An automated superfusion technique for measuring circular muscle contraction. Effects of serotonin on intra- and extracranial arteries.

A new in vitro technique is described and its advantages are demonstrated: "true" circular contraction is measured; arteries are in cascade, permitting comparison of intra- and extracranial arteries from the same animal; the mechanical influences on contractility are reduced; long-lasting experiments of up to 50 h can be performed; the procedure is fully automated. The maximal effect of an agonist was not only markedly modified during the first 2--4 h after fixing the arteries in the apparatus but also slightly during the next 3--4 h. After the initial stabilization period, the arterial response to an agonist remained highly reproducible for 24--48 h (standard deviation not exceeding 7%). This was demonstrated in all the types of arteries tested. With serotonin as agonist, there was a significant difference in --log ED50 values for intracranial arteries (basilar 8.70, middle cerebral 8.72) vs. extracranial (lateral nasal 8.15; facial 8.14) and peripheral (branch of saphenous 8.14) arteries.     

5-Hydroxytryptamine supersensitivity as a new theory of headache and central pain: A clinical pharmacological approach with p-chlorophenylalanine

Vascular supersensitivity to 5-hydroxytryptamine, but not to noradrenaline is observed in volunteers suffering from untreatable migraine, following treatment with parachlorophenylalanine, a specific serotonin depletor. A similar supersensitivity at brain level is claimed to explain an unusual systemic pain syndrome developed in 4 patients affected by migraine and treated with this serotonin depleting agent; hyperalgesia, hyperpathia, spontaneous pain, according to the picture of central pain, are demonstrable. The pain syndrome is reversible with the drug discontinuation; it reappears promptly when the treatment is started again.The pain from serotonin depletion may represent a chemical approach to the mechanism of central pain, such as thalamic syndrome, and may give a new suggestive light to the serotonin interpretation of migraine and some daily headaches.The increased vascular and nervous responsitivity in patients suffering from migraine, to monoamines and correlated drugs (5-HT, noradrenaline, metaraminol, LSD-25 and psylocibine), may be interpreted in terms of central and peripheral monoamine supersensitivity.This work was supported by a grant of the National Council of Researches, Rome, Italy.     

Prevalence of migraine and response to sumatriptan in patients self-reporting tension/stress headache

ABSTRACT

Objective: This study was conducted to evaluate the prevalence of migraine and its responsiveness to migraine-specific therapy in patients with selfreported tension-type headache.

Methods: Patients were adults (n = 423) consulting one of 54 North American study sites including primary care clinics, neurology clinics, and headache clinics. The study comprised an initial diagnosis phase to determine the headache diagnosis of patients entering the study with self-reported tension/stress headache, including that previously diagnosed by a health care provider. Patients reporting tension/stress headache were evaluated and diagnosed as having migraine with or without aura, probable migraine, tension-type headache, or another headache type. Exclusion criteria included prior diagnosis of migraine or probable migraine and the presence of headache for at least 15 days monthly during either of the 2 months before screening. The initial phase was followed by a randomized, double-blind treatment phase to evaluate the efficacy of sumatriptan 100?mg tablets for the treatment of a single migraine attack in those meeting International Headache Society (IHS) criteria for migraine during the diagnosis phase.

Results: Of 423 patients reporting tension/stress headache at study entry, 84% (n = 357) were diagnosed at the clinic visit as fulfilling IHS criteria for migraine without aura or migraine with aura, and 65% (n = 276) were diagnosed with migraine only (i.e., with no other concurrent headache diagnosis). Three hundred thirty-two (332) patients entered the double-blind treatment phase. Headache relief rates 2?h post-dose, the primary efficacy endpoint, did not significantly differ between sumatriptan and placebo (?p = 0.099). However, improvements were significantly (?p < 0.05) greater with sumatriptan than placebo on several other headache-related efficacy measures.

