Prostacyclin causes splenic dilation and haematological change in dogs

1. The effect of vasodilators on spleen volume and the blood storage function is not yet well elucidated. To this end, in the present study the effects of prostacyclin, a potent vasodilator, on splenic diameter and blood cell concentrations in arterial and splenic venous blood were evaluated in anaesthetized dogs. 2. The main splenic artery and vein were dissected for measurement of splenic arterial blood flow and intra-arterial administration and for sampling of splenic venous blood, respectively. The diameter of the spleen was measured continuously by sonomicrometry. Counts of white blood cells (WBC), red blood cells (RBC) and platelets in blood sampling from the aorta and splenic vein were estimated by an automatic blood cell counter. 3. Bolus injections of prostacyclin (1-100 ng/kg) into the splenic artery produced dose-dependent increases in splenic arterial blood flow and splenic diameter associated with significant decreases in splenic venous concentrations of WBC, RBC and platelets. When splenic blood flow was kept constant, similar changes in splenic diameter and blood cell counts were observed with prostacyclin injection. 4. Splenic dilation and haematological changes induced by prostacyclin were relatively more potent than those induced by prostaglandin E(2), acetylcholine, nitroglycerin or isoproterenol when doses producing a comparable increase in splenic blood flow were compared. 5. Infusion of prostacyclin (100 ng/kg per min) into the splenic artery caused a marked increase in splenic diameter, with immediate reductions in splenic venous concentrations of WBC, RBC and platelets, followed by significant reductions in these cell counts in the general circulation. 6. These results indicate that prostacyclin produces potent and flow-independent splenic dilation that may contribute to a decrease in circulating blood cell concentrations.     

脾功能亢进微波消融治疗的临床研究

目的探讨微波消融治疗脾功能亢进的最佳方法。方法54名肝炎后肝硬化门脉高压脾功能亢进患者在彩超引导下经皮网格状脾穿刺微波消融术,分别在术前及术后7、30、90、180、360天检测外周血WBC、RBC、PLT及脾动静脉内径（D）、最大血流速度（Vmax）、平均血流速度（Vmean）、计算脾血流量（Q）。结果54名患者WBC、PLT术后7天较术前明显升高（P〈0．05）,脾脏动静脉Vmax、Vmean、Q降低（P〈0．05）,并且网格状消融后产生的纤维条索能预防消融后的脾脏代偿性增生。结论采用网格状经皮脾穿刺消融术可有效治疗脾功能亢进,降低门静脉压力,改善脾亢引起的血细胞过低,结合胃镜下食道静脉套扎术可预防上消化道出血发生。     

Effect of human splenic contraction on variation in circulating blood cell counts

1. The human spleen sequesters 200-250 mL densely packed red blood cells. Up to 50% of this viscous blood is actively expelled into the systemic circulation during strenuous exercise or simulated apnoea (breath-hold) diving. The contribution of splenic contraction to changes in the circulating volume of red blood cells (RBCV), as well as the venous concentration of white blood cells (WBC) and platelets (PLT), was investigated following repeated breath-hold apnoeas. 2. Eighteen trained apnoea divers and 18 intact and six splenectomized subjects without diving experience repeated five maximal apnoeas with face immersion in cold water, with 2 min intervals between successive attempts. Venous blood samples were taken before and between consecutive apnoeas, as well as at 0, 10 and 20 min after the last breath hold. Arterial pressure, heart rate and transcutaneous partial pressure of oxygen and carbon dioxide were monitored continuously. 3. Plasma protein concentration decreased by 5.8, 2.2 and 9% in apnoea divers, untrained and splenectomized subjects, respectively, indicating an expansion of plasma volume. The RBCV and venous concentration of WBC, corrected for changes in plasma volume, increased in both trained apnoea divers (4.9+/-1.0 and 14.9+/-3.1%, respectively) and intact subjects (1.7+/-0.8 and 7.2+/-1.8%, respectively), whereas in splenectomized subjects there was no change in RBCV and a delayed increase in WBC concentration. Furthermore, an initial lymphocytosis detected during repeated breath holds in divers and intact subjects was completely absent in splenectomized subjects. None of the groups showed significant changes in PLT concentrations. The well-recognized diving response to apnoea (bradycardia and increased blood pressure) was seen during all breath-hold attempts in all subjects. 4. Repeated breath-holds (apnoeas) contribute to increased RBCV and venous blood concentrations of WBC through splenic contraction.     

