Prostacyclin (epoprostenol) induces headache in healthy subjects

The role of prostanoids in nociception is well established. The headache eliciting effects of prostacyclin (prostaglandin I(2), (PGI(2))) and its possible mechanisms had previously not been systematically studied in man. We hypothesized that infusion of PGI(2) might induce headache and vasodilatation of cranial vessels. A stable analog of PGI(2) epoprostenol (10 ng/kg/min) was infused for 25 min into 12 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (V(mean MCA)) by the transcranial doppler and diameter of the superficial temporal artery (STA) by a high-resolution ultrasonography unit. During the immediate phase (0-30 min) and the post-infusion phase (30-90 min), 11 subjects reported headache on the PGI(2) day and no subjects reported headache on the placebo day (p=0.002). During epoprostenol (0-30 min) and in the post-infusion phase (30-90 min), the area under the curve (AUC) for headache score was significantly larger than during and after placebo (p=0.005). PGI(2) caused headache associated with the dilatation of STA (AUC, p<0.001), but no significant dilatation of the MCA (AUC, p=0.508). These data indicate that PGI(2) induced headache might be due to activation and sensitization of sensory afferents around extracranial arteries.     

The urinary excretion of prostaglandins E2 and F2α in essential hypertension

The 24 h urinary excretions of prostaglandins E2 (E2/d) and F2 alpha (F2 alpha/d) were measured in twenty-five normal subjects and in thirty-five patients with essential hypertension [seventeen with low renin (LRH) and eighteen with normal renin (NRH) hypertension]. E2/d was lower in patients with LRH than in normal subjects (P less than 0.01), whereas no difference was found between patients with NRH and the controls. F2 alpha/d was similar in patients with LRH and in the normal subjects, but was significantly greater in patients with NRH (P less than 0.02). The ratio of prostaglandin E2 to prostaglandin F2 alpha was decreased in hypertensive patients (P less than 0.02), although in the NRH subgroup the difference was not statistically significant. It appears that LRH is associated with impaired production of prostaglandin E2, while a deranged relationship between the two prostaglandins exists in all the patients with essential hypertension. These changes in prostaglandin production could possibly contribute to the pathogenesis of hypertension, by increasing renal vascular resistance and decreasing sodium excretion. Alternatively, they might be a secondary phenomenon, reflecting changes in renal prostaglandin metabolism induced by the hypertensive state.     

Renal prostaglandins E2 and F2α throughout normal human pregnancy

Twenty-five normal pregnant women were studied sequentially at 4-week intervals, beginning from weeks 8-16 until delivery. In eighteen women the study was repeated 6 weeks after delivery. The 24-h urinary excretion of PGE2 and PGF2 alpha, plasma renin activity (PRA), plasma aldosterone and fractional excretion of sodium (FENa) were measured at each visit. PGE2 and PGF2 alpha increased progressively throughout pregnancy (867 +/- 81 and 1048 +/- 94 ng 24 h-1 respectively, before week 15 and 1581 +/- 175 and 2625 +/- 305 ng 24 h-1, respectively, after week 35) and returned to normal values 6 weeks after delivery (748 +/- 107 and 1503 +/- 165 ng 24 h-1, respectively). PRA and aldosterone increased in a similar fashion, but values of prostaglandins did not correlate with those of PRA or aldosterone. PGE2 correlated directly with FENa but this correlation was weak. These results may suggest that tubulo-interstitial prostaglandins play a role in the regulation of sodium homeostasis during pregnancy.     

The cholinomimetic agent carbachol induces headache in healthy subjects

The parasympathetic nervous system is likely to be involved in migraine pathogenesis. We hypothesized that the cholinomimetic agonist carbachol would induce headache and vasodilation of cephalic and radial arteries. Carbachol (3 µg/kg) or placebo was randomly infused into 12 healthy subjects in a double-blind crossover study. Headache was scored on a verbal rating scale from 0–10. Velocity in the middle cerebral artery (V_MCA) and diameter of the superficial temporal artery (STA) and radial artery (RA) were recorded. Nine participants developed headache after carbachol compared with three after placebo. The area under the curve for headache was increased after carbachol compared with placebo both during infusion (0–30 min) ( P  = 0.042) and in the postinfusion period (30–90 min) ( P  = 0.027). Carbachol infusion caused a drop in V_MCA ( P  = 0.003) and an increase in STA diameter ( P  = 0.006), but no increase in the RA diameter ( P  = 0.200). In conclusion, the study demonstrated that carbachol caused headache and dilation of cephalic arteries in healthy subjects.     