Conclusions: Migraine headache may go unrecognized in patients with self-reported tension headache. Among patients having self-reported tension headache and diagnosed with migraine during the study, response to acute treatment with sumatriptan was inconclusive. Improvement with sumatriptan versus placebo was observed for some measures and not for others. The results should be interpreted in the context of study limitations including use of patient self-reports to assess headache diagnosis and possible lack of representativeness arising from the predominantly white sample.     

Developmental changes in endothelium-dependent vasodilation and the influence of superoxide anions in perinatal rabbit pulmonary arteries

1. ACh-induced vasodilation was investigated in pulmonary arteries from 8 and 2 day pre-term foetal, neonatal (0–12 h and 4 day old) and adult rabbits. The effects of superoxide anion generation [with hypoxanthine (HX, 0.1 mM)/xanthine oxidase (XO, 15 mu ml⁻¹)], endogenous superoxide dismutase (SOD) inhibition [with the Cu-Zn SOD inhibitor triethylenetetramine (TETA, 1 mM)], endogenous superoxide anion scavenging [by superoxide dismutase (SOD, 50 u ml⁻¹)] and inhibition of endothelial nitric oxide synthase (eNOS) [with, N^ω-nitro-L-arginine methylester (L-NAME, 0.1 mM)], on basal and ACh-induced NO activity were studied by examining phenylephrine-induced contraction and ACh-induced vasodilation respectively.
2. L-NAME and endothelium removal abolished all ACh-induced vasodilation and 1 μM sodium nitroprusside fully dilated all vessels. ACh-induced vasodilation was absent in the 8 day pre-term foetus and 0–12 h neonate but present at all other ages. L-NAME itself contracted 2 day pre-term foetal vessels. At 0–12 h, SOD, but not the phosphodiesterase 5 inhibitor zaprinast (1 μM), uncovered ACh-induced vasodilation. At this age SOD reduced phenylephrine-induced contraction which was not influenced by TETA, L-NAME or HX/XO, and L-NAME itself did not cause contraction. This suggests both ACh-induced and basal NO activity are compromise in these vessels by endogenous superoxide anion production and deficiencies in endogenous SOD activity.
3. In 4 day vessels, but not adult vessels, L-NAME, TETA and HX/XO augmented contractions to phenylephrine, and L-NAME itself induced vasoconstriction, suggesting that basal NO and SOD activities were present by 4 days but were not evident in the adult. ACh-induced NO activity, and the influence of endogenous SOD on this, were present in the adult (and 4 day) vessels as superoxide generation with HX/XO significantly reduced ACh-induced vasodilation and this effect was inhibited by SOD and augmented by TETA.
4. Increased oxygen tensions >500 mmHg attenuated ACh-induced vasodilation in the foetal but not neonatal rabbits. Raising the oxygen tension from ∼20 to ∼120 mmHg revealed ACh-induced vasodilation in the 8 day pre-term vessels.
5. In summary, superoxide anion accumulation combined with deficiencies in SOD activity may transiently compromise basal and ACh-induced NO activity at birth. Experimental oxygen tensions markedly influence ACh-induced vasodilation in foetal rabbit pulmonary arteries.

     

The effect of rizatriptan,ergotamine, and their combination on human peripheral arteries: a double-blind,placebo-controlled,crossover study in normal subjects

AIMS: To compare the peripheral vasoconstrictor effects of ergotamine, rizatriptan, and their combination, in normal subjects. METHODS: This was a double-blind, four-way, crossover study. Sixteen young male volunteers, selected as responders to the vasoconstrictor effect of 0.5 mg ergotamine i.v., were administered 10 mg oral rizatriptan, 0.25 mg i.v. ergotamine, 10 mg oral rizatriptan+0.25 mg i.v. ergotamine, and placebo. The vasoconstrictor effect on peripheral arteries was measured with strain gauge plethysmography up to 8 h after dosing. The 8 h assessment period was divided into two 4 h intervals to assess the immediate (0-4 h) vs sustained effect (4-8 h) of treatment. RESULTS: For the 0-4 h interval, the decreases in peripheral systolic blood pressure gradients were: placebo (-1 mmHg [95% CI: -3, 1])相似文献   

