Muscle nerve sympathetic activity in migraine. Lack of abnormality

Microelectrode recordings of muscle nerve sympathetic activity (MSA) in the peroneal nerve were performed in eight patients with common migraine, when they were free of headache and during a spontaneously occurring attack of migraine. During the migraine headache all subjects remained on the same level of MSA as in the control situation and the responses to manoeuvres (slow deep breathing, the Valsalva manoeuvre, sustained hand grip, immersion of one hand into ice water) showed no qualitative or quantitative change. Assessment of vagal influence on the heart showed no change from control situation to attack of migraine. The study provides direct evidence against the existence of any abnormality of MSA during ongoing migraine headache and does not support the assumption that migraine is a generalized vasomotor disorder. No conclusions about possible dysfunction in other parts of the sympathetic nervous system can be drawn.     

Exercise training to reduce sympathetic nerve activity in heart failure patients. A systematic review and meta-analysis

Objective

To determine the effects of exercise training on sympathetic nerve activity in heart failure patients.

Effects of mental state on heart rate and blood pressure variability in men and women

Summary. The effect of different mental states on autonomic modulation of the cardiovascular system was assessed in healthy, normotensive men (n=18) and women (n=12). Heart rate variability (HRV), systolic blood pressure variability (BPV) and arterial baroreflex function were assessed during 4 tests at rest ((10 min+5 min recovery)×4):

• 1 Control (spontaneous breathing, (SB)
• 2 Mental distraction (SB+word puzzle)
• 3 Conscious control of breathing (paced at SB rate) and
• 4 Mental stress (SB+computer quiz).

There were no significant gender differences in the responses to the interventions in terms of arterial (spontaneous) baroreflex (SPBX) control of HR, and indices of time and frequency domains of HRV and BPV, with the exception of the sympathetic indicator of HRV (low frequency power/total power; P<0.01) which was lower in women during control and mental stress tests. Conscious control of breathing at SB did not alter HRV, BPV or SPBX in either men or women. Mental distraction and mental stress led to decreases in indices of time and frequency domains of HRV and BPV in all subjects, as well as increases in HR during distraction and in systolic BP during stress. These findings suggest that in studies of cardiovascular control:

• 1 Paced breathing at SB can be used for individuals with irregular breathing patterns
• 2 The extent of mental stress achieved is intervention-specific and for the most part, independent of gender and
• 3 Resting assessment of HRV, BPV and SPBX can be made by having subjects sit quietly without interventions in a controlled laboratory setting.

     

Human in vivo study of the renin–angiotensin–aldosterone system and the sympathetic activity after 8 weeks daily intake of fermented milk

Objective: Milk fermented by lactic acid bacteria is suggested to have antihypertensive effect in humans. In vitro and animal studies have established an angiotensin‐converting enzyme (ACE) inhibitor effect of peptides in fermented milk. However, other modes of action must be considered, because until today no human studies have confirmed an ACE inhibition in relation to the intake of fermented milk. Materials and methods: We undertook a double‐blinded randomized placebo‐controlled study including 94 borderline‐hypertensive persons to study the effect on human physiology of Lactobacillus helveticus fermented milk. The subjects were randomized into three groups: Cardi04‐300 ml, Cardi04‐150 ml or placebo. All components of the renin–angiotensin–aldosterone system were measured several times. Sympathetic activity was estimated by plasma noradrenaline and cardiovascular response to head‐up tilt at baseline and after 8 weeks of intervention. Results: No ACE inhibition of the fermented milk was demonstrated, as none of the components of the renin–angiotensin–aldosteron system changed. Plasma noradrenaline response to tilt test after intervention stayed unchanged between groups (P = 0·38), but declined in the group Cardi04‐300 from 2·01 ± 0·93 nmol l^?1 at baseline to 1·49 ± 0·74 nmol l^?1 after 8 weeks (P = 0·002). There was no change in 24‐h ambulatory blood pressure or heart rate between groups. Conclusions: Despite a known ACE inhibitory effect in vitro and in animals, milk fermented with Lb. helveticus did not inhibit ACE in humans. Our results suggest that the intake of fermented milk decreases sympathetic activity, although not to an extent mediating reductions of blood pressure and heart rate in borderline‐hypertensive subjects.     

