Effects of combination of angiotensin receptor blocker and calcium channel blocker on ox-LDL levels and cardiovascular dysfunction in Dahl rats.
In an effort to assess the cardiovascular benefits of combined angiotensin receptor blockage and calcium channel antagonism, we assessed the chronic effects of the angiotensin type 1 receptor blocker candesartan, the calcium channel blocker benidipine, and the use of a combination therapy in Dahl salt-sensitive (DS) rats. DS rats receiving a high salt diet were treated with either benidipine (4 mg/kg), candesartan (1 mg/kg) or both. Rat blood pressure was measured using a tail-cuff method. Following 12 weeks, the effect on heart weight, plasma-oxidized low-density lipoprotein (ox-LDL) level, endothelium-dependent vasorelaxation, and histology of the heart and aorta was assessed. Blood pressure, heart weight and plasma ox-LDL levels increased, while endothelium-dependent vasorelaxation decreased in the DS rats. Candesartan and benidipine inhibited the increase in blood pressure and heart weight, and the decrease in endothelium-dependent vasorelaxation. The use of benidipine alone or a combination significantly inhibited the increase in ox-LDL levels, whereas candesartan alone had no significant effect on ox-LDL levels. The present findings indicate that, if the monotherapy using ARB could not achieve adequate control of blood pressure, the combination therapy with ARB and benidipine provides the additional reductions in hypertension and cardiac hypertrophy. Moreover, the combination therapy inhibits cardiovascular dysfunction and ox-LDL levels more effectively than use of ARB alone. These results contribute to the possibility of lowering ox-LDL levels as a means of enhancing cardiovascular protection.
Takayama
Makoto
M
Department of Pharmacology and Molecular Biology, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co. Ltd, 1188 Shimotogari, Sunto-gun, Shizuoka-ken, Japan. makoto.takayama@kyowa.co.jp
Arakawa
Emi
E
Yao
Kozo
K
Ina
Yasuhiro
Y
Sato
Hitoshi
H
Hasegawa
Kazuhide
K
Kohno
Hiroaki
H
Ohno
Tetsuji
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology / Q000648:ultrastructure; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004095:Dihydropyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D007022:Hypotension / Q000139:chemically induced; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D008077:Lipoproteins, LDL; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; C099252:oxidized low density lipoprotein; D010656:Phenylephrine; C061004:benidipine; C081643:candesartan