Dual ACE and NEP inhibitor MDL-100,240 prevents and regresses severe angiotensin II-dependent hypertension partially through bradykinin type 2 receptor.
OBJECTIVE
To investigate the effects of the dual angiotensin-converting enzyme (ACE) + neutral endopeptidase (NEP) inhibitor, MDL-100,240 (MDL), on hypertension and cardiovascular damage in male heterozygous transgenic Ren2 rats.


METHODS
Blood-pressure-matched 5-week-old transgenic rats were allocated to receive a placebo, MDL (40 mg/kg body weight) or ramipril (5 mg/kg body weight) for 8 weeks. During the last 4 weeks, the bradykinin B2 receptor antagonist, icatibant (0.5 mg/kg body weight), was also administered subcutaneously via osmotic minipumps to 50% of the transgenic rats receiving MDL or ramipril. We measured blood pressure, heart weight, structural changes in the aorta and small resistance mesenteric arteries, and the plasma concentrations of adrenomedullin, aldosterone, atrial natriuretic peptide and cGMP. To verify if MDL could regress long-standing hypertension and full-blown cardiovascular damage, 3-month-old transgenic rats received MDL subcutaneously (3 and 10 mg/kg body weight, osmotic minipumps) for 4 weeks.


RESULTS
Compared with placebo, MDL decreased blood pressure (P < 0.001) and prevented left ventricular hypertrophy (P < 0.001), being as effective as ramipril. Hypertrophy and dilatation of the aorta and hypertrophy of the resistance arterioles were all prevented by MDL. Plasma aldosterone was decreased by MDL (P < 0.001), but not by ramipril. Icatibant blunted the decrease in blood pressure (P < 0.001), decreased cGMP concentrations and blunted the decrease in cross-sectional area of the resistance arteries in MDL-treated, but not in ramipril-treated, transgenic rats. In 3-month-old transgenic rats, MDL normalized blood pressure, regressed left ventricular hypertrophy and decreased adrenomedullin concentrations.


CONCLUSIONS
The dual ACE+NEP inhibitor MDL prevented and regressed severe hypertension and cardiovascular damage, even in this model of severe angiotensin II-dependent hypertension with pronounced cardiovascular damage. Enhancement of the effects of bradykinin has a role in such favourable outcomes.
Rossi
Gian Paolo
GP
Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy. gianpaolo.rossi@unipd.it
Cavallin
Martina
M
Rizzoni
Damiano
D
Bova
Sergio
S
Mazzocchi
Giuseppina
G
Agabiti-Rosei
Enrico
E
Nussdorfer
Gastone G
GG
Pessina
Achille C
AC
D053607:Adrenomedullin; D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000009:adverse effects*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D008955:Models, Cardiovascular; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009929:Organ Size / Q000187:drug effects; D010455:Peptides / Q000097:blood / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use; D017257:Ramipril / Q000627:therapeutic use; D051381:Rats / Q000235:genetics; D017207:Rats, Sprague-Dawley / Q000235:genetics; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013599:Systole / Q000187:drug effects; D016896:Treatment Outcome; D014662:Vasoconstrictor Agents / Q000009:adverse effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001552:Benzazepines; D015415:Biomarkers; D004791:Enzyme Inhibitors; D010455:Peptides; D011725:Pyridines; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C085683:MDL 100240; D053607:Adrenomedullin; D000450:Aldosterone; D015260:Neprilysin; D017257:Ramipril