Blood pressure and heart rate variability analysis of orthostatic challenge in normal human pregnancies

The aim of the present study was to evaluate pregnancy-related changes in autonomic regulatory functions in healthy subjects. We studied cardiovascular autonomic responses to head-up tilt (HUT) in 28 pregnant women during the third trimester of pregnancy and 3 months after parturition. The maternal ECG and non-invasive beat-to-beat blood pressure were recorded in the horizontal position (left-lateral position) and during HUT in the upright position. Stroke volume was assessed from blood pressure signal by using the arterial pulse contour method. Heart rate variability (HRV) was analysed in frequency domain, and baroreflex sensitivity by the cross-spectral and the sequence methods. In the horizontal position, all frequency components of HRV were lower during pregnancy than 3 months after parturition (P < 0.01 to <0.001), while pregnancy had no influence on normalized low frequency and high frequency powers. During pregnancy haemodynamics was well balanced with only minor changes in response to postural change while haemodynamic responses to HUT were more remarkable after parturition. In pregnant women HRV and especially its very low frequency component increased in response to HUT, whereas at 3 months after parturition the direction of these changes was opposite. Parasympathetic deactivation towards term is likely to contribute to increased heart rate and cardiac output at rest, whereas restored sympathetic modulation with modest responses may contribute stable peripheral resistance and sufficient placental blood supply under stimulated conditions. It is important to understand cardiovascular autonomic nervous system and haemodynamic control in normal pregnancy before being able to judge whether they are dysregulated in complicated pregnancies.     

No effect of carbohydrate feeding on glycogen synthase in human muscle during exercise

Summary. The effect of carbohydrate (CHO) feedings on exercise-mediated changes in glycogen synthase fractional (GSF) activity has been investigated. Subjects cycled at -70% of maximal oxygen uptake on two occasions: the first to fatigue (135±17 min; meanæ) (control, CON), and the second at the same workload and duration as the first, but with the addition of frequent ingestion of CHO during exercise (0.27 g kg^-1 body weight every 15 min). Biopsies were taken from the quadriceps femoris muscle before and immediately after exercise. Plasma glucose and insulin decreased during CON exercise, but remained elevated throughout CHO exercise (end of exercise: glucose = 4.4±0.2 mM CON vs. 5.8±0.2 CHO, P < 0.01; insulin = 9±l mU ml^-1 CON vs. 19±3 CHO, P < 0.05). Glycogen decreased to - 10% of the basal value during CON and to -20% during CHO, and there was no significant difference in net glycogenosis between treatments. GSF activity averaged 0.25±0.03 and 0.22±0.05 at rest, and increased to 0.51 ±0.08 and 0.48±0.09 after exercise in CON and CHO, respectively (P > 0.05 between treatments). It is concluded that under the present conditions CHO feedings do not alter the exercise-mediated changes in GSF activity. The increase in GSF during exercise is attributed at least in part to the decrease in muscle glycogen (which increases the suitability of GS as substrate for GS phosphatase).     

The effects of low dose insulin infusions on the renin angiotensin and sympathetic nervous systems in normal man

