Metabolic effects of papaverine and pentamine combinations with nicotinic and succinic acids in experimental vascular pathology in rabbits

It has been shown in rabbit experiments that a 7-day administration of papaverine and pentamine in doses of 1 mg/kg without administering nicotinic (4 mg/kg) and succinic (50 mg/kg) acids and in conjunction with their administration given in courses led to a distinct change in carbohydrate-phosphorus metabolism in blood vessels of rabbits with pituitrin hypertension. The drug combination removed unfavourable metabolic shifts seen in the vessels in the experimental pathology more effectively than separate drug administration.     

Trans-membrane difference of the vascular wall potentials and electrolyte content under the effect of nicotine and pentamine]

In experiments with anesthetized cats the effect of nicotine and pentamine with their intravenous administration into the organism on the transmembraneous difference on the carotid artery potentials and electrolytes exchange in the vascular wall was analyzed. Nicotine (60 and 120 gamma/kg) was found to increase the difference of potentials in the vascular wall of the carotid artery and pentamine (1 and 10 mg/kg)--to reduce it. Nicotine raised the level of potassium and downgraded the sodium concentration in the vascular wall, while changes in the proportion of calcium and magnesium ions proved to be insignificant and were demonstrable only in individual vessels. Pentamine increased the potassium and sodium content in the wall of blood vessels, excercising but little effect on the level of calcium and magnesium ions. A relation between changes in the transmembraneous difference of potentials and variations of the ionic composition in the vascular wall, mostly of potassium and sodium ions, is suggested.     

Effect of vasodilator preparations on the ATPase activity of the erythrocyte membranes of rabbits with experimental vascular pathology

Experiments on rabbits with pituitrin hypertension have demonstrated activation of Na+, K+-ATPase of red cell membranes. Meanwhile ATPase activity declined in vasorenal hypertension. The vasodilatory drugs (papaverine, pentamine, euphylline, nicotinic acid) administered in courses normalized both the activity of transport ATPases of cell membranes and carbohydrate metabolism of blood vessels, which was disturbed in experimental vascular pathology.     

cAMP and vascular action of endothelin.

Endothelin, a potent vasoconstricting peptide, induced maximal contraction of the rat tail artery within 3 min of administration. Endothelin also caused a dose-dependent decrease in tissue levels of cAMP. Concentrations of cAMP decreased about 60% 1 min after endothelin (10(-8) M) administration, but returned to basal levels in 5 min. By contrast, tissue levels of cGMP were not changed by endothelin. Modulation of cAMP production may provide one mechanism for the vascular action of endothelin.     

Apremilast ameliorates carfilzomib-induced pulmonary inflammation and vascular injuries

Acute lung injury (ALI) due to chemotherapy occurs frequently. It presents a challenge for clinicians managing therapies for different types of cancers. Carfilzomib (Kyprolis™) is a new proteasome inhibitor that shows promise for the treatment of relapsing multiple myeloma. However, several cases of severe ALI have raised concern about the use of carfilzomib against relapsed multiple myelomas. To improve the efficacy of carfilzomib, a new anti-inflammatory drug for psoriasis treatment, apremilast (Otezla™) was investigated for its protective effects against carfilzomib-induced ALI in rats. RT-PCR analyses revealed that carfilzomib administration in rats markedly increased the levels of tumor necrosis factor-alpha and nuclear factor-kappa B and myeloperoxidase activity with a concomitant increase in lipid peroxidation. The anti-inflammatory cytokine, interleukin-10, was downregulated following carfilzomib administration. Reduction in glutathione levels indicated diminished cellular antioxidant defenses in response to carfilzomib-induced ALI. ALI was confirmed by histopathological observations in lung tissue slices. Apremilast administration reduced lung inflammation in terms of reduction in myeloperoxidase activity and levels of tumor necrosis factor-alpha and alveolar infiltrating cells. Apremilast reversed all observed toxic effects of carfilzomib and prevented ALI in rats.     