肝硬化伴脾亢患者肝移植术后脾功能变化的研究

目的观察肝硬化伴脾亢患者肝移植术后外周血细胞及脾脏大小的变化,探讨肝移植对脾功能亢进的影响。方法30例行肝移植保留脾脏手术的乙肝肝硬化伴脾亢患者,测定术前及术毕,术后1、2、3、5、7、14、21、28d红细胞、白细胞、血小板计数（PLT）、凝血酶原时间（PT）、活化部分凝血酶原时间（APTT）。术前,术后1、2、3、4周B超测定脾脏上下径、肋间厚度、脾门处脾静脉直径。结果术毕时PLT较切皮前明显增加（P〈0.05）,术后2d又显著降低。术后3dPLT和RBC均明显增加,一直持续至术后28d（P〈0.05或P〈0.01）;与切皮前相比,WBC从术毕开始增加,持续至术后2d（P〈0.05或P〈0.01）,术后3d开始下降到术前水平,并持续至术后28d（P〉0.05）;与术前相比,术后3周脾脏上下径及厚度开始明显减小（P〈0.05）,脾静脉直径术后4周明显减小（P〈0.05）;与切皮前相比,PT从术后2d开始降低并持续至术后28d（P〈0.05或P〈0.01）;术毕及术后1d APTT均较切皮前明显增加（P〉0.05）,术后2d又明显降低,并持续至术后28d（P〈0.01）。结论肝移植能有效的治疗肝硬化伴脾功能亢进症,肝移植可保留功能亢进的脾脏。     

Actions of prostaglandin F2α on the splenic vascular and capsular smooth muscle in the dog

1. The actions of prostaglandin F(2alpha), which is known to be released by the spleen on sympathetic nerve stimulation, have been investigated in the isolated blood perfused spleen of the dog.2. Low arterial concentrations of F(2alpha) (less than 10 mug/100 ml) caused marked reductions in splenic vascular resistance.3. High arterial concentrations of F(2alpha) (above 10 mug/100 ml) caused increases in splenic vascular resistance.4. Little action on splenic volume was observed by any arterial concentration of F(2alpha).5. The reductions in splenic vascular resistance caused by low arterial concentrations of F(2alpha) were reversed by blocking doses of phenoxybenzamine.6. No appreciable interaction between F(2alpha) and the splenic responses to sympathetic nerve stimulation, adrenaline and noradrenaline was observed.7. The role of the prostaglandins released by the spleen is discussed.     

The actions of endothelins-1 and -3 on the vascular and capsular smooth muscle of the isolated blood perfused spleen of the dog.

1. Endothelin-1 (ET-1), endothelin-3 (ET-3) and noradrenaline (NA) were administered as intra-arterial bolus injections into the isolated, blood-perfused spleen of the dog to assess agonist properties and relative molar potencies on the vascular and capsular smooth muscle. 2. An initial small vasodilatation was observed occasionally at low doses (1.0-10 pmol) of ET-1. 3. ET-1, ET-3 and NA all caused graded increases in splenic arterial vascular resistance. The molar ED50 for the splenic vasoconstrictor response to ET-1 was significantly less (P less than 0.001) than that to ET-3; both peptides were significantly more potent as vasoconstrictor agents than NA. The maximum increase in splenic arterial vascular resistance was not significantly different for either ET-1, ET-3 or NA. 4. The time course of the splenic vasoconstrictor response to ET-1 was significantly (P less than 0.01) longer than that to equieffective doses of ET-3 or NA. 5. The splenic vasoconstrictor responses to ET-1 and ET-3 were accompanied by reductions in spleen volume. The rank order of molar potency in causing splenic capsular contraction was ET-1 greater than ET-3 greater than NA. The maximum reduction in splenic volume was significantly greater for NA than for either ET-1 or ET-3. The two peptides (ET-1, ET-3) were equiefficacious in contracting splenic capsular smooth muscle. 6. The high molar potency of ET-1 as a splenic arterial vasoconstrictor, over 1,700 times more potent than NA, suggests that it may play an important local role in the control of splenic haemodynamics.     

