The differential effect of arginine vasopressin on skin blood flow in man

Physiological elevation of plasma vasopressin in man results in a small reduction in skeletal muscle blood flow but the action on skin blood flow has not been reported. We have studied eight male subjects during infusion of arginine vasopressin (AVP) at 2 units/h for 90 min. Plasma levels of AVP, measured by radioimmunoassay, rose to 68.5 (7.0) pg/ml, mean (SEM). Forearm and finger blood flow was measured with an electronic plethysmograph, hand interdigital skin-fold blood flow with a laser-Doppler blood flow meter and facial temperature with a thermocouple. All subjects developed marked facial pallor during infusion of AVP, facial temperature falling from 34.2 (0.2) to 32.7 (0.1) degrees C (P less than 0.001) then rising to 33.7 (0.1) degrees C (P less than 0.01) after AVP was stopped. Hand interdigital skin-fold blood flow also fell from 2.6 (0.02) to 2.3 (0.02) V (P less than 0.001) and rose sharply to 3.6 (0.2) V (P less than 0.001) on stopping the infusion. There were small changes in forearm and finger blood flow: both rose, from 6.3 (0.1) to 6.9 (0.1) (P less than 0.001) and 46.1 (1.0) to 54.3 (0.7) ml min-1 100 ml-1 (P less than 0.001) respectively. Neither fell when AVP was stopped. Heart rate remained unchanged throughout. These results indicate that high physiological levels of AVP, comparable with those attained during physical stress, produced a fall in blood flow in the face and interdigital skin-fold of the hand consistent with a fall in nutritional blood flow to skin.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of arginine vasopressin,lysine vasopressin or oxytocin on ADP or arginine vasopressin-induced Ca2+ increase in human platelets

Oxytocin (OT), lysine vasopressin (L⁸VP), arginine vasopressin (A⁸VP) or arginine vasotocin (A⁸VT) are found in plasma from several species and stimulate various cell types by activation of the polyphosphoinositide metabolism and mobilization of intracellular calcium. We therefore studied the effects of the nonapeptides OT, A⁸VT, L⁸VP or A⁸VP on cytoplasmic calcium (Ca²⁺) and the effect of the nonapeptides on A⁸VP-induced Ca²⁺ mobilization. The preincubation of platelets with ‘physiological’ concentrations of A⁸VP (2–4 pmol l^–1) did not enhance the intracellular calcium increase caused by the agonists used. However, the ADP-induced calcium increase was enhanced by prior addition of subthreshold concentrations of A⁸VP (less than 1 nmol l^–1) to the platelet suspension (by 10%, P=0·027, n=12). Neither OT nor A⁸VT in concentrations from 10^–5 μmol l^–1 to 1 μmol l^–1 increased the cytoplasmic calcium concentration. We found that both OT and A⁸VT blocked the effect of subsequent exposure to A⁸VP. ADP (0·4 μmol l^–1) did not block the effect of A⁸VP.     

The effect of lithium therapy on arginine vasopressin secretion and thirst in man

Lithium therapy is known to reduce the renal responsiveness to arginine vasopressin (AVP: the antidiuretic hormone in man) and a proportion of treated patients develop polyuria and polydipsia. In this study seven nonpolyuric female patients receiving lithium treatment for an affective disorder (lithium group) were age-matched with seven healthy females (control group). The mean response of plasma AVP to osmotic stimulation was significantly enhanced in the lithium group but the mean osmotic threshold for AVP release was unchanged. Thirst appreciation in the lithium group commenced and increased overall at an osmotic stimulus 5 mmol/kg less than the control group. It is suggested that primary thirst does play a role in the expression of lithium-induced polyuria.     

