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Cantharidin enhances norepinephrine-induced vasoconstriction in an endothelium-dependent fashion

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期294卷 620-626页

作者： Knapp, J Bokník, P Linck, B Lüss, H Müller, FU Petertönjes, L Schmitz, W Neumann, J Univ Munster Inst Pharmakol & Toxikol D-48129 Munster Germany

In this study we characterized the effects of the protein phosphatase (PP) type 1 and type 2A inhibitor cantharidin (Cant) and its structural analogs cantharidic acid and endothall on PP activity, force of contraction, and myosin light chain phosphorylation in rat aorta. All compounds inhibited PP activity in homogenates of rat aorta with a rank order of potency of Cant = cantharidic acid > endothall. However, only Cant increased force of contraction and myosin light chain phosphorylation in intact isolated rat aortic rings. Based on these findings, we investigated the effects of Cant on alpha-adrenoceptor-mediated vasoconstriction. Cant (1 and 3 mu M) enhanced norepinephrine-induced contraction in endothelium-intact rat aorta. In contrast, Cant did not affect norepinephrine-induced contraction in endothelium-denuded rat aorta. We suggest that inhibition of PP1 and/or PP2A activities by Cant enhances vascular contractility in endothelium-intact rat aorta by increasing the phosphorylation state of endothelial regulatory proteins.

关键词：主动脉胸/药物作用主动脉胸/酶学主动脉胸/生理学斑蝥素/药理学催化作用药物协同作用内皮血管/药物作用内皮血管/酶学内皮血管/生理学酶抑制剂/药理学肌收缩/药物作用肌松弛/药物作用肌松弛/生理学肌平滑血管/药物作用肌平滑血管/酶学肌平滑血管/生理学肌球蛋白轻链/代谢肌球蛋白轻链磷酸酶去甲肾上腺素/药理学黑软海绵素A/药理学磷酰化大鼠 Wistar 血管收缩/药物作用血管收缩/生理学血管收缩药/药理学动物男(雄)性大鼠

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Firing properties of single vasoconstrictor neurones in human subjects with high levels of muscle sympathetic activity

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JOURNAL OF PHYSIOLOGY-LONDON 1999年第1期516卷 293-301页

作者： Macefield, VG Wallin, BG Gothenburg Univ Sahlgrens Univ Hosp Dept Clin Neurophysiol Inst Clin Neurosci S-41345 Gothenburg Sweden

1. Single-unit recordings were made from 19 postganglionic muscle vasoconstrictor axons via tungsten microelectrodes in the peroneal nerve in seven healthy subjects with many multiunit sympathetic discharges at rest ('high group', 75 +/- 5 multi-unit bursts per 100 heart beats, mean +/- S.E.M.). The results were compared with previous data from 14 units in subjects with 21 +/- 2 multi-unit bursts per 100 heart beats ('low group'). 2. In the 'high group' the units fired spontaneously in 35 +/- 4% of all cardiac intervals. One unit only ever fired once per cardiac interval, 14 units (74%) generated maximally two to three spikes, and four units (21%) up to four to five spikes. Of those cardiac intervals in which a unit fired, a single spike occurred. in 78%, two spikes in 18%, three spikes in 4% and four spikes in less than 1% of cardiac intervals. Measured as the inverse of all interspike intervals, the mean rate was 0.33 +/- 0.04 Hz and the mean intraburst frequency 22.2 +/- 1.6 Hz. Most results were similar to those in the 'low group', but in the 'low group' heart rate was higher (64.5 vs. 50.4 beats min(-1)) and mean firing frequency was higher (0.49 +/- 0.06 Hz). 3. During increases of multi-unit buret activity evoked by sustained inspiratory-capacity apnoea the firing probability of nine unite in the 'high group' increased from 33 +/- 6 to 56 +/- 3% of the cardiac intervals. Simultaneously, the incidence of single spikes decreased and the incidence of multiple spikes per cardiac interval increased, resulting in an increase of mean firing frequency from 0.23 +/- 0.04 Hz at rest to 1.04 +/- 0.14 Hz during the apnoea. 4. We conclude that single muscle vasoconstrictor neurones usually fire only a solitary spike during sympathetic bursts both in subjects with a high and in subjects with a low number of bursts at rest. Presumably, differences in the numbers of bursts are clue mainly to differences in firing probability and recruitment of sympathetic fibres. During acut

