Temporary losartan or captopril in young SHR induces malignant hypertension despite initial normotension.
BACKGROUND
Exposure of normotensive rats to angiotensin-converting enzyme (ACE) inhibitors in early life causes hypertrophy of intrarenal arteries. Similar defects have been found in knockout mice lacking angiotensinogen, ACE, or angiotensin II type 1 (AT1) receptors. On the other hand, transient inhibition of the renin-angiotensin system from 2 weeks of age in spontaneously hypertensive rats (SHR), either with ACE inhibitors or with AT1 receptor antagonists partially prevents the increase in blood pressure. However, permanent treatment of SHR from conception onwards with ACE inhibitors completely prevents hypertension. Although these studies demonstrated protection from hypertension-induced changes in the heart and large arteries, renal arteries were not studied and follow-up did not extend beyond 6 months of age. We postulated that while brief exposure to ACE inhibitors or AT1 receptor antagonists in young SHR would temporarily decrease blood pressure, it would also be associated with development of intrarenal arterial malformation, and ultimately have deleterious effects.


METHODS
Direct effects on intrarenal arterial morphology of an ACE inhibitor (captopril, 100 mg/kg/day) and an AT1 receptor antagonist (losartan, 50 mg/kg/day), administered from the last week of gestation until 8 weeks of age were examined in SHR. After stopping treatment at 8 weeks, we continued to monitor blood pressure until spontaneous death.


RESULTS
Systolic blood pressure at 8 weeks was normalized by captopril and losartan (SHR control 187 +/- 8 mm Hg; captopril 118 +/- 5 mm Hg; and losartan 120 +/- 9 mm Hg). However, by 30 weeks, blood pressure had increased to control SHR levels. At 4 weeks, the media of renal arteries and arterioles was hypertrophied. Marked smooth muscle cell hyperplasia of cortical arteries resulted in significantly increased wall thickness by 8 weeks, despite similar external diameter. Arterial wall structure was disrupted, with fragmentation of elastic fibers and irregular distribution of collagen type I fibers. After stopping treatment, the rats gradually began to show poor health and all had died by 1 year of age, while all 1-year-old control SHR females were in good health. The cause of morbidity and mortality in the rats treated in early life was clearly malignant hypertension. Severe hypertrophy of renal arterioles was found, as well as cerebral hemorrhage.


CONCLUSIONS
Despite initial normalization of blood pressure interference with the renin-angiotensin system during a crucial stage of development in SHR can initiate marked smooth muscle cell hyperplasia and disruption of the wall structure of the intrarenal arteries. Subsequent progression of this intrarenal process after cessation of treatment suggests an independent process that eventually results in malignant hypertension and early death.
Racasan
Simona
S
Department of Nephrology, University Hospital, Utrecht, The Netherlands.
Hahnel
Bruni
B
van der Giezen
Dionne M
DM
Blezer
Erwin L
EL
Goldschmeding
Roel
R
Braam
Branko
B
Kriz
Wilhem
W
Koomans
Hein A
HA
Joles
Jaap A
JA
D000818:Animals; D000833:Animals, Suckling; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure; D002216:Captopril / Q000494:pharmacology*; D005260:Female; D006977:Hypertension, Renal / Q000139:chemically induced* / Q000401:mortality* / Q000473:pathology; D019808:Losartan / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017534:Radial Artery / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D012077:Renal Artery / Q000473:pathology
D000959:Antihypertensive Agents; D002216:Captopril; D019808:Losartan