Effect of sympathomimetic amines on the histamine forming capacity of human leucocytes

1 The effects of alpha- and beta-adrenoceptor stimulants on the histamine-forming capacity (HFC) of human isolated leucocytes have been studied, in vitro.2 It was confirmed that antigen significantly stimulates the HFC of human leucocytes.3 beta-Adrenoceptor stimulants, such as isoprenaline and salbutamol (10(-6)-10(-3)M) significantly inhibited the HFC of human leucocytes in the presence and absence of antigen. At concentrations lower than 10(-6)M, this effect was not observed. In general the degree of inhibition of HFC by beta-adrenoceptor stimulants followed their potency as beta-adrenoceptor stimulants.4 alpha-Adrenoceptor stimulants significantly stimulated leucocyte HFC; noradrenaline within a limited concentration of 10(-6)M, while stimulation was seen consistently with phenylephrine at concentrations of 10(-7)-10(-4)M. Adrenaline, which stimulates both alpha- and beta-adrenoceptors, produced small inhibition, no effect, or a degree of stimulation.5 Phentolamine, an alpha-adrenoceptor blocking agent, produced an effect opposite to that of the alpha-adrenoceptor stimulants, i.e. a significant inhibition of the HFC of human isolated leucocytes.     

The effects of bretylium on C fibre excitation and noradrenaline release by acetylcholine and electrical stimulation

1. The effects of bretylium on the excitation of postganglionic adrenergic C fibres by acetylcholine and the release of noradrenaline by acetylcholine and electrical stimulation of the splenic nerves have been studied using the in situ and cross perfused cat spleen.2. Close arterial injections of acetylcholine (10-200 mug) evoked a brisk asynchronous discharge in fine filaments of the splenic nerve which reduced the height of the orthodromic C fibre compound action potential.3. Hexamethonium abolished both the excitation of C fibres and release of noradrenaline by acetylcholine, whereas the liberation of noradrenaline by electrical stimulation of the splenic nerves remained unchanged.4. Bretylium (0.5 and 1.0 mg) given close arterially blocked the output of noradrenaline and contractions of the spleen that occurred in response to nerve stimulation (30 c/s) but had much less effect on the responses to acetylcholine.5. Bretylium (2-4 mg) given close arterially blocked the output of noradrenaline and contractions of the spleen caused by both nerve stimulation (30 c/s) and acetylcholine.6. The close arterial injection of (+)-amphetamine sulphate (100 mug) after bretylium (2-4 mg) partially restored the output of noradrenaline and contractions of the spleen to both nerve stimulation and acetylcholine.7. The difference in the sensitivity to blockade by bretylium of the effects of nerve stimulation and the sympathomimetic effects of acetylcholine did not exist if the more "physiological" frequency of stimulation of 10 c/s was employed.8. The close arterial injection of acetylcholine (100 mug) caused a mean average fibre discharge frequency of 5.4 spikes/sec.9. Bretylium in amounts sufficient to completely block the sympathomimetic effects of acetylcholine did not alter the excitation of C fibres by acetylcholine.10. The significance of these results is discussed both in relation to the mode of action of bretylium and to the use of these differential effects of bretylium as evidence for the "cholinergic link" hypothesis.     

The effects of piperoxan on uptake of noradrenaline and overflow of transmitter in the isolated blood perfused spleen of the cat.