Effects of midodrine on blood flow in dog vascular beds

Effects of alpha-(2,5-dimethoxyphenyl)-beta-glycinamide-ethanol hydrochloride (midodrine, ST-1085) on blood flow in different vascular beds were examined in anesthetized dogs. Intravenously administered midodrine at doses of 0.3 and 0.6 mg/kg induced a transient increase followed by a long-lasting decrease in femoral arterial blood flow. Renal arterial blood flow exhibited an initial decrease followed by returning toward the control level, and thereafter decreased again. Vertebral, common carotid, superior mesenteric and coronary arterial blood flow, and cardiac output gradually decreased. Midodrine did not have any effects on cerebral tissue blood flow. The changes were more remarkable at a dose of 0.6 mg/kg than at 0.3 mg/kg. Each arterial blood flow change was statistically analyzed 20, 30 and 60 min after the administration of 0.6 mg/kg of midodrine. The decrease of coronary arterial blood flow by the treatment with midodrine was significantly smaller than those of superior mesenteric and femoral arterial blood flow at 20 and 30 min after midodrine administration. The decrease of renal arterial blood flow was significantly smaller than those of superior mesenteric arterial blood flow at 20 and 30 min, and femoral arterial blood flow at 20, 30 and 60 min after the administration. The decrease of vertebral arterial blood flow was also smaller than that of femoral arterial blood flow at 20, 30 and 60 min after the administration.     

Early vascular benefits of statin therapy

Large-scale trials established that statin administration in hypercholesterolaemic individuals and patients with coronary heart disease (CHD) significantly reduces the risk of vascular events and death. This benefit was primarily attributed to their actions on lipids. This review focuses on the benefits (clinical and experimental) of statins observed soon (approximately 12 weeks) after their administration. Statins rapidly increase nitric oxide production and improve endothelial function (e.g. increased flow-mediated dilatation). Similarly, antioxidant properties decrease the susceptibility of low density lipoprotein cholesterol to oxidation. Statins inhibit the migration of macrophages and smooth muscle cell proliferation leading to an antiproliferative effect and the stabilisation of atherosclerotic plaques. Anti-inflammatory effects include a reduction in serum C-reactive protein levels, inflammatory and proinflammatory cytokines (e.g. IL-6, IL-8), adhesion molecules (e.g. ICAM-1, VCAM-1) and other acute phase proteins. Statins influence the haemostatic system. They reduce tissue factor expression and platelet activity, whereas fibrinolysis can be enhanced. Statins improve microalbuminuria, renal function, hypertension and arterial wall stiffness. A significant reduction of the carotid intima media thickness (IMT) was also reported early after statin treatment. These early effects of statins probably contribute to the significant reduction in vascular events seen in some 'short-term' studies. There is a need to further elucidate the rapid and non-lipid lowering properties of statins.     

白果内酯对血管性痴呆小鼠的保护作用

目的观察白果内酯(Bilobalide,BB)对血管性痴呆小鼠学习记忆功能的影响。方法采用双侧颈总动脉反复缺血—再灌注加尾动脉放血的方法建立小鼠血管性痴呆模型。血管性痴呆实验小鼠随机分为9组:假手术组、模型组,尼莫同组(Nimo,13.5 mg.kg-1),石杉碱甲片组(Hupe,0.06 mg.kg-1),BB(1.25、2.5、5、10、50 mg.kg-1)组,术后连续给药60 d。采用跳台和避暗实验,观察血管性痴呆小鼠学习和记忆的能力;化学比色法,检测脑组织匀浆中胆碱酯酶、SOD活性和MDA、NO含量;HE染色,观察脑组织病理形态学的变化。结果 BB可以缩短模型小鼠学习反应时间,延长记忆时间,减少错误次数;增加小鼠脑组织SOD活性和降低MDA含量,降低胆碱酯酶活性和NO含量。病理结果显示,BB对血管痴呆小鼠脑组织皮层和海马CA1区病理形态学变化有一定的改善作用。结论白果内酯对血管性痴呆小鼠具有一定的保护作用。     

Early vascular benefits of statin therapy

SUMMARY

Large-scale trials established that statin administration in hypercholesterolaemic individuals and patients with coronary heart disease (CHD) significantly reduces the risk of vascular events and death. This benefit was primarily attributed to their actions on lipids. This review focuses on the benefits (clinical and experimental) of statins observed soon (approximately 12 weeks) after their administration.

Statins rapidly increase nitric oxide production and improve endothelial function (e.g. increased flow-mediated dilatation). Similarly, antioxidant properties decrease the susceptibility of low density lipoprotein cholesterol to oxidation. Statins inhibit the migration of macrophages and smooth muscle cell proliferation leading to an antiproliferative effect and the stabilisation of atherosclerotic plaques. Anti-inflammatory effects include a reduction in serum C-reactive protein levels, inflammatory and proinflammatory cytokines (e.g. IL-6, IL-8), adhesion molecules (e.g. ICAM-1, VCAM-1) and other acute phase proteins. Statins influence the haemostatic system. They reduce tissue factor expression and platelet activity, whereas fibrinolysis can be enhanced. Statins improve microalbuminuria, renal function, hypertension and arterial wall stiffness. A significant reduction of the carotid intima media thickness (IMT) was also reported early after statin treatment.

