Phosphoinositide 3-kinase contributes to diabetes-induced abnormal vascular reactivity in rat perfused mesenteric bed

Phosphatidylinositol 3-kinase (PI3K) is a signaling enzyme that plays key roles in vascular growth, proliferation, and cellular apoptosis and is implicated in modulating vascular smooth muscle contractility. The aim of this study was to determine whether PI3K contributes to development of diabetes-induced abnormal vascular reactivity to selected vasoactive agonists. The effect of 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a selective PI3K inhibitor, on isolated perfused mesenteric vascular bed from streptozotocin (STZ)-diabetic rats was investigated. Changes in perfusion pressure, which reflected peripheral resistance, were measured using isolated perfused mesenteric vascular beds. Our results showed that STZ treatment produced an increase in the vasoconstrictor response to norepinephrine (NE), angiotensin II (Ang II) and endothelin-1 (ET-1), and an attenuated vasodilator response to carbachol and histamine in the isolated perfused mesenteric vascular bed from STZ-diabetic animals. Chronic inhibition of PI3K with LY294002 resulted in prevention of diabetes-induced abnormal vascular reactivity to the vasoactive agonists. However, the high blood glucose levels were not normalized. Results of this study indicate that selective inhibition of PI3K can attenuate the development of diabetes-induced abnormal vascular responsiveness in the isolated perfused mesenteric vascular bed.     

The redistribution of cardiac output in the dog during heat stress

In conscious Greyhound dogs, radioactive microsphere techniques have been used to measure cardiac output, its regional distribution, and proportion of the cardiac output passing through arteriovenous anastomoses (AVA's) in a thermoneutral environment and during severe heat stress. Heat stress resulted in a 74% increase in cardiac output and 4–6% of the cardiac output passed through AVA's. compared with about 1% under thermoneutral conditions: blood flow rate increased in skin of the lower legs and ears, tongue, maxillo turbinals, nasal mucosa, respiratory muscles and spleen, decreased in the thyroids, brain and spinal cord, and did not change significantly in the non-respiratory muscles, heart, pituitary, adrenals, kidneys, liver, stomach and intestines. Thus the circulatory requirements of the heat stressed dogs were met partly by an increase in cardiac output and partly by changes in its distribution. In contrast, the Merino sheep meets such a situation entirely by a redistribution of cardiac output. The present results may be taken as evidence that the Greyhound dog is less heat tolerant than the Merino sheep. The decreased brain blood flow during heat stress is similar to that which occurs in the sheep, but contrast with previous results obtained on anaestherized dogs. The less marked redistribution of cardiac output in the dog compared with the sheep, may explain the apparent difference in energy cost of panting in the two species.     

Disruption of the rat mesenteric arterial bed endothelial function by air perfusion

The impact of air perfusion on the endothelial function of the rat mesenteric arterial bed (MAB; perfused with Krebs' bicarbonate plus indomethacin) was compared to that of the NO synthase inhibitor, N^ω-nitro-L-arginine methyl ester (L-NAME). Air shifted the dose-response curve for the alpha-adrenoceptor agonist, norepinephrine (NE) to the left (ED_50%: 2.9 ± 0.7 to 0.9 ± 0.7 μg, P < 0.05); maximal vasoconstriction did not change. L-NAME produced a similar increase in midrange sensitivity (ED_50% 1.4 ± 0.7 μg, P < 0.05) and a 20% increase in maximum (152 ± 6 to 183 ± 7 mmHg, P < 0.05). Electromechanical stimulation with potassium chloride (KCL) was not modified by reserpine. Neither air nor L-NAME modified midrange sensitivity to KCL. L-NAME produced a 17% increase in maximum (91 ± 4 to 107 ± 5 mmHg, P < 0.05); reserpine abolished the latter effect. Air and L-NAME diminished endothelium-dependent vasodilation elicited by carbachol. Air did not modify endothelium-dependent vasodilation elicited by sodium nitroprusside; this response was potentiated by L-NAME. In summary, air and L-NAME produced similar effects on receptor-dependent activation of the endothelial L-arginine nitric oxide (NO) pathway. Potentiation by L-NAME of the maximal electromechanical response suggests the existence of a tone-dependent NO system. Abolition of the latter response by reserpine suggests that this system is of sympathetic origin.     