关键词：呼吸暂停/病理生理学轴突/生理学电刺激微电极肌骨骼/神经支配肌骨骼/生理学神经元/生理学交感神经纤维节后/生理学交感神经系统/生理学血管收缩/生理学成年人人类男(雄)性

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Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension

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PHYSIOLOGICAL REVIEWS 2000年第4期80卷 1337-1372页

作者： Hampl, V Herget, J Charles Univ Prague Sch Med 2 Dept Physiol Prague 15000 5 Motol Czech Republic

Chronic pulmonary hypertension is a serious complication of a number of chronic lung and heart diseases. In addition to vasoconstriction, its pathogenesis includes injury to the peripheral pulmonary arteries leading to their structural remodeling. Increased pulmonary vascular synthesis of an endogenous vasodilator, nitric oxide (NO), opposes excessive increases of intravascular pressure during acute pulmonary vasoconstriction and chronic pulmonary hypertension, although evidence for reduced NO activity in pulmonary hypertension has also been presented. NO can modulate the degree of vascular injury and subsequent fibroproduction, which both underlie the development of chronic pulmonary hypertension. On one hand, NO can interrupt vascular wall injury by oxygen radicals produced in increased amounts in pulmonary hypertension. NO can also inhibit pulmonary vascular smooth muscle and fibroblast proliferative response to the injury. On the other hand, NO may combine with oxygen radicals to yield peroxynitrite and other related, highly reactive compounds. The oxidants formed in this manner may exert cytotoxic and collagenolytic effects and, therefore, promote the process of reparative vascular remodeling. The balance between the protective and adverse effects of NO is determined by the relative amounts of NO and reactive oxygen species. We speculate that this balance may be shifted toward more severe injury especially during exacerbations of chronic diseases associated with pulmonary hypertension. Targeting these adverse effects of NO-derived radicals on vascular structure represents a potential novel therapeutic approach to pulmonary hypertension in chronic lung diseases.

关键词：慢性病内皮血管/药物作用内皮血管/代谢酶抑制剂/药理学自由基/代谢自由基/药理学高血压肺性/病因学高血压肺性/代谢肺/血液供给肺/药物作用肺/胚胎学一氧化氮/代谢一氧化氮/药理学一氧化氮合酶/拮抗剂和抑制剂一氧化氮合酶/代谢一氧化氮合酶Ⅱ型一氧化氮合酶Ⅲ型肺循环/药物作用肺循环/生理学血管阻力/药物作用血管阻力/生理学血管收缩/药物作用血管收缩/生理学血管舒张/药物作用血管舒张/生理学成年人动物人类婴儿新生

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Voltage-independent calcium entry in hypoxic pulmonary vasoconstriction of intrapulmonary arteries of the rat

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第3期525卷 669-680页

作者： Robertson, TP Hague, D Aaronson, PI Ward, JPT Univ London Kings Coll GKT Sch Med Dept Resp Med & Allergy London SE1 9RT England

1. It has been proposed that hypoxic pulmonary vasoconstriction (HPV) is mediated via K+ channel inhibition and Ca2+ influx through voltage-gated channels. HPV depends strongly on the degree of preconstriction, and Lte therefore examined thtr effect of Ca2+ channel blockade on tension and intracellular [Ca2+] ([Ca2+](i)) during HPV in rat intrapulmonary arteries (IPAs), whilst maintaining preconstriction constant. We also investigated the role of intracellular Ca2+ stores. 2. HPV demonstrated a transient constriction (phase I) superimposed on a sustained constriction (phase II). Nifedipine (1 mu M) partially inhibited phase I, but did not affect phase II. In arteries exposed to 80 mM K+ and nifedipine or diltiazem the rises in tension and [Ca2+](i) were blunted during phase I, but were unaffected during phase II. 3. At low concentrations (< 3 mu M), La3+ almost abolished the phase I constriction and rise in [Ca2+](i), but had no effect on phase II, or constriction in response to 80 mM K+. Phase II was inhibited by higher concentrations of La3+ (IC50 similar to 50 mu M). 4. IPA treated with thapsigargin (1 mu M) in Ca2+-free solution to deplete Ca2+ stores showed sustained constriction upon re-exposure to Ca2+ and an increase in the rate of Mn2+ influx, suggesting capacitative Ca2+ entry The concentration dependency of the block of constriction by La3+ was similar to that for phase I of HPV. Pretreatment of TPA with 30 mu M CPA reduced phase I by > 80%, but had no significant effect on phase II. 5. We conclude that depolarization-mediated Ca2+ influx plays at best a minor role in the transient phase I constriction of HPV, and is not involved in the sustained phase II constriction. Instead, phase I appears to be mainly dependent on capacitative Ca2+ entry related to release of thapsigargin-sensitive Ca2+ stores, whereas phase II is supported by Ca2+ entry via a separate voltage-independent pathway.

