Cardioprotective effects of vasopeptidase inhibition vs. angiotensin type 1-receptor blockade in spontaneously hypertensive rats on a high salt diet.
The aim of our study was to compare the cardioprotective effects of vasopeptidase inhibition with those of angiotensin type 1 (AT1)-receptor blockade, a diuretic and the combination of AT1-receptor blockade and a diuretic in an experimental rat model of essential hypertension on a high salt diet. Spontaneously hypertensive rats (SHR) (n =73) were divided into 6 groups to receive the following diet and drug regimens for 8 weeks: 1) low salt controls (NaCl 0.5%); 2) high salt controls (NaCl 6%); 3) omapatrilat (40 mg/kg/d) on a high salt diet; 4) losartan (30 mg/kg/d) on a high salt diet; 5) hydrochlorothiazide (HCTZ; 10 mg/kg/d) on a high salt diet; and 6) losartan+HCTZ (30+10 mg/kg/d) on a high salt diet. Blood pressure was measured by tail-cuff plethysmography. The histological score of myocardial damage, myocardial collagen volume fraction (CVF), connective tissue growth factor (CTGF) expression and cardiomyocyte apoptosis were determined. As an antihypertensive, omapatrilat showed greater efficacy than monotherapy with losartan or HCTZ, and was equally effective as the combination of losartan+HCTZ. Assessed by myocardial damage score, omapatrilat and losartan protected cardiac morphology better than HCTZ or the drug combination. Omapatrilat decreased CVF to a greater extent than the other therapies, whereas losartan was most effective in decreasing CTGF expression. All drug treatments, except HCTZ, decreased cardiomyocyte apoptosis. Our findings provide evidence that both vasopeptidase inhibition and AT1-receptor blockade exert cardioprotective properties beyond their blood pressure-lowering effects. Cardioprotection was associated with prevention of cardiomyocyte apoptosis and inhibition of extracellular matrix formation.
Gröholm
Tina
T
Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland.
Finckenberg
Piet
P
Palojoki
Eeva
E
Saraste
Antti
A
Bäcklund
Tom
T
Eriksson
Anders
A
Laine
Mika
M
Mervaala
Eero
E
Tikkanen
Ilkka
I
D000450:Aldosterone / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017209:Apoptosis; D001345:Autoradiography; D001835:Body Weight; D002316:Cardiotonic Agents / Q000494:pharmacology; D055513:Connective Tissue Growth Factor; D005355:Fibrosis; D006852:Hydrochlorothiazide / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D011480:Protease Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000097:blood; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; C526316:CCN2 protein, rat; D002316:Cardiotonic Agents; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011480:Protease Inhibitors; D011725:Pyridines; D017673:Sodium Chloride, Dietary; D013841:Thiazepines; D006852:Hydrochlorothiazide; D055513:Connective Tissue Growth Factor; C106266:omapatrilat; D000450:Aldosterone; D012083:Renin; D019808:Losartan