Recombinant human matrix metalloproteinase-2 impairs cardiovascular β-adrenergic responses.
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 β-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 β(1) -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 μg/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 the cardiac index and left ventricular dP/dt(max) , and these effects were attenuated by rhMMP-2. The previous administration of doxycycline blunted rhMMP-2-induced changes in dobutamine responses. While the infusion of rhMMP-2 did not increase plasma and cardiac MMP-2 levels, it increased cardiac gelatinolytic activity, and doxycycline blunted this effect. Our findings show that rhMMP-2 exerts no major haemodynamic effects in lambs. However, rhMMP-2 impairs the responses elicited by activation of β-adrenoreceptors.
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.
Karina C
KC
Ferraz
Ozélia
O
Sousa-Santos
Evandro M
EM
Neto-Neves
Elen
E
Rizzi
Jaqueline J
JJ
Muniz
Raquel F
RF
Gerlach
Jose E
JE
Tanus-Santos
D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D004280:Dobutamine / Q000494:pharmacology*; D004318:Doxycycline / Q000494:pharmacology*; D006439:Hemodynamics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000008:administration & dosage / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins; D012756:Sheep
D058665:Adrenergic beta-1 Receptor Agonists; D018342:Receptors, Adrenergic, beta-1; D011994:Recombinant Proteins; D004280:Dobutamine; D020778:Matrix Metalloproteinase 2; D004318:Doxycycline