1 The competitive alpha-adrenoceptor blocking agent, piperoxan, in concentrations up to 2 x 10(-4) M, produced large dose-dependent increases in transmitter overflow from the isolated blood perfused spleen of the cat following nerve stimulation at 10 hertz. 2 At concentrations greater than 2 x 10(-4) M, piperoxan produced a rise in perfusion pressure, a contraction of the splenic capsule, and a marked dose-dependent decrease in transmitter overflow. 3 Phenoxybenzamine (10(-4) M) and desmethylimipramine (3 x 10(-5) M) produced further increases in transmitter overflow when added after piperoxan. 4 Piperoxan (5.8 to 6.6 x 10(-6) M) had no effect on the recovery of 3H in the venous blood following the close arterial infusion or injection of (3H)-(--)-noradrenaline, indicating that the drug does not inhibit uptake of the amine. 5 Piperoxan produced dose-dependent inhibition of responses of the splenic vasculature to close arterial injection of 1 microgram of (--)-noradrenaline but was much less effective at inhibiting responses to nerve stimulation. At 2 x 10(-6) M piperoxan produced a considerable reduction of the response to injected noradrenaline but potentiated the response to nerve stimulation. 6 In isolated strips of cat splenic capsule, piperoxan produced a shift to the right of the dose-response curve to noradrenaline with no change of the maximum response. There was no evidence of a postsynaptic sensitizing effect of the type observed in the rat vas deferens.     

The vascular responses of the spleen to intravenous infusions of catecholamines, angiotensin and vasopressin in the anaesthetized cat

1. Splenic arterial flow and splenic weight were recorded in cats anaesthetized with sodium pentobarbitone. The responses of the spleen to catecholamines, angiotensin and vasopressin were investigated.2. Catecholamines caused responses mediated by alpha- and beta-adrenoceptors in the arteriolar smooth muscle, but only insignificant beta-adrenoceptor responses could be elicited from the capsular smooth muscle. The difficulties in elucidating the mechanism of action of catecholamines on arteriolar smooth muscle are discussed.3. Angiotensin caused marked vasoconstriction, but contraction of the capsular smooth muscle was less marked. Vasopressin caused vasoconstriction but had no effect on capsular smooth muscle. Thus these peptides constrict the resistance vessels but produce much weaker contraction of the capsule.4. These responses are discussed in relation to the splenic responses to acute haemorrhage.     

On the ability of domperidone to selectively inhibit catecholamine-induced relaxation of circular smooth muscle of guinea-pig stomach

The effects of noradrenaline and dopamine, and their interactions with alpha- and beta-adrenoceptor antagonists and with domperidone, were studied on circular smooth muscle strips taken from the cardia, fundus, body and antrum of the guinea-pig stomach. Noradrenaline and dopamine caused relaxations of all tissues which were generally susceptible to antagonism by either propranolol or phentolamine in concentrations shown to antagonize the relaxations caused by isoprenaline or phenylephrine respectively. In addition, dopamine, in concentrations subthreshold for relaxation, caused contraction of the muscle strips which increased in intensity from the cardia to the antral region: these contractions were antagonized by phentolamine and yohimbine but were insensitive to prazosin: prazosin selectively inhibited the phenylephrine relaxations. With the exception of a modest reduction in the responses of the cardia to dopamine, all tissue responses to noradrenaline and dopamine were resistant to reserpine. Domperidone and haloperidol were found to selectively inhibit the phenylephrine- noradrenaline- and dopamine-induced relaxations of the stomach strips and to enhance the contractile component of dopamine's action: this ability of domperidone to facilitate a dopamine induced contraction, which was most marked in the body and antral regions, was prevented by phentolamine. It is thus concluded that domperidone antagonizes noradrenaline- and dopamine-induced relaxations at one adrenoceptor site having characteristics consistent with an alpha 1-adrenoceptor type whilst failing to antagonize at a further dopamine-sensitive adrenoceptor site involved in contraction of circular smooth muscle of the stomach and having characteristics consistent with an alpha 2-adrenoceptor.     

Adrenoceptor-mediated changes of action potential and force of contraction in human isolated ventricular heart muscle.

1. The effects of alpha-adrenoceptor stimulation on the action potential and force of contraction were investigated in human isolated ventricular heart muscle and compared with those of beta-adrenoceptor stimulation. 2. The maximal stimulation by isoprenaline of beta-adrenoceptors produced large changes in the force of contraction, which were accompanied by moderate increases in the height of the action potential. The maximal inotropic effect produced by stimulation of alpha-adrenoceptors with phenylephrine, in the presence of propranolol (1 mumol 1(-1)) was much smaller (about 10% of that seen in response to beta-adrenoceptor stimulation), and no significant changes of the action potential configuration were observed. 3. The effects of noradrenaline and adrenaline on the force of contraction were not affected by prazosin. 4. It is concluded that the adrenoceptor-mediated changes of the force of contraction (in the presence of either noradrenaline or adrenaline) in the human ventricle are due virtually exclusively to the stimulation of beta-adrenoceptors.     

