The treatment of the hepatorenal syndrome with intra-renal administration of prostaglandin E1

Three patients with the hepatorenal syndrome were treated with prostaglandin E₁ administered through a selective renal arterial catheter. Prostaglandin E₁ was given in progressively increasing doses (2 to 100 ng/kg/min) over a 60-minute period. Control plasma prostaglandin E levels were elevated in all three patients, 0.98, 0.91, and 0.83 ng/ml, respectively. At the end of the infusion, plasma prostaglandin E levels had risen to 10.4, 2.63, and 10.3 ng/ml in the three patients respectively. Plasma renin activity increased during the course of the infusion in two of the patients. The plasma aldosterone concentration did not change during the prostaglandin E₁ infusion. Intrarenal prostaglandin E₁ failed to increase urine volume or urinary sodium concentration in three patients with the hepatorenal syndrome.     

Plasma Steroid and Luteinizing Hormone Levels during Prostaglandin F2α Administration in Luteal Phase of Menstrual Cycle

An intravenous infusion of prostaglandin F₂α (12.5-250μg/min) was administered in four volunteers in the mid-late luteal phase and three in the early luteal phase of the menstrual cycle.Frequent measurement of plasma progesterone, oestrogens, and luteinizing hormone (LH) showed that administration of high doses depressed plasma progesterone levels in the late luteal phase and caused concomitant side effects. Levels of progesterone in the early luteal phase were unaffected. In both phases oestrogen and LH levels were little altered. In two subjects, hourly progesterone levels measured throughout the day at a similar time in a subsequent control menstrual cycle showed an appreciable variation in one but steady levels in the second. This variation may contribute to the magnitude of the fall in progesterone noted during the infusion of prostaglandins.     

Ascorbic acid increases cardiovagal baroreflex sensitivity in healthy older men

Cardiovagal baroreflex sensitivity (BRS) declines with advancing age in healthy men. We tested the hypothesis that oxidative stress contributes mechanistically to this age-associated reduction. Eight young (23 +/- 1 yrs, means +/- SE) and seven older (63 +/- 3) healthy men were studied. Cardiovagal BRS was assessed using the modified Oxford technique (bolus infusion of 50-100 microg sodium nitroprusside, followed 60 s later by a 100- to 150-microg bolus of phenylephrine hydrochloride) in triplicate at baseline and during acute intravenous ascorbic acid infusion. At baseline, cardiovagal BRS (slope of the linear portion of the R-R interval-systolic blood pressure relation during pharmacological changes in arterial blood pressure) was 56% lower (P < 0.01) in older (8.3 +/- 1.6 ms/mmHg) compared with young (19.0 +/- 3.1 ms/mmHg) men. Ascorbic acid infusion increased plasma concentrations similarly in young (62 +/- 9 vs. 1,249 +/- 72 micromol/l for baseline and during ascorbic acid; P < 0.05) and older men (62 +/- 4 vs. 1,022 +/- 55 micromol/l; P < 0.05) without affecting baseline blood pressure, heart rate, carotid artery compliance, or the magnitude of change in systolic blood pressure in response to bolus sodium nitroprusside and phenylephrine hydrochloride infusion. Ascorbic acid (vitamin C) infusion increased cardiovagal BRS in older (Delta58 +/- 16%; P < 0.01), but not younger (Delta - 4 +/- 4%) men. These data provide experimental support for the concept that oxidative stress contributes mechanistically to age-associated reductions in cardiovagal BRS in healthy men.     

Local vasodilatation with metacholine, but not with nitroprusside, increases forearm glucose uptake

Insulin is known to increase blood flow in parallel to glucose uptake in skeletal muscle. However, it is not known if an increase in blood flow by itself is associated with an increase in glucose uptake in the absence of hyperinsulinemia. To investigate further this matter, the effect of increased blood flow on forearm glucose uptake was studied in the fasting state during intra-arterial infusions of two different vasodilators, metacholine and nitroprusside, in 19 hypertensive subjects. Both metacholine (4 microg/min) and nitroprusside (10 microg/min) increased resting forearm blood flow, measured by venous occlusion plethysmography, to a similar degree (180 % and 170 %, respectively, p<0.0001 for both). However, metacholine infusion increased the forearm glucose uptake from 2.0+/-0.9 (S.D.) during rest to 5.5+/-3.0 umol/min/100 ml tissue (p<0.0001), while no significant change in glucose uptake was seen during nitroprusside infusion (2.3+/-1.4 micromol/min/100 ml tissue). In conclusion, vasodilatation induced by metacholine, but not by nitroprusside, increased glucose uptake in the forearm of hypertensive patients. Thus, an increase in forearm blood flow does not necessarily improve glucose uptake in the forearm during the fasting state.     

