Naruse Mitsuhide, Tanabe Akiyo, Hara Yoshiko, Takagi Sachiko, Imaki Toshihiro, Takano Kazue
Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical University, Tokyo, Japan.
J Cardiovasc Pharmacol. 2004 Nov;44 Suppl 1:S1-3. doi: 10.1097/01.fjc.0000165711.99484.d1.
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.
血管紧张素 II 刺激而血管紧张素转换酶抑制剂降低内皮素 -1 的表达。1 型血管紧张素拮抗剂(血管紧张素受体阻滞剂)对高血压患者内皮素 -1 组织表达的影响尚不清楚。我们研究了 1 型血管紧张素拮抗剂单独使用以及与醛固酮受体拮抗剂螺内酯联合使用对内皮素 -1 mRNA 心脏表达的影响。从 4 周龄开始,对雄性自发性高血压易卒中大鼠 /Izm 口服给予血管紧张素受体阻滞剂(坎地沙坦,每天 1.0 mg/kg),持续 4 周、12 周和 28 周(血管紧张素受体阻滞剂组)。将不影响血压的低剂量螺内酯(每天 10 mg/kg,皮下注射)与 1 型血管紧张素拮抗剂联合使用 28 周(1 型血管紧张素拮抗剂 + 螺内酯组)。测定内皮素 -1 mRNA 的心脏表达。在血管紧张素受体阻滞剂组中,虽然治疗 4 周后内皮素 -1 mRNA 的心脏表达显著降低,但治疗 12 周和 28 周后显著增加。在血管紧张素受体阻滞剂 + 螺内酯组中,虽然收缩压没有比血管紧张素受体阻滞剂组进一步降低,但内皮素 -1 mRNA 的心脏表达降低到未治疗组的水平。这些结果表明,对内皮素 -1 表达的影响可能会改变血管紧张素受体阻滞剂的心脏保护作用。建议联合使用血管紧张素受体阻滞剂和低剂量螺内酯,通过抑制内皮素 -1 表达进一步实现心脏保护。