Document Detail

Temporary losartan or captopril in young SHR induces malignant hypertension despite initial normotension.
MedLine Citation:
PMID:  14717927     Owner:  NLM     Status:  MEDLINE    
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. CONCLUSION: 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.
Simona Racasan; Bruni Hahnel; Dionne M van der Giezen; Erwin L Blezer; Roel Goldschmeding; Branko Braam; Wilhem Kriz; Hein A Koomans; Jaap A Joles
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Kidney international     Volume:  65     ISSN:  0085-2538     ISO Abbreviation:  Kidney Int.     Publication Date:  2004 Feb 
Date Detail:
Created Date:  2004-01-13     Completed Date:  2004-09-14     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  575-81     Citation Subset:  IM    
Department of Nephrology, University Hospital, Utrecht, The Netherlands.
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MeSH Terms
Animals, Suckling
Antihypertensive Agents / pharmacology*
Blood Pressure
Captopril / pharmacology*
Hypertension, Renal / chemically induced*,  mortality*,  pathology
Losartan / pharmacology*
Muscle, Smooth, Vascular / drug effects,  pathology
Prenatal Exposure Delayed Effects*
Radial Artery / pathology
Rats, Inbred SHR
Renal Artery / pathology
Reg. No./Substance:
0/Antihypertensive Agents; 114798-26-4/Losartan; 62571-86-2/Captopril

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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