Renal and Cardiovascular Effect of Prostaglandin A2 in Hypertensive Patients

Abstract. The haemodynamic and renal effects of synthetic prostaglandin A₂ (PGA₂) have been studied in 10 hypertensive subjects during a) a short lasting infusion of hypotensive doses of 3–9μg/kg min. of PGA₂; b) a continuous infusion starting with subdepressive doses and extended with hypotensive doses.—The rapid hypotensive effect observed with high doses was accompanied by an increase in cardiac output and renal blood flow without significant changes in the peripheral vascular bed. Hepatic blood flow was decreased. These observations show a preferential renal redistribution of cardiac output. During the administration of subdepressive doses of PGA., a marked renal effect was observed, consisting in an increase in free water clearance and diuresis with no significant modifications of general haemodynamics. The natriuretic effect was much less pronounced suggesting that PGA₂ is not a specific natriuretic hormone.—The haemodynamic and renal effects of endogenous PGs may play an important role in renal functions and in blood pressure regulation.     

Effects of intra-arterial prostaglandin E1 in patients with peripheral arterial occlusive disease

The effects of intraarterially administered prostaglandin E1 (PGE1) on macrocirculatory, microcirculatory and metabolic parameters in patients with peripheral arterial occlusive disease were studied. Nutritive calf muscle blood flow, as determined with the xenon-clearance technique, and muscle tissue oxygen pressure increased markedly in patients with obliterations of the femoral artery. Transcutaneous PO2 as indicator for cutaneous blood flow increased in prestenotic regions dose-dependently whereas there was a clear poststenotic decrease during the infusion period. High lactate/pyruvate ratios in the femoral vein were significantly decreased by PGE1 treatment. PO2 in the femoral vein increased significantly. Thus, PGE1 has some beneficial effects on muscle circulation in these patients.     

Prostaglandin E2 in jejunal fluids and its potential diagnostic value for selecting patients with indomethacin-sensitive diarrhoea

Since prostaglandins (PGs) appear to be important in the pathogenesis of secretory diarrhoea, a radioimmunoassay for determination of PGE2 was applied to purified samples of jejunal fluids aspirated at the ligament of Treitz. Studies on validation of the assay system included quantification of PGE2 following alkali-treatment of the samples, variation of the sample volume, and fractionation of immunoreactive- and tracer PGE2. In addition, the specificity of the assay system was confirmed by gas chromatography--mass spectrometry. In healthy volunteers (n = 22) the PGE2 concentration range was 5--205 pg/ml (99% confidence limits). Alcohol addicts (n = 27) with diarrhoea or steatorrhoea had PGE2 levels within the normal range. Values beyond the 99% upper confidence limit were observed in ten out of seventeen patients with chronic diarrhoea (205--340 pg/ml) and two out of fifteen patients with intermittent diarrhoea (265 and 275 pg/ml) classified as irritable bowel syndrome. In six patients with high PGE2 concentrations indomethacin treatment (25 mg x 4 daily) halved the associated diarrhoea and reduced PGE2 concentrations to normal levels. Subsequently, a double-blind multiple randomized clinical trial was carried out in two single patients. Indomethacin proved to be effective in preventing diarrhoea only in the patient with a raised PGE2 level (P less than 0.005).     