关键词：缺氧/病理生理学咖啡因/药理学钙/药代动力学钙通道阻滞药/药理学钙通道/生理学螯合剂/药理学地尔硫|艹卓|/药理学二核苷磷酸类/药理学依他酸/药理学电刺激酶抑制剂/药理学咪唑类/药理学离子通道闸门/药物作用离子通道闸门/生理学镧/药理学膜电位/药物作用膜电位/生理学硝苯地平/药理学磷酸二酯酶抑制剂/药理学肺动脉/化学肺动脉/生理学肺循环/生理学大鼠 Wistar 兰尼碱/药理学毒胡萝卜内酯/药理学血管收缩/药物作用血管收缩/生理学维拉帕米/药理学动物男(雄)性大鼠

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Skeletal muscle vasodilatation during sympathoexcitation is not neurally mediated in humans

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第1期525卷 253-262页

作者： Reed, AS Tschakovsky, ME Minson, CT Halliwill, JR Torp, KD Nauss, LA Joyner, MJ Mayo Clin & Mayo Fdn Mayo Med Sch Rochester MN 55905 USA Mayo Clin & Mayo Fdn Dept Physiol Rochester MN 55905 USA Mayo Clin & Mayo Fdn Dept Anesthesiol Rochester MN 55905 USA

1. Evidence for the existence of sympathetic vasodilator nerves in human skeletal muscle is controversial. Manoeuvres such its contralateral ischaemic handgripping to fatigue that cause vasoconstriction in the resting forearm evoke vasodilatation after local alpha-adrenergic receptor blockade, raising the possibility that both constrictor and dilator fibres are present. The purpose of this study mas to determine whether this dilatation is neurally mediated. 2. Ten subjects (3 women, 7 men) performed ischaemic handgripping to fatigue before and after acute local anaesthetic block of the sympathetic nerves (stellate ganglion) innervating the contralateral (resting) upper extremity Forearm blood flow was measured with venous occlusion plethysmography in the resting forearm. 3. In control studies there was forearm vasoconstriction during contralateral handgripping to fatigue. During contralateral handgripping after stellate block, blood flow in the resting forearm increased from 6.1 +/- 0.7 to 18.7 +/- 2.2 ml dl(-1) min(-1) (P < 0.05). Mean arterial pressure measured concurrently increased from similar to 90 to 130 mmHg and estimated vascular conductance rose from 6.5 +/- 0.7 to 14.0 +/- 1.5 units, indicating that most of the rise in forearm blood flow mas due to vasodilatation. 4. Brachial artery administration of beta-blockers (propranolol) and the nitric oxide (NO) synthase inhibitorN(G)-monomethlyl-L-arginine (L-NMMA) after stellate block virtually eliminated all of the vasodilatation to contralateral handgrip. 5. Since vasodilatation was seen after stellate block, our data suggest that sympathetic dilator nerves are not responsible for limb vasodilatation seen during sympathoexcitation evoked by contralateral ischaemic handgripping to fatigue. The results obtained with propranolol and L-NMMA suggest that beta-adrenergic mechanisms and local NO release contribute to the dilatation.