Prostaglandin F2α-induced stimulation of estrone and estradiol-17β secretion in cattle

Four of 5 Holstein heifers given intra-ovarian injections of 300 μg of prostaglandin F_2α (PGF_2α) showed transient, but statistically significant, depressions in plasma progesterone levels which returned to near normal levels within 24 hr. The same 4 animals also exhibited significant elevations in plasma estrone and estradiol-17β levels during the initial 24 hr. period following treatment, although no animals were observed in estrus during this time. Plasma levels of progesterone, estrone, estradiol-17β and PGF showed little change in control heifers receiving intra-ovarian injections of the buffer solution used as a vehicle for PGF_2α. It is concluded that PGF_2α stimulates estrogen secretion, presumably by follicular elements of the ovary.     

Comparison of two methods of altering blood pressures for assessing neonatal cerebral blood flow autoregulation

The cerebral blood flow of newborn lambs at reduced and elevated arterial blood pressures, induced by intravenous infusion of sodium nitroprusside and phenylephrine hydrochloride as well as blood withdrawal and reinfusion, were compared. Both blood withdrawal and sodium nitroprusside infusion reduced mean arterial pressure from 83 to 60 mmHg (1 mmHg = 133 Pa). Reinfusion of blood increased arterial pressure to 94 mmHg. Phenylephrine hydrochloride infusion increased arterial pressure to 102 mmHg. The cerebral blood flows at corresponding arterial pressures were similar (coefficient of correlation = 0.88, P less than 0.01). Cerebral blood flow before and after infusion of phenylephrine hydrochloride and sodium nitroprusside into the brain via the carotid artery did not change. The results indicate that blood-borne phenylephrine hydrochloride and sodium nitroprusside, in concentrations that would alter arterial blood pressure significantly from its resting level, do not change cerebral blood flow directly.     

The effect of prostaglandin E2 infusion in the fetal lamb on fetal plasma acth, prolactin and cortisol concentrations

PGE₂ (2 μg/min) has been infused for 1h into the fetal jugular vein of 8 chronically catheterized fetuses on 13 occasions from 112 to 138 days gestation. Infusion of ethanol vehicle alone was conducted in fetuses from 111 – 139 days gestation. PGE₂ administration produced a significant increase in fetal plasma cortisol after 30 min. No significant change was observed in fetal plasma prolactin concentration. Fetal plasma ACTH concentration was significantly elevated above resting concentration after 30 min. of PGE₂ infusion. Metabolic clearance rate of PGE₂ was 860 ml/min or 350 ml/kg/min. Intrauterine pressure was not changed during the infusion at any gestational age.     

Angiotensin II-stimulated secretion of arginine vasopressin is inhibited by atrial natriuretic peptide in humans

We investigated the effect of the intravenous infusion of atrial natriuretic peptide (ANP) on the response of plasma arginine vasopressin (AVP) levels to intravenous infusion of angiotensin II (ANG II) in healthy individuals. Intravenous infusion of ANP (10 ng·kg(-1)·min(-1)) slightly but significantly decreased plasma AVP levels, while intravenous infusion of ANG II (10 ng·kg(-1)·min(-1)) resulted in slightly increased plasma AVP levels. ANG II infused significant elevations in arterial blood pressure and central venous pressure (CVP). Because the elevation in blood pressure could have potentially inhibited AVP secretion via baroreceptor reflexes, the effect of ANG II on blood pressure was attenuated by the simultaneous infusion of nitroprusside. ANG II alone produced a remarkable increase in plasma AVP levels when infused with nitroprusside, whereas the simultaneous ANP intravenous infusion (10 ng·kg(-1)·min(-1)) abolished the increase in plasma AVP levels induced by ANG II when blood pressure elevation was attenuated by nitroprusside. Thus, ANG II increased AVP secretion and ANP inhibited not only basal AVP secretion but also ANG II-stimulated AVP secretion in humans. These findings support the hypothesis that circulating ANP modulates AVP secretion, in part, by antagonizing the action of circulating ANG II.     

A double blind placebo controlled crossover study of prostacyclin in man.

