Impairment of afferent arteriolar myogenic responsiveness in the galactose-fed rat is prevented by tolrestat.
By permitting the separation of increased aldose reductase activity from hyperglycaemia and insulin deficiency, galactose-fed rats have constituted a useful model for investigating diabetic complications. Such rats manifest an impaired afferent arteriolar responsiveness to pressure similar to that of rats 4 to 6 weeks after induction of diabetes with streptozotocin. In the present study, we investigated whether treatment of galactose-fed rats with the aldose reductase inhibitor tolrestat prevent this autoregulatory defect and whether the blunted afferent arteriolar responsiveness to pressure is associated with impaired responsiveness to angiotensin II. Pressure-induced vasoconstriction of afferent arterioles was assessed in kidneys made hydronephrotic to allow direct visualization of renal microvessels by computer-assisted image processing. Vessel diameters were quantitated following stepwise increments of renal perfusion pressure (RAP; from 80 to 180 mm Hg) in kidneys of control rats and rats fed a diet for 2 weeks with 50% galactose with or without tolrestat. Subsequent to the pressure studies, angiotensin II (0.3 nmol/l) was added to the perfusate, and vessel diameters were reassessed. Control rats exhibited progressive afferent arteriolar vasoconstriction when RAP was increased from 80 to 180 mm Hg (-17.2 +/- 1.0%; p < 0.001). In contrast, myogenic responses to increases in pressure were absent in the arterioles of the galactose-fed rats (-4.1 +/- 1.9%; N.S.). Treatment with tolrestat completely prevented this impairment in afferent arteriolar responsiveness (-16.5 +/- 1.8%; p < 0.001). The angiotensin II-induced vasoconstriction did not differ between control rats and galactose-fed rats. We conclude that increased aldose reductase activity contributes to impaired renal auto-regulation in galactose-fed rats, a model of diabetic nephropathy, but is not involved in the loss of afferent arteriolar responsiveness to angiotensin II.
Forster
H G
HG
Nephrology Section, Department of Veterans Affairs Medical Center, Miami, Florida 33125, USA.
ter Wee
P M
PM
Hohman
T C
TC
Epstein
M
M
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015331:Cohort Studies; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004032:Diet; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004376:Galactitol / Q000378:metabolism; D005690:Galactose / Q000008:administration & dosage; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009281:Naphthalenes; D014662:Vasoconstrictor Agents; C040550:tolrestat; D000804:Angiotensin II; D004376:Galactitol; D000449:Aldehyde Reductase; D005690:Galactose