关键词：肾上腺素能β受体拮抗剂/药理学血压肾上腺素/血液前臂手肌疲劳肌骨骼/血液供给肌骨骼/神经支配肌骨骼/生理学一氧化氮/代谢体积描记术普萘洛尔/药理学局部血流星状神经节/药物作用交感神经系统/药物作用交感神经系统/生理学血管收缩/药物作用血管收缩/生理学血管舒张/药物作用血管舒张/生理学 ωN-甲基精氨酸/药理学青少年成年人女(雌)性人类男(雄)性

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Endothelin_B receptors are functionally important in mediating vasoconstriction in the systemic circulation in patients with left ventricular systolic dysfunction

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 1999年第4期33卷 932-938页

作者： Cowburn, PJ Cleland, JGF McArthur, JD MacLean, MR McMurray, JJV Dargie, HJ Morton, JJ Univ Glasgow MRC Clin Res Initiat Heart Failure Dept Cardiol Glasgow Lanark Scotland Univ Glasgow Western Infirm Glasgow G11 6NT Lanark Scotland Dept Cardiol Acad Unit Kingston Upon Hull Yorks England

OBJECTIVES This study was designed to assess the functional importance of endothelin (ET)(B) receptors in patients with left ventricular systolic dysfunction (LVSD) by comparing the hemodynamic effects of ET-1, a nonselective ETA and ETB agonist, with ET-3, a selective ETB receptor agonist. BACKGROUND Knowledge of the functional importance of ETB receptors in mediating vasoconstriction in chronic heart failure will help determine whether antagonists at both ETA and ETB receptors are required to fully prevent vasoconstriction to endogenously produced ET-1. METHODS We infused ET-1 (5 and 15 pmol/min) and ET-3 (5 and 15 pmol/min) into two separate groups of eight patients with LVSD with similar baseline hemodynamic indices. Hemodynamics were measured using a pulmonary thermodilution catheter and an arterial line. RESULTS Endothelin-l infusion led to systemic vasoconstriction, with a rise in mean arterial pressure (mean +/- SEM 100 +/- 3 to 105 +/- 3 mm Hg, p < 0.02) and systemic vascular resistance (1,727 +/- 142 to 2,055 +/- 164 dys/cm(-5), p < 0.001) and a fall in cardiac index (2.44 +/- 0.21 to 2.22 +/- 0.20 liters/min/m p < 0.01). Endothelin-3 infusion also led to systemic vasoconstriction, with a rise in mean arterial pressure (99 +/- 6 to 105 +/- 6 mm Hg, p < 0.01) and systemic vascular resistance (1,639 +/- 210 to 1,918 +/- 245 dyn/s/cm(-5), p < 0.01) and a fall in cardiac index (2.66 +/- 0.28 to 2.42 +/- 0.24 liters/min/m(2), p < 0.05). Pulmonary hemodynamic measurements did not change significantly in either group. CONCLUSIONS Both ET-1 and ET-3 infusions led to systemic vasoconstriction;the hemodynamic changes observed were of a similar magnitude at the same molar concentration. This suggests that ETB receptors are functionally important in mediating vasoconstriction, at least in the systemic circulation, in patients with LVSD. (J Am Coil Cardiol 1999;33:932-8) (C) 1999 by the American College of Cardiology.

关键词：慢性病内皮缩血管肽1/生理学内皮缩血管肽3/生理学血流动力学/生理学受体内皮素B 受体内皮缩血管肽/生理学心缩期/生理学血管收缩/生理学心室功能障碍左/病理生理学心室功能左/生理学老年人女(雌)性人类男(雄)性中年人

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Acute effects of urinary bladder distention on the coronary circulation in patients with early atherosclerosis

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第2期36卷 453-460页

作者： Lee, TM Su, SF Chen, NF Tsai, CH Natl Taiwan Univ Hosp Dept Surg Cardiol Sect Taipei 10002 Taiwan Natl Taiwan Univ Hosp Dept Internal Med Taipei 10002 Taiwan Natl Cheng Kung Univ Coll Med Tainan 70101 Taiwan

