Endothelin A antagonist LU-135252 and trandolapril in the treatment of the Cohen-Rosenthal diabetic hypertensive rat.
BACKGROUND
Hypertension and non-insulin-dependent diabetes mellitus (NIDDM) often occur simultaneously and the combination requires vigorous control of hypertension. This can generally be achieved by a combination of antihypertensive drugs. The present study examines the antihypertensive and possible hypoglycemic effects of combined therapy with endothelin A (ETA) receptor antagonist LU-135252 and angiotensin-converting enzyme (ACE) inhibitor trandolapril in male Cohen-Rosenthal Diabetic Hypertensive (CRDH) rats.


METHODS
Rats were divided into four groups as follows: group I served as control; group II--LU-135252 30 mg/kg/day; group III--trandolapril 0.1 mg/kg/day and group IV--both LU-135252 30 mg/kg/day and trandolapril 0.1 mg/kg/day. Systolic blood pressure (SBP) and plasma glucose levels were evaluated at the beginning of the experiment and after 2, 4 and 6 weeks.


RESULTS
SBP decreased significantly in all treated groups after 2, 4 and 6 weeks of treatment compared to baseline. Maximum decrease was in group IV (combination) from 174.8+/-3.7 to 136.1+/-2.4 mmHg (22%) (p<0.0001); in group III (trandolapril) from 165.8+/-2.7 to 137.5+/-2.9 mmHg (17%) (p=0.0002); and in group II (LU-135252) and from 169.1+/-3.1 to 147.8+/-2.5 mmHg (12%) (p=0.0004). Glucose levels in plasma decreased significantly after 6 weeks of treatment. Maximum decrease was in group IV: from 501.0+/-42.8 to 178.6+/-7.3 mg/dl (62%) (p<0.0001); in group III from 428.2+/-47.7 to 146.8+/-5.6 mg/dl (63%) (p<0.0001); and in group II from 491.2+/-39.3 to 272.2+/-28.3 mg/dl (42%) (p=0.0002).


CONCLUSIONS
The SBP decrease was additive when both drugs were given together. Thus, combination of ETA antagonist and ACE inhibitor appears to offer a rational fixed-dose antihypertensive therapy, which is superior to that of either drug alone. The decrease in glucose level, which was the least impressive while on LU-135252 alone, was more prominent during combination after 2 weeks, although without further decrease.
Hofman
Cipy
C
The Hypertension Unit, Sackler Faculty of Medecine, Tel Aviv University, Tel Aviv, Israel.
Gabai
Efraim
E
Peleg
Edna
E
Munter
Klaus
K
Rosenthal
Talma
T
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D048909:Diabetes Complications / Q000188:drug therapy* / Q000235:genetics*; D004338:Drug Combinations; D065130:Endothelin A Receptor Antagonists; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics*; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D010666:Phenylpropionates / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D013395:Sucrose / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001786:Blood Glucose; D004338:Drug Combinations; D065130:Endothelin A Receptor Antagonists; D007211:Indoles; D010666:Phenylpropionates; D011743:Pyrimidines; C052035:trandolapril; C107831:darusentan; D013395:Sucrose