Double blockade of angiotensin II (AT(1) )-receptors and ACE does not improve weight gain and glucose homeostasis better than single-drug treatments in obese rats.
OBJECTIVE
Combination therapies are becoming increasingly important for the treatment of high blood pressure. Little is known about whether double blockade of angiotensin II (AT(1) ) receptors and angiotensin-converting enzyme (ACE) exert synergistic metabolic effects.


METHODS
Spontaneously hypertensive rats were allowed to choose between palatable chocolate bars and standard chow and were simultaneously treated with the AT(1) blocker telmisartan (8 mg·kg(bw) (-1) ·day(-1) ), the ACE inhibitor ramipril (4 mg·kg(bw) (-1) ·day(-1) ) or a combination of the two (8 + 4 mg·kg(bw) (-1) ·day(-1) ) for 12 weeks.


RESULTS
Although food-dependent energy intake was increased by telmisartan and telmisartan + ramipril compared with ramipril or controls, body weight gain, abundance of fat and plasma leptin levels were decreased. Increased insulin levels in response to an oral glucose tolerance test were comparably attenuated by telmisartan and telmisartan + ramipril, but not by ramipril. During an insulin tolerance test, glucose utilization was equally as effectively improved by telmisartan and telmisartan + ramipril. In response to a stress test, ACTH, corticosterone and glucose increased in controls. These stress reactions were attenuated by telmisartan and telmisartan + ramipril.


CONCLUSIONS
The combination of telmisartan + ramipril was no more efficacious in regulating body weight and glucose homeostasis than telmisartan alone. However, telmisartan was more effective than ramipril in improving metabolic parameters and in reducing body weight. The association between the decrease in stress responses and the diminished glucose levels after stress supports our hypothesis that the ability of telmisartan, as an AT(1) receptor blocker, to alleviate stress reactions may contribute to its hypoglycaemic actions.
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
Anja
A
Miesel
Helge
H
Müller-Fielitz
Olaf
O
Jöhren
Florian M
FM
Vogt
Walter
W
Raasch
D000273:Adipose Tissue / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D004359:Drug Therapy, Combination; D005247:Feeding Behavior / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D020738:Leptin / Q000097:blood; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology; D017257:Ramipril / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D000077333:Telmisartan; D015430:Weight Gain / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D001786:Blood Glucose; D020738:Leptin; D000804:Angiotensin II; D000324:Adrenocorticotropic Hormone; D017257:Ramipril; D000077333:Telmisartan; D003345:Corticosterone