Recombinant human matrix metalloproteinase-2 impairs

Basic & Clinical Pharmacology & Toxicology

Doi: 10.1111/bcpt.12001

Recombinant Human Matrix Metalloproteinase-2 Impairs Cardiovascular b-Adrenergic Responses
Karina C. Ferraz1, Ozélia Sousa-Santos2, Evandro M. Neto-Neves2, Elen Rizzi2, Jaqueline J. Muniz1, Raquel F. Gerlach3 and Jose E. Tanus-Santos2
1

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil, 2Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil, and 3Department of Morphology, Stomatology and Physiology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil (Received 28 June 2012; Accepted 9 August 2012) Abstract: Growing evidence supports the involvement of matrix metalloproteinases (MMPs) in the pathogenesis of many cardiovascular diseases. Particularly, imbalanced MMP-2 activity apparently plays a critical role in cardiovascular remodelling. While some studies have suggested that MMP-2 may affect the vascular tone and impair b-adrenoreceptor function, no previous study has examined the acute haemodynamic effects of MMP-2. We examined the effects of recombinant human MMP-2 (rhMMP-2) administered intravenously to anaesthetized lambs at baseline conditions and during b1-adrenergic cardiac stimulation with dobutamine. We used 26 anaesthetized male lambs in two study protocols. First, rhMMP-2 (220 ng/kg/min. over 60 min.) or vehicle was infused in the lambs, and no significant haemodynamic changes were found. Therefore, we infused dobutamine at 5 lg/kg/ min. i.v. (or saline) over 180 min. in lambs that had received the same rhMMP-2 infusion preceded by doxycycline i.v. at 10 mg/kg (or saline). Plasma and cardiac MMP-2 levels were assessed by gelatin zymography, and gelatinolytic activity was assessed by spectrofluorimetry. Dobutamine decreased systemic vascular resistance index, and this effect was attenuated by rhMMP-2 infusion. Moreover, dobutamine increased