Metoclopramide,domperidone and dopamine in man: actions and interactions

Summary The effects of oral doses of the dopamine antagonist antiemetics metoclopramide and domperidone on baseline and dopamine stimulated renal function and systemic haemodynamics were assessed in a placebo controlled crossover study in 9 healthy volunteers.Metoclopramide did not change baseline ERPF, GFR or FF over 2 h post dosing but it significantly reduced baseline U_NaV, U_KV, urine flow, urinary dopamine excretion, supine and erect diastolic blood pressure and supine systolic blood pressure. Domperidone and placebo did not cause these effects.Metoclopramide caused a marked rise and domperidone a small fall in plasma aldosterone concentration (PAC) but placebo was without effect. Neither antiemetic altered plasma renin activity (PRA) but a small fall occurred with placebo.Two hours after pretreatment with placebo dopamine (2 g/kg/min) increased effective renal plasma flow (ERPF), glomerular filtration rate (GFR), sodium excretion rate (U_NaV), urine flow rate, urinary dopamine excretion rate, supine systolic blood pressure and supine and erect pulse rate and decreased the potassium excretion rate (U_KV), filtration fraction (FF) and supine diastolic blood pressure.Metoclopramide pretreatment, did not attenuate the dopamine induced rise in ERPF, GFR, urine flow, urinary dopamine excretion or supine systolic blood pressure but it did attenuate the rise in pulse rate, the fall in diastolic pressure, and the antikaliuretic effect of dopamine leading to a net kaliuresis when compared to placebo. Domperidone was similar to placebo.Neither metoclopramide nor domperidone given orally caused clinically important antagonism of the renal haemodynamic effects of dopamine. However the effects of metoclopramide on blood pressure and electrolyte excretion may have clinical importance.Metoclopramide has significant pharmacodynamic effects which are probably not due to DA₂ antagonism but may be mediated by DA₁ antagonism or be non-specific.Abbreviations DA dopamine - ERPF effective renal plasma flow - FF filtration fraction - GFR glomerular filtration rate - PAC plasma aldosterone concentration - PRA plasma renin activity - UV urine flow rate - U_NaV urinary sodium excretion rate (natriuresis) - U_KV urinary potassium excretion rate (kaliuresis) - HPLC high performance liquid chromatography.     

Acute changes in forearm haemodynamics produced by cigarette smoking in healthy normotensive non-smokers are not influenced by propranolol or pindolol

Summary The aim of the present study was to examine the effect of cigarette smoking in healthy non-smokers on blood pressure and forearm haemodynamics after acute oral administration of non-selective -adrenoceptor blockers with and without intrinsic sympathomimetic activity, viz. pindolol 15 mg and propranolol 80 mg. A preliminary study was done to compare cigarette smoking and sham smoking to evaluate the time-course of the haemodynamic effects of cigarette smoking. The second experiment was then carried out in the same six volunteers, according to a double-blind randomized placebo-controlled crossover design, to evaluate the possible effect of pre-treatment with -adrenoceptor blockers on blood pressure, heart rate and forearm haemodynamics (forearm blood flow, brachial artery diameter and brachio-radial pulse-wave velocity) measured at baseline, during smoking and every five minutes up to 1 h afterwards.No major difference from placebo in blood pressure or forearm haemodynamics was found and pre-treatment with beta-blockers did not prevent the acute vascular effects of cigarette smoking.     

Constant K+/Na+ excretion ratio during peak diuresis after piretanide but insignificant K+ loss during 24 hours

Summary The effect of piretanide on Na⁺ and K⁺ excretion and on renal haemodynamics has been studied in 14 subjects with a GFR (Inulin clearance) ranging from 140 to 2 ml · min^–1.After a two day fluid and salt balance control period, oral piretanide 6 mg induced a natriuresis and kaliuresis, which was proportional to the GFR of the patients. The ratio of drug-induced K⁺ to Na⁺ excretion was always 0.13, independent of individual GFR. This was only true for the duration of the action of piretanide,, which was 6 h in subjects with normal GFR and 5 h in patients with impaired kidney function. Surprisingly, after, i. e. for 24 h after drug administration, less potassium was lost than in the pretreatment period. Neither the GFR nor the renal blood flow (PAH clearance) of the patients were affected by piretanide.In conclusion, piretanide given once a day was an effective natriuresic agent, even in end-stage renal disease, and it produced relatively little K⁺-loss when given once daily.     

Central venous pressure and pulmonary artery pressure monitoring

Stroke volume is a key determinate of cardiac output. It is affected by the preload, contractility and afterload of the myocardium. It is possible to gain insight into the right and left ventricular preload following the insertion of a central venous catheter and pulmonary artery catheter to measure central venous pressure and pulmonary capillary wedge pressure, respectively. Abnormal measurements can indicate a pathophysiological state and guide management.     

