Angiotensin AT(1) receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodilatation in normotensive diabetic rats.
OBJECTIVE
The renin angiotensin system is emerging as a potential therapeutic target for diabetic retinopathy. This study examines the effects of angiotensin-converting-enzyme inhibition by captopril and angiotensin AT(1) receptor antagonism using candesartan-cilexetil on retinal blood flow and acetylcholine-stimulated vasodilatation in normotensive diabetic rats.


METHODS
Non-diabetic or streptozotocin-induced diabetic rats were treated for 2 weeks with captopril (100 mg/kg/day) or candesartan cilexetil (2 mg/kg/day). Retinal haemodynamics were measured using video fluorescein angiography. Effects of exogenous acetylcholine on retinal haemodynamics were examined following intravitreal injection. Total retinal diacylglycerol was labelled using diacylglycerol kinase, separated by thin-layer chromatography, and quantified using autoradiography.


RESULTS
Diabetic rats had prolonged retinal mean circulation time and decreased retinal blood flow compared with non-diabetic rats. Treatment of diabetic rats with either captopril or candesartan blocked the development of these blood flow abnormalities. Intravitreal injection of acetylcholine (10(-5) mol/l) in non-diabetic rats increased retinal blood flow by 53.9+/-22.0% relative to baseline whereas this response to acetylcholine was blunted in diabetic rats (4.4+/-19.6%, p<0.001). Candesartan treatment of diabetic rats restored the acetylcholine-stimulated retinal blood flow response to 60.0+/-18.7% compared with a 56.2+20.1% response in candesartan-treated non-diabetic rats. Total retinal diacylglycerol levels were increased in diabetic rats (3.75+/-0.98 nmol/mg, p<0.05) compared with non-diabetic rats (2.13+/-0.25 nmol/mg) and candesartan-treatment of diabetic rats normalized diacylglycerol levels (2.10+/-0.25 nmol/mg, p<0.05).


CONCLUSIONS
This report provides evidence that angiotensin-converting enzyme inhibition and AT(1) receptor antagonism ameliorates retinal haemodynamic dysfunctions in normotensive diabetic rats.
Horio
N
N
Research Division and Beetham Eye Institute, Joslin Diabetes Center and Harvard Medical School, One Joslin Place, Boston, USA.
Clermont
A C
AC
Abiko
A
A
Abiko
T
T
Shoelson
B D
BD
Bursell
S-E
SE
Feener
E P
EP
D000109:Acetylcholine / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002216:Captopril / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005451:Fluorescein Angiography; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects*; D012171:Retinal Vessels / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D013777:Tetrazoles; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D002216:Captopril; D000109:Acetylcholine; C077793:candesartan cilexetil