Radioimmunoassay of Prostaglandins Fα, E1 and E2 in Human Plasma

Abstract. Antibodies against prostaglandins (PG)F₂α, E₁ and E₂ were obtained in rabbits immunized with respectively PG F₂α, PG E₁ and PG E₂ conjugated to bovine serum albumin by carbodiimide. A radioimmunoassay capable of measuring 7 pg of PG Fα, 2 pg of PG E₂ and 14 pg of PG Ej in human peripheral plasma is described. Plasma samples (pH 3, citric acid) are extracted with cyclohexane: ethyl acetate, 1:1 and then chromatographed on silicic acid columns to separate the prostaglandins into three fractions: fraction I, PG A, PG B and some unknown immunoraactive compounds; fraction II, PG E and fraction III PG Fα. The recovery is 80 %± 6. 2. Mean plasma levels iu adults of PG Fa and PG E, expressed in pg/ml: -PG Fα 12 ± 2. 8 (n = 25 men), 8 ± 2. 3 (n = 18 women, follicular phase), 7 ± 1. 4 (n = 18 women, luteal phase). -PG E₁ 40. 5 + 7. 6 (n = 13 men), 38 + 17. 1 (n = 10 women). -PG E₂ 4. 5 ± 1 (n = 12 adult subjects).
The major characteristics of the method described herein are the following: - a large volume of plasma has to be processed (10 ml or more for PG Fa and PG E₁, 5 ml or more for PG E₂). - a chromatographic step is necessary to separate the different prostaglandins which makes it possible to circumvent problems of immunological cross reactivity and interference with unknown immunoreactive compounds. - great care has been taken in collection of blood samples, especially to insure complete removal of blood cells namely platelets.     

Increased cerebrovascular pCO2 reactivity in migraine with aura- a transcranial Doppler study during hyperventilation

Cerebrovascular reactivity during hypocapnia was tested in 20 migraineurs (8 with aura, 12 without aura) and 30 sex- and age-matched healthy subjects, and during nitroglycerin-induced headache in 12 healthy subjects. Before and during hyperventilation, mean blood-flow velocity (V_mean) in the middle cerebral artery was measured with transcranial Doppler. In each subject a pCO₂ reactivity index (RI) was calculated as DV_mean/baseline V_mean)/ DpCO₂. Interictally, patients with migraine with aura showed higher RI ( p < 0.05 ANOVA and multiple range test) than controls, whereas migraineurs without aura did not differ from healthy subjects. Ictal and interictal RIs were similar in 9 patients suffering from migraine without aura. No side-to-side differences were detected in RI. During nitroglycerin-induced headache, the RIs were no different from those recorded during migraine attacks and in non-nitroglycerin-provoked healthy controls (p > 0.05, ANOVA and multiple range test). The exaggerated response in migraine with aura might predispose for the characteristic changes in rCBF seen during attacks.     

The effect of circulating adenosine on cerebral haemodynamics and headache generation in healthy subjects

Adenosine is an endogenous neurotransmitter that is released from the brain during hypoxia and relaxes isolated human cerebral arteries. Many cerebral artery dilators cause migraine attacks. However, the effect of intravenous adenosine on headache and cerebral artery diameter has not previously been investigated in man and reports regarding the effect of intravenous adenosine on cerebral blood flow are conflicting. Twelve healthy participants received adenosine 80, 120 microg kg(-1) min(-1) and placebo intravenously for 20 min, in a double-blind, three-way, crossover, randomized design. Headache was rated on a verbal scale (0-10). Regional cerebral blood flow (rCBF) with 133Xe inhalation and single-photon emission computed tomography (SPECT) and MCA flow velocity (V(MCA)) with transcranial Doppler, were measured in direct sequence. Six participants developed headache during 80 microg kg(-1) min(-1) and six during 120 microg kg(-1) min(-1) compared with none on placebo (P = 0.006). The headache was very mild and predominantly described as a pressing sensation. When correcting data for adenosine-induced hyperventilation, no significant changes in rCBF (P = 0.22) or V(MCA) (P = 0.16) were found between treatments. A significant dilation of the superficial temporal artery (STA) was seen (P < 0.001). These results show that circulating adenosine has no effect on rCBF or V(MCA), while it dilates the STA and causes very mild headache.     