Prostacyclin sodium (PGI₂) was administered in a double blind crossover trial to 6 normal males at infusion rates of 2, 4 and 8 ng/kg/minute. Substantial (p < 0.001) shifts of the log dose response curve of ADP induced platelet aggregation occured during the highest infusion rate of PGI₂. This was associated with a small but significant fall in diastolic blood pressure (?6.3± 1.6 mm Hg, p < 0.01) and a rise in heart rate (+25.5 ± 6.5 beats/minute, p < 0.001). Plasma renin activity rose in a dose related manner with PGI₂ but plasma aldosterone and plasma norepinephrine did not change. Marked facial flushing occured with PGI₂.     

Induction of renin release by exogenous prostaglandins in hyporeninemic hypoaldosteronism

A deficiency in renal prostaglandin synthesis has been proposed as the cause of the syndrome of hyporeninemic hypoaldosteronism. To determine if renin release could be stimulated by pharmacologic infusions of PGA₁, we infused PGA₁ 0.075 to 0.60 μg/kg/min to nine patients with the syndrome. Total renal PGE production as measured by urinary PGE excretion was normal (650 ± 169 vs 400 ± 55 ng/24hr in normal subjects). Renin (PRA) was markedly depressed in all patients despite stimulation with upright posture and furosemide (1.0 ± 0.4 vs 9.3 ± 0.7 ng/ml/hr, p<0.001). But in two patients PGA₁ induced an increase in renin similar to that of normal subjects. PRA increased to a lesser degree in two other patients and plasma aldosterone slightly increased. Five showed no response. Infusions of nitroprusside in doses and duration that mimicked the hypotensive effects of PGA₁ failed to increase PRA or aldosterone. The data suggest that total renal PGE production is normal in patients with the syndrome of hyporeninemic hypoaldosteronism. Although orthostasis, furosemide and nitroprusside do not increase renin, prostaglandin A₁ infusion appears to be a potent stimulus to renin release in some of the patients.     

Drug-Induced Changes in Blood Pressure Lead to Changes in Extracellular Concentrations of Epinephrine, Dihydroxyphenylacetic Acid, and 5-Hydroxyindoleacetic Acid in the Rostral Ventrolateral Medulla of the Rat

Neurochemical changes in the extracellular fluid of the rostral ventrolateral medulla (RVLM) were produced by changes in arterial blood pressure. Blood pressure was raised or lowered with systemic infusions of phenylephrine or nitroprusside and neurochemicals were recovered from RVLM by in vivo microdialysis. A dialysis probe 300 microns in diameter and 500 microns in length was stereotaxically implanted in the RVLM of the urethane-anesthetized rat. Sterile physiological Ringer's solution was perfused at a rate of 1.5 microliter/min. The perfusate was collected under ice-cold conditions every 15 min for the assay of epinephrine, dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), ascorbic acid, and uric acid. After stable baseline neurochemical concentrations were achieved, animals were infused with phenylephrine or nitroprusside intravenously to raise or lower the blood pressure. Increasing blood pressure 50 mm Hg above the baseline value by phenylephrine led to a significant reduction in heart rate and a reduction in extracellular epinephrine and DOPAC concentrations. The 5-HIAA concentration was increased during the hypertensive drug infusion. There were no changes in the concentrations of ascorbic acid or uric acid. Hypotension produced by nitroprusside (-20 mm Hg) led to neurochemical changes which were the reciprocal of those seen during hypertension. During hypotension, heart rate increased as did the extracellular fluid epinephrine concentration. The 5-HIAA concentration fell with hypotension and remained depressed following the nitroprusside infusion. Ascorbic acid and uric acid concentrations did not change during hypotension but ascorbic acid did increase after the nitroprusside infusion stopped. These data provide direct evidence that epinephrine release in RVLM is linked to changes in systemic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of prostaglandin A1 infusion in hypertensive patients with renal artery stenosis

Clinical data, arteriographic findings, peripheral and renal vein plasma renin activity (PRA) studies and responses to prostaglandin A₁ infusion are presented from observations in seven hypertensive patients with renal artery stenosis. PGA₁ infusion caused an increase in PRA and urine sodium excretion but no significant change in blood pressure. Exaggerated increases in PRA were observed in five patients. With cessation of PGA₁ infusion PRA returned toward pre-infusion levels. In two patients bilateral renal and peripheral vein PRA's were determined before and during PGA₁ infusion. PGA₁ caused a greater increase in renal vein PRA than in peripheral vein PRA indicating a direct enhancement of renin secretion. These studies indicate possible relationships between the vasoactive prostaglandins and the renin-angiotensin system in the pathogenesis of hypertension due to renal artery stenosis.     