下肢动脉64排螺旋CT血管造影技术及临床应用（附85例分析）

目的探讨下肢动脉64层螺旋CT血管造影（64-MSCTA）技术及方法,评价其临床应用价值。方法85例临床疑有下肢动脉病变患者行64-MSCTA检查,扫描范围下腹部至足尖,层厚1.25mm,螺距1．375。采用自动触发扫描技术完成扫描。三维成像方法包括容积再现（VR）、最大密度投影（MIP）、多平面重建（MPR）及高级血管分析（AVA）等。评价成像技术对图像的影响,分析及讨论其诊断结果。结果85例患者中,下肢动脉硬化闭塞症72例,急性血栓形成3例,下肢动脉瘤2例,基本正常8例。下肢动脉病变征像包括软硬斑块、狭窄、闭塞、扩张、侧支循环及血栓形成。其中12例进行手术治疗,10例行DSA检查,所见与64-MSCTA一致。结论64-MSCTA检查技术显示下肢动脉结构、病变清楚,诊断准确率高。该技术将成为诊断下肢动脉疾患及评估手术疗效的首选影像学检查方法。     

Evidence for 5-HT2B and 5-HT7 receptor-mediated relaxation in pulmonary arteries of weaned pigs

This study characterizes the relaxant response to 5-hydroxytryptamine (5-HT) in prostaglandin F₂ (PGF₂)-precontracted pulmonary arteries of weaned pigs. In arterial rings with intact endothelium, the relaxation to 5-HT was biphasic. The high affinity component of relaxation to 5-HT (0.1–10 nM) was abolished by mechanical removal of the endothelium or after the addition of l-NAME (200 M), and was inhibited by the 5-HT_2B/2C receptor antagonist SB 206553 (1 M), but not the 5-HT_2C receptor antagonist SB 242084 (0.1 M). Endothelium-intact arteries were also relaxed by the selective 5-HT_2B receptor agonist BW 723C86 (pD₂ 7.7). The relaxant response to BW 723C86 was inhibited by 1 M SB 206553 (pK_B 6.8). The low affinity component of relaxation to 5-HT (30 nM) remained unaffected after mechanical removal of the endothelium or the addition of l-NAME. In endothelium-denuded arterial rings, 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), and frovatriptan produced monophasic relaxations with pD₂ values of 6.5, 7.5, 5.9, and 4.7 respectively. Relaxant responses to the agonists were antagonized by the selective 5-HT₇ receptor antagonist SB 269970 (pK_B 8.2–8.9). The relaxant response to the potent 5-HT₇ receptor agonist 5-CT was also antagonized by methiothepin (pK_B 9.6), pimozide (pK_B 8.2), mesulergine (pK_B 7.7), methysergide (pK_B 7.4), clozapine (pK_B 7.6), and spiperone (pK_B 7.4). The estimated pK_B values argue in favor of an involvement of 5-HT₇ receptors in the direct vasorelaxant action of 5-HT in the pulmonary arteries of weaned pigs. The relaxant response to 5-CT was associated with an increase in cAMP that was surmountably antagonized by SB 269970 (pK_B 8.6). The present in vitro bioassay can be used to characterize new drugs with potential agonist or antagonist properties at functional 5-HT₇ receptors.     