Stimulation by intragastrically administered E2 prostaglandins of human gastric mucus output

Abstract. Prostaglandin E₂ and 15(R)15 methyl prostaglandin E₂ were instilled intragastrically to study gastric mucus output in healthy male subjects during an infusion of pentagastrin. Mucus was measured by determining total, free, and bound N-acetyl neuraminic acid (NANA) in gastric recoveries. NANA is a sialic acid located at the end terminals on the carbohydrate chains of mucus glycoprotein. It contributes to viscosity and prevents enzymatic degradation of mucus.
The methyl analogue of prostaglandin E₂ increased the gastric output of NANA and inhibited gastric acid secretion in a dose-dependent fashion. NANA produced in response to the analogue was bound to mucus glycoprotein. Prostaglandin E₂ increased the output of NANA without affecting the gastric acid secretion. Both prostaglandin E₂ and its methyl analogue increased volumes, pH, and NANA content of gastric aspirates withdrawn prior to start of the pentagastrin infusion, indicating a stimulation of the alkaline gastric secretion.
The results show that oral E₂ prostaglandins have dual effects on gastric secretion, and that their ability to stimulate mucus production is not secondary to gastric acid inhibition. Further studies are needed to examine whether their effect is mainly to increase the incorporation of NANA into mucus glycoproteins, or to stimulate the release and/or production of gastric mucus, and also to quantitate the gastric nonparietal secretion.
The stimulatory properties of E₂ prostaglandins on gastric mucus and alkaline secretion may be one mechanism by which they protect the gastric mucosa against experimentally induced damage.     

Functionally inactive apolipoprotein E3 in a type III hyperlipoproteinaemic patient

Abstract. Type III hyperlipoproteinaemia (HLP) is, amongst others, characterized by the E_2/2 phenotype as determined by isoelectric focusing of apolipoprotein E. However, one of our clinically symptomatic type III HLP patients showed a E_3/3 phenotype.
After complexation with phospholipid vesicles, apo E from this patient was, in contrast with apo E from a type IV HLP patient (E_3/4 phenotype), unable to compete with low density lipoprotein (LDL) for binding to the specific LDL receptors on cultured human fibroblasts. This defect in binding to the LDL receptor was not due to an impaired lipid binding capability. The clinical symptomatic type III hyperlipoproteinaemia of our patient is probably due to a functionally inactive apo E₃.     

Middle cerebral artery blood flow velocimetry among healthy fetuses with a single umbilical artery.

OBJECTIVE: A single umbilical artery (SUA) is an independent risk factor for perinatal morbidity and mortality in healthy fetuses. The aims of the study were (1) to determine middle cerebral artery (MCA) blood flow velocimetric values among fetuses without structural or chromosomal anomalies with an SUA and to compare them with nomograms of patients with a 3-vessel cord and (2) to measure the pulsatility index (PI) of the umbilical artery among these patients. METHODS: The PI values of the MCA and umbilical arteries were determined prospectively among 98 healthy fetuses with an SUA. The PI values were compared with nomograms of patients with a 3-vessel umbilical cord. For the MCA, peak systolic velocity (PSV) was also measured. Patients carrying fetuses with intrauterine growth restriction or congenital anomalies were excluded from the study. Middle cerebral artery PI values below the fifth percentile and PSV values above the 95th percentile adjusted for gestational age were considered abnormal. RESULTS: Gestational age ranged between 22 and 37.9 weeks (median, 30.3 weeks). After adjusting for gestational age, no alterations in the MCA PI and umbilical PI were found in comparison with the normal range for a 3-vessel cord known in the literature. Middle cerebral artery PSV values were also within the normal range for gestational age in all patients. CONCLUSIONS: The MCA PI and PSV values among healthy fetuses with an isolated SUA were similar to nomograms for fetuses with a 3-vessel umbilical cord. Therefore, abnormal MCA PI and PSV values among fetuses with an SUA should be treated the same as in patients with a 3-vessel umbilical cord.     

A transcranial doppler study in interictal migraine and tension-type headache

PURPOSE: To use transcranial Doppler (TCD) sonography to determine if patients with migraine without aura have interictal hemodynamic abnormalities compared with patients who have episodic tension-type headache (TH). METHODS: Thirty-six migraine patients without aura and 51 TH patients (age range, 16-50 years) who were diagnosed according to the criteria of the International Headache Society 1988 participated in the study. Forty-four healthy volunteers, matched for age and sex, formed the control group. Time-averaged mean velocity (TAMV), pulsatility index (PI), and breath-holding index (BHI) were measured via TCD sonography in the middle cerebral artery. RESULTS: TAMV was higher in migraine without aura than in episodic TH (p = 0.034). There were no differences between groups regarding PI or BHI. CONCLUSION: Our findings support the arteriolar vasodilatation theory in migraine without aura.     