To examine the effects of physiological insulin concentrations on the renin-angiotensin and sympathetic nervous systems, healthy volunteers were studied by the euglycaemic glucose clamp technique with sequential 60 min 0.5 and 1.0 mU kg-1 min-1 insulin infusions and, subsequently, by a control infusion simulating clamp conditions. Plasma renin activity increased from 0.8 +/- 0.1 ng ml-1 h-1 basally to 1.0 +/- 0.2 ng ml-1 h-1 during the 0.5 mU infusion to 1.4 +/- 0.1 ng ml-1 h-1 during the 1 mU infusion but did not change during control infusion (0.9 +/- 0.3 ng ml-1h-1 to 0.9 +/- 0.2 ng ml-1h-1 to 1.0 +/- 0.1 ng ml-1h-1) (P less than 0.001 insulin vs. control by ANOVAR). Plasma angiotensin II increased during insulin (21.2 +/- 1.8 to 25.2 +/- 2.3 to 29.3 +/- 2.4 pg ml-1) but not during control infusion (24.0 +/- 2.8 to 23.6 +/- 2.6 to 23.5 +/- 2.5 pg ml-1) (P less than 0.001 insulin vs. control). Serum aldosterone did not change significantly during either infusion (insulin: 239 +/- 89 pmol l-1 to 237 +/- 50 pmol l-1 to 231 +/- 97 pmol l-1, control: 222 +/- 79 to 237 +/- 50 to 213 +/- 97 pmol l-1). Plasma noradrenaline increased to a greater extent during insulin (1.03 +/- 0.2 to 1.14 +/- 0.8 to 1.27 +/- 0.17 nmol l-1) than control infusion (0.86 +/- 0.09 to 0.97 +/- 0.09 to 0.99 +/- 0.09 nmol 1-1 (P less than 0.01 insulin vs. control). Changes in mean systolic blood pressure during insulin infusion were significantly different from control (+ 3 vs. -4 mmHg, P less than 0.001). In conclusion acute hyperinsulinaemia within the physiological range increases circulating hormones of the renin-angiotensin and sympathetic nervous systems and also increases systolic blood pressure.     

The effects of clonidine on arterial baroreflex sensitivity and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with left ventricular dysfunction

Background: Clonidine is a potent sympatholytic drug with central neural effects. The aim of this study was to evaluate the effects of clonidine on arterial baroreflex sensitivity (BRS) and cardiopulmonary (CP) baroreflex control of muscle sympathetic nerve activity (MSNA) in patients with left ventricular (LV) dysfunction. Method: Twenty patients were randomly assigned to either clonidine or placebo groups (10 in each group). BRS (by phenylephrine method) and CP baroreflex (by lower body negative pressure) effects on sympathetic nerve activity (circulating norepinephrine and MSNA recordings) were measured before and after a 4‐week treatment period. Results: Clonidine lowered blood pressure and heart rate. Clonidine was accompanied not only by a decrease in plasma noradrenaline (from 444 ± 196 to 260 ± 144 pg ml^?1) but also by a reduction in directly measured MSNA (from 47 ± 16 to 36 ± 16 bursts min^?1). BRS increased significantly from 3·01 ± 1·19 to 6·86 ± 2·84 ms mmHg^?1 after clonidine. When expressed as per cent change in MSNA during CP baroreceptor stimulation, CP baroreflex control of MSNA was significantly increased from 9·26 ± 8·93% to 28·83 ± 11·96% after clonidine. However, there were no significant changes in the measured variables in the control group. Conclusion: Clonidine enhanced BRS and CP baroreflex control of MSNA while reducing baseline sympathetic activity in patients with LV dysfunction.     

Effects of dextronatrin on blood pressure, hematocrit, urinary sodium excretion and sympathetic nerve activity of rats

The purpose of this investigation was to study in unanesthetized rats the blood pressure, renal and hematocrit responses to dextronatrin, a structural analogue of atrial natriuretic peptides (ANP). The peptide was infused intravenously for 20 min at doses of either 1 or 20 micrograms/min in binephrectomized rats as well as in rats with intact kidneys. The experiments were started 2 h after preparation of the rats under ether anesthesia. In binephrectomized rats, the small dose of dextronatrin lowered blood pressure and raised hematocrit. In those rats, the larger dose of the investigational peptide had no blood pressure lowering effect, but still increased hematocrit. Dextronatrin had no effect on heart rate, both in rats with and without kidneys. Dextronatrin given at the 1 microgram/min dose to normal rats caused a significant increase in urinary Na excretion. The large dose, however, did not modify this parameter. The effect of dextronatrin (1 microgram/min for 20 min) on splanchnic nerve activity was evaluated in other normal rats after a recovery period of 24 h from surgical procedure. Integrated nerve activity was found to significantly increase in parallel with heart rate while blood pressure was reduced. Taken together, these results show that a low dose of dextronatrin lowers blood pressure and induces an increase in urinary Na excretion and hematocrit. They also indicate that the blood pressure and renal effects of the peptide are abolished when a high dose is administered. In addition, it appears that the shift of fluid from the intra- to the extravascular compartment, reflected in binephrectomized rats by an increase in hematocrit, does not depend on the level of systemic blood pressure. Finally, the present observations suggest that the blood pressure lowering effect of dextronatrin is accompanied in the conscious rat by a stimulation of the sympathetic nervous system.     

Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans.

Euglycemic hyperinsulinemia evokes both sympathetic activation and vasodilation in skeletal muscle, but the mechanism remains unknown. To determine whether insulin per se or insulin-induced stimulation of carbohydrate metabolism is the main excitatory stimulus, we performed, in six healthy lean subjects, simultaneous microneurographic recordings of muscle sympathetic nerve activity, plethysmographic measurements of calf blood flow, and calorimetric determinations of carbohydrate oxidation rate. Measurements were made during 2 h of: (a) insulin/glucose infusion (hyperinsulinemic [6 pmol/kg per min] euglycemic clamp), (b) exogenous glucose infusion at a rate matched to that attained during protocol a, and (c) exogenous fructose infusion at the same rate as for glucose infusion in protocol b. For a comparable rise in carbohydrate oxidation, insulin/glucose infusion that resulted in twofold greater increases in plasma insulin concentrations than did glucose infusion alone, evoked twofold greater increases in both muscle sympathetic nerve activity and calf blood flow. Fructose infusion, which increased carbohydrate oxidation comparably, but had only a minor effect on insulinemia, did not stimulate either muscle sympathetic nerve activity or calf blood flow. These observations suggest that in humans hyperinsulinemia per se, rather than insulin-induced stimulation of carbohydrate metabolism, is the main mechanism that triggers both sympathetic activation and vasodilation in skeletal muscle.     

Acute and training effects of resistance exercise on heart rate variability

Heart rate variability (HRV) has been used as a non‐invasive method to evaluate heart rate (HR) regulation by the parasympathetic and sympathetic divisions of the autonomic nervous system. In this review, we discuss the effect of resistance exercise both acutely and after training on HRV in healthy individuals and in those with diseases characterized by autonomic dysfunction, such as hypertension and fibromyalgia. HR recovery after exercise is influenced by parasympathetic reactivation and sympathetic recovery to resting levels. Therefore, examination of HRV in response to acute exercise yields valuable insight into autonomic cardiovascular modulation and possible underlying risk for disease. Acute resistance exercise has shown to decrease cardiac parasympathetic modulation more than aerobic exercise in young healthy adults suggesting an increased risk for cardiovascular dysfunction after resistance exercise. Resistance exercise training appears to have no effect on resting HRV in healthy young adults, while it may improve parasympathetic modulation in middle‐aged adults with autonomic dysfunction. Acute resistance exercise appears to decrease parasympathetic activity regardless of age. This review examines the acute and chronic effects of resistance exercise on HRV in young and older adults.     

赖诺普利对高血压病血小板活化和胰岛素抵抗的影响

目的 :探讨赖诺普利对高血压患者血小板活化功能、胰岛素抵抗的干预作用。方法 :对 12 0例高血压患者用赖诺普利治疗 4周 ,治疗前后观察血中血小板颗粒膜蛋白、空腹血糖、空腹胰岛素、计算胰岛素敏感指数并与 60例正常人对照。结果 :赖诺普利有效降低高血压患者血压 ( P <0 0 5 )。并且显著降低空腹血糖、胰岛素、血小板颗粒膜蛋白 ,升高胰岛素敏感指数。结论 :高血压病存在胰岛素抵抗、血小板粘附力增强。赖诺普利在有效降压同时 ,可以纠正基础代谢紊乱     

Exteroceptive suppression of temporalis muscle activity during migraine attack and migraine interval before and after treatment with sumatriptan