In vivo voltammetry in the B3 group of serotonin neurons of the rat medulla oblongata after drug-induced modifications of arterial pressure

Differential normal pulse voltammetry (DNPV) using an electrochemically treated carbon fiber electrode was applied to the investigation of the in vivo changes in extracellular 5-hydroxyindoleacetic acid (5HIAA) in the B3 group of serotonin neurons during experimental manipulations of arterial pressure. Drug-induced hypertension (phenylephrine infusion) caused, during the infusion, an increase in extracellular 5HIAA concentration which continued to rise, reaching +100% 2 hours after stopping the infusion. In contrast, drug-induced hypotension (sodium nitroprusside infusion) was not associated with any change in extracellular 5HIAA during the infusion while the return to the initial arterial pressure caused a progressive increase in the electrochemical signal, reaching +50% one hour after stopping the infusion. These data show that the extracellular 5HIAA concentration is increased when the arterial pressure increases, a result which suggests that B3 serotonin neurons could have a vasodepressor role in the central regulation of arterial pressure.     

Effects of prostaglandin B1 on basal and stimulated circulating levels of insulin, glucose and free fatty acids

The influence of an infusion of PGB₁ upon circulating levels of insulin, glucose and free fatty acids in anesthetized dogs both in the basal state and following stimulation with intravenous glucose or norepinephrine was not significantly different from saline-treated controls. Since no increment in immunoreactive PGE was found in thoracic aorta plasma during PGB₁ infusion, it is unlikely that the observed trends in the insulin, glucose and free fatty acid data during PGB₁ infusion were due to simultaneous endogenous PGE formation.     

The effects of changes in heart rate and aortic systolic pressure on left ventricular myocardial oxygen consumption in lambs

To determine whether changes in heart rate and aortic systolic pressure contribute equally to the determination of left ventricular myocardial oxygen consumption, we independently varied heart rate and pressure and compared the resultant oxygen consumption for similar rate-pressure products. In 6 young lambs which underwent atrioventricular node ablation, we varied heart rate by ventricular pacing at 250 beats/min, 300 beats/min, and 120 beats/min while aortic pressure remained stable and varied aortic systolic pressure by infusion of phenylephrine (to 132 +/- 15 mm Hg and 155 +/- 14 mm Hg) and by infusion of sodium nitroprusside (to 79 +/- 6 mm Hg) while heart rate was maintained stable at 200 beats/min. The 3 levels of change in aortic systolic pressure were chosen so that the ratepressure product during the pressure changes matched the rate-pressure product during the heart rate changes. We found that left ventricular myocardial oxygen consumption was the same at all 3 levels of the rate-pressure product whether heart rate was changed and pressure remained stable or pressure was changed and heart rate remained stable. Also, the correlation between oxygen consumption and the rate-pressure product was similar for both heart rate and pressure changes. During nitroprusside infusion at a fixed heart rate, oxygen extraction was significantly lower than during pacing at a heart rate of 120 beats/min when the rate-pressure product was comparable because of the direct vasodilatory effects of nitroprusside. We conclude that heart rate and aortic systolic pressure contribute equally to left ventricular myocardial oxygen consumption at the same rate-pressure product, even though there may be differences in myocardial blood flow and oxygen extraction.     

Stimulation of brain aromatic alkylamine N-methyltransferase activity by FAD and methylcobalamin

We studied the effects of methylcobalamin alone and with various reducing systems (FADH₂, FAD or its analogues in combination with NADH or β-mercaptoethanol) on the activity of partially purified aromatic alkylamine N-methyltransferase (AANMT) from rat brain. As expected, the specific activity of AANMT in the presence of methylcobalamin alone was enhanced (125% of control). Surprisingly, in the presence of FAD alone (but not FADH₂$\text{et cetera}$) it was 175% of control; and int the presence of methylcobalamin plus FAD plus β-mercaptoethanol it reached 307% of control. Preliminary evidence suggests that FAD induces allosteric kinetics for the activated enzyme with respect to the methyl donor 5-methyltetrahydrofolic acid (5-MTHF).     