Sumatriptan contracts large coronary arteries of beagle dogs through 5-HT1-like receptors

Summary The effects of 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), methysergide and sumatriptan were studied on endothelium-denuded rings of beagle dog large coronary arteries. Submicromolar concentrations of the compounds contracted the rings with the order of potency 5-CT > 5-HT >sumatriptan = methysergide. Concentrations greater than 2 M of both 5-HT and 5-CT, and 60 mol/l methysergide also caused concentration-dependent relaxation. Sumatriptan did not cause relaxation. Peak intrinsic activities relative to the plateau contraction to sumatriptan (1.00), were 5-CT 0.47, 5-HT 0.87 and methysergide 0.51. Ketanserin 1 mol/l affected neither contractile responses nor relaxant responses to 5-CT, methysergide and sumatriptan and only caused marginal blockade of the contractile effects of 5-HT. Methiothepin 200 nM shifted the concentration-contractile response curves by around 2 log units, as expected from its affinity for 5-HT₁-like receptors.The rank order of contractile potency of the agonists, the antagonism by methiothepin and the resistance to blockade by ketanserin are consistent with a nearly exclusive involvement of 5-HT₁-like receptors. Isolated large coronary arteries from beagle dogs may be a suitable model for the study of human coronary artery 5-HT₁-like receptors that are involved in the spasm observed with 5-HT and sumatriptan. Correspondence to A. J. Kaumann at the above address     

养血清脑颗粒对脑梗死后头痛、头晕的临床疗效观察

目的观察养血清脑颗粒对脑梗死后患者头痛、头晕症状的临床疗效。方法 65例脑梗死后出现头痛、头晕的患者为研究对象,随机分成观察组(34例)和对照组(31例),对照组给予常规治疗,观察组在常规治疗基础上联合养血清脑颗粒治疗。比较两组临床疗效,治疗前后血液流变学指标[血浆粘度、全血低切粘度、花生四烯酸诱导的血小板最大聚集率(MARAA)、二磷酸腺苷诱导的血小板最大聚集率(MARADP)]水平,治疗前后头痛评分、头晕程度,治疗前后生活质量改善情况。结果治疗后,观察组总有效率为94.1%,高于对照组的74.2%,差异具有统计学意义(P<0.05)。治疗前,两组患者的血浆粘度、全血低切粘度、MARAA、MARADP水平比较,差异均无统计学意义(P>0.05);治疗后,观察组患者的血浆粘度、全血低切粘度、MARAA、MARADP水平均低于对照组,差异均具有统计学意义(P<0.05)。治疗前,两组患者的疼痛数字评分法(NRS)评分比较,差异无统计学意义(P>0.05);治疗后,观察组患者的NRS评分为(1.36±0.22)分,低于对照组的(3.52±1.11)分,差异具有统计学意义(P<0.05)。观察组患者的头晕程度优于对照组,差异具有统计学意义(Z=3.9489, P<0.05)。治疗前,两组患者的躯体功能、心理健康、情绪角色、社会功能评分比较,差异均无统计学意义(P>0.05);治疗后,观察组患者的躯体功能、心理健康、情绪角色、社会功能评分均高于对照组,差异均具有统计学意义(P<0.05)。结论对于脑梗死后头痛、头晕患者的治疗,在西药常规治疗基础上联合养血清脑颗粒治疗,对提高临床疗效、改善血液流变学、减低头痛头晕程度、提升生活质量方面有重大意义。     

腰麻后即刻硬膜外腔注入与手术结束时注入生理盐水预防剖宫产术后头痛效果比较

目的：探讨腰麻后即刻硬膜外腔注入与手术结束时注入生理盐水预防剖宫产术后头痛的临床效果。方法：选择正常足月孕妇100例．分为腰麻后即刻注入组（A组）和手术结束时注入组（B组）,每组各50例。腰麻后即刻注入组（A组）选择LⅥ间隙行腰穿,进入蛛网膜下腔且见脑脊液流出后注入10％葡萄糖1ml＋0．75％布比卡因1．5ml,退出腰穿针约0．5cm。无脑脊液流出后注入生理盐水10ml。手术结束时注入组（B组）,选择L3-4间隙行硬膜外穿刺,成功后经硬膜外穿刺针置入腰穿针,进入蛛网膜下腔且见脑脊液流出后注入10％葡萄糖1ml＋0．75％布比卡因1．5ml,退出腰穿针,置入硬膜外导管进入硬膜外腔约3．5cm,手术结束时经硬膜外导管注入生理盐水10ml。术后住院期间每天访视并记录产妇是否出现头痛。结果：A组术后头痛2例,发生率为4％。B组术后头痛3例,发生率为6％。结论：腰麻后即刻硬膜外腔注入与手术结束时注入生理盐水均能够有效预防剖宫产术后头痛。     