OBJECTIVES We sought to examine whether distention of the urinary bladder, a physiologic stimulus, could induce impaired coronary circulation in patients with early atherosclerosis. BACKGROUND Distention of the urinary bladder reflexively causes an increase in sympathetic activity. The effect of such distention on the coronary circulation in patients with early atherosclerosis remains unknown. METHODS To assess the effect of bladder distention on coronary dynamic forces, epicardial and microvascular responses were measured with an intracoronary Doppler how wire in 40 patients with early atherosclerosis (<50% diameter stenosis). Patients were randomized into two groups according to whether they did not (group 1, n = 20) or did have (group 2, n = 20) pretreatment with an alpha(1)-adrenergic receptor blocker (oral doxazosin, 2 mg). Coronary flow velocity was monitored by quantitative coronary angiography at baseline, during urinary bladder distention and after intracoronary nitroglycerin injection. METHODS Bladder distention significantly decreased the coronary diameter in the stenotic segments (p < 0.001), decreased coronary blood flow (p < 0.001) and increased coronary resistance (p < 0.001), as compared with baseline values, in group 1 patients. In group 2 patients with bladder distention, the angiographic variables did not show significant changes, as compared with baseline values. No significant differences were noted between the groups in the responses of the angiographic Variables after nitroglycerin administration. CONCLUSIONS The present study shows, for the first time, that urinary bladder distention caused vasoconstriction of coronary conduit and resistance vessels involved mechanisms related to alpha, adrenoceptors. Pretreated administration of doxazosin reversed the changes toward baseline. Vasoconstriction during bladder distention can be relieved after nitroglycerin administration, suggesting an unchanged responsiveness of vascular smooth muscle cells to

关键词：血流速度/生理学冠状动脉疾病/病理生理学冠状动脉循环/生理学冠状血管/生理学多沙唑嗪/药理学血流动力学前瞻性研究受体肾上腺素能/生理学抗交感神经药/药理学膀胱/生理学血管阻力血管收缩/生理学女(雌)性人类男(雄)性中年人

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Mechanisms underlying spontaneous rhythmical contractions in irideal arterioles of the rat

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JOURNAL OF PHYSIOLOGY-LONDON 1999年第2期521卷 507-516页

作者： Hill, CE Eade, J Sandow, SL Australian Natl Univ John Curtin Sch Med Res Div Neurosci Canberra ACT 2601 Australia

1. Mechanisms underlying spontaneous rhythmical contractions hare been studied in irideal arterioles of the rat using video microscopy and electrophysiology. 2. Rhythmical contractions (4 min(-1)) were more common during the second and third postnatal weeks and were always preceded by large, slow depolarizations (5-40 mV). 3. Spontaneous contractions were unaffected by tetrodotoxin (1 mu M), neurotransmitter receptor antagonists, the sympathetic neurone blocker, guanethidine (5 mu M) or sensory neurotoxin, capsaicin (1 mu M). 4. Stimulation of sensory nerves inhibited spontaneous activity and this was not prevented by L-NAME (10 mu M). 5. L-NAME (10 mu M) caused an increase in frequency of spontaneous contractions, while forskolin (30 nM), in the presence of L-NAME, abolished spontaneous, but not nerve-mediated, contractions. 6. Spontaneous activity was not affected by felodipine (1 nM) or nifedipine (1 mu M), but was abolished by cadmium chloride (1 mu M) or superfusion with calcium-free solution. 7. Caffeine (1 mM), thapsigargin (2 mu M) and cyclopiazonic acid (3 mu M), but not ryanodine (3 mu M), abolished spontaneous and nerve-mediated contractions. After preincubation in L-NAME (10 mu M), cyclopiazonic acid abolished spontaneous contractions only. 8. Spontaneous depolarizations and contractions were abolished by 18 alpha-glycyrrhetinic acid (20 mu M) 9. Results suggest that spontaneous rhythmical contractions are myogenic and result from the cyclical release of calcium from intracellular stores, without a contribution from voltage-dependent calcium channels. Intercellular coupling through gap junctions appears to be essential for co-ordination of these events which could be modulated by nitric oxide and increases in cAMP. The possibility that different intracellular stores underly spontaneous and nerve-mediated contractions is discussed.

关键词：腺苷三磷酸/药理学年龄因素小动脉/生理学氯化镉/药理学咖啡因/药理学钙/药理学辣椒辣素/药理学中枢神经系统刺激剂/药理学环AMP/药理学二核苷磷酸类/药理学酶抑制剂/药理学非洛地平/药理学福司柯林/药理学缝隙接合部/生理学虹膜/血液供给膜电位/药物作用膜电位/生理学肌平滑血管/生理学 NG-硝基精氨酸甲酯/药理学神经肽Y/拮抗剂和抑制剂神经肽Y/药理学肽类环/药理学周期性血小板聚集抑制剂/药理学磷酸吡哆醛/类似物和衍生物磷酸吡哆醛/药理学大鼠 Wistar 兰尼碱/药理学毒胡萝卜内酯/药理学血管收缩/生理学血管舒张药/药理学动物女(雌)性男(雄)性大鼠

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THE DEVELOPMENT OF HEMOGLOBIN-SOLUTIONS AS RED-CELL SUBSTITUTES - HEMOGLOBIN-SOLUTIONS

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TRANSFUSION SCIENCE 1995年第1期16卷 5-17页

作者： GOULD, SA SEHGAL, LR SEHGAL, HL MOSS, GS Department of Surgery Michael Reese Hospital and Medical Center Chicago University of Illinois College of Medicine 60201 USA.