Effects of four orally administered analogues of prostaglandin E1 and E2 on glucose tolerance and on the secretion of pancreatic and gastrointestinal hormones in man

Oral glucose tolerance tests (75 g, 300 ml) were performed in 12 healthy volunteers, with prior administration of placebo, misoprostol (400 micrograms), rioprostil (300 micrograms), enprostil (70 micrograms), or nocloprost (200 micrograms), in a double-blind, randomized manner. None of the drugs significantly affected glucose tolerance, although with misoprostal some volunteers displayed an impaired glucose tolerance. Nocloprost was without effect on gastric inhibitory polypeptide (GIP) and did not influence insulin or C-peptide concentrations. Misoprostol and rioprostil reduced integrated incremental responses of GIP by 57% (P less than or equal to 0.001) and 45% (P less than or equal to 0.01), respectively, and both gave rise to an initial (approximately 10 min) delay of insulin and C-peptide responses, without a significant overall reduction in integrated incremental responses. Enprostil almost totally inhibited the GIP response (by 94%; P less than or equal to 0.001), delayed initial insulin and C-peptide responses, but reduced the integrated incremental C-peptide response (which corresponds to the overall release of insulin) by only 14% (P less than or equal to 0.05). Enprostil more substantially reduced the integrated incremental response of insulin by 36% (P less than or equal to 0.01), and also reduced the ratio of insulin and C-peptide incremental responses (P less than or equal to 0.001). In conclusion, prostaglandin E analogues which caused a reduction in GIP responses, and thereby disrupting the enteroinsular axis to varying degrees, delayed the time-course of insulin secretion without a significant impact on glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of prostaglandin E1 during preparation of platelet concentrates

Summary. A paired study in 10 autologous volunteer donors was undertaken to investigate the efficacy of adding prostaglandin E₁ (PGE₁) in vitro during routine platelet concentrate (PC) production. After 5 days storage, PCs prepared with PGE₁ were compared with control PCs. In vivo platelet recovery, survival and biodistribution were determined following autologous infusion of indium-111 labelled platelets into volunteers, together with the in vitro evaluation of platelet function and biochemistry. PGE₁ facilitated easier and faster platelet resuspension following centrifugation. After storage there were few significant in vitro differences between PCs prepared with PGE₁ and control PCs. The artifactual leucocyte concentration was significantly lower in the presence of PGE₁, suggesting less platelet aggregates had been formed during storage and β-thromboglobulin release was significantly reduced by PGE₁, 14.0±6.0 μg per 10⁹platelets compared with 22.3±9.8μg per 10⁹platelets in control PCs, (P < 0.01), indicating PGE₁ reduced both platelet aggregation and activation probably at the initial preparation stage, known to produce the greatest trauma. Initial in vivo platelet recovery for PCs prepared with PGE₁ was similar to that of control PCs, 41.1 ± 12.5% vs. 44.4±80%, respectively, and there were no differences in organ distribution at 24h. However, in vivo multiple hit survival was reduced in the presence of PGE₁, 5.8 ± 1.6 days compared with 6.9 ± 1.4 days in control PCs (P < 0.05). Despite the ability of PGE₁ to facilitate platelet resuspension and inhibit platelet aggregation and activation during preparation of the PCs, the reduced in vivo survival time may preclude the use of PGE₁ during routine PC preparation.     

Effect of carbenoxolone on gastric prostaglandin E2 levels in patients with peptic ulcer disease following vagal and pentagastrin stimulation

