Vascular dysfunction in adriamycin nephrosis: different effects of adriamycin exposure and nephrosis.
BACKGROUND
Nephrosis-induced endothelial dysfunction is assumed to play a main role in cardiovascular morbidity. Adriamycin-induced proteinuria is a well-established rat model for nephrotic syndrome. However, induction of nephrosis by intravenous adriamycin administration might exert direct adriamycin cardiovasculotoxicity that could obscure or modify nephrosis-induced vascular dysfunction. The present study, therefore, investigated in vitro vascular function in the isolated thoracic aorta and isolated perfused hearts of rats with adriamycin nephrosis, as compared to non-nephrotic adriamycin exposed rats.


METHODS
Adult rats received a single slow intravenous injection of either adriamycin (1.5 mg/kg, adriamycin nephrotic rats) or saline (healthy controls). In a third group of rats, the cardiovascular system, but not the kidneys, were exposed to adriamycin by transient clipping of renal arteries during adriamycin injection (adriamycin control rats).


RESULTS
Exposure of the kidneys to adriamycin induced severe proteinuria with corresponding systemic nephrosis, as apparent from hypercholesterolaemia. Adriamycin exposure of the vascular bed led to marked blunting of the aortic response to the endothelium-dependent vasodilator, acetylcholine (ACh), both in non-nephrotic and nephrotic rats. The nephrotic state reduced the bradykinin-induced increase in coronary flow and enhanced the aortic constrictor response to angiotensin II associated with reduced basal aortic NO-activity, as shown by the comparison between adriamycin nephrotic rats and healthy and adriamycin controls.


CONCLUSIONS
Vascular adriamycin exposure and nephrosis affect vascular function in a distinct and qualitatively different fashion in adriamycin-induced nephrotic syndrome. The differential effects of nephrosis and vascular adriamycin exposure have to be accounted for in the interpretation of vascular studies in adriamycin nephrosis.
Ulu
Nadir
N
Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration (GUIDE), University Medical Center Groningen, Groningen, The Netherlands. n.ulu@med.umcg.nl
Buikema
Hendrik
H
van Gilst
Wiek H
WH
Navis
Gerjan
G
D000818:Animals; D001795:Blood Pressure Determination; D002319:Cardiovascular System / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects*; D008297:Male; D009404:Nephrotic Syndrome / Q000139:chemically induced* / Q000473:pathology; D011507:Proteinuria / Q000139:chemically induced / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012680:Sensitivity and Specificity
D004317:Doxorubicin