Although the efficacy of hemoglobin-based oxygen carriers was established more than 60 years ago, all Frier clinical trials have demonstrated significant toxicity characterized by renal dysfunction, gastrointestinal distress, and systemic vasoconstriction. The mechanisms of these toxicities now appear to be understood. Tetrameric forms of the hemoglobin molecule extravasate from the circulation and interact with endothelial derived relaxing factor, leading to unopposed vasoconstriction. Although numerous efforts are underway to chemically modify the native tetramer, it is likely that all tetrameric forms of the hemoglobin molecule will continue to extravasate. We have focused on developing a polymerized form of hemoglobin that is virtually free of unreacted tetramer. The development and characterization of this polymerized pyridoxylated hemoglobin solution (Poly SFH-P) is described. Clinical trials have been completed successfully in volunteers, and are now underway to assess the safety and efficacy of Poly SFH-P as a clinically useful red cell substitute in the treatment of acute blood loss in the setting of trauma and surgery.

关键词：安全溶液血管收缩/生理学

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Effects of a nitrate-free interval on tolerance, vasoconstrictor sensitivity and vascular superoxide production

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2000年第2期36卷 628-634页

作者： Münzel, T Mollnau, H Hartmann, M Geiger, C Oelze, M Warnholtz, A Yehia, AH Förstermann, U Meinertz, T Univ Hamburg Hosp Eppendorf Abt Kardiol D-20246 Hamburg Germany Hebrew Univ Jerusalem Jerusalem Israel Johannes Gutenberg Univ Mainz Dept Pharmacol D-6500 Mainz Germany

OBJECTIVES In the present study, we tested whether a nitrate-free interval is able to prevent increases in vascular superoxide (O-2(.-)) and the development of hypersensitivity to vasoconstrictors and whether this may result in restoration of vascular nitroglycerin (NTG) sensitivity. BACKGROUND Intermittent NTG-patch treatment (12 h patch on/patch off) has been shown to increase ischemic periods in patients with stable coronary arteries, suggesting a rebound-like situation during the patch-off period. Recently, we demonstrated that long-term treatment with NTG induces tolerance, which was in part related to increases in vascular O-2(.-) and increased vasoconstrictor sensitivity. METHODS New Zealand white rabbits received a continuous application of NTG patches (0.4 mg/h) or an intermittent application of NTG patches (12 h patch on, 12 h patch off) for three days. Isometric tension studies were performed with aortic rings, and vascular O-2(.-) was estimated using lucigenin-derived chemiluminescence (5 mu mol/liter). Expression of the copper/zinc (Cu/Zn) superoxide dismutase (SOD) was assessed by Western blotting, and SOD activity was measured by autooxidation of 6-hydroxydopamine. RESULTS Continuous treatment with NTG caused tolerance to NTG, cross-tolerance to the endothelium-dependent vasodilator acetyicholine, increased vascular O-2(.-), reduced Cu/Zn SOD expression and increased sensitivity to vasoconstrictors such as phenylephrine, serotonin and angiotensin II. On/off treatment with NTG improved tolerance, corrected endothelial dysfunction and decreased vascular O-2(.-). In addition the reduction in SOD expression was less pronounced, whereas increases in the sensitivity to vasoconstrictors such as phenylephrine and serotonin remained nearly unchanged. CONCLUSIONS Enhanced vasoconstrictor sensitivity may explain, at least in part, the rebound phenomena observed in patients during a 12-h NTG patch-off period. (C) 2000 by the American College of Cardiology.

关键词：乙酰胆碱/药理学印迹法蛋白质药物耐受性内皮血管/药物作用内皮血管/代谢硝酸甘油/药理学氧化性应激/生理学超氧化物歧化酶/代谢时间因素血管收缩/药物作用血管收缩/生理学血管舒张药/药理学动物女(雌)性男(雄)性兔

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