The effect of indomethacin on the renal response to arginine vasopressin in man

The renal response to graded intravenous infusions of arginine vasopressin (AVP) was investigated in a two part study in six volunteers. First, under maximal water diuresis, seven control incremental infusions of AVP were given from zero to 12 fmol min-1 kg-1. Second, the AVP infusions were repeated after pretreatment with indomethacin, 150 mg daily for 36 h. After the AVP infusions, plasma AVP concentrations did not change significantly and remained within the physiological range; in contrast, urinary AVP excretion rate increased steadily. Indomethacin did not alter the plasma or urinary concentrations of AVP. AVP caused a fall in urine flow rate from a state of maximal diuresis to one of maximal antidiuresis. After indomethacin, fractional free water clearance was reduced by an average of 26% at the zero, 2 and 4 fmol min-1 kg-1 infusion rates of AVP. A significant increase in fractional sodium clearance of approximately 50% occurred during the AVP infusions, which was abolished after pretreatment with indomethacin. After indomethacin, urinary prostaglandin E2 (PGE2) excretion rate was reduced by an average of 40% at the zero and 2 fmol min-1 kg-1 infusion rates of AVP. At higher AVP infusion rates, no significant inhibition of PGE2 was observed. Urinary kallikrein excretion rate decreased steadily to one-third of its original value after AVP and this change remained unaltered by indomethacin. The findings show that infusions of AVP, resulting in plasma concentrations in the physiological range, evoke a maximal antidiuretic response, which is accompanied by natriuresis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pressor effect of arginine vasopressin in progressive autonomic failure

The blood pressure (BP) and heart rate (HR) responses to 5 min incremental intravenous infusions of noradrenaline (NA) and arginine vasopressin (AVP) were investigated both in patients with progressive autonomic failure (PAF) and in normal volunteers. Stepwise infusion of NA at rates of 300-3000 pmol min-1 kg-1 produced a bradycardia and a dose related increase in BP in normal subjects. In subjects with PAF there was no significant HR response but the dose-BP response was shifted to the left with significant pressor responses at infusion rates of 60-300 pmol min-1 kg-1. Stepwise infusion of AVP at 0.2-5.0 pmol min-1 kg-1 caused transient bradycardia but no pressor response in seven normal volunteers. Further increases in AVP infusion in three other subjects achieved plasma AVP levels as high as 3000-4000 pmol/l, and still no significant pressor response was observed. Stepwise infusion of AVP at 0.05-2.0 pmol min-1 kg-1 in the eight subjects with PAF resulted in a pressor response without any change in HR. During this infusion plasma AVP increased from 0.8 +/- 0.2 (mean +/- SEM) to 30 +/- 2 pmol/l. A significant pressor response was already apparent at a plasma AVP level of 5.5 +/- 1.8 pmol/l.     

The role of arginine vasopressin in alcohol tolerance

Administration of the neuropeptide, arginine vasopressin, to animals that have acquired functional tolerance to ethanol will maintain such tolerance, even in the absence of further ethanol ingestion by the animals. In mice, this action of the peptide is mediated by central nervous system V1 receptors and requires intact brain noradrenergic systems. Autoradiographic studies have shown that some V1 receptors are localized presynaptically on catecholaminergic neuronal terminals in the mouse lateral septum, suggesting that vasopressin may act via modulation of catecholamine release. In addition, vasopressin has been found to increase mRNA levels for the proto-oncogene, c-fos, in septum and hippocampus, possibly by an action at postsynaptic receptors. Expression of c-fos, which has been hypothesized to play a role in central nervous system neuroadaptation, could transform short-term actions of vasopressin into long-term effects on ethanol tolerance. Studies with vasopressin antagonists indicate that the endogenous peptide influences tolerance, and therefore the effect of chronic ethanol ingestion on vasopressin synthesis and release was studied. In mice and rats, hypothalamic vasopressin mRNA is decreased by chronic ethanol exposure, although effects on plasma vasopressin levels differ in the two species. The effect of ethanol on extrahypothalamic vasopressin synthesis in brain is under investigation. The results suggest mechanisms by which vasopressin can produce long-term changes in central nervous system function, and provide evidence for a disturbance of vasopressin regulation during chronic ethanol ingestion.     

The role of arginine vasopressin in thermoregulation during fever.

Fever is common in postoperative neurosurgical patients. When fever is present, thermoregulatory responses regulate body temperature within a range that appears to have an upper limit. Endogenous substances, such as arginine vasopressin (AVP), modulate the thermoregulatory response during fever and are referred to as endogenous antipyretics. Endogenous antipyretics attenuate fever by influencing the thermoregulatory neurons in the preoptic region and anterior hypothalamus and in adjacent septal areas. Well known for its antidiuretic and vasopressive properties, AVP plays an important role in antipyresis via the ventral septal area of the limbic system. Evidence suggests that there may be a synergistic relationship between AVP receptors and cyclo-oxygenase enzyme during antipyresis, and the presence of AVP may enhance the efficacy of nonsteroidal antipyretic drugs. On the other hand, there is evidence that increased levels of AVP released during fever may play a role in febrile seizures. Although the antipyretic effect of AVP release during fever is beneficial, excessively high levels of AVP may be detrimental.     