Comparison of the vasoconstrictor effects of the selective 5-HT1D-receptor agonist L-775,606 with the mixed 5-HT1B/1D-receptor agonist sumatriptan and 5-HT in human isolated coronary artery

AIMS: Vasoconstriction in human coronary artery can be mediated via activation of both 5-HT2 and 5-HT1B-receptors. Coronary vasoconstriction is a rare, but potential adverse effect of the antimigraine drug sumatriptan. In order to investigate the receptor population involved we compared the vasoconstrictor effects of sumatriptan (a mixed 5-HT1B/1D-receptor agonist) with those of L-775, 606 (a selective 5-HT1D-receptor agonist) and 5-HT (the endogenous ligand) in human isolated coronary arteries. METHODS: Coronary arteries were obtained from human hearts removed prior to transplant surgery. Several endothelium denuded ring segments (4 mm in length) were obtained from each artery and mounted for isometric tension recording. Each segment was first exposed to 45 mm KCl and then to 5-HT (1 nm-100 microm ). Concentration-effect curves to L-775,606 (1-(3-(5-(1,2, 4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)p ipe razine) and sumatriptan were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments. RESULTS: Twenty-five segments from seven different coronary arteries were studied. Concentration-effect curves were fitted to the data using nonlinear regression analysis. The maximum contraction for L-775,606 was significantly less than that for sumatriptan with Emax values (% relative to 45 mm KCl=100%) of 30.1+/-4.22 and 41.5+/-2.7, respectively. L-775,606 was significantly (30-fold) less potent than sumatriptan in causing contraction compared with sumatriptan (EC50 values were 6.0 microm and 0.2 microm, respectively). For comparison the Emax value for 5-HT was 77.2% and the EC50 value was 0.2 microm. CONCLUSIONS: The selective 5-HT1D-receptor agonist L-775,606 has less propensity towards vasoconstriction in human isolated coronary artery (endothelium-denuded) than was mixed 5-HT1B/1D-receptor agonist sumatriptan. The contractions produced were at concentrations where L-775,606 would be expected to occupy 5-HT1B-receptors.     

Alteration of flow-induced dilatation in mesenteric resistance arteries of L-NAME treated rats and its partial association with induction of cyclo-oxygenase-2

