Vascular function in chronic end-organ damage: pharmacological characterization of vasomotor function in systemic vasculature

Introduction: Nephrosis-induced endothelial dysfunction is assumed to play a main role in the 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 hypercholesterolemia. Adriamycin exposure of the vascular bed led to marked blunting of the aortic response to the endothelium-dependent vasodilator acetylcholine both in nonnephrotic 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 versus healthy and adriamycin controls. 26 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. Vascular dysfunction in adriamycin nephrosis Introduction Anthracyclines are widely used for the therapy of a variety of malignant diseases, but their therapeutic dose is limited by severe side-effects such as myelosuppression and cardiotoxicity. Anthracyclines such as daunorubicin and adriamycin (doxorubicin) are also established tools to induce experimental nephrosis, the onset and severity of which depending on the total drug dose used and dosage schedule employed.1,2 In the rat, a single intravenous injection of a relatively low dose adriamycin (1.5 mg/kg) causes glomerular cell injury leading to a gradual increase in proteinuria and subsequent/concomitant changes in plasma cholesterol until 4-8 weeks after which it remains relatively stable. After several weeks, glomerular sclerotic lesions may be detected. And as this occurs in the absence of hypertension and without marked early renal function loss,3 the rat adriamycin nephrosis model provides a relatively “pure” experimental model to study proteinuria-induced glomerulosclerosis and target organ damage in the nephrotic syndrome. Employing the model as such, we previously found that rather than the severity of proteinuria however, the state of systemic nephrosis with dyslipidemia is a main determinant of the severity of renal damage.4 27 Such findings emphasize the importance of systemic nephrosis in the pathophysiology of target organ damage in this model. It could therefore also provide a model to study nephrosis-related vascular dysfunction. Hence, this seems of significant importance because nephrosis-induced vascular and particularly endothelial dysfunction is believed to play a main role in the cardiovascular morbidity and mortality in the nephrotic syndrome. The rat anthracyclin-induced nephrosis model has indeed been used to study nephrosisrelated endothelial dysfunction. Ito et al., for example, reported significant blunting of acetylcholine-induced endothelium-dependent relaxation in aortas isolated from rats with nephrosis that was induced by daunorubicin, and suggested a possible role for hypercholesterolemia herein.5 Furthermore an association between lipid/lipoprotein abnormalities and endothelial dysfunction in experimental nephrosis has been shown previously.6 One possible drawback, however, could be that induction of nephrosis by intravenous anthracyclin administration might exert a direct vasculotoxicity that could obscure or modify