The effect of different calcium antagonists and a calcium agonist on the metabolism of propranolol by isolated rat hepatocytes

Summary— The influence of the dihydropyridine calcium entry blockers nicardipine, amlodipine, nifedipine, isradipine and of the dihydropyridine calcium entry promotor BAY K 8644 on the disappearance rate of propranolol by isolated rat hepatocytes was compared to the effect of diltiazem and verapamil, two non-dihydropyridine calcium channel blockers and known inhibitors of hepatic cytochrome P450 mixed function oxidases. All compounds dose-dependently inhibited the disappearance rate of propranolol. Nicardipine and isradipine were more potent in inhibiting the disappearance rate of propranolol than the other dihydropyridines and than diltiazem and verapamil. The inhibitory effect of nicardipine on the disappearance rate of propranolol was not stereoselective and was not influenced by age.     

精氨酸加压素在应激性体温过高中的作用

目的：探讨精氨酸加压素（AVP）是否具有降低应激性体温过高的作用。方法：用无线遥测技术测量大鼠的体温变化,观察腹腔注射AVP和精氨酸加压素V1受体阻断剂（AVP V1阻断剂）对大鼠应激性体温过高的影响。结果：腹腔注射AVP能明显降低大鼠应激性体温过高,而注射AVP V1阻断剂则能提高应激性体温过高的反应。结论：AVP不仅有降低大鼠应激性体温过高的作用,而且证明内源性AVP在应激性体温过高中有负调节作用。     

Carrier-mediated efflux of ketone bodies in isolated rat hepatocytes

The rate of efflux of ketone bodies has been studied in isolated hepatocytes prepared from starved rats and preloaded with D-3-[14C]hydroxybutyrate. Efflux of ketone bodies was temperature-dependent, saturable and inhibited by alpha-cyano-3-hydroxycinnamate and phloretin. The rate of efflux was also reduced by 6 mmol/l lactate and pyruvate added to the external medium. Under conditions of simulated metabolic acidosis in the hepatocyte suspension medium, ketone body efflux rate was reduced. The experimental data suggest that hepatic plasma membrane ketone body transit is carrier-mediated.     

Effect of arginine vasopressin on renal medullary blood flow. A videomicroscopic study in the rat.

The role of arginine vasopressin (AVP) in the regulation of renal medullary blood flow is uncertain. To determine if AVP has a direct vasoconstrictive action on vasa recta, the effect of AVP on erythrocyte velocity (VRBC), diameter, and blood flow (QVR) in descending vasa recta (DVR) and ascending vasa recta (AVR) was studied in the exposed renal papilla of four groups of chronically water diuretic rats using fluorescence videomicroscopy. There were three periods: control (period 1), experimental (period 2), and recovery (period 3). In periods 1 and 3, all groups received hypotonic saline. In period 2, group I rats (AVP) received AVP (45 ng/h per kg body wt); group II (time) received hypotonic saline alone; group III (AVP plus V1-inhibitor) received AVP plus its vascular antagonist, d(CH2)5Tyr(Me)AVP; and group IV (V1-inhibitor) received the vascular antagonist alone. Another group of rats (group V) was employed to demonstrate that the rise in blood pressure induced by a 3- or 10-ng/kg injection of AVP was virtually abolished by the prior infusion of the V1-inhibitor. The urine of group III as well as group I rats was concentrated (Uosm = 721 +/- 62 H2O vs. 670 +/- 39 mosM/kg), while urine remained dilute in groups II and IV. In period 2, VRBC and QVR in DVR and AVR decreased in group I, did not decrease in group III, and increased in groups II and IV. The vascular antagonist thus completely abolished the AVP-induced decrease in QVR in group III. These findings unequivocally establish that AVP in physiological amounts reduces medullary blood flow, at least in part, by a direct vasoconstrictive action on the medullary microcirculation. They also show that an effect of AVP on medullary blood flow is not necessary for its antidiuretic effect.     

Metabolism of reverse triiodothyronine by isolated rat hepatocytes.