A comparison of the differential effects of vasoactive intestinal peptide and peptide histidine isoleucine on the vascular and capsular smooth muscle of the dog spleen.

1. The actions of the two peptides, vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) have been compared to that of isoprenaline on the smooth muscle systems of the isolated blood-perfused dog spleen. 2. Intra-arterial injections of VIP and PHI caused graded increases in splenic arterial blood flow at constant perfusion pressure indicative of splenic arterial vasodilatation. 3. VIP was significantly more potent than PHI, with their respective molar ED50 values being 9.9 +/- 3.7 and 830 +/- 141 pmol (P less than 0.002). VIP was approximately 10 and 200 times more potent than isoprenaline and PHI respectively. 4. The maximum reduction in splenic arterial vascular resistance was the same (P greater than 0.5) in response to intra-arterial VIP and PHI, although both peptide maxima were significantly less (P less than 0.05, 0.01 respectively) than that obtained with isoprenaline. 5. Small increases in spleen volume accompanied the splenic vasodilator responses to both peptides. They were probably passive in origin, secondary to splenic arterial vasodilatation. 6. The selective beta 2-adrenoceptor antagonist, ICI 118,551, did not antagonize the splenic arterial vasodilator response to VIP or PHI but markedly attenuated the effect of isoprenaline. 7. These observations indicate that VIP and PHI, when either co-released locally or present together in the systemic circulation, may exert a differential action on different components of the circulation.     

The role of β-adrenoceptors in the responses of the hepatic arterial vascular bed of the dog to phenylephrine, isoprenaline, noradrenaline and adrenaline

1 The sympathetically-innervated hepatic arterial vascular bed of the dog was perfused from a femoral artery. Hepatic arterial blood flow and perfusion pressure were recorded continuously, and the hepatic arterial vascular resistance (HAVR) calculated from these measurements.

2 Intra-arterial injections of phenylephrine caused dose-dependent rises in HAVR, indicating hepatic arterial vasoconstriction, at all doses above threshold. No secondary reductions in HAVR followed these responses.

3 Intra-arterial injections of isoprenaline caused only dose-dependent reductions in HAVR at doses above threshold.

4 Intra-arterial injections of noradrenaline typically caused an initial increase in HAVR which was followed at all but the highest doses by a secondary, delayed, reduction in HAVR.

5 Intra-arterial injections of adrenaline, like those of noradrenaline, resulted in hepatic arterial vasoconstriction followed by hepatic arterial vasodilatation.

6 On a molar basis, the most potent hepatic arterial vasoconstrictor was noradrenaline, followed by adrenaline and phenylephrine.

7 The maximum reductions in HAVR caused by adrenaline (mean reduction = 21.9%) and noradrenaline (16.9%) were significantly smaller than those due to isoprenaline (_P < 0.001).

8 Propranolol attenuated the hepatic arterial vasodilator responses due to isoprenaline, and the secondary falls in HAVR following intra-arterial adrenaline and noradrenaline.

9 Propranolol did not modify the vasoconstrictor responses to phenylephrine.

10 Both adrenaline and noradrenaline were more potent hepatic arterial vasoconstrictors after propranolol than in the absence of β-adrenoceptor blockade. The potentiation of the vasoconstrictor effects of adrenaline was statistically significant.

11 After propranolol, adrenaline was a more potent hepatic arterial vasoconstrictor than noradrenaline.

12 Since the β-adrenoceptors in the hepatic arterial vasculature were not blocked by atenolol, but were stimulated by salbutamol, it is concluded that they are predominantly of the β₂-type.

13 The vasoconstrictor actions of phenylephrine, noradrenaline and adrenaline were all antagonized by the systemic administration of phentolamine, all three dose-response curves being shifted to the right.