These early effects of statins probably contribute to the significant reduction in vascular events seen in some 'short-term' studies. There is a need to further elucidate the rapid and non-lipid-lowering properties of statins.     

New linear polyamine derivatives in spider venoms.

Linear free polyamines were characterized in the venom of the spiders Agelenopsis aperta, Hololena curta, and Paracoelotes birulai by RP-HPLC coupled to mass spectrometry. The several linear polyamines found were tetramine, pentamine, and hexamine derivatives. Some of these natural products were identified as N-hydroxylated, guanidylated, or acetylated compounds. In addition, the biosynthetical pathway leading to the formation of acylpolyamines in spider venoms is discussed.     

Effect of izoturon and its combination with ganglionic blockaders and alpha-adrenoblockaders on systemic hemodynamics in traumatic shock

Isoturone (5 mg/kg) administered in a single dose intravenously to unanesthetized cats in a torpid phase of traumatic shock increases arterial blood pressure (BP) and total peripheral vascular resistance (TPVR). The drug restores BP level mainly due to an increase of TPVR against background of neurovegetative blockade induced by pentamine, phentolamine and combinations of phentolamine with hexonium in the presence of a severe trauma. Vascular sensitivity to isoturone in traumatic shock is preserved and considerably increases during the use of the vasopressor in different types of neurovegetative blockade.     

Pharmacological revascularisation in coronary and peripheral vascular disease

Therapeutic angiogenesis is a novel approach to the treatment of ischaemic or occlusive coronary and peripheral vascular disease. The therapeutic concept is based on the restoration of distal blood flow by the enlargement of existing vessels and tissue perfusion by the induction of new capillaries. Initial studies have focused on the direct application of endothelial growth factors, vascular endothelial growth factor and fibroblast growth factor, or the delivery of genes using either a plasmid or adenoviral vector. Recently, new angiogenic agents such as hypoxia inducible factor-1α, fibroblast growth factor-4, Del-1 and hepatocyte growth factor have entered clinical testing. Moreover, stem-cell therapy or factors mobilising bone marrow progenitor cells have provided evidence for a new avenue for therapeutic angiogenesis. Numerous preclinical studies and several initial clinical trials have provided encouraging data in support of the feasibility of promoting biological revascularisation by the administration of angiogenic factors or cells.     

Kavain attenuates vascular contractility through inhibition of calcium channels

Kavain is a biologically active compound from the Oceanic plant Piper methysticum (kava). Traditional medicinal uses of the kava root are many. Kava is increasingly being utilized by Western societies for its anxiolytic effects. Recent reports indicate that kavain blocks ion channels in neural tissue, relaxes precontracted ileum, and relaxes precontracted airway. Thus, we investigated the potential ability of this plant-derived compound to alter vascular smooth muscle function. Thoracic aortae were isolated from Sprague-Dawley rat and cut into 4 mm rings. Rings were placed in tissue baths and suspended from force-displacement transducers for the measurement of isometric tension. In a dose-dependent manner, kavain (10(-6) M to 10(-3) M) was found to relax aortic rings precontracted with phenylephrine (PE). This response was not dependent on functional endothelium. In addition, kavain pretreatment (3 x 10(-5) M or 3 x 10(-4) M) attenuated vascular smooth muscle contraction evoked by PE. However, kavain failed to attenuate PE-mediated contraction in calcium (Ca(++))-free buffer, indicating that intracellular signaling processes were likely not affected. Also, kavain did attenuate the contraction elicited by administration of Ca(++) to depolarized tissue. Interestingly, in rings pre-treated with the selective L-type Ca(++) channel blocker nifedipine, kavain-mediated relaxation was inhibited. Lastly, in rings selectively contracted with an L-type calcium channel activator, kavain elicited dose-dependent (and ultimately complete) relaxation. These data strongly suggest that kavain impairs vascular smooth muscle contraction, likely through inhibition of Ca(++) channels.     

