Lassila Markus, Davis Belinda J, Allen Terri J, Burrell Louise M, Cooper Mark E, Cao Zemin
Baker Heart Research Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia.
Clin Sci (Lond). 2003 Apr;104(4):341-7.
The aim of the present study was to compare the antihypertrophic effects of blockade of the renin-angiotensin system (RAS), vasopeptidase inhibition and calcium channel antagonism on cardiac and vascular hypertrophy in diabetic spontaneously hypertensive rats (SHR). SHR with streptozotocin-induced diabetes were treated with one of the following therapies for 32 weeks: the angiotensin-converting enzyme (ACE) inhibitor captopril (100 mg/kg); the angiotensin AT(1) receptor antagonist valsartan (30 mg/kg); a combination of captopril with valsartan; the vasopeptidase inhibitor mixanpril (100 mg/kg); or the calcium channel antagonist amlodipine (6 mg/kg). Systolic blood pressure and cardiac and mesenteric artery hypertrophy were assessed. Mean systolic blood pressure in diabetic SHR (200+/-5 mmHg) was reduced by captopril (162+/-5 mmHg), valsartan (173+/-5 mmHg), mixanpril (176+/-2 mmHg) and amlodipine (159+/-4 mmHg), and was further reduced by the combination of captopril with valsartan (131+/-5 mmHg). Captopril, valsartan and mixanpril reduced heart and left ventricle weights by approx. 10%. The combination of captopril and valsartan further reduced heart weight (-24%) and left ventricular weight (-29%). Amlodipine did not affect cardiac hypertrophy. Only mixanpril and the combination of captopril and valsartan significantly reduced mesenteric weight. The mesenteric wall/lumen ratio was reduced by all drugs, and to a greater extent by the combination of captopril and valsartan. We conclude that optimizing the blockade of vasoconstrictive pathways such as the RAS, particularly with the combination of ACE inhibition and AT(1) receptor antagonism, is associated with antitrophic effects in the context of diabetes and hypertension. In contrast, calcium channel blockade, despite similar effects on blood pressure, confers less antitrophic effects in the diabetic heart and blood vessels.
本研究的目的是比较肾素-血管紧张素系统（RAS）阻断、血管肽酶抑制和钙通道拮抗对糖尿病自发性高血压大鼠（SHR）心脏和血管肥大的抗肥厚作用。用链脲佐菌素诱导糖尿病的SHR接受以下治疗之一，为期32周：血管紧张素转换酶（ACE）抑制剂卡托普利（100mg/kg）；血管紧张素AT(1)受体拮抗剂缬沙坦（30mg/kg）；卡托普利与缬沙坦联合使用；血管肽酶抑制剂米沙坦（100mg/kg）；或钙通道拮抗剂氨氯地平（6mg/kg）。评估收缩压以及心脏和肠系膜动脉肥大情况。糖尿病SHR的平均收缩压（200±5mmHg）被卡托普利（162±5mmHg）、缬沙坦（173±5mmHg）、米沙坦（176±2mmHg）和氨氯地平（159±4mmHg）降低，并且卡托普利与缬沙坦联合使用时进一步降低（131±5mmHg）。卡托普利、缬沙坦和米沙坦使心脏和左心室重量减轻约10%。卡托普利和缬沙坦联合使用进一步减轻心脏重量（-24%）和左心室重量（-29%）。氨氯地平不影响心脏肥大。只有米沙坦以及卡托普利和缬沙坦联合使用显著减轻肠系膜重量。所有药物均降低肠系膜壁/腔比值，卡托普利和缬沙坦联合使用降低幅度更大。我们得出结论，优化血管收缩途径如RAS的阻断，特别是ACE抑制和AT(1)受体拮抗联合使用，在糖尿病和高血压背景下具有抗肥厚作用。相比之下，钙通道阻断尽管对血压有类似作用，但在糖尿病心脏和血管中抗肥厚作用较小。
