Gschwend S, Henning R H, Pinto Y M, de Zeeuw D, van Gilst W H, Buikema H
Department of Clinical Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, Groningen, The Netherlands.
Br J Pharmacol. 2003 Aug;139(7):1317-25. doi: 10.1038/sj.bjp.0705367.
(1) Increased vascular resistance in chronic heart failure (CHF) has been attributed to stimulated neurohumoral systems. However, local mechanisms may also importantly contribute to set arterial tone. Our aim, therefore, was to test whether pressure-induced myogenic constriction of resistance arteries in vitro--devoid of acute effects of circulating factors--is increased in CHF and to explore underlying mechanisms. (2) At 12 weeks after coronary ligation-induced myocardial infarction or SHAM-operations in rats, we studied isolated mesenteric arteries for myogenic constriction, determined as the active constriction (% of passive diameter) in response to stepwise increase in intraluminal pressure (20 - 160 mmHg), in the absence and presence of inhibitors of potentially involved modulators of myogenic constriction. (3) We found that myogenic constriction in mesenteric arteries from CHF rats was markedly increased compared to SHAM over the whole pressure range, the difference being most pronounced at 60 mmHg (24+/-2 versus 4+/-3%, respectively, P<0.001). (4) Both removal of the endothelium as well as inhibition of NO production (L-N(G)-monomethylarginine, 100 micro M) significantly increased myogenic constriction (+16 and +25%, respectively), the increase being similar in CHF- and SHAM-arteries (P=NS). Neither endothelin type A (ET(A))-receptor blockade (BQ123, 1 micro M) nor inhibition of perivascular (sympathetic) nerve conduction (tetrodotoxin, 100 nM) affected the myogenic response in either group. (5) Interestingly, increased myogenic constriction in CHF was fully reversed after angiotensin II type I (AT(1))-receptor blockade (candesartan, 100 nM; losartan, 10 micro M), which was without effect in SHAM. In contrast, neither angiotensin-converting enzyme (ACE) inhibition (lisinopril, 1 micro M; captopril, 10 micro M) or AT(2)-receptor blockade (PD123319, 1 micro M), nor inhibition of superoxide production (superoxide dismutase, 50 U ml(-1)), TXA(2)-receptor blockade (SQ29,548, 1 micro M) or inhibition of cyclooxygenase-derived prostaglandins (indomethacin, 10 micro M) affected myogenic constriction. (6) Sensitivity of mesenteric arteries to angiotensin II (10 nM - 100 micro M) was increased (P<0.05) in CHF (pD(2) 7.1+/-0.4) compared to SHAM (pD(2) 6.2+/-0.3), while the sensitivity to KCl and phenylephrine was not different. (7) Our results demonstrate increased myogenic constriction in small mesenteric arteries of rats with CHF, potentially making it an important target for therapy in counteracting increased vascular resistance in CHF. Our results further suggest active and instantaneous participation of AT(1)-receptors in increased myogenic constriction in CHF, involving increased sensitivity of AT(1)-receptors rather than apparent ACE-mediated local angiotensin II production.
（1）慢性心力衰竭（CHF）中血管阻力增加归因于神经体液系统的激活。然而，局部机制也可能对设定动脉张力起重要作用。因此，我们的目的是测试在体外，排除循环因子的急性影响后，CHF大鼠阻力动脉的压力诱导肌源性收缩是否增强，并探究其潜在机制。（2）在大鼠冠状动脉结扎诱导心肌梗死或假手术后12周，我们研究了分离的肠系膜动脉的肌源性收缩，通过腔内压力逐步升高（20 - 160 mmHg）时的主动收缩（被动直径的百分比）来确定，分别在不存在和存在潜在参与调节肌源性收缩的调节剂抑制剂的情况下进行。（3）我们发现，在整个压力范围内，CHF大鼠肠系膜动脉的肌源性收缩与假手术组相比显著增强，在60 mmHg时差异最为明显（分别为24±2%和4±3%，P<0.001）。（4）去除内皮以及抑制一氧化氮生成（L-N(G)-单甲基精氨酸，100 μM）均显著增加肌源性收缩（分别增加16%和25%），CHF和假手术组动脉的增加相似（P=无显著性差异）。A型内皮素（ET(A)）受体阻断剂（BQ123，1 μM）或抑制血管周围（交感）神经传导（河豚毒素，100 nM）均未影响两组的肌源性反应。（5）有趣的是，I型血管紧张素II（AT(1)）受体阻断（坎地沙坦，100 nM；氯沙坦，10 μM）后，CHF中增强的肌源性收缩完全逆转，而对假手术组无影响。相反，血管紧张素转换酶（ACE）抑制（赖诺普利，1 μM；卡托普利，10 μM）或AT(2)受体阻断（PD123319，1 μM），以及抑制超氧化物生成（超氧化物歧化酶，50 U/ml(-1)）、血栓素A2（TXA(2)）受体阻断（SQ29548，1 μM）或抑制环氧化酶衍生的前列腺素（吲哚美辛，10 μM）均未影响肌源性收缩。（6）与假手术组（pD(2) 6.2±0.3）相比，CHF组（pD(2) 7.1±0.4）肠系膜动脉对血管紧张素II（10 nM - 100 μM）的敏感性增加（P<0.05），而对氯化钾和去氧肾上腺素的敏感性无差异。（7）我们的结果表明，CHF大鼠小肠系膜动脉的肌源性收缩增强，这可能使其成为对抗CHF中血管阻力增加的重要治疗靶点。我们的结果进一步表明，AT(1)受体在CHF中增强的肌源性收缩中起积极且即时的作用，涉及AT(1)受体敏感性增加而非明显的ACE介导的局部血管紧张素II生成。
