Differential effect of chronic inhibition of calcium channel and angiotensin II type 1-receptor on aldosterone synthesis in spontaneously hypertensive rats.
We have investigated the in vivo effect of chronic blockade of Ca(2+)-channels and angiotensin II type 1 (AT(1))-receptors on aldosterone (Aldo)-synthesis in the adrenal glands of spontaneously hypertensive rats (SHR). Male SHR were administered Ca(2+)-antagonist, amlodipine (10 mg/kg per day) or AT(1)-receptor-antagonist, TCV-116 (1 mg/kg per day) from 7 until 11 weeks of age. Systolic blood pressure (SBP) and heart rate (HR) were significantly higher in SHR than Wistar-Kyoto (WKY) rats. Both treatments resulted in equivalent and significant reduction in SBP in SHR. Aldo-secretion in SHR, which was significantly higher than in WKY rats, was profoundly suppressed by TCV-116 compared with amlodipine. Both treatments resulted in thickening of the zona glomerulosa, which immunohistochemically contains Aldo, at the end of therapy. Competitive reverse transcription-polymerase chain reaction (RT-PCR) showed that CYP11A (P450scc) mRNA regulating the first step of Aldo-synthesis was significantly reduced from week 9 of age by amlodipine, and that CYP11B2 (P450aldo) mRNA regulating the last step of Aldo-synthesis was potently suppressed from 9 weeks of age by TCV-116. Our results indicate that chronic treatment with different antihypertensive agents directly modulates adrenocortical aldosterone synthesis in SHR in vivo via different mechanisms.
Otsuka
F
F
Department of Medicine III, Okayama University Medical School, 2-5-1 Shikata-cho, 700-8558, Okayama, Japan. endocrin@cc.okayama-u.ac.jp
Ogura
T
T
Kataoka
H
H
Kishida
M
M
Takahashi
M
M
Mimura
Y
Y
Yamauchi
T
T
Makino
H
H
D000302:Adrenal Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis* / Q000378:metabolism; D017311:Amlodipine / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001774:Blood Chemical Analysis; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D006339:Heart Rate / Q000187:drug effects; D007120:Immunochemistry; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011188:Potassium / Q000652:urine; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000652:urine; D013777:Tetrazoles; D015384:Zona Glomerulosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D017311:Amlodipine; D000450:Aldosterone; D012964:Sodium; D019405:Cytochrome P-450 CYP11B2; D002786:Cholesterol Side-Chain Cleavage Enzyme; C077793:candesartan cilexetil; D011188:Potassium