The influence of oral carbenoxolone sodium (50 mg X 3 daily) on prostaglandin E2 release into gastric juice has been examined in nine peptic ulcer patients (duodenal ulcer, n = 6; prepyloric ulcer, n = 1; gastric ulcer, n = 2) during modified sham feeding and following bolus stimulation of acid secretion by pentagastrin (6 micrograms/kg). Carbenoxolone increased the overall mean of prostaglandin E2 concentrations in gastric juice following modified sham feeding by 32 +/- 9% (mean +/- SEM; P less than 0.02) and decreased the acidity slightly but significantly (P less than 0.05). A marked rise in prostaglandin E2 levels (46 +/- 11%; n = 5; P less than 0.02) was observed in for duodenal ulcer patients and the patient with a prepyloric ulcer responding to therapy (i.e., pain relief and ulcer healing within 4 weeks of treatment). A significant peak (P less than 0.05) related to modified sham feeding was observed only during medication, while a late gradual increase in prostaglandin E2 levels--not associated with vagal stimulation--occurred both in control and carbenoxolone experiments. No significant differences were observed following pentagastrin stimulation. The initial peak in prostaglandin E2 levels observed during medication favours the notion that the mechanism of drug action relies on inhibition of enzymatic degradation while the late increase in prostaglandin E2 levels may be explained by artificial prostaglandin formation during the aspiration procedure.     

α1 and α2-adrenergic control of large and small coronary arteries during exercise in conscious dogs under β-blockade

Summary— The aim of this study was to determine the relative roles of α₁-and α₂-adrenoceptors at the level of large epicardial and small resistance coronary arteries when sympathetic tone is increased by exercise in conscious dogs. The responses of left circumflex coronary artery diameter and blood flow were investigated at rest and during graded treadmill exercise (5, 10 and 12 km/h) in six chronically instrumented dogs during control conditions (saline) and after administration of propranolol (1 mg/kg) either alone or in combination with either prazosin (50 μg/kg), or idazoxan (300 μg/kg), or the association of prazosin + idazoxan (same doses). In control conditions, graded treadmill exercise resulted in a progressive increase in coronary artery diameter (+ 3.8 ± 0.6% from 3479 ± 80 μm) and in a decrease in coronary vascular resistance (- 46.0 ± 4.5% from 8.49 ± 1.51 mmHg/cm/s). Propranolol significantly constricted large (- 4.4 ± 0.6% from 3486 ± 87 μm) and limited dilation of small coronary arteries during exercise. These coronary effects of propranolol remained unchanged following additional α₂-adrenoceptor blockade by idazoxan but were abolished following α₁-adrenoceptor blockade by prazosin, given either alone or combined with idazoxan. Thus, α₁- but not α₂-adrenoceptors are responsible for propranolol-induced constriction of large coronary arteries and limitation of small coronary arteries dilation during exercise in conscious dogs.     

Increase in PGE2 and TXA2 in the Saliva of Common Migraine Patients. Action of Calcium Channel Blockers

PGE2 and TXA2 levels and their modulation by nicardipine, a calcium blocking agent, have been studied in patients suffering from migraine. The levels of both metabolites were determined in saliva obtained during the migraine attacks, during the intervals between attacks, and after 2 months of treatment with nicardipine (20 mg every 8 h.) or placebo. The therapeutic response was evaluated on the basis of the number of migraine attacks. The results show a significant increase in the levels of both eicosanoids during the migraine attacks. In contrast to the placebo group, the number of migraine attacks and the levels of both arachidonic acid metabolites are markedly lower in the nicardipine group. Our results suggest calcium entry into the cytosol as an explanation for the increase in PGE2 and TXA2. Nicardipine interferes with calcium mobilization, thereby inhibiting arachidonic acid metabolite synthesis.     

CO2 measurements during transcranial Doppler examinations in headache patients: methodological considerations

Transcranial Doppler (TCD) examinations are increasingly being used in studies of headache pathophysiology. Because blood velocity is highly dependent on pCO₂, these parameters should be measured simultaneously. The most common way of performing measurements during TCD examinations is as end-tidal pCO₂ witch a capnograph. When patients are nauseated and vomit, as in migraine, the mask or mouthpiece connected to the capnograph represents a problem. We therefore evaluated whether a transcutaneous pCO₂ electrode was as useful as the capnograph for pCO₂ measurements in TCD examinations. We conclude that this is not the case, and recommend capnographic end-tidal pCO₂ measurements during TCD examinations. However, transcutaneous pCO₂ measurements may represent a supplement to spot measurements of end-tidal pCO₂ in stable conditions when long-term monitoring is needed, and the mask or mouthpiece of the capnograph has to be taken on and off between recordings.