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The influence of calcium channel blockers on cyclosporin a nephrotoxicity.

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thesis
posted on 19.11.2015, 08:50 by P. G. McNally
Intrarenal vasoconstriction is a characteristic feature of cyclosporin A nephrotoxicity. This thesis investigates the effect of nifedipine, a dihydropyridine calcium channel blocker and potent renal vasodilator, on various aspects of experimental and clinical cyclosporin A nephrotoxicity. In the surgically intact spontaneously hypertensive rat (two-kidney model), short-term administration of cyclosporin A (14 days) induced a marked reduction in glomerular filtration rate and effective renal plasma flow, and an increase in renal vascular resistance. These changes were both reversible on stopping treatment and without histological evidence of renal cell injury. Concomitant nifedipine from day 1 prevented these adverse alterations in renal haemodynamics. However, administering nifedipine after cyclosporin A (from day 7) failed to improve renal function. By contrast, neither renal denervation nor nifedipine prevented cyclosporin A-induced renal dysfunction in uninephrectomized rats. The mechanism mediating these alterations in renal vascular tone is unclear, however, studies in isolated blood vessels demonstrate that it is independent of phosphoinositide hydrolysis. In man, short-term administration of nifedipine (28 days) to stable cyclosporin A-treated renal allograft recipients led to a significant, albeit small, increase in glomerular filtration rate, without a parallel increase in effective renal plasma flow or reduction in renal vascular resistance. Using cell culture techniques, this beneficial effect was not secondary to a reduction in the uptake of cyclosporin A into proximal tubular cells. Thus, these results suggest that nifedipine can under certain experimental and clinical conditions ameliorate cyclosporin A-induced renal dysfunction. The protective mechanism afforded appears to involve both vascular and non-vascular mechanisms. Adaptive changes in renal haemodynamics occurring after uninephrectomy may account for the poor response in this model. Finally, the failure of renal denervation to preserve renal function infers that the sympathetic nervous system is not mediating cyclosporin A-induced alterations in renal vascular tone.

History

Date of award

01/01/1990

Author affiliation

College of Medicine, Biological Sciences and Psychology

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

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