Effects of suboptimal doses of the AT1 receptor blocker, telmisartan, with the angiotensin-converting enzyme inhibitor, ramipril, on cerebral arterioles in spontaneously hypertensive rat.
OBJECTIVE
Antihypertensive treatment with standard clinical doses of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) reverses cerebral arteriolar remodeling, thus restoring dilatation and the lower limit of cerebral blood flow (CBF) autoregulation (LL CBF AR). In humans, a combination of standard clinical doses of the two drugs does not produce greater protection against stroke than that obtained with single-drug treatments and increases the risk of side-effects. We hypothesized that a combination of suboptimal doses of the ARB, telmisartan (TEL) and of the ACEI, ramipril (RAM), could be a well tolerated and effective treatment of hypertension-induced remodeling of cerebral arterioles.


METHODS
We studied the impact of 3-month oral treatment with TEL (0.5 or 0.8 mg/kg per day) or RAM (0.1 or 0.25mg/ kg per day) alone or in combination (TEL0.8 + RAM0.1 or TEL0.5 + RAM0.25) on the cerebral circulation of the spontaneously hypertensive rats (SHRs). Normotensive Wistar-Kyoto rats (WKYs) were taken as controls.


METHODS
Cerebral arteriolar pressure, CBF and internal diameter were measured via an open-skull preparation at baseline and during hypotension before and after deactivation (EDTA).


RESULTS
Combinations normalized cerebral arteriolar pressure, whereas drugs alone had no significant impact. TEL0.8 + RAM0.1 showed the greatest effect on arteriolar internal diameter (SHRs 42+/-16, WKYs 59+/-16microm, TEL0.5 + RAM0.25 50+/-6, TEL0.8 + RAM0.1 62+/-18, P<0.05) and normalized LL CBF AR (SHRs 77+/-28, WKYs 53+/-17 mmHg, TEL0.8 + RAM0.1 50+/-10, P<0.05).


CONCLUSIONS
The combination of suboptimal doses of TEL and RAM with an 8 : 1 ratio has the greatest effect on cerebral circulation and could represent well tolerated and efficient treatment of cerebral ischemia and stroke.
Dupuis
François
F
aEA3452 Drug targets, formulation and preclinical drug evaluation, Faculty of Pharmacy, Nancy-University, Nancy, France.
Vincent
Jean-Martin
JM
Limiñana
Patrick
P
Chillon
Jean-Marc
JM
Capdeville-Atkinson
Christine
C
Atkinson
Jeffrey
J
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001160:Arterioles / Q000187:drug effects* / Q000503:physiopathology; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004359:Drug Therapy, Combination; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D017257:Ramipril / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D017257:Ramipril; D000077333:Telmisartan