Serial changes in blood pressure, renal function, endothelin and lipoprotein (a) during the first 9 days of cyclosporin therapy in males.
OBJECTIVE
To elucidate the sequential mechanisms underlying cyclosporin-induced hypertension and nephrotoxicity.


METHODS
A study of healthy males over the first 9 days of drug ingestion to permit the detection of serial changes in renal function and blood pressure in a situation free from the confounding variables of concomitant disease or drugs.


METHODS
Double-blind, placebo-controlled, randomized crossover study with cyclosporin (5 mg/kg twice a day) or placebo. Blood pressure and urinary sodium excretion were measured each day, and glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured on days 1, 4, 7 and 9. Cholesterol, lipoprotein (a) and endothelin were measured on days 1 and 9.


RESULTS
GFR decreased by 9% with cyclosporin and was significantly lower than with placebo on day 4 of therapy. ERPF fell by 24%. The fall in GFR correlated significantly with suppressed plasma renin activity (P < 0.0001). Cyclosporin-induced hypertension occurred in the absence of any change in urinary sodium output or in plasma endothelin. Cyclosporin did not affect lipoprotein (a) levels during 9 days of cyclosporin therapy.


CONCLUSIONS
Cyclosporin-induced hypertension and renal vasoconstriction are well established after 9 days of cyclosporin 5 mg/kg twice a day. We found no evidence to implicate either circulating endothelin or renal sodium retention in the onset of cyclosporin-induced hypertension. Cyclosporin-induced renal vasoconstriction appeared to occur when the protective mechanism of plasma renin activity suppression became exhausted.
Sturrock
N D
ND
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, UK.
Lang
C C
CC
MacFarlane
L J
LJ
Dockrell
M E
ME
Ryan
M
M
Webb
D J
DJ
Struthers
A D
AD
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects; D004311:Double-Blind Method; D016232:Endothelins / Q000097:blood*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D017270:Lipoprotein(a) / Q000097:blood*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D013997:Time Factors
D016232:Endothelins; D017270:Lipoprotein(a); D016572:Cyclosporine