Zymosan activated plasma infusion in sheep: Effects of ethanol administration

Zymosan activated plasma infusion induces pulmonary sequestration of neutrophils and the release of TXA₂ into the pulmonary vascular bed causing profound and transient pulmonary hypertension.Since ethanol (ETOH) inhibits several inflammatory functions of neutrophils, including adherence and aggregation, we examined the ability of anesthetic doses of ETOH to alter the hemodynamic and cellular response to the infusion of zymosan activated plasma (ZAP) in vivo. Twenty five ml of autologous ZAP was intravenously infused into five control and seven (ETOH-treated sheep during mechanical ventillation. In control sheep the mean pulmonary artery pressure (PAP) transiently increased from 14.7±1.4 mm Hg (mean±SEM) to a pead of 38+8 mm Hg by three minutes after beginning the infusion of ZAP. Blood leukocyte concentration transiently decreased 19% below the baseline value due to pulmonary sequestration of polymorphonuclear leukocytes (PMN). Plasma TXB₂ levels measured by radioimmunoassay (RIA) increased from 0.2 to 5.4 ng/ml six minutes after the initiation of ZAP infusion.In five sheep, intravenous infusion of 200 ml of 96% ETOH yielded very high plasma concentrations (882±101 mg%) and completely inhibited both the rise of PAP and the increase of plasma TXB₂ levels after ZAP infusion. However, blood leukocytes transiently decreased 58% below the baseline value. Lower plasma levels of ETOH (200 and 400 mg%) did not prevent either the increase of PAP or the elevation of plasma TXB₂ after ZAP infusion.     

Effect of alpha-human atrial natriuretic polypeptide on anterior pituitary function in men

In order to examine the effects of alpha-human atrial natriuretic polypeptide (alpha-hANP) on the basal plasma concentrations of GH, TSH, LH, FSH and PRL in humans, synthetic alpha-hANP was infused into 10 normotensive, euvolemic, healthy volunteers. There were observed marked hypotensive, diuretic and natriuretic effects during the alpha-hANP infusion. The basal plasma concentrations of GH, TSH, LH and FSH, showed no significant change following the alpha-hANP infusion. However, significant suppression of the plasma PRL concentration was observed with the alpha-hANP administration. The mean plasma PRL concentration tended to be decreased during 20 min of alpha-hANP infusion, however, there the differences were not statistically significant. A significant reduction in the mean plasma PRL concentration (-20%, P less than 0.5) was observed 10 min after the end of infusion, following the reversion to the preinfusion level at 70 min after the end of infusion. Such a significant and delayed suppression was not seen in the case of placebo infusion. The data suggest that the circulating hANP may reduce the release of PRL.     

Methyl B12 protects PC12 cells against cytotoxicity induced by Aβ25−35

Alzheimer's disease (AD) is the most common aging-associated dementia. The population of AD patients is increasing as the world age grows. Currently, there is no cure for AD. Given that methyl vitamin B12 (methylcobalamin) deficiency is related to AD and Aβ-induced oxidative damage and that methylcobalamin can scavenge reactive oxygen species (ROS) by direct or indirect ways, we studied the effect of methylcobalamin on the cytotoxicity of Aβ. PC12 cells were chronically exposed (24 hours) to Aβ_25-35 (25 μM) to establish an AD cell model. The cells were pretreated with or without methylcobalamin (1-100 μM) to investigate the role of methylcobalamin. Cell viability and apoptosis were tested, followed by testing of mitochondrial damage, oxidative stress, and mitochondrial calcium concentration. We observed that methylcobalamin improved the cell viability by decreasing the ratio of apoptosis cells in this AD cell model. Further experiments suggested that methylcobalamin functioned as an antioxidant to scavenge ROS, reducing the endoplasmic reticulum-mitochondria calcium flux through IP3R, preventing mitochondria dysfunction, ultimately protecting cells against apoptosis and cell death. Taken together, our results presented, for the first time, that methyl vitamin B12 can protect cells from Aβ-induced cytotoxicity and the mechanism was mainly relevant to the antioxidative function of methyl B12.     

Role of prostaglandis in the control of renin secretion in the dog (II)

Infusion of prostaglandin E₁ (PGE₁) into the renal artery of anesthetized dogs (1.03 μg/min) caused increases in urine flow rate (V), renal plasma flow (RPF) and renin secretion rate without any change in mean arterial blood pressure (MABP), whereas infusion of prostaglandin F₂α (PGF_2α), (1.03 μg/min) caused no consistent change in V, RPF, or renin secretion rate. Infusion of prostaglandin E₂ (PGE₂) (1.03 μg/min) into the renal artery of “non-filtering” kidneys caused renin secretion rate to rise from 567.7 ± 152.0 U/min(M ± SEM) during control periods to 1373.6 ± 358.5 U/min after 60 minutes of infusion of PGE₂ (P < 0.01), without significant change in MABP (P > 0.1). The data suggest that PGE₁ and PGE₂ play a role in the control of renin secretion. The data further suggest that PGE may control renin secretion through a direct effect on renin-secreting granular cells.