Hemodynamic effects of hydroxocobalamin in conscious dogs

Hydroxocobalamin has been shown to be a rapid and powerful antidote in acute cyanide poisoning and to prevent cyanide poisoning during sodium nitroprusside administration. However, its hemodynamic effects remain unknown. The authors therefore investigated the effects in chronically instrumented conscious dogs (n = 8) that were randomly given hydroxocobalamin (20, 70, and 140 mg.kg-1) or saline. Determination of peak cobalt plasma concentrations showed that 20 and 70 mg.kg-1 hydroxocobalamin correspond to "therapeutic doses," whereas 140 mg.kg-1 corresponds to a supratherapeutic dose. Hydroxocobalamin did not modify heart rate, mean arterial pressure, left ventricular (LV) end-diastolic pressure, and PR and QT intervals, regardless of the dose administered. The largest dose (140 mg.kg-1) induced a decrease in the maximum increase of LV pressure (-7 +/- 3%; P less than 0.05), maximum aortic blood flow acceleration (-17 +/- 5%; P less than 0.05), and cardiac output (-19 +/- 6%; P less than 0.05), whereas systemic resistance increased (+41 +/- 9%; P less than 0.05). In six other dogs, local administration of hydroxocobalamin (0.5, 1.5, and 5.0 mg.kg-1.min-1) confirmed that, in large doses, this drug has direct vasoconstrictor properties affecting both conductance (decrease in iliac artery diameter: -2.5 +/- 0.8%) and resistance (decrease in iliac artery blood flow: -19.5 +/- 3.4%) vessels. Thus, hydroxocobalamin should be a safe cyanide antidote, considering the lack of hemodynamic effects within the therapeutic range of doses.     

EFFECTS OF CYANIDE ANTIDOTES USED WITH SODIUM NITROPRUSSIDE INFUSIONS: SODIUM THIOSULPHATE AND HYDROXOCOBALAMIN GIVEN PROPHYLACTICALLY TO DOGS

Cyanide antidotes were given to dogs before an infusion of sodiumnitroprusside 1.5mg kg for 1 h. Dogs given thiosulphate 75 mgkg^–1had significantly lower plasma and red cell cyanide concentrationswhile plasma thiocyanate concentrations were significantly increasedin comparison with control. These changes were associated withonly minimal disturbance of tissue oxygenation. There was noeffect on red cell cyanide or thiocyanate concentrations indogs treated with hydroxocobalamin 1.5mgkg^–1, but plasmacyanide concentrations were significantly greater than in thosereceiving no antidote although there was less evidence of impairedoxygenation. There was no evidence of a synergistic action betweenthiosulphate and hydroxocobalamin. The vascular response tonitroprusside was unchanged in the thiosulphate-treated dogs,but was significantly greater in those given hydroxocobalamin.The implications for prophylaxis and treatment of cyanide poisoningfollowing nitroprusside overdose are discussed.     

The lack of transplacental movement of the cyanide antidote thiosulfate in gravid ewes

A previous study reported that the co-infusion of IV sodium thiosulfate (STS) with sodium nitroprusside (SNP) to near-term gravid ewes prevented both maternal and fetal cyanide toxicity. We questioned whether maternally administered STS crossed the ovine placenta to enhance fetal transulfuration of cyanide, or whether the fetus was dependent on maternal detoxification of cyanide after diffusion of cyanide into the maternal circulation. Ten anesthetized, near-term gravid ewes underwent hysterotomies with delivery of fetal heads for venous catheterization. Five control ewes received IV isotonic sodium chloride solution, whereas five experimental ewes received IV STS (50 mg/kg over 15 min). Serial plasma thiosulfate concentrations in ewes and fetuses were measured over 135 min. Areas under the time-plasma thiosulfate concentration curves were calculated for experimental and control ewes at 2758+/-197 and 508+/-74 min x mg(-1) x L(-1), respectively (P < 0.008). Mean areas under the curve for experimental and control fetuses were 236+/-34 and 265+/-23 min x mg(-1) x L(-1), respectively (P > 0.5). Maternally administered STS may prevent fetal cyanide poisoning from SNP administration without relying on STS crossing the placenta into the fetal circulation. Fetal cyanide may cross down a concentration gradient from fetal to maternal circulation, to be transulfurated to thiocyanate in maternal tissues. IMPLICATIONS: We evaluated the mechanism of action of sodium thiosulfide (STS) in sodium nitroprusside-induced cyanide toxicity in the ewe. Fetal cyanide poisoning is alleviated by maternal administration of STS, although this cyanide antidote apparently does not cross the placenta.     

