Bradykinin and matrix metalloproteinases are involved the structural alterations of rat small resistance arteries with inhibition of ACE and NEP.
OBJECTIVE
Increased vascular resistance is a hallmark of hypertension and involves structural alterations, which may entail smooth muscle cell hypertrophy or hyperplasia, or qualitative or quantitative changes in extracellular matrix (ECM) proteins. Since the renin-angiotensin-aldosterone system modulates these changes, we investigated the effects of 8 weeks of treatment with an angiotensin-converting enzyme (ACE) inhibitor, ramipril (RAM), or a dual ACE and neutral endopeptidase (NEP) inhibitor, MDL-100240 (MDL), on mesenteric small artery structure and ECM proteins in mRen2-transgenic rats (TGRs), an animal model of hypertension with severe cardiovascular damage.


METHODS
Thirty-five 5-week-old rats were included in the study: six TGRs received RAM; five TGRs RAM + the bradykinin receptor inhibitor, icatibant; six TGRs, MDL; and five TGRs MDL + icatibant, while eight TGRs and five normotensive Sprague-Dawley controls were kept untreated. Mesenteric small arteries were dissected and mounted on a micromyograph. The media-to-lumen ratio (M/L) was then calculated. Vascular metalloproteinase (MMP) content was evaluated by zymography.


RESULTS
In untreated TGRs severe hypertension was associated with inward eutrophic remodelling of small arteries. Both RAM and MDL prevented the increase in blood pressure and M/L and decreased MMPs. Icatibant blunted the effect of MDL on BP, M/L and MMPs.


CONCLUSIONS
Changes in collagenase activity induced by ramipril and MDL are associated with prevention of small artery structural alterations in TGRs. Furthermore, MDL-induced enhancement of bradykinin could play a role in both the prevention of vascular structural alterations and in the stimulation of MMPs.
Rizzoni
Damiano
D
Department of Medical and Surgical Sciences, University of Brescia, DMCS - Clinica Medica 4, University of Padua, Italy. rizzoni@med.unibs.it
Rossi
Gian Paolo
GP
Porteri
Enzo
E
Sticchi
Daniele
D
Rodella
Luigi
L
Rezzani
Rita
R
Sleiman
Intissar
I
De Ciuceis
Carolina
C
Paiardi
Silvia
S
Bianchi
Rossella
R
Nussdorfer
G G
GG
Agabiti-Rosei
Enrico
E
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D001552:Benzazepines / Q000494:pharmacology*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D004195:Disease Models, Animal; D004347:Drug Interactions; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D009213:Myography; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D065168:Bradykinin Receptor Antagonists; D011725:Pyridines; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; C085683:MDL 100240; C065679:icatibant; D020782:Matrix Metalloproteinases; D015260:Neprilysin; D017257:Ramipril; D001920:Bradykinin