14 The results are discussed with regard to the possible control of the hepatic arterial vasculature by naturally-occurring catecholamines.

     

DISSOCIATION BETWEEN CORTICOTROPHIN AND CATECHOLAMINE RESPONSES TO ISOPRENALINE IN HUMANS

1. The pituitary-adrenocortical, sympathoadrenomedullary and renin-angiotensin-aldosterone systems contribute to circulatory and metabolic homeostasis during stress. One possible site of co-ordination of these systems is the beta-adrenoceptor. 2. To determine whether circulating beta-adrenoceptor agonists can act hormonally to stimulate these systems simultaneously, plasma concentrations of corticotrophin (ACTH), noradrenaline, adrenaline and plasma renin activity were measured during graded intravenous infusions of isoprenaline in 20 people. 3. Administration of isoprenaline caused dose-related increases in noradrenaline (94% at the highest dose) and renin activity (189%), but decreases in ACTH (25%) and adrenaline (20%), findings inconsistent with simultaneous activation of these systems by circulating beta-adrenoceptor agonists.     

蜜桔黄酮辐射损伤小鼠防护作用研究

目的：探讨蜜桔黄酮（FT）辐射损伤小鼠的防护作用。方法：以辐射损伤小鼠作为研究对象,照射前后以不同剂量FT口服灌胃给药,模型组和对照组灌服相应量的氯化钠注射液。观察小鼠体重,脾脏重量,脾指数的变化,外周血中RBC、WBC、PLT、Hb的变化,计数骨髓有核细胞数、骨髓DNA含量。结果：与模型组比较,各给药组小鼠的体重,外周血象中白细胞数、血小板含量,骨髓DNA含量和有核细胞数,脾指数等均比单纯照射的模型组有明显改变,其中以高剂量组的改变最为明显,并存在显著性统计学差异（P〈0.05）。结论：FT中的活性成分对小鼠造血系统有明显的辐射防护作用,并能刺激小鼠脾细胞增殖,改善免疫功能。     

影响血常规检测结果相关因素临床研究

目的 探讨影响血常规检测结果 因素分析及预防对策.方法 随机选择2010年5月至2010年12月滨海县中医院90例门诊健康体检志愿者作为研究对象,采用Backman Counter全自动血细胞计数仪观察静脉血和末梢血常规检查结果 ;比较在室温下(18～22℃)分别于即刻、30min、2h、6h常规测定差异.结果 末梢血检测中白细胞(WBC)、红细胞(RBC)和血红蛋白(Hb)检测的平均值均高于静脉血检测值,血小板计数(PLT)平均值低于静脉血平均值(P<0.05),中间细胞百分比(MXD)无差异(P>0.05);2h内静脉血血常规WBC、MXD、RBC、Hb、PIT各项参数与即刻测定结果 比较无显著性差异(P>0.05),放置6b后PLT与即刻比较下降明显而MXD比例升高(P<0.05);WBC、RBC、Hb参数比较无显著性差异(P>0.05).结论 血常规化验结果 受很多因素的影响,全自劝血细胞计数仪做血常规检测时选用静脉血,应在2h内对样本进行测定,以消除由此要求过失误差.     