Molecularly engineered truncated tissue factor with therapeutic aptamers for tumor-targeted delivery and vascular infarction

Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy. Among vascular coagulation agents, the extracellular domain of coagulation-inducing protein tissue factor, truncated tissue factor (tTF), is the most widely used. Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation, free tTF cannot be used for cancer treatment on its own but must be combined with other moieties. We here developed a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors, thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects. This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.KEY WORDS: Tumor targeted delivery, Truncated tissue factor (tTF), AS1411 aptamer, Thrombosis, Tumor infarction     

Elevated vascular γ‐butyrobetaine levels attenuate the development of high glucose‐induced endothelial dysfunction

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Effects of the anti-platelet agent cilostazol on peripheral vascular disease in patients with diabetes mellitus.

Effects of cilostazol (OPC-13013, CAS 73963-72-1), a selective inhibitor of platelet cAMP-phosphodiesterase, on peripheral vascular disease in diabetes mellitus were studied. Cilostazol in a dose of 200 to 300 mg/d was administered to 5 diabetic patients with arteriosclerosis obliterans. Skin temperature of the finger and the toe, which reflects blood flow to the tissue, was selected as an objective index of cilostazol effects and measured by infra-red thermography at a constant temperature of 26 degrees C. Before administration, digital skin temperatures were low in 9 limbs of 5 patients. 200 mg/d of cilostazol significantly (p less than 0.001) increased the digital skin temperatures of 8 limbs, the increase (mean +/- SD) ranging from 29.9 +/- 1.4 degrees C to 33.2 degrees C +/- 1.2 degrees C for the average skin temperatures and from 28.7 +/- 2.1 degrees C to 33.1 +/- 1.5 degrees C for the lowest ones. An increase in the dose to 300 mg/d resulted in further elevation of skin temperatures of the digits. Cilostazol constantly elicited an increase in blood flow to the digits within the range of its therapeutic dose. This effect was observed about 1 month after initiation of administration and persisted while administration was continued. The measurement of digital skin temperatures by infrared thermography provided a noninvasive means to individualize the dosage of cilostazol and to monitor the cilostazol effect and patient complicance during long-term administration. It is concluded that cilostazol exerts a potent and steady vasodilatory effect on peripheral circulation in patients with diabetes mellitus.     

Sarpogrelate hydrochloride, a selective 5-HT2A antagonist, improves vascular function in patients with peripheral arterial disease

Peripheral arterial disease (PAD) is 1 of the major manifestations of atherosclerosis. PAD is associated with endothelial dysfunction. Sarpogrelate hydrochloride, a selective 5-HT2A antagonist, has been widely used as an anti-platelet agent for the treatment of PAD. There is no information on whether endothelial function is improved after initiation of sarpogrelate treatment in patients with PAD. The purpose of this study was to evaluate the effects of sarpogrelate on endothelial function in patients with PAD. We divided PAD patients into 2 groups: those treated with sarpogrelate at a dose of 100 mg 3 times per day orally for 12 weeks (sarpogrelate group, n = 10), and those who remained on conventional therapy (control group, n = 11). Forearm blood flow (FBF) and leg blood flow (LBF) responses to reactive hyperemia (RH) and sublingual administration of nitroglycerin (NTG) were measured using strain-gauge plethysmography. After 12 weeks of sarpogrelate administration, FBF and LBF responses during RH showed significant increases from 13.2 +/- 1.7 to 18.1 +/- 2.2 mL/min per 100 mL tissue (P < 0.01) and from 8.2 +/- 0.9 to 14.2 +/- 2.1 mL/min per 100 mL tissue (P < 0.05), respectively. Sarpogrelate-induced augmentation of FBF and LBF responses to RH was maintained at 24 weeks. No change was observed in the control group at each follow-up time point. The changes in FBF and LBF after sublingual NTG were similar during follow-up periods in the 2 groups. These findings suggest that long-term oral administration of sarpogrelate improves vascular function in patients with PAD.     

Celecoxib,a selective cyclooxygenase-2 inhibitor,inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model

