Effect of essential hypertension on kidney function as measured in rat by dynamic MRI.
In this study, dynamic MRI was applied to investigate the effect of genetic hypertension on the renal clearance of Gd(DTPA). Assuming that the paramagnetic agent was essentially cleared through the kidney by glomerular filtration, a first-order kinetic model was used to estimate a rate constant k(cl) describing the transport from the renal cortex to the inner medulla. Experiments were carried out on 12-15-week-old spontaneously hypertensive rats (young-SHR) and age-matched Wistar-Kyoto rats (young-WKY). An additional group of 22-25-week-old SHR (old-SHR) was investigated to assess the long-term effect of chronic hypertension on kidney function. The glomerular filtration rate as measured by the inulin method correlated well with k(cl) results as measured by MRI. A clearance index 30% lower than young-WKY was observed in young-SHR, reflective of a kidney dysfunction. In old-SHR, k(cl) was only 50% of the young-WKY value. As computed from Gd(DTPA) concentration profiles, this translated into delayed time-to-peak (TTP) values, decreased peak Gd(DTPA) concentrations ([Gd](peak)), and a slow elimination of Gd(DTPA) from the blood pool, renal cortex, and inner medulla (e.g., high t(1/2) values). Finally, using the same MRI approach, the data showed that the acute administration of the calcium antagonist verapamil at an antihypertensive dose was followed by a near normalization of SHR renal function. These results indicate that chronic hypertension remains a major pathogenic factor in the progression of glomerular degeneration, as opposed to a primary glomerular defect independent of systemic pressure.
Laurent
Didier
D
Core Technology Area, Novartis Pharmaceuticals Corporation, Summit, New Jersey 07901, USA. didier.laurent@pharma.novartis.com
Poirier
Kevin
K
Wasvary
James
J
Rudin
Markus
M
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003287:Contrast Media; D019786:Gadolinium DTPA; D005919:Glomerular Filtration Rate; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D051381:Rats; D011921:Rats, Inbred WKY; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D003287:Contrast Media; D014700:Verapamil; D019786:Gadolinium DTPA