Effects of aging and AT-1 receptor blockade on NO synthase expression and renal function in SHR.
In an earlier study, we found increased NO production and NO synthase (NOS) expression in renal and vascular tissues of prehypertensive and adult spontaneously hypertensive rats (SHR). This study was designed to determine the effects of aging and AT-1 receptor blockade (losartan 30 mg/kg/day beginning at 8 weeks of age) on NO system in this model. Compared to the Wistar Kyoto (WKY) control rats, untreated SHR showed severe hypertension, elevated urinary NO metabolite (NO(chi)) excretion, marked upregulations of renal and vascular eNOS and iNOS proteins, normal renal function and heart weight at 9 weeks of age. Hypertension control with either AT-1 receptor or calcium channel blockade (felodipine 5 mg/kg/day) mitigated upregulation of NOS isoforms in the young SHR. With advanced age (63 weeks), the untreated SHR showed increased proteinuria, renal insufficiency, cardiomegaly, reduced urinary NO(chi) excretion and depressed renal and vascular NOS protein expressions as compared to the corresponding WKY group. AT-1 receptor blockade prevented proteinuria, renal insufficiency, cardiomegaly, and renal and vascular NOS deficiency. Thus, in young SHR, hypertension results in compensatory upregulation of renal and vascular NOS, which can be attenuated by vigorous antihypertensive therapy. With advanced age, untreated SHR exhibit cardiomegaly, renal dysfunction and marked reductions of eNOS and iNOS compared with the aged WKY rats. Hypertension control with AT-1 receptor blockade initiated early in the course of the disease prevents target organ damage and preserves renal and vascular NOS.
Vaziri
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Division of Nephrology and Hypertension, Department of Medicine, UCI Medical Center, University of Irvine, 101 The City Drive, Bldg. 53, Rm. 125, Rt. 81, Orange, CA 92868, USA. ndvaziri@uci.edu
Wang
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Kivlighn
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Shahinfar
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D000375:Aging / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001013:Aorta, Thoracic; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D015736:Felodipine / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology* / Q000652:urine; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology*; D019808:Losartan / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood / Q000652:urine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D044140:Receptor, Angiotensin, Type 1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D019808:Losartan; D015736:Felodipine