Effects of AT1 receptor antagonist and spironolactone on cardiac expression of ET-1 mRNA in SHR-SP/Izm.
Angiotensin II stimulates and angiotensin-converting enzyme inhibitor decreases endothelin-1 expression. Effects of the angiotensin-type 1 antagonist (angiotensin receptor blocker) on tissue expression of endothelin-1 in hypertension remained unknown. We investigated the effects of angiotensin-type 1 antagonist with and without co-administration of the aldosterone receptor antagonist spironolactone on cardiac expression of endothelin-1 mRNA. Angiotensin receptor blocker (candesartan, 1.0 mg/kg per day) was orally administered to male spontaneously hypertensive stroke-prone rats/Izm from 4 weeks of age for 4 weeks, 12 weeks and 28 weeks (angiotensin receptor blocker group). Lowdose spironolactone (10 mg/kg per day, s.c.), which does not affect blood pressure, was co-administered with angiotensin-type 1 antagonist for 28 weeks (angiotensin-type 1 antagonist + spironolactone group). Cardiac expression of endothelin-1 mRNA was determined. In the angiotensin receptor blocker group, although cardiac expression of endothelin-1 mRNA was significantly decreased after 4 weeks of treatment, it was significantly increased after 12 weeks and 28 weeks of treatment. In the angiotensin receptor blocker + spironolactone group, while systolic blood pressure did not show a further decrease from that in the angiotensin receptor blocker group, cardiac expression of endothelin-1 mRNA was decreased to the level in the untreated group. These results suggest that effects on endothelin-1 expression could modify the cardioprotective effects of angiotensin receptor blocker. Coadministration of angiotensin receptor blocker with low-dose spironolactone is recommended for further cardioprotection via suppression of endothelin-1 expression.
Naruse
Mitsuhide
M
Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical University, Tokyo, Japan. mtsnaruse@endm.twmu.ac.jp
Tanabe
Akiyo
A
Hara
Yoshiko
Y
Takagi
Sachiko
S
Imaki
Toshihiro
T
Takano
Kazue
K
D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013148:Spironolactone / Q000008:administration & dosage / Q000494:pharmacology*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D019332:Endothelin-1; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D013777:Tetrazoles; D013148:Spironolactone; C077793:candesartan cilexetil