Effect of interferon gamma on intrahepatic haemodynamics of the cirrhotic rat liver

Sublethal injury of the liver with carbon tetrachloride (CCI₄) induces the modulation of hepatic stellate cells to their myofibroblast (MFB) phenotype. Pretreatment or concomitant treatment with interferon gamma (IFNγ) has been shown to inhibit this phenomenon. The aim of this study was to investigate the influence of IFNγ treatment (50 000 IU s.c. each day for 5 days) in rats with an established cirrhosis. Cirrhosis was induced with nine doses of CCI⁴. Comparison of biopsies before and after treatment with IFNγ showed that the number of MFB present, identified by their α-smooth muscle actin immunoreactivity, was markedly reduced. Pressure-flow curves were constructed in isolated perfused liver preparations from IFNγ-treated and saline-treated cirrhotic rats and analysed to obtain the extrapolated zero-flow intercept (P⁰, an index of hepatic vascular distensibility) and the vasodilator-induced change in resistance at a flow rate of 1 mL/min per g (ΔR₁ an indication of the level of intrinsic vascular tone). In IFNγ-treated rats, portal venous pressure measured in vivo was significantly reduced compared with controls (11.9±1.2 vs 16.0 ± 0.5 mmHg, P < 0.05), P₀ was lower (2.03 ± 0.18 vs 2.87 ± 0.32 mmHg, P < 0.05) and ΔR₁ was decreased (0.39 ± 0.15 vs 1.02 ± 0.19 mmHg/mL per min per g, P < 0.05). The findings indicate that treatment with IFNγ is effective in reducing MFB density in established CCI₄-cirrhosis in the rat and results in a marked improvement in intrahepatic haemodynamics.     

Exercise as a provocative test in early renal disease in Type 1 (insulin-dependent) diabetes: albuminuric,systemic and renal haemodynamic responses

Summary The value of exercise as a provocative test for early renal disease in Type 1 (insulin-dependent) diabetes was reevaluated. Three carefully characterized groups of males were studied: 10 non-diabetic controls, 16 diabetic patients (group 1) with normal urinary albumin excretion (< 15 g/min) and 14 Albustix-negative diabetics (group 2) with increased urinary albumin excretion (15–122 g/min). Assignment to a study group was made on the basis of three 24-h urine collections, and the groups were well matched for age, weight, height, and serum creatinine concentration. The two diabetic groups were similar with regard to duration of disease (13±6 versus 16±3 years), metabolic control (HbA_1c: 8.4±1.4 versus 8.7±1.3%) and degree of diabetic complications (beat-to-beat variation and retinopathy). An exercise protocol of 450 and 600 kpm/min workloads was employed. In the resting state group 2 patients had elevated systolic blood pressure compared with the normal subjects (132±13 versus 119±9 mmHg), and their glomerular filtration rate was significantly reduced compared with group 1 (123±19 versus 138±15ml/min per 1.73m², p < 0.05). During exercise the urinary albumin excretion rate increased significantly in all three groups (normal subjects: 6±0.7 to 8±1.3 (g/min); group 1: 6±0.6 to 9±1 g/min and group 2: 48±10 to 113±23 g/min), the relative increase being higher in group 2 (p < 0.01). The changes in systemic haemodynamics were similar in all three groups in spite of a reduced maximum working capacity in group 2 (949±249 versus group 1:1163±200 and normal subjects 1267±264 kpm/min (p < 0.05). The renal haemodynamic changes were qualitatively similar for the three groups, but the filtration fraction during exercise increased in groups 1 and 2 to almost identical values and were significantly higher than in normal subjects (group 1 + group 2: 0.29±0.02 versus normal subjects: 0.26±0.03, p < 0.02). These findings suggest that an elevated transcapillary pressure gradient, as obtained during moderate exercise, will not cause an abnormal increase in albumin excretion per se. A functional glomerular lesion, already recognisable at rest (elevated albumin excretion) must also be present.     

Splanchnic haemodynamics in patients with coeliac disease: effects of a gluten-free diet

BACKGROUND: Coeliac disease is characterized by structural and functional changes in the small bowel which may also result in haemodynamic changes. AIMS: To establish whether splanchnic haemodynamics can be modified by a gluten-free diet. PATIENTS: Ten coeliac patients and 10 paired healthy subjects. METHODS: Echo-Doppler measurements were made of splanchnic vessels both fasting and after a standard meal before and after 9 months of a gluten-free diet. RESULTS: In comparison to controls, coeliac patients had higher superior mesenteric artery blood velocity and flow, with lower resistance indexes and higher portal vein velocity and flow, particularly 3 h after a meal. Postprandial hyperaemia was reduced and delayed in time. Intrasplenic resistance indexes were also significantly lower both fasting and after a meal. After 9 months of a gluten-free diet, no significant differences were observed between coeliac patients and controls, both fasting and after a meal. CONCLUSIONS: Splanchnic haemodynamics is significantly changed in coeliac patients, mainly after a meal. On treatment with a gluten-free diet, both fasting and postprandial haemodynamics became normal.     

产后逐瘀胶囊对人工流产术后康复的影响

目的 探讨产后逐瘀胶囊对人工流产术后孕妇康复的影响.方法 选取行人工流产术结束分娩的孕妇120例,随机分为治疗组及对照组,各60例,2组术后常规给予头孢拉定胶囊、奥硝唑片口服,治疗组在常规用药的基础上口服产后逐瘀胶囊,3粒/次,3次/d,2组均1周为1疗程,观察2组孕妇术后阴道出血量及时间,并采用彩色超声检测仪测量子宫三径、内膜厚度及子宫动脉血流动力学指标.结果 治疗组孕妇人工流产术后阴道血量及时间、术后子宫三径线显著低于对照组(P＜0.05);2组术后子宫内膜厚度比较无统计学意义(P＞0.05),治疗组术后2周子宫动脉收缩期峰值流速(PSV)显著高于对照组(P＜0.05),2组子宫动脉搏动指数(PI)、阻力指数(RI)比较无统计学意义(P＞0.05);治疗组随访月经复潮情况显著优于对照组(P＜0.05).结论 产后逐瘀胶囊可显著减少人工流产术后孕妇阴道出血量,缩短出血时间,并可有效改善子宫血流动力学指标,利于人工流产术后子宫康复及月经周期的恢复.