Reverse triiodothyronine (rT3) is metabolized predominantly by outer ring deiodination to 3,3'-diiodothyronine (3,3'-T2) in the liver. Metabolism of rT3 and 3,3'-T2 by isolated rat hepatocytes was analyzed by Sephadex LH-20 chromatography, high performance liquid chromatography, and radioimmunoassay, with closely agreeing results. Deiodinase activity was inhibited with propylthiouracil (PTU) and sulfotransferase activity by sulfate depletion or addition of salicylamide or dichloronitrophenol. Normally, little 3,3'-T2 production from rT3 was observed, and 125I- was the main product of both 3,[3'-125I]T2 and [3',5'-125I]rT3. PTU inhibited rT3 metabolism but did not affect 3,3'-T2 clearance as explained by accumulation of 3,3'-T2 sulfate. Inhibition of sulfation did not affect rT3 clearance but 3,3'-T2 metabolism was greatly diminished. The decrease in I- formation from rT3 was compensated by an increased recovery of 3,3'-T2 up to 70% of rT3 metabolized. In conclusion, significant production of 3,3'-T2 from rT3 by rat hepatocytes is only observed if further sulfation is inhibited.     

Vasodilatory effect of arginine vasopressin is mediated by nitric oxide in human forearm vessels.

Arginine vasopressin (AVP) causes biphasic changes in vascular resistance in human forearms; vasoconstriction at lower doses and vasodilation at higher doses. Vasoconstriction is mediated by the V1 receptor. However, the mechanism of AVP-induced vasodilation is not known. We investigated whether AVP-induced vasodilation is mediated by nitric oxide (NO) in human forearms by examining the effects of L-arginine (a precursor of NO) and NG-monomethyl-L-arginine (L-NMMA, a blocker of NO synthase) on AVP-induced vasodilation. AVP was infused intraarterially at doses of 0.05, 0.1, 0.2, 0.5, and 1.0 ng/kg per min (n = 8). The lower doses of AVP (< or = 0.1 ng/kg per min) increased, whereas the higher doses of AVP (> or = 0.5 ng/kg per min) decreased forearm vascular resistance (FVR) (P < 0.01). Intraarterially infused L-arginine at 10 mg/min did not alter arterial pressure, baseline FVR, or heart rate. L-arginine did not alter the magnitude of AVP-induced vasoconstriction at the lower doses, but L-arginine augmented the magnitude of AVP-induced vasodilation at doses of 0.2 (P < 0.05), 0.5 (P < 0.01), and 1.0 (P < 0.05) ng/kg per min. In another group (n = 6), intraarterially infused L-NMMA (4 mumol/min for 5 min) increased baseline FVR without systemic effects, and inhibited acetylcholine-induced vasodilation (P < 0.01). L-NMMA at this dose inhibited AVP-induced vasodilation (P < 0.01) but did not affect vasoconstriction. L-arginine reversed the inhibitory effect of L-NMMA. Our results suggest that the vasodilatory effect of AVP may be mediated by NO in human forearms.     

Ethanol inhibition of codeine and morphine metabolism in isolated rat hepatocytes

Suspensions of isolated hepatocytes from male Wistar rats were prepared according to a two step Ca++-free collagenase perfusion method. Codeine, morphine or norcodeine were incubated with hepatocytes at 37 degrees C for up to 90 min in the absence and presence of ethanol. The elimination rate constant (Kel) of codeine and morphine was reduced with approximately one-third and one-fourth, respectively, in the presence of 60 mM ethanol, whereas the presence of ethanol did not alter the Kel of norcodeine significantly. The inhibition of codeine metabolism was dose-dependent, extending from approximately 15% at 10 mM ethanol to 40 to 50% at 100 mM. A 3-fold increase in the ratio of morphine concentration (formed from codeine) to the amount of codeine metabolized was observed in the presence of ethanol as compared to control cells. The mean morphine concentration was 170% higher in the ethanol-treated suspensions than in the controls. The ratio of norcodeine concentration to codeine metabolized was unchanged. The inhibition of morphine metabolism was accompanied by a similar reduction of morphine-3-glucuronide formation. The accumulation of morphine observed in the cell medium in the presence of ethanol might be due to inhibition of other metabolic pathways from codeine, thus shunting to morphine formation, combined with the inhibitory effect of ethanol on morphine metabolism per se.     

Effect of corticosteroids on arginine vasopressin after pediatric cardiac surgery

Introduction

Arginine vasopressin’s (AVP) efficacy in the treatment of refractory hypotension is, in part, dependent upon preinfusion endogenous AVP concentration. Corticosteroids, also commonly used to treat refractory hypotension, have been shown to suppress endogenous AVP release. We aimed to determine if corticosteroids affect endogenous AVP concentrations in children recovering from cardiac surgery.

