therapy*; D007854:Lead / Q000097:blood; D007855:Lead Poisoning / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000627:therapeutic use*; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000975:Antioxidants; D019332:Endothelin-1; D061965:Matrix Metalloproteinase Inhibitors; D009566:Nitrates; D009573:Nitrites; D053607:Adrenomedullin; D007854:Lead; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D015740:Calcitonin Gene-Related Peptide; D004318:Doxycycline