Vanadate-evoked relaxation of the perfused rat mesenteric vascular bed

Sodium orthovanadate (SOV) can contract smooth muscle; however, little is known about its effect on the vascular endothelium. We compared the vasorelaxant effects of acetylcholine (ACh) and SOV in the preconstricted, isolated perfused mesenteric vascular bed (MVB) of Sprague-Dawley rats. The maximal relaxation response evoked by SOV (40-45%) was lower than ACh (92-94%) but the IC50 values were similar. At concentrations > 1 mM, SOV elevated the basal tone. Endothelial denudation resulted in a substantial reduction of relaxation responses to both agents, whereas either nitric oxide synthase (NOS) inhibitors or high KCl partially reduced the responses. A combination of NOS inhibitors along with either a calcium-activated potassium channel (KCa) blocker, tetrabutylammonium (TBA), or high KCI inhibited the responses to a similar extent as endothelium denudation. Neither clotrimazole nor TBA attenuated ACh responses; however, maximal responses to SOV in the presence of TBA or clotrimazole were reduced. Indomethacin had no effect on responses to either agonists. These results indicate that like ACh, SOV-mediated vasorelaxation of the MVB involves recruitment of both endothelial derived hyperpolarizing factor (EDHF) and endothelial derived nitric oxide (NO) and not vasodilator eicosanoids. As the relaxation to SOV was dose-dependent at a low concentration range, it is likely that vanadate is involved in the regulation of total peripheral resistance.     

Tempol improves vascular function in the mesenteric vascular bed of senescent rats

Ageing is associated with structural and functional alterations of the vasculature. The nature of age-related vascular disorders is not completely understood. Oxidative stress is hypothesized to play a crucial role in the pathophysiology of vascular complications. We investigated the effects of chronic treatment with the superoxide dismutase mimetic tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl) on vascular function in the mesenteric vasculature of aged rats. Young (3 weeks) and old (40 weeks) Sprague-Dawley rats were treated with tempol (1 mM in drinking water) or vehicle for 3 weeks. Arterial blood pressure was slightly, but significantly, higher in old than in young rats. Tempol had no effect on arterial blood pressure. The vasoconstrictor responses to norepinephrine (NE) and serotonin (5-HT) were exaggerated in the mesenteric vascular bed (MVB) removed from old rats. Vasodilator responses to acetylcholine (ACh), papaverine (PPV), and isoprenaline (ISO) were reduced in the MVB of old rats in comparison with young rats. Chronic treatment of old rats with tempol normalized their responses to NE and 5-HT. The dilator responses to ACh, PPV, and ISO were similar between old rats receiving tempol and young rats. The present findings suggest that oxidative stress contributes to vascular dysfunction in the mesentery of old rats. The vasculoprotective effects of tempol remain to be elucidated.     

下体负压对家兔血液动力学的影响

观察了家兔在-20、-40、-60mmHg下体负压下心输出量、心搏量、心率、血压以及心电图、脑电图、视网膜电图的变化。实验结果表明:心搏量与心输出量明显减少,在-60mmHg下作用10分钟两者可下降到负压前对照值的15％。心率大多数加快,以代偿心输出量的下降。如出现持续性心率过缓和心律不齐,标志代偿失调。收缩压、舒张压、平均动脉压、脉压均呈规律性下降。根据血压反应可将动物分为耐力良好、尚好、较差三种类型。心电图变化主要表现为冠脉供血不足,心肌缺氧特征,并伴有高尖状P波。脑电图出现缺氧性慢波、波幅降低。视网膜电图的b波波幅逐渐下降,持续期缩短,80％以上有b负波,这些变化可能与脑部及视网膜供血不足有关。     

过热兔血中毒性物质的探讨

本文观察到13只受热兔(肛温超过40℃)与正常兔交叉循环后,正常兔血压、心输出量均明显降低,30′、60′、90′时收缩压由循环前的109.2mmHg分别降为88.1,85.1,68.9mmHg(P<0.01),舒张压由循环前的80.5mmHg降为68.5,69.6,56.4mmHg(P<0.01)。心输出量循环前为477.2ml/min,循环30′时降为381.4ml/min,60′时为320.9ml/min(P<0.01)。心率无明显改变。还观察到血清及组织电解质在受热兔及与之交叉循环的正常兔中均发生了某些改变。受热兔血清钾、镁明显升高,钙明显降低;脑中钠、钙、镁明显升高;肝、肠中钾明显降低,钠明显升高。与其交叉循环的正常兔发生了十分一致的变化。与受热兔交叉循环的正常兔肛温并未升高,未发生明显改变。结果表明,过热兔血中存在有使正常兔血压及心输出量降低,组织电解质分布发生改变的因素。     

Raised tone reveals ATP as a sympathetic neurotransmitter in the porcine mesenteric arterial bed