Materials and methods

We reviewed the records of children who underwent cardiac surgery between January 2008 and January 2009 and had AVP concentrations available as part of a prior prospective study. Doses of hydrocortisone, methylprednisolone, and dexamethasone administered within the first 48 hours after cardiopulmonary bypass were quantitated. Multivariable linear regression was performed to determine if corticosteroids had a significant effect on 48-hour plasma AVP concentration.

Results

Sixty-nine children with plasma AVP concentrations available were reviewed, 34 (49%) of which received corticosteroids within 48 hours after cardiopulmonary bypass. On multivariable regression, greater number of corticosteroid doses but not cumulative corticosteroid dosage was significantly associated with low 48-hour AVP concentration (β = − 4.0; 95% confidence intervals, − 6.5 to − 1.4).

Conclusions

Children who receive multiple doses of corticosteroids after cardiac surgery, regardless of potency, are likely to have low endogenous AVP concentrations. Children who remain unstable despite corticosteroids may respond favorably to exogenous AVP therapy.     

The cardioprotective effect of dexmedetomidine on global ischaemia in isolated rat hearts

AIM: Dexmedetomidine is a highly specific and selective alpha-2 adrenergic agonist that is now widely used in the intensive care setting. Many intensive care unit (ICU) patients are at risk of respiratory or cardiac arrest. This study was conducted to determine whether dexmedetomidine exhibits a cardioprotective effect on global ischaemia and subsequent myocardial infarction. METHODS: Isolated rat hearts were subjected to 30 min of global ischaemia followed by 120 min reperfusion, with administration of 0, 1 and 10nM dexmedetomidine during the pre-ischaemic period (n=7 each group). Secondly, 1 microM yohimbine, an alpha-2 antagonist, was given during the pre-ischaemic period, alone or in combination with 10 nM dexmedetomidine (n=7 each group). RESULTS: Dexmedetomidine administration reduced coronary flow significantly (103.6+/-4.7%, 77.9+/-3.7, 63.7+/-6.1%, of the baseline values for 0, 1 and 10 nM dexmedetomidine, respectively), and yohimbine administration reversed this effect (88.0+/-2.2%). Dexmedetomidine improved the infarct size at each concentration (45.3+/-3.6, 30.2+/-3.3, and 21.2+/-2.3% of the total left ventricular mass for 0, 1, and 10nM dexmedetomidine, respectively), which was also reversed by yohimbine (43.6+/-1.4%). CONCLUSION: Dexmedetomidine exhibited a cardioprotective effect on global ischaemia in the isolated rat heart model, which was mediated by alpha-2 adrenergic stimulation.     

The effect of acute uraemia on gluconeogenesis in isolated perfused rat livers

Abstract. The effect of acute uraemia on glucose and urea formation by isolated perfused livers of fasting rats was investigated. The basal gluconeogenesis following nephrectomy was significantly increased as compared to normal and sham operated controls. Enhanced glucose formation was associated with an increase in both urea synthesis and output of the poorly metabolizable amino acids valine, leucine, and isoleucine. In the presence of a mixture of amino acids (serine, threonine, lysine, glutamic acid, ornithine, and citrulline) all added at near physiological concentrations, the stimulating effect of uraemia on gluconeogenesis was further enhanced. This was paralleled by an increased formation of urea and an increased uptake of the amino acids. It is concluded that acute uraemia may stimulate glucose synthesis by increased substrate supply. This seems to be achieved by at least two different mechanisms, namely increased protein degradation and accelerated amino acid utilization.     

The stimulatory effect of amylin on mucus secretion in isolated rat trachea

A modified Ussing chamber technique was used to characterize the effects of amylin on rat tracheal mucus secretion. The effects of amylin were studied at both the mucosal and the submucosal side of isolated rat trachea. Applied at the mucosal side, amylin had no direct effect on mucus secretion, but significantly decreased the acetylcholine (1 mM)-induced tachyphylaxia when this substance was presented a second time (first stimulation: 490%; second stimulation: 334%; second stimulation plus amylin: 407%). At the submucosal side, amylin significantly stimulated mucus secretion (controls: 100%; 1 μM amylin: 193%; 100 nM amylin: 170%; 10 nM amylin: 127%; 1 nM amylin: 127%). Together with the recent observation of specific amylin receptors in rat lung membranes, these data suggest a physiological role for amylin in the regulation of tracheal mucus secretion.