Organ specificity of antihypertensive therapy on ocular albumin vascular clearance and albuminuria in the hypertensive diabetic rat.
OBJECTIVE
The contributions of hypertension and diabetes to microvascular dysfunction in the kidney and eye were investigated. Two indices of microvascular dysfunction, urinary albumin excretion rate (AER) and albumin vascular clearance (AVC) in the eye, were studied in control and streptozocin diabetic Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR).


METHODS
Studies were performed on four groups of untreated rats--nondiabetic and diabetic WKY and nondiabetic and diabetic SHR--and on three groups of diabetic SHR treated with a converting enzyme inhibitor (perindopril), a calcium-channel blocker (lacidipine), or triple therapy (hydrochlorothiazide, reserpine, and hydralazine). In all rats, AER and AVC were measured at 16 weeks.


RESULTS
There was a progressive increase in both parameters in the order WKY, diabetic WKY, SHR, and diabetic SHR. When compared with nondiabetic WKY, diabetic SHR showed an approximately 30-fold increase in AER and an approximately threefold increase in AVC. Treatment of diabetic SHR with perindopril or triple therapy normalized AER compared to an equihypotensive dose of lacidipine, which had no effect. By contrast, the three antihypertensive regimens showed a different order of efficacy in preventing increases in ocular AVC. In diabetic SHR, the increase in retinal AVC was prevented largely by lacidipine, whereas the other two antihypertensive regimens showed lesser effects [AVC expressed as percentage nondiabetic WKY: untreated diabetic SHR 278% +/- 47%, lacidipine 93% +/- 10% (P < 0.001), triple therapy 132% +/- 37% (P < 0.05), and perindopril 167% +/- 9% (P < 0.05)]. Lacidipine also prevented the increase in AVC of the anterior and posterior uvea. By contrast, increases in AVC observed in the diabetic SHR were not prevented by perindopril in the posterior uvea or by triple therapy in the anterior uvea. Thus, hypertension and diabetes increased ocular AVC and AER, and effective antihypertensive therapy substantially prevented changes in both parameters. However, despite equivalent levels of blood pressure control for each regimen, discordant effects were noted on AVC and AER. Perindopril was associated with significantly lower AER than lacidipine, whereas lacidipine was more potent in preventing increases in ocular AVC.


CONCLUSIONS
Results of this study suggest that different antihypertensive regimens in the diabetic rat may exert organ-specific effects on the retina and kidney despite equivalent effects on systemic blood pressure. These data also raise the possibility that retinal microvascular dysfunction in diabetes is ameliorated more readily by calcium-channel blockade than by converting-enzyme inhibition, whereas the reverse applies to renal microvascular dysfunction, as reflected by albuminuria.
Gin
T
T
Melbourne University Department of Ophthalmology, Royal Victorian Eye & Ear Hospital, Australia.
Joon
T L
TL
Panagiotopoulos
S
S
Cooper
M
M
Taylor
H
H
Jerums
G
G
D000419:Albuminuria / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002199:Capillary Permeability; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000378:metabolism*; D004095:Dihydropyridines / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006830:Hydralazine / Q000627:therapeutic use; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism*; D007211:Indoles / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009928:Organ Specificity; D020913:Perindopril; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012110:Reserpine / Q000627:therapeutic use; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D012709:Serum Albumin / Q000493:pharmacokinetics*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007211:Indoles; D012709:Serum Albumin; D006852:Hydrochlorothiazide; C060285:lacidipine; D006830:Hydralazine; D012110:Reserpine; D020913:Perindopril