部分脾动脉栓塞与脾切除治疗脾功能亢进症的疗效比较

目的通过对部分脾动脉栓塞和脾切除治疗脾功能亢进症的治疗费用、疗效及并发症进行分析,评价两种方法治疗脾功能亢进症的特点。方法92例脾功能亢进症行部分脾动脉栓塞治疗患者作为脾栓塞组,208例脾功能亢进症行脾切除治疗患者作为脾切除组。比较两组患者住院天数及住院费用;术前、术后的白细胞(WBC)、红细胞(RBC)、血小板(PLT)水平;并发症发生情况。结果两组患者手术均安全、顺利、成功。脾栓塞组住院天数(23.39±10.15)d短于脾切除组的(31.54±11.08)d,住院费用中位数2.77万元少于脾切除组的4.82万元,差异均具有统计学意义(P<0.05)。术前,两组患者的WBC、RBC、PLT水平比较,差异均无统计学意义(P>0.05);脾栓塞组术后3、7、14、21 d的WBC、PLT水平均低于脾切除组,术后3 d的RBC水平高于脾切除组,差异均具有统计学意义(P<0.05);两组患者术后7、14、21 d的RBC水平比较,差异均无统计学意义(P>0.05)。脾栓塞组患者的腹水感染、脾周脓肿、门静脉血栓形成、发热、肝性脑病、腹泻发生率分别为25.00%、2.17%、0、88.04%、1.09%、2.17%,与脾切除组的42.79%、0、25.00%、98.08%、19.71%、0比较,差异均具有统计学意义(P<0.05);两组患者的腹水、腹痛、左下肺不张、肺炎、腹腔血肿、其他发生率比较,差异均无统计学意义(P>0.05)。结论部分脾动脉栓塞和脾切除均为治疗脾功能亢进症的有效方法,近期治疗效果明确。部分脾动脉栓塞更适合肝功能差、不能耐受外科手术的患者。     

Pressor responses to ephedrine are not impaired in dopamine beta-hydroxylase knockout mice

BACKGROUND AND PURPOSE: Ephedrine and amphetamine can cause substantial increases in systemic arterial pressure. However, the role of endogenous noradrenaline release in mediating the pressor response to ephedrine is controversial. Studies using pharmacologic agents to decrease the synthesis, storage, and release of catecholamines have supported both a direct and an indirect mechanism of action for ephedrine. The purpose of the present study was to determine if endogenous noradrenaline release is required for cardiovascular responses to ephedrine and amphetamine using a genetic mouse model. EXPERIMENTAL APPROACH: Increases in systemic arterial pressure and heart rate in response to ephedrine and amphetamine were investigated and compared in dopamine beta-hydroxylase knockout (Dbh -/-) mice that cannot synthesize noradrenaline. Dbh +/- littermates have normal noradrenaline and adrenaline tissue levels, and served as controls in all experiments. KEY RESULTS: In Dbh -/- mice the increases in systemic arterial pressure and heart rate in response to i.v. injections of ephedrine were not impaired whereas responses to amphetamine were markedly reduced, when compared with responses in Dbh +/- mice. The pressor response to tyramine was abolished whereas pressor responses to noradrenaline, phenylephrine, dopamine, and angiotensin II were similar in Dbh -/- and Dbh +/- mice. CONCLUSIONS AND IMPLICATIONS: The present results in Dbh -/- mice provide support for the hypothesis that pressor responses to ephedrine are directly mediated whereas responses to amphetamine are dependent on the release of noradrenaline and suggest that Dbh +/- and Dbh -/- mice are useful for the study of direct and indirect mechanisms.     

Modulation by endogenous prostanoids of the vasoconstrictor activity of endothelin-1 in the canine isolated, perfused spleen.

1. Endothelin-1 (ET-1, 0.4-200 pmol) was injected into the arterial circuit of the isolated perfused spleen of the dog in which splenic arterial perfusion pressure and spleen weight were recorded continuously. 2. Serial collection was made of splenic venous effluent before and after intra-arterial injection of ET-1 and assayed by direct radioimmunoassay for prostaglandin E2 (PGE2), 6-oxo-PGF1 alpha and thromboxane B2 (TXB2). 3. ET-1 caused graded arterial vasoconstriction of prolonged duration with small reductions in spleen weight at higher doses. 4. ET-1 cause a dose-related release of PGE2, 6-oxo-PGF1 alpha and TXB2 into the splenic venous effluent. The mean peak increase above the basal levels following 200 pmol of ET-1 was 800% for PGE2, 233% for 6-oxo-PGF1 alpha and 205% for TXB2. 5. Intra-arterial infusion of indomethacin significantly reduced the basal release of all three eicosanoids and significantly elevated the basal splenic vascular resistance. The release of all three eicosanoids in response to ET-1 and adrenaline (Ad) was significantly reduced by indomethacin and the accompanying increases in the splenic arterial vascular resistance were significantly potentiated at low doses of ET-1. The splenic arterial vascular responses to Ad were unchanged by indomethacin infusion. 6. These results indicate that the release of eicosanoids may modulate the splenic vascular responses to ET-1.