1. We investigated the response to pressure (myogenic tone) and flow of rat mesenteric resistance arteries cannulated in an arteriograph which allowed the measurement of intraluminal diameter for controlled pressures and flows. Rats were treated for 3 weeks with N^G-nitro-L-arginine methyl ester (L-NAME, 50 mg kg⁻¹ day⁻¹) or L-NAME plus the angiotensin I converting enzyme inhibitor (ACEI) quinapril (10 mg kg⁻¹ day⁻¹).
2. Mean blood pressure increased significantly in chronic L-NAME-treated rats (155±4 mmHg, n=8, vs control 121±6 mmHg, n=10; P<0.05). L-NAME-treated rats excreted significantly more dinor-6-keto prostaglandin F_1α (dinor-6-keto PGF_1α), the stable urinary metabolite of prostacyclin, than control rats. The ACEI prevented the rise in blood pressure and the rise in urinary dinor-6-keto PGF_1α due to L-NAME.
3. Isolated mesenteric resistance arteries, developed myogenic tone in response to stepwise increases in pressure (42±6 to 847±10 mN mm⁻¹, from 25 to 150 mmHg, n=9). Myogenic tone was not significantly affected by the chronic treatment with L-NAME or L-NAME+ACEI.
4. Flow (100 μl min⁻¹) significantly attenuated myogenic tone by 50±6% at 150 mmHg (n=10). Flow-induced dilatation was significantly attenuated by chronic L-NAME to 22±6% at 150 mmHg (n=10, P=0.0001) and was not affected in the L-NAME+ACEI group.
5. Acute in vitro N^G-nitro-L-arginine (L-NOARG, 10 μM) significantly decreased flow-induced dilatation in control but not in L-NAME or L-NAME+ACEI rats. Both acute indomethacin (10 μM) and acute NS 398 (cyclo-oxygenase-2 (COX-2) inhibitor, 1 μM) did not change significantly flow-induced dilatation in controls but they both decreased flow-induced dilatation in the L-NAME and L-NAME+ACEI groups. Acute Hoe 140 (bradykinin receptor inhibitor, 1 μM) induced a significant contraction of the isolated mesenteric arteries which was the same in the 3 groups.
6. Immunofluorescence analysis of COX-2 showed that the enzyme was expressed in resistance mesenteric arteries in L-NAME and L-NAME+ACEI groups but not in control. COX-1 expression was identical in all 3 groups.
7. We conclude that chronic inhibition of nitric oxide synthesis is associated with a decreased flow-induced dilatation in resistance mesenteric arteries which was compensated by an overproduction of vasodilator prostaglandins resulting in part from COX-2 expression. The decrease in flow-induced dilatation was prevented by the ACEI, quinapril.

     

Effect of TRPA1 activator allyl isothiocyanate (AITC) on rat dural and pial arteries

BackgroundTransient receptor potential ankyrin 1 (TRPA1) channels may have a role in migraine as some substances known to cause headache activate the channel. In the craniovascular system such activation causes a calcitonin gene-related peptide (CGRP)-dependent increase in meningeal blood flow. TRPA1 channels in the endothelium of cerebral arteries cause vasodilation when activated. The headache preventive substance feverfew inhibits activation of TRPA1 channels. In this study we aim to compare and characterize the effect of the TRPA1 agonist allyl isothiocyanate (AITC) on the diameter of rat dural and pial arteries in vivo.MethodsThe genuine closed-cranial window technique in rats was used to examine changes in dural and pial artery diameter and mean arterial blood pressure (MABP) after intracarotid infusion of AITC. Blockade experiments were performed by intravenous infusion of olcegepant, HC-030031, sumatriptan or capsazepine immediately after infusion of AITC, in four different groups of rats.ResultsAITC caused a significant dilation of dural arteries, which was inhibited by HC-030031, olcegepant and sumatriptan, but not by capsazepine.In pial arteries AITC caused a significant dilation, which was not inhibited by any of the pre-treatments, suggesting a poor penetration of the blood-brain barrier or autoregulation due to dimethyl sulfoxide (DMSO) mediated decrease in MABP during HC-030031 infusion.AITC did not cause a significant change in MABP.ConclusionAITC causes dilation of dural arteries via a mechanism dependent on CGRP and TRPA1 that is sensitive to sumatriptan. AITC causes a small but significant dilation of pial arteries.     

The role of 5-HT on the cardiovascular and renal systems and the clinical potential of 5-HT modulation

The main peripheral sources of 5-hydroxytryptamine (5-HT) are as a neurotransmitter and local hormone in the gastrointestinal tract, and stored in circulating platelets and pulmonary neuroepithelial bodies. 5-HT has been shown to have many possible physiological and pathophysiological roles on the cardiovascular and renal systems. Thus, 5-HT may contribute to valvular heart disease, coronary artery disease, pulmonary hypertension, pulmonary embolism, pre-eclampsia, peripheral vascular disease and diabetic nephropathy. Consequently, modulators of the 5-HT system have diverse clinical potential. For instance, selective 5-HT subtype 3 receptor (5-HT₃) antagonists may have potential in the treatment of the pain associated with myocardial infarction. MCI-9042 (sarpogrelate) or other 5-HT_2A antagonists may have clinical potential for the treatment of vasospastic angina, ischaemic heart disease, reperfusion injury and hindlimb ischaemia. Several modulators of 5-HT (5-HT transporter inhibitors, 5-HT_1B and _2B antagonists) may have potential alone or in combination in the treatment of pulmonary hypertension. In hypertension, agonists at the 5-HT₇ and antagonists at the 5-HT_2B may reduce blood pressure, and in diabetes, sarpogrelate may protect against nephropathy.     

