Nakamura T
Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Hokkaido Igaku Zasshi. 1997 Sep;72(5):503-16.
A chronic model of hypertension, induced by continuous inhibition of nitric oxide synthase (NOS), was used to examine whether chronic NOS inhibition is associated with the heightened sympathetic activity and how nitric oxide (NO) produced by NOS contributes to maintain structural integrity of coronary artery and myocardial interstitium. Osmotic pumps were implanted intraperitoneally for 4 or 8 weeks to male Wistar rats. Solution in the osmotic pumps contained 0.2 M L-NG-nitroarginine methylester (LNAME) [low dose (LD)] or 1 M LNAME [high dose (HD)], or saline (SA). Sproke-prone spontaneous hypertensive rats (SHRSP) served as hypertensive controls. After 4 weeks the pumps in some rats were exchanged to the ones containing same solution (SA-SA, LD-LD, and HD-HD), or LNAME was discontinued and replaced by SA (LD-SA, and HD-SA). After 4 weeks, blood pressure (BP) of the LNAME-treated rats gradually rose from 112 to 142 (LD) and 180 (HD) mmHg. When the LNAME treatment was continued for the next 4 weeks, BP remained high (140 mmHg) in LD-LD. When LNAME was discontinued, BP returned to control levels (LD-SA: 110 mmHg; HD-SA: 122 mmHg). Heart rate (HR) decreased soon after initiation of the LNAME treatment, and remained lower in LD and LD-LD for 8 weeks, while it was gradually elevated and reached to the control level in HD. Discontinuation of the LNAME treatment normalized HR (LD-SA and HD-SA). Plasma dopamine levels were lower in the LNAME-treated rats and the withdrawal of LNAME normalized them. Plasma norepinephrine levels were significantly higher in HD than SA and LD, and it returned to control level in 8 weeks. Plasma renin concentrations were unchanged throughout the study. Microscopic examination (ME) revealed more severe thickening of coronary arterioles and fibrosis of myocardial interstitium in HD than in SHRSP. ME also revealed severe histiocyte infiltration in HD rats, while no kidney damages. These results suggest that, in the chronic model of hypertension induced by sustained LNAME administration, not only NO derived from endothelial NOS (NOS-3), but also the heightened sympathetic drive caused by central NOS (NOS-1) inhibition modifies progression of the disease. Furthermore, NOS-2 induced by histiocyte infiltration and its inhibition by LNAME may have resulted in the severe structural changes in the lesions. Thus, various NOSs may take part in maintaining cardiovascular integrity.
通过持续抑制一氧化氮合酶（NOS）诱导建立高血压慢性模型，以研究慢性NOS抑制是否与交感神经活动增强有关，以及NOS产生的一氧化氮（NO）如何有助于维持冠状动脉和心肌间质的结构完整性。将渗透泵腹腔内植入雄性Wistar大鼠4周或8周。渗透泵中的溶液含有0.2M L-NG-硝基精氨酸甲酯（LNAME）[低剂量（LD）]或1M LNAME[高剂量（HD）]，或生理盐水（SA）。易中风自发性高血压大鼠（SHRSP）作为高血压对照组。4周后，部分大鼠的泵更换为含相同溶液的泵（SA-SA、LD-LD和HD-HD），或停止使用LNAME并替换为SA（LD-SA和HD-SA）。4周后，LNAME处理组大鼠的血压（BP）从112mmHg逐渐升至142（LD）和180（HD）mmHg。当LNAME处理再持续4周时，LD-LD组的BP仍维持在高位（140mmHg）。当停止使用LNAME时，BP恢复到对照水平（LD-SA：110mmHg；HD-SA：122mmHg）。LNAME处理开始后心率（HR）很快下降，在LD和LD-LD组中8周内一直较低，而在HD组中逐渐升高并达到对照水平。停止LNAME处理后HR恢复正常（LD-SA和HD-SA）。LNAME处理组大鼠的血浆多巴胺水平较低，停止使用LNAME后恢复正常。HD组的血浆去甲肾上腺素水平显著高于SA组和LD组，并在8周内恢复到对照水平。整个研究过程中血浆肾素浓度无变化。显微镜检查（ME）显示，HD组冠状动脉小动脉增厚和心肌间质纤维化比SHRSP组更严重。ME还显示HD组大鼠有严重的组织细胞浸润，但无肾脏损伤。这些结果表明，在持续给予LNAME诱导的高血压慢性模型中，不仅内皮型NOS（NOS-3）衍生的NO，而且中枢型NOS（NOS-1）抑制引起的交感神经驱动增强均会改变疾病进展。此外，组织细胞浸润诱导的NOS-2及其被LNAME抑制可能导致了病变中的严重结构变化。因此，各种NOS可能参与维持心血管的完整性。
