title: Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model.
abstract: Most patients with essential hypertension do not exhibit substantial renal damage. Renal autoregulation by preventing glomerular transmission of systemic pressures has been postulated to mediate this resistance. Conversely, malignant nephrosclerosis (MN) has been postulated to develop when severe hypertension exceeds a critical ceiling. If the concept is valid, even modest blood pressure (BP) reductions to below this threshold regardless of antihypertensive class (1) should prevent MN and (2) lead to the healing of the already developed MN lesions. Both predicates were tested using BP radiotelemetry in the stroke-prone spontaneously hypertensive rats receiving 1% NaCl as drinking fluid for 4 weeks. Severe hypertension (final 2 weeks average systolic BP, >200 mm Hg) and MN (histological damage score 36±5; n=27) developed in the untreated stroke-prone spontaneously hypertensive rats but were prevented by all antihypertensive classes (enalapril [n=15], amlodipine [n=13], or a hydralazine/hydrochlorothiazide combination [n=15]) if the final 2-week systolic BP remained <190 mm Hg. More impressively, modest systolic BP reductions to 160 to 180 mm Hg (hydralazine/hydrochlorothiazide regimen) initiated at ≈4 weeks in additional untreated rats after MN had already developed (injury score 35±4 in the right kidney removed before therapy) led to a striking resolution of the vascular and glomerular MN injury over 2 to 3 weeks (post-therapy left kidney injury score 9±2, P<0.0001; n=27). Proteinuria also declined rapidly from 122±9.5 mg/24 hours before therapy to 20.5±3.6 mg 1 week later. These data clearly demonstrate the barotrauma-mediated pathogenesis of MN and the striking capacity for spontaneous and rapid repair of hypertensive kidney damage if new injury is prevented.
authors: From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.). kgriffi@lumc.edu.
authors: Karen A
authors: KA
authors: Griffin
authors: From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.).
authors: Aaron
authors: A
authors: Polichnowski
authors: From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.).
authors: Natalia
authors: N
authors: Litbarg
authors: From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.).
authors: Maria
authors: M
authors: Picken
authors: From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.).
authors: Manjeri A
authors: MA
authors: Venkatachalam
authors: From the Departments of Medicine (K.A.G., A.P., A.K.B.) and Pathology (M.P.), Loyola University Chicago and Hines VA Hospital, Maywood, IL; Department of Medicine, University of Illinois Hospital, Chicago, IL (N.L.); and Department of Pathology, University of Texas Health Science Center, San Antonio, (M.A.V.).
authors: Anil K
authors: AK
authors: Bidani
mesh_terms: D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000494:pharmacology; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D006852:Hydrochlorothiazide / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D009400:Nephrosclerosis / Q000503:physiopathology* / Q000517:prevention & control; D051381:Rats; D011918:Rats, Inbred SHR; D012016:Reference Values; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D006852:Hydrochlorothiazide; D017311:Amlodipine; D006830:Hydralazine; D004656:Enalapril
keywords: calcium channel blockers; hypertension; renal circulation; renin-angiotensin system