外周5-羟色胺系统与糖尿病及其并发症防治关系的研究进展

糖尿病及相关并发症严重威胁人类的健康,但由于其发病机制未被阐明,阻碍了抗糖尿病药物的开发与推广。临床和动物实验结果表明5-羟色胺（5-hydroxytryptamine,5-HT）和糖尿病的发生、发展有紧密的关联,随着研究的不断深入,外周5-HT系统显示出作为治愈糖尿病重要靶点的潜力。本文首先对外周5-HT在糖尿病及其并发症发生和发展过程中的作用进行阐述,接着对5-HT调节糖尿病的机制进行探讨,随后对与糖尿病并发症相关的5-HT受体进行系统的总结,最后对如何利用药物通过5-HT系统防治糖尿病提出展望。     

Role of endothelium and nitric oxide in histamine-induced responses in human cranial arteries and detection of mRNA encoding H1- and H2-receptors by RT-PCR

1. Histamine induces relaxation of human cranial arteries. Studies have revealed that the relaxant histamine H₁-receptor predominates in human cerebral and the H₂-receptor in temporal arteries, while H₁- and H₂-receptors are of equal importance in the middle meningeal artery. The purpose of the present study was to examine the role of the endothelium and nitric oxide in histamine-induced responses and to show the presence of mRNA encoding H₁- and H₂-receptors in human cranial arteries.
2. Electrophoresis of polymerase chain reaction (PCR) products from human cerebral, middle meningeal and temporal arteries, demonstrated products corresponding to mRNA encoding both H₁- and H₂-receptors in arteries with and without endothelium. The amplified PCR products were sequenced and showed 100% homology with the published sequences of these histamine receptors.
3. A sensitive in vitro system was used to study vasomotor responses to histamine. In precontracted cerebral, middle meningeal and temporal arteries with and without endothelium, histamine caused a concentration-dependent relaxation with I_max values between 87% and 81% and pIC₅₀ values between 8.14 and 7.15. In arteries without endothelium the histamine-induced relaxation was significantly less potent (I_max values between 87% and 66% and pIC₅₀ values between 7.01 and 6.67) than in cranial arteries with an intact endothelium.
4. The addition of histamine to arteries without endothelium and pretreated with the histamine H₂-antagonist, cimetidine (10⁻⁵ M), caused a concentration-dependent contraction of the cranial arteries with E_max values between 86% and 29% and pEC₅₀ values between 7.53 and 6.77. This contraction was blocked by the histamine H₁-receptor antagonist, mepyramine (10⁻⁷ M), and even turned into a relaxation with I_max values between 84% and 14% and pIC₅₀ values between 7.42 and 5.86.
5. The nitric oxide synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME, 3×10⁻⁵ M) significantly inhibited the relaxant response to histamine in cerebral and temporal arteries (pIC₅₀ values between 7.43 and 7.13). The combined treatment with L-NAME (3×10⁻⁵ M) and cimetidine (10⁻⁵ M) caused a further displacement of the concentration-response curve (pIC₅₀ values between 7.14 and 6.57) and decreased the maximum relaxant responses in all three cranial arteries (I_max values between 62% and 39%).
6. In conclusion, this is the first study which show mRNA encoding histamine H₁- and H₂-receptors in human cranial arteries. The results indicate that histamine-induced relaxation of human cranial arteries is partially mediated via an endothelial H₁-receptor coupled to the production of nitric oxide and partially via a H₂-receptor associated with the smooth muscle cells. In addition, there is evidence for a contractile H₁-receptor in the smooth muscle cells in these arteries.