The relative importance of ATP as a functional sympathetic neurotransmitter in blood vessels has been shown to be increased when the level of preexisting vascular tone or pressure is increased, in studies carried out in rat mesenteric arteries. The aim of the present study was to determine whether tone influences the involvement of ATP as a sympathetic cotransmitter with noradrenaline in another species. We used the porcine perfused mesenteric arterial bed and porcine mesenteric large, medium and small arteries mounted for isometric tension recording, because purinergic cotransmission can vary depending on the size of the blood vessel. In the perfused mesenteric bed at basal tone, sympathetic neurogenic vasocontractile responses were abolished by prazosin, an α₁-adrenoceptor antagonist, but there was no significant effect of α,β-methylene ATP, a P2X receptor-desensitizing agent. Submaximal precontraction of the mesenteric arterial bed with U46619, a thromboxane A₂ mimetic, augmented the sympathetic neurogenic vasocontractile responses; under these conditions, both α,β-methylene ATP and prazosin attenuated the neurogenic responses. In the mesenteric large, medium and small arteries, prazosin attenuated the sympathetic neurogenic contractile responses under conditions of both basal and U46619-raised tone. α,β-Methylene ATP was effective in all of these arteries only under conditions of U46619-induced tone, causing a similar inhibition in all arteries, but had no significant effect on sympathetic neurogenic contractions at basal tone. These data show that ATP is a cotransmitter with noradrenaline in porcine mesenteric arteries; the purinergic component was revealed under conditions of partial precontraction, which is more relevant to physiological conditions.     

肠淋巴液引流对失血性休克大鼠红细胞流变性的影响

目的:观察肠淋巴液引流对失血性休克大鼠红细胞流变性指标以及血液黏度的作用。方法:Wistar雄性大鼠均分为假休克组、休克组(复制失血性休克模型)、引流组(复制失血性休克模型,自低血压1 h引流休克肠淋巴液)。在低血压3 h或相应时间,经腹主动脉取血,检测红细胞参数、红细胞电泳、红细胞沉降率(ESR)以及血液黏度,计算红细胞聚集指数、红细胞变形指数。结果:与假休克组比较,休克组红细胞数量、红细胞比积(HCT)、血红蛋白(Hb)、平均红细胞血红蛋白浓度(MCHC)、红细胞电泳率与迁移率、红细胞变形指数、全血黏度、全血低切与高切相对黏度和还原黏度显著降低,休克组平均红细胞体积、红细胞电泳时间、ESR、血沉方程K值与校正K值、红细胞聚集性指数、血浆黏度显著升高;引流组MCHC、红细胞电泳率与迁移率、全血黏度、全血低切与高切还原黏度均显著降低,引流组红细胞体积分布宽度(RDW-SD)显著增加。同时,引流组HCT、RDW-SD、红细胞变形指数、全血黏度、全血低切与高切相对黏度显著高于休克组;ESR、血沉方程K值与校正K值、红细胞聚集性指数、血浆黏度显著低于休克组。结论:休克肠淋巴液引流可改善失血性休克大鼠红细胞流变行为,从而改善血液流变性。     

Effects of estrogens and selective estrogen receptor modulators on vascular reactivity in the perfused mesenteric vascular bed

Estrogens and selective estrogen receptor modulators (SERMs), such as raloxifene (RAL) and tamoxifen (TAM), acutely relax arteries, but the long-term effects of estrogens and SERMs on vascular reactivity in the mesenteric vasculature have not been well defined. In this study, we used an isolated, perfused mesenteric vascular bed technique to investigate the effect of chronic treatment of estrogens and SERMs on vascular reactivity of the mesenteric bed. Ovariectomized female Sprague-Dawley rats were treated by gavage with vehicle (control, 2-hydroxypropyl-beta-cyclodextrin), ethinyl estradiol, estradiol benzoate, equilin (EQ), TAM, or RAL for 3 wk. EQ and TAM increased vasoconstriction in response to all three vasoconstrictors tested (KCl, norepinephrine, and 5-HT). Ethinyl estradiol increased vasoconstriction in response to KCl and 5-HT, whereas responses to estradiol benzoate and RAL were less consistent. Only EQ (134 +/- 4 mmHg) and TAM (104 +/- 4 mmHg) changed mean arterial blood pressure compared with control (117 +/- 4 mmHg). These data demonstrate that 3-wk gavage treatment with estrogens and SERMs affects vascular reactivity in the mesenteric vascular bed. However, the three formulations of estrogen did not produce equivalent effects, and the effects of the SERMs were different from those of the estrogens.     

The effect of hypothermia on the cardiovascular system and the pressor actions of angiotensin II

1. 1.|The effect of hypothermia (24°C) on the pressor action of angiotensin II (ANG II) was studied in anaesthetized rats.

2. 2.|Hypothermia prolonged the pressor response to ANG II leading to an increase in the estimated half-life of ANG II.