Overexpression of vascular endothelial growth factor (VEGF) is implicated in the development of vascular leakage and retinal neovascularization in diabetic subjects. The objective of this study was to determine whether celecoxib, a selective cyclooxygenase-2 enzyme inhibitor, reaches ocular tissues following oral administration and inhibits the retinal VEGF expression and vascular leakage in a streptozotocin-induced diabetic rat model. After administering a single intraperitoneal injection of streptozotocin (60 mg/kg) to Sprague-Dawley rats and ensuring the induction of diabetes at the end of 24 h, celecoxib was administered b.i.d. by oral gavage (50 mg/kg). On day 8, the animals were sacrificed and the retinal VEGF and cyclooxygenase-2 mRNA levels, ocular tissue celecoxib concentrations, and the vitreous/plasma protein ratio were determined. In diabetic rats, the retinal VEGF mRNA expression was 2.3-fold compared to controls, with a corresponding increase in cyclooxygenase-2 mRNA expression. Celecoxib treatment inhibited VEGF mRNA expression without any significant reduction in cyclooxygenase-2 mRNA. Furthermore, the retinal vascular leakage estimated as vitreous to plasma protein ratio increased in diabetic animals from 0.35+/-0.1 to 1.1+/-0.1 and celecoxib treatment significantly decreased this ratio to 0.4+/-0.1. Celecoxib levels were 24.8+/-6.6, 1.9+/-1, 1.7+/-0.8, and 6.9+/-0.9 ng/mg in the retina, vitreous, lens, and cornea, respectively. The plasma celecoxib levels were 85+/-24 ng/ml. Thus, celecoxib reaches the retina after oral administration and reduces diabetes-induced retinal VEGF mRNA expression and vascular leakage by inhibiting the activity of cyclooxygenase-2 enzyme.     

Differential neural activation of vascular alpha-adrenoceptors in oral tissues of cats

The aim of this study was to determine the relative contribution of alpha(1)- and alpha(2)-adrenoceptors involved in sympathetic-evoked vasoconstrictor responses in tissues perfused by the lingual arterial circulation in pentobarbital anesthetized cats. Blood flow in the lingual artery was measured by ultrasonic flowmetry. Laser-Doppler flowmetry was utilized to measure oral tissue vasoconstrictor responses in the maxillary gingiva and from the surface of the tongue. Electrical stimulation of the preganglionic superior cervical sympathetic nerve resulted in frequency-dependent blood flow decreases at all three sites. These responses were stable over time and were uniformly antagonized by administration of phentolamine (0.3 - 3.0 mg kg(-1)). The selective alpha(1)-adrenoceptor antagonist, prazosin (10 - 300 microg kg(-1)), attenuated vasoconstriction in the lingual artery and gingiva, but was ineffective in blocking vasoconstriction in the tongue. Subsequent administration of rauwolscine (300 microg kg(-1)) antagonized remaining vasoconstrictor responses. In contrast, rauwolscine (10 - 300 microg kg(-1)), given alone, blocked evoked vasoconstriction in the tongue, and was without effect on gingival or lingual artery vasoconstrictor responses. Subsequent administration of prazosin (300 microg kg(-1)) largely antagonized remaining neurally elicited responses. These results suggest that neural vasoconstrictor responses in some regional vascular beds in the cat oral cavity are mediated by both alpha(1)- and alpha(2)-adrenoceptors. In contrast, tongue surface vasoconstrictor responses to sympathetic nerve activation appear to be mediated primarily by alpha(2)-adrenoceptors.     

In vitro neuronal and vascular responses to 5-HT in rats chronically exposed to MDMA.

1. This study examined the effects of chronic exposure of rats to 3,4-methylenedioxymethamphetamine (MDMA) on [(3)H]5-hydroxytryptamine ([(3)H]5-HT) re-uptake into purified rat brain synaptosomes, 5-HT-induced isometric contraction of aortic rings and [(3)H]5-HT re-uptake into rat aorta. 2. Rats were administered MDMA (20 mg kg(-1) i.p.) twice daily over 4 days. One, 7, 14 or 21 days post treatment, whole brain synaptosomes and descending thoracic aortic rings were prepared for investigation. 3. Chronic MDMA treatment significantly reduced the maximum rate (V(max)) of specific high-affinity [(3)H]5-HT re-uptake 1 day after treatment and for up to 21 days post-final administration of MDMA. Direct application of MDMA (100 microM) abolished synaptosomal re-uptake of [(3)H]5-HT in vitro. 4. Chronic MDMA administration significantly reduced the maximum contraction (E(max)) to 5-HT at 1 and 7 days after treatment, but not at 14 or 21 days. 5. Chronic MDMA administration had no effect on sodium-dependent [(3)H]5-HT re-uptake into aorta 1 day after treatment, nor did 100 microM MDMA have any direct effect on [(3)H]5-HT uptake into aortic rings in vitro. 6. These results show, for the first time, an altered responsiveness of vascular tissue to MDMA after chronic administration. In addition, they demonstrate a difference in the sensitivity of central and peripheral 5-HT uptake systems to chronic MDMA exposure, and suggest that the action of MDMA in the cardiovascular system does not arise from a direct effect of MDMA on peripheral 5-HT transport.