     

Dose-dependent effects of isosorbide-5-mononitrate on the venous arterial and coronary arterial system of conscious dogs

Summary Isosorbide-5-mononitrate (IS-5-MN), the main metabolite of isosorbide dinitrate shows antianginal efficacy and is being used increasingly as a drug for practical therapy. In conscious dogs we therefore measured the effects of increasing doses of IS-5-MN on hemodynamic parameters and the diameter of the circumflex artery. We found a dose dependent reduction of the mean right atrial pressure, the systolic blood pressure and a dilatation of the circumflex artery. For all three parameters threshold dosages were between 0.01 and 0.03 mg/kg. On the contrary peripheral and coronary resistance did not change at doses 0.3 mg/kg. The heart rate was significantly increased only at doses above 1 mg/kg and the diastolic blood pressure also showed a tendency to fall only at doses above 1 mg/kg. Cardiac output and coronary flow were not significantly altered over the entire dose range investigated, with the exception of a transient rise in coronary blood flow after the injection of 2.5 mg/kg IS-5-MN.From our results we can deduce that in the low dose range reduction of preload and dilatation of large arteries are the main effects of IS-5-MN. In contrast, no reduction of the coronary or peripheral resistance is to be expected.     

Changes in the haemodynamics of large arteries induced by single doses of nicardipine,enalapril, atenolol and urapidil

Summary Haemodynamic changes in the carotid and brachial arteries produced by single doses of four antihypertensive drugs (nicardipine, enalapril, atenolol, and urapidil) have been studied in 12 patients with essential hypertension. Measurements were performed noninvasively using a mechanographic method and B-mode pulsed Doppler ultrasonography.Within 7 h all of the drugs had caused a significant reduction in blood pressure, whereas heart rate showed a significant change only after atenolol. All the drugs produced a marked reduction in brachial pulse-wave velocity. Only nicardipine caused a significant reduction in vessel wall tension both in the carotid and brachial arteries, while brachial peripheral resistance was significantly reduced by all the drugs except atenolol. Neither atenolol nor enalapril caused any significant reduction in carotid peripheral resistance.The results show that all four antihypertensive drugs led to a beneficial increase in arterial compliance despite their different effects on peripheral resistance.     

Systemic availability of ergotamine tartrate after three successive doses and during continuous medication

Summary Plasma ergotamine concentrations were determined by radioimmunoassay in 10 healthy subjects after a 2 mg oral dose of ergotamine, administered at 24 h intervals on three consecutive days. After the first dose the mean peak plasma level of 0.35±0.05 (SEM) ng/ml was found 1–2 h after administration. In the samples obtained 2 h after the second and third doses, plasma ergotamine levels did not exceed the first peak value. On the other hand, after the third and last dose the plasma ergotamine began to rise slowly, reaching maximum of 0.70± 0.10 ng/ml on the 6th day after administration. This supports the concept of accumulation of the drug or of immunoreactive metabolites. CSF ergotamine was determined in 4 patients, who underwent lumbar puncture for other diagnostic purposes, 1 to 2 h after the 2 mg oral dose. A concentration of 0.40± 0.03 ng/ml was observed. In seven out of 18 migraine patients who were taking ergotamine preparations daily (mean 11.7 mg/week), ergotamine could not be detected in plasma 1 h after administration of the dose. In the remaining migraine patients, the pattern of plasma ergotamine after both the daily and the test doses was similar to that of the 10 healthy subjects. The results in volunteers and migraine patients suggest notable variation in bioavailability of the drug. It seems that in most subjects there is accumulation or tissue redistribution of ergotamine or its immunoreactive metabolites, although in a significant number of migraine patients who use the drug daily, ergotamine does not appear to be biologically available.