We compared the early (ESI) and late (ES2) exteroceptive suppression (ES) periods of temporalis muscle activity in 18 migraine patients during both the migraine interval and migraine attack and investigated the effect of sumatriptan and placebo on ES parameters. The measurements were performed in a balanced sequence at four different times on each patient, twice during the migraine interval and once in each of two migraine attacks. First ES1 and ES2 were measured (stimulus intensity 20 mA, stimulus duration 0.2 ms, stimulation frequency 2 Hz, averaging of 10 responses), then the medication was given on a double-blind basis with an autoinjector using either 6 mg sumatriptan or a placebo solution. Thirty minutes after application the measurements were repeated. No significant differences were found in early and late exteroceptive suppression latencies and durations between baseline measurements. Treatment did not affect the latencies of ESI and ES2. While sumatriptan caused a significant increase in ES1 duration (p £ 0.05) both during the migraine interval and during the migraine attack, placebo showed no significant effect on ES1 duration. Treatment with sumatriptan during the migraine attack was accompanied by a significant increase in the duration of ES2 (p £ 0.05), but no significant changes in the durations of the late suppression periods were observed under any other conditions. The results do not support the assumption that under the experimental conditions chosen migraine attacks are accompanied by a paroxysmal change in the brain-stem mechanisms involved in the modulation of the ES parameters. Since sumatriptan during the migraine interval selectively lengthens ES1 but not ES2, it can be assumed that the substance has a primary effect on brain-stem mechanisms in migraine patients that cannot be explained in terms of secondary pain-induced mechanisms.     

正加速度暴露对不同程度冠状动脉狭窄小型猪血浆儿茶酚胺和交感神经系统活性的影响

目的研究正加速度(+Gz)对不同程度冠状动脉狭窄小型猪血浆儿茶酚胺水平和交感神经系统活性的影响。方法以巴马小型猪为研究对象,采用左前降支丝线环扎法建立冠脉轻度狭窄(50%)、中度狭窄(50%~69%)、重度狭窄组(≥70%)动物模型,分别给予间断高强度+Gz暴露,观察各组心率变化以及血浆肾上腺素(Ad)、去甲肾上腺素(NE)、多巴胺(DA)水平变化。结果基础心率重度狭窄组明显高于健康对照组及轻度狭窄组(P0.05),高强度+Gz暴露后即刻、10 min各组心率均显著增快(P0.01),中度狭窄和重度狭窄组心率较健康对照组进一步增快(P0.01),重度狭窄组心率增快持续超过30 min,其余各组心率在+Gz暴露后30 min恢复正常;+Gz暴露前,重度狭窄组血浆Ad、NE水平明显高于对照组及轻度狭窄组(P0.01),暴露后各组血浆AD、NE水平均显著增高(P0.01),轻度、中度狭窄组至暴露后30 min时恢复正常,重度狭窄组持续超过30 min(P0.01)。暴露后10 min时中度及重度狭窄组血浆Ad、NE水平均较对照组及轻度狭窄组显著增高(P0.01);+Gz暴露前各组DA水平差异无统计学意义(P0.05),+Gz暴露后即刻各组血浆DA水平均显著增高(P0.05),其中重度狭窄组DA水平显著高于其余各组(P0.05),各组血浆DA水平于10 min时恢复正常。结论 +Gz暴露可激活冠脉狭窄小型猪交感神经系统、增加血浆儿茶酚胺(Ad、NE、DA)水平,冠脉狭窄≥50%情况下交感神经系统激活更为强烈。     

L-精氨酸对体外循环中胰岛素抵抗及炎性反应因子的影响

目的探讨左旋精氨酸（L—Arg）对体外循环（CPB）下机体在缺血再灌注损伤后胰岛素抵抗的缓解作用。方法40例CPB下行心脏瓣膜置换术患者随机分成对照组和治疗组,分别于麻醉前（TO）、CPB15min（T1）、开放升主动脉后15min（T2）和停CPB后2h（T3）测定血浆血糖、胰岛素、血浆肿瘤坏死因子α（TNF—α）、白细胞介素6（IL-6）、白细胞介素8（IL-8）水平,计算胰岛素敏感指数（ISI）和胰岛素抵抗指数对数LgMOHA。结果两组组间比较显示T2、T3各指标较体外循环前T0、T1升高,差异有统计学意义（P〈0．05）;两组T1较体外循环前T0升高,差异有统计学意义（P〈0．05）。两组组间比较显示T1、T0各指标比较差异无统计学意义;两组T2、T3各指标比较有统计学意义（P〈0．05）。TNF-α、IL-6、IL-8与ISI相关分析显示具有负相关关系,TNF-α、IL-6、IL-8与Lg—HOMA相关分析显示具有正相关关系。结论CPB期间存在明显的胰岛素抵抗现象;L—Arg可改善术中胰岛素抵抗的程度。     