3. 3.|Hypothermia also caused a significant increase in stroke volume and a significant decrease in heart rate with no change in cardiac output.

4. 4.|It is conclued that hypothermia causes a prolongation of the pressor action of ANG II probably by reducing the activity of the catabolic enzymes leading to an increase in ANG II half-life.

Influence of NG-monomethyl-L-arginine on endothelium-dependent relaxations in the perfused mesenteric vascular bed of the rat

Endothelium-dependent relaxation mediated by the formation of nitric oxide (NO) from L-arginine, is prevented by the arginine analog NG-monomethyl L-arginine (L-NMMA) (Palmer et al., Biochem. Biophys. Res. Comm. 153:1251-1256 (1988)). In the rat mesenteric arterial bed, incubation with L-NMMA did not prevent acetylcholine-induced relaxation, which, however, was reversed when L-NMMA was added during its maximum effect. A similar profile of action was observed with methylene blue, an inhibitor of guanylate cyclase. Methylene blue, but not L-NMMA, increased basal perfusion pressure. These data indicate that in the mesenteric arterial bed, NO formation via the L-NMMA-sensitive pathway occurs during stimulation with acetylcholine, but not under basal conditions.     

The effect of caffeine on prostaglandin output from the perfused mesenteric vascular bed of the rat

Caffeine significantly (p < 0.05) increased the output of prostacyclin (PGI₂) from the perfused rat mesenteric vascular bed. The outputs of PGE₂ and PGF_2α were also increased by caffeine. This stimulatory response to caffeine did not show rapid desensitization. Ryanodine also increased PG output, suggesting that caffeine may be acting via the stimulation of a ryanodine receptor. The increased production of a vasodilator such as PGI₂ from blood vessels following exposure to caffeine may explain why caffeine has a beneficial effect in angina.     

Intracellular renin increases the inward calcium current in smooth muscle cells of mesenteric artery of SHR. Implications for hypertension and vascular remodeling

The influence of intracellular renin on the inward calcium current in isolated smooth muscle cells from SHR mesenteric arteries was investigated. Measurements of calcium current were performed using the whole cell configuration of pCLAMP. The results indicated that: 1) renin (100 nM) dialyzed into smooth muscle cells, increased the inward calcium current; 2) verapamil (10–9 M) administered to the bath inhibited the effect of renin on the inward calcium current; 3) concurrently with the increase of calcium current a depolarization of 6.8 +/− 2.1 mV (n = 16)(P < 0.05) was found in cells dialyzed with renin; 4) intracellular dialysis of renin (100 nM) into smooth muscle cells isolated from mesenteric arteries of normal Wystar Kyoto rats showed no significant change on calcium current; 5) aliskiren (10–9 M) dialyzed into the cell together with renin (100 nM) abolished the effect of the enzyme on the calcium current in SHR; 6) Ang II (100 nM) dialyzed into the smooth muscle cell from mesenteric artery of SHR in absence of renin, decreased the calcium current-an effect greatly reduced by valsartan (10–9 M) added to the cytosol; 7) administration of renin (100 nM) plus angiotensinogen (100 nM) into the cytosol of muscles cells from SHR rats reduced the inward calcium current; 8) extracellular administration of Ang II (100 nM) increased the inward calcium current in mesenteric arteries of SHR. Conclusions: intracellular renin in vascular resistance vessels from SHR due to internalization or expression, contributes to the regulation of vascular tone and control of peripheral resistance-an effect independently of Ang II. Implications for hypertension and vascular remodeling are discussed.     

The influence of phenelzine and tranylcypromine on the release of prostaglandins from the rat mesenteric vascular bed

We investigated the effects of phenelzine and tranylcypromine on the release of prostacyclin, thromboxane A2, prostaglandin E2, and prostaglandin E1 from the isolated perfused rat mesenteric vascular bed. Perfusion of the preparation with phenelzine in concentrations of 15, 45, and 135 microM for 150 min led to attenuated release of all four prostaglandins measured. Inhibition generally occurred with the lowest dose used and was most prominent with the highest concentration. Tranylcypromine also decreased prostaglandin formation. However, low doses were not effective in the suppression of prostacyclin release. Both drugs had an inhibitory effect on production of prostaglandin E1, which is a metabolite of dihomo-gamma-linolenic acid, the precursor of arachidonic acid, but this was only shown to be significant with phenelzine. In this work we demonstrate that phenelzine and tranylcypromine have an inhibitory effect on the production of 2-series prostaglandins derived from arachidonic acid, and possibly a similar effect on prostaglandins of the 1-series derived from dihomo-gamma-linolenic acid.