Transient AT1 receptor-inhibition in prehypertensive spontaneously hypertensive rats results in maintained cardiac protection until advanced age.
OBJECTIVE
In young spontaneously hypertensive rats (SHR), transient angiotensin II type 1 receptor (AT1R) blockade decreases blood pressure for a prolonged period. We tested the hypothesis that transient AT1R blockade in SHR leads to cardiac protection until advanced age.


METHODS
Wistar-Kyoto rats, SHR and transiently losartan-treated SHR (SHR-Los) (20 mg/kg per day; weeks 4-8 of age) were followed up until week 72 (n=9 each group), including repeated echocardiography, radiotelemetric investigations and 24-h urine collection. End-point measurements comprised left ventricular function parameters, left ventricular histomorphology and molecular biology (types I and III collagen, brain natriuretic peptide, AT1R mRNA) as well as renal morphology.


RESULTS
Prehypertensive treatment with losartan, but not with the general vasodilator hydralazine, reduced blood pressure until age 48 weeks. In untreated SHR, the end-diastolic volume increased from week 36 and the left ventricular ejection fraction fell from week 48. In contrast, age-related changes in end-diastolic volume and ejection fraction were comparable in SHR-Los and Wistar-Kyoto rats up to age 60 weeks. At age 72 weeks, the ejection fraction was reduced in SHR-Los but higher than that in untreated SHR (ejection fraction: Wistar-Kyoto rats, 58 +/- 3%; SHR, 39 +/- 3%; SHR-Los, 46 +/- 3%; P < 0.01 and P < 0.05, respectively). The heart weight/body weight ratio (SHR-Los, 4.7 +/- 0.1 g/kg; SHR, 5.2 +/- 0.2 g/kg) and cardiac brain natriuretic peptide mRNA levels were improved by treatment. Left ventricular histomorphology and 24-h albuminuria were significantly improved in SHR-Los (41 +/- 5 mg/day; SHR, 80 +/- 22 mg/day; P < 0.05).


CONCLUSIONS
In young SHR, transient AT1R blockade, not blood pressure lowering, attenuates the development of hypertension and exerts cardioprotective effects up to age 72 weeks.
Baumann
Marcus
M
Cardiovascular Research Institute Maastricht, Department of Pharmacology and Toxicology, University Maastricht, The Netherlands. m.baumann@farmaco.unimaas.nl
Janssen
Ben J A
BJ
Hermans
J J Rob
JJ
Peutz-Kootstra
Carine
C
Witzke
Oliver
O
Smits
Jos F M
JF
Struijker Boudier
Harry A J
HA
D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000419:Albuminuria / Q000209:etiology / Q000517:prevention & control; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004334:Drug Administration Schedule; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D014665:Vasodilator Agents; D006830:Hydralazine; D019808:Losartan