运动和胰岛素对高血糖大鼠骨骼肌JNK和p38信号传导系统的调节作用

目的：观察运动和胰岛素对高血糖大鼠骨骼肌细胞应激激活蛋白激酶-JNK和p38信号通道活性的作用，为糖尿病的运动疗法提供分子生物学依据。方法：12周龄、体重200-230g的SD大鼠18只，腹腔内注射链脲佐菌素，建立持续高血糖模型。然后随机分为运动组、胰岛素组和对照组。运动组采用活动平板，坡度10％，速度20m／min，运动20min后取标本；胰岛素组给予皮下注射胰岛素，30min后取标本；对照组不参与运动也不给予胰岛素注射。运用化学发光法测定骨骼肌JNK和p38活性。结果：骨骼肌JNK活性在运动组分别高于对照组和胰岛素组，胰岛素组JNK活性与对照组无显著差异。骨骼肌p38活性在运动组和胰岛素组较对照组显著增高。结论：在高血糖状态下，运动使得骨骼肌JNK和p38激酶的活性增高，提示通过对JNK和p38信号转导通道的调节作用，参与了骨骼肌结构和代谢功能的适应性改变；胰岛素可以激活骨骼肌p38通道但对JNK的活性无影响，提示通过对p38的激活，改善了葡萄糖转载体的内在活性。     

Mechanism of oestrogen and progesterone effects on lipid and carbohydrate metabolism: alteration in the insulin: glucagon molar ratio and hepatic enzyme activity

As in women receiving oestrogens the administration of 17beta-oestradiol to ovariectomized female rats caused a rise in fasting plasma triglycerides and a fall in plasma glucose. Progesterone, on the other hand, had no significant effects. In the oestradiol treated rats, the portal vein basal insulin levels were slightly reduced. Oestradiol, however, had a marked suppressive effect on the alpha cells of the pancreas resulting in a greater reduction in basal glucagon and impaired glucagon response to alanine infusions. The relative insulin to glucagon (I/G) molar concentration ratio in portal vein blood was increased. Oestradiol also produced a dose dependent increase in the activity of the liver lipogenic enzymes, acetyl CoA carboxylase and fatty acid synthetase. On the other hand, the activity of the gluconeogenic rate limiting enzyme phosphoenol-pyruvate carboxykinase (PEPCK) was inhibited. The cross-over pattern of gluconeogenic intermediates confirmed inhibition of gluconeogenesis at this step, an effect which is similar to that induced by relative insulin 'excess'. Progesterone produced an increase in the portal vein insulin concentrations. Both the basal and the alanine-stimulated glucagon levels were also increased. The I/G molar ratio in portal vein blood of progesterone treated rats remained unaltered and the hepatic lipogenic and gluconeogenic enzyme activities were similar to control animals. These data suggest that insulin activity is increased relative to glucagon in the liver of oestradiol-treated rats due to the rise in portal vein I/G ratio. The changes in liver lipogenic and gluconeogenic enzymes and the alterations in fasting plasma triglycerides and glucose in response to oestrogens could be secondary to this effect.     

Inhibitory effects of different ATP-sensitive potassium channel openers on electrically generated and carbachol-induced contractions of porcine and human detrusor muscle