Cyanide release from sodium nitroprusside during coronary bypass in hypothermia

Erythrocyte cyanide levels were determined by a sensitive fluorimetric method on four occasions during coronary bypass in hypothermia in 18 consecutive patients treated with sodium nitroprusside (SNP) with an infusion rate less than 1 microgram x kg-1 x min-1. Every second patient received the cyanide antidote thiosulphate simultaneously with the SNP-infusion. At normal body temperature, as well as during hypothermia in cases receiving thiosulphate, the cyanide levels rose slowly but significantly with the infusion rate. Higher erythrocyte cyanide levels in relation to the infusion rates, up to 8.0 mumol/l, were found during hypothermia in two of the cases not receiving thiosulphate. We conclude that SNP is broken down to cyanide even under hypothermia and that low body temperature may impair the conversion of cyanide to thiocyanate, probably by affecting the metabolic pathways providing the sulphur substrate. This effect may add to other factors decreasing sulphur availability in critically ill patients, and simultaneous administration of thiosulphate is therefore recommended to ensure a safe SNP treatment during and after coronary bypass operations.     

SODIUM THIOSULPHATE DECREASES BLOOD CYANIDE CONCENTRATIONS AFTER THE INFUSION OF SODIUM NITROPRUSSIDE

Plasma and red cell cyanide, and plasma thiocyanate, concentrationswere measured in 30 patients undergoing elective nitro-prusside-inducedhypotension. One randomly selected group (n = 15), who received0.21–0.70 mg kg^–1 over periods of 50– 160min, were given a bolus of sodium thio-sulphate 10.6–38.5mg kg^–1 immediately on cessation of the nitroprussideadministration. The other group, who received infusions of 0.11–0.85mg kg^–1 for periods of 59—197 min, received no antidote.Cyanide concentrations, expressed as a percentage of the immediatepost-infusion values, were significantly lower in the treatedgroup in all subsequent blood samples (at 10, 30 and 60 min;plasma cyanide P < 0.05; red cell cyanide P < 0.001).Improved cyanide metabolism was further demonstrated by a sharpincrease in mean plasma thiocyanate concentration (P < 0.05)in the group receiving the antidote.     

Captopril reduces the dose requirement for sodium nitroprusside induced hypotension

The authors studied 12 patients who required deliberate hypotension for spinal fusion operations in order to investigate the efficacy of captopril for reducing dose requirement for sodium nitroprusside (SNP). Six patients, selected at random, were pretreated with captopril, 3 mg/kg po, and the remaining six patients served as controls. All patients received a similar anesthetic technique, consisting of thiopental 3 mg/kg, pancuronium 0.1 mg/kg, morphine 0.5 mg/kg, plus nitrous oxide 70% in oxygen. SNP was used to maintain mean arterial pressure (MAP) at 50-55 mmHg during deliberate hypotension lasting 140 +/- 13 minutes (mean +/- SE). Patients who received captopril required less SNP than untreated patients both early during hypotension (1.4 +/- 0.5 micrograms X kg-1 X min-1 vs. 4.8 +/- 0.8 micrograms X kg-1 X min-1, P less than 0.05), as well as late during hypotension (2.2 +/- 0.2 micrograms X kg-1 X min-1 vs. 5.6 +/- 0.6 micrograms X kg-1 X min-1, P less than 0.05). Whole blood cyanide was significantly lower in the patients pretreated with captopril than the untreated controls both early in the hypotensive period (2.7 +/- 0.6 mumol/l vs. 13 +/- 4 mumol/l, P less than 0.05) and also late in the hypotensive period (3.7 +/- 0.8 mumol/l vs. 30 +/- 10 mumol/l, P less than 0.05). MAP was reduced by captopril pretreatment both following induction of anesthesia (64 +/- 4 mmHg captopril vs. 80 +/- 4 mmHg control, P less than 0.05) and during surgery before deliberate hypotension (86 +/- 5 mmHg captopril vs. 100 +/- 4 control, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of remifentanil in combination with isoflurane or propofol for short-stay surgical procedures

There are few data in the literature that describe the use of remifentanil when administered as a component of an inhalation or total i.v. anaesthetic (TIVA) technique. We studied 251 male and female patients, aged 18-75 years, ASA I-II, undergoing inguinal hernia repair, arthroscopic knee surgery or varicose vein surgery of at least 30 min duration without premedication. Patients were randomized to receive a remifentanil loading dose of 1.0 microgram kg-1 followed by a continuous infusion of 0.5 microgram kg-1 min-1 in combination with isoflurane (end-tidal concentration 0.6%), (Group I, n = 115) or propofol (initial infusion rate 9 mg kg-1 h-1 reduced to 6 mg kg-1 h-1 after 10 min), (Group P, n = 118). The remifentanil infusion rate was reduced by 50%, 5 min after tracheal intubation. Intraoperative stresses were treated with a remifentanil bolus (1 microgram kg-1) followed by an increase in the remifentanil infusion rate. At the insertion of the last suture, the remifentanil infusion and concomitant anaesthetic were switched off simultaneously. Times to spontaneous respiration, adequate respiration and tracheal extubation were significantly shorter in group I compared with group P (6.4 min vs 7.6 min, P < 0.01; 7.6 min vs 9.3, P < 0.003; 7.8 min vs 9.5 min, P < 0.015). Overall mean systolic blood pressures during surgery were greater in group P compared with group I (P < 0.05) but the absolute differences were clinically insignificant (4-5 mm Hg).      

Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type I diabetic patients.