The inhibitory effects of different potassium channel openers (PCOs) on electrically generated and carbachol-induced contractions of porcine and human detrusor muscle were examined. PCOs could be an interesting substance class for treatment of detrusor overactivity. Experiments were performed on muscle strips suspended in a tissue bath. Human tissue originated from patients who underwent total cystectomy. The concentration-relaxation curves of the first-generation PCOs cromakalim and pinacidil and the untypical PCO minoxidil were performed using carbachol-precontracted detrusor muscle strips of pigs and humans. Additionally, the inhibitory effects of cromakalim, pinacidil and minoxidil on electrically generated contractions of porcine detrusor muscle were examined. Furthermore, the inhibitory effect of the second-generation, bladder-selective PCO ZM 226600 on electrically generated contractions of the human detrusor muscle was determined. Frequency-response curves were performed before and after incubation with one PCO used in two different concentrations. In humans, cromakalim and pinacidil led to a maximum decrease of 73.5 and 68.4% and showed mean pD2 values of 6.65 and 5.5, respectively. In pigs, cromakalim and pinacidil led to a maximum decrease of 90.6 and 93.6% and showed mean pD2 values of 6.39 and 5.01, respectively. Minoxidil did not significantly decrease the precontraction at the highest used concentration in both species. Cromakalim exhibited the biggest inhibitory effect being significant at 10(-5) and 10(-6) M. Pinacidil showed only a significant inhibitory effect at 10(-5) M which was smaller than that of cromakalim. At 3 x 10(-6) M only a very small effect occurred at 1 Hz. Minoxidil did not inhibit the contractions at both examined concentrations except for a very small effect at 1 Hz. In humans, ZM 226600 exhibited at 10(-6) and 10(-5) M a significant inhibitory effect. At 10(-7) M it was only significant at one frequency.     

A comparison of the effects of IGF-I and insulin on glucose metabolism, fat metabolism and the cardiovascular system in normal human volunteers

Abstract. The metabolic and cardiovascular effects of recombinant human IGF-I were compared to insulin in six normal subjects. Subjects were studied twice and intravenously received an infusion of [6,6-²H₂]glucose (0–480 min) and in random order either IGF-I 20μg kg^-1 h^-1 (43.7 pmol kg^-1 min^-1) or insulin 0.5 mU kg^-1 min^-1 (3.4 pmol kg^-1 min^-1) with an euglycaemic clamp. One subject was withdrawn following a serious adverse event. During the IGF-I infusion glucose appearance rate (Ra) decreased from 1.79 ± 0.13 at baseline (150–180 min) to 0.35 ± 0.26 mg kg^-1 min^-1 ( P < 0.01) at 360min, and glucose utilization rate (Rd) increased from 1.79 ± 0.28 to 4.17 ± 0.84 mg kg^-1 min^-1 ( P < 0.01). There was no change in free fatty acids (FFA) and an increase (percentage change from pre-infusion mean) in cardiac output + 37.3%± 9% ( P < 0.01), heart rate + 13%± 2% ( P < 0.01) and stroke volume + 21%± 7% ( P < 0.05). During the insulin infusion glucose Ra decreased from 1.89 ± 0.13 to 0.34 ± 0.33 mg kg^-1 min^-1 ( P < 0.01) and FFA from 0.546 mmoll^-1 to 0.198 mmoll^-1 ( P < 0.01), glucose Rd increased from l.89 ± 0.18 to 5.41 ± l.47mg kg^-1 min^-1 ( P < 0.01) and there were no significant changes in the cardiovascular variables.     

Pharmacological effects of primaquine ureas and semicarbazides on the central nervous system in mice and antimalarial activity in vitro

New primaquine (PQ) urea and semicarbazide derivatives 1 – 4 were screened for the first time for central nervous system (CNS) and antimalarial activity. Behavioural tests were performed on mice. In vitro cytotoxicity on L‐6 cells and activity against erythrocytic stages of Plasmodium falciparum was determined. Compound 4 inhibited ‘head‐twitch’ responses and decreased body temperature of mice, which suggests some involvement of the serotonergic system. Compound 4 protected mice against clonic seizures and was superior in the antimalarial test. A hybrid of two PQ urea 2 showed a strong antimalarial activity, confirming the previous findings of the high activity of bis(8‐aminoquinolines) and other bisantimalarial drugs. All the compounds decreased the locomotor activity of mice, what suggests their weak depressive effects on the CNS, while PQ derivatives 1 and 2 increased amphetamine‐induced hyperactivity. None of the compounds impaired coordination, what suggests a lack of their neurotoxicity. All the tested compounds presented an antinociceptive activity in the ‘writhing’ test. Compounds 3 and 4 were active in nociceptive tests, and those effects were reversed by naloxone. Compound 4 could be a useful lead compound in the development of CNS active agents and antimalarials, whereas compound 3 may be considered as the most promising lead for new antinociceptive agents.