To examine the mechanisms of hyperglycemia-induced insulin resistance, eight insulin-dependent (type I) diabetic men were studied twice, after 24 h of hyperglycemia (mean blood glucose 20.0 +/- 0.3 mM, i.v. glucose) and after 24 h of normoglycemia (7.1 +/- 0.4 mM, saline) while receiving identical diets and insulin doses. Whole-body and forearm glucose uptake were determined during a 300-min insulin infusion (serum free insulin 359 +/- 22 and 373 +/- 29 pM, after hyper- and normoglycemia, respectively). Muscle biopsies were taken before and at the end of the 300-min insulin infusion. Plasma glucose levels were maintained constant during the 300-min period by keeping glucose for 150 min at 16.7 +/- 0.1 mM after 24-h hyperglycemia and increasing it to 16.5 +/- 0.1 mM after normoglycemia and by allowing it thereafter to decrease in both studies to normoglycemia. During the normoglycemic period (240-300 min), total glucose uptake (25.0 +/- 2.8 vs. 33.8 +/- 3.9 mumol.kg-1 body wt.min-1, P less than 0.05) was 26% lower, forearm glucose uptake (11 +/- 4 vs. 18 +/- 3 mumol.kg-1 forearm.min-1, P less than 0.05) was 35% lower, and nonoxidative glucose disposal (8.9 +/- 2.2 vs. 19.4 +/- 3.3 mumol.kg-1 body wt-1min-1, P less than 0.01) was 54% lower after 24 h of hyper- and normoglycemia, respectively. Glucose oxidation rates were similar. Basal muscle glycogen content was similar after 24 h of hyperglycemia (234 +/- 23 mmol/kg dry muscle) and normoglycemia (238 +/- 22 mmol/kg dry muscle). Insulin increased muscle glycogen to 273 +/- 22 mmol/kg dry muscle after 24 h of hyperglycemia and to 296 +/- 33 mmol/kg dry muscle after normoglycemia (P less than 0.05 vs. 0 min for both). Muscle ATP, free glucose, glucose-6-phosphate, and fructose-6-phosphate concentrations were similar after both 24-h treatment periods and did not change in response to insulin. We conclude that a marked decrease in whole-body, muscle, and nonoxidative glucose disposal can be induced by hyperglycemia alone.     

The course of blood concentrations of propofol administered at a constant rate, combined with fentanyl

The blood concentration of propofol was studied in 14 ASA 1 informed patients, who were to undergo orthopaedic or plastic surgery lasting at least 90 min. Anaesthesia was induced with a 2 mg.kg-1 bolus of propofol together with 0.86 microgram.kg-1 fentanyl. This was followed by a constant rate infusion of propofol and fentanyl, 5 mg.kg-1.h-1 and 3 micrograms.kg-1.h-1 respectively. The mean duration of propofol infusion was 153 +/- 63 min, with extremes of 90 and 315 min. Propofol concentration was measured using gas phase chromatography on total arterial blood; the lower limit of detection was 0.05 mg.l-1. During the infusion, blood concentrations were found between 2 and 4 mg.l-1. It was 2.25 mg.l-1 at the fifth min; this was 80% of the concentration found at the 120th min. There was in fact no statistically significant difference between the values found at the 90th, 120th and 150th min. On stopping the infusion, the concentrations fell rapidly during the first 5 min, and then more slowly. By the 30th min, it had reached a value 4.5 times less than that at the end of the infusion. However, individual variations were found, which could explain delayed recovery. The calculated pharmacokinetic parameters were: elimination half-life = 41.7 +/- 20 min, clearance = 2.14 +/- 0.55 l.min-1 and equilibrium distribution volume = 43.4 +/- 15.2 l. These results are discussed. It is therefore possible to give propofol continuously at a constant rate without having any accumulative effect.     

Stimulation of lipolysis in humans by physiological hypercortisolemia

The effect of glucocorticoids on adipose tissue lipolysis in animals and humans is controversial. To determine whether a physiological increase in plasma cortisol, similar to that observed in diabetic ketoacidosis and other stress conditions, stimulates lipolysis, palmitate kinetics were measured in seven nondiabetic volunteers on two occasions with [1-14C]palmitate as a tracer. Subjects received a 6-h infusion of either 2 micrograms.kg-1.min-1 hydrocortisone or saline in random order. On both occasions, a pancreatic clamp (0.12 micrograms.kg-1.min-1 somatostatin, 0.05 mU.kg-1.min-1 insulin, and 3 ng.kg-1.min-1 growth hormone) was used to maintain plasma hormone concentrations at desired levels. Plasma cortisol concentrations increased to approximately 970 nM during cortisol infusion. Palmitate rate of appearance (Ra) and concentration increased by approximately 60% during cortisol infusion but did not change during saline infusion. Increments in palmitate Ra and concentration over the 6-h study were significantly greater during cortisol than saline infusion when compared by area-under-the-curve analysis (152 +/- 52 vs. -48 +/- 23 mumol.kg-1 and 12.2 +/- 4.1 vs. -4.9 +/- 4.1 mmol.min-1.L-1, respectively; P less than 0.02). Plasma glucose concentrations did not change significantly during cortisol (5.0 +/- 0.3 vs. 6.1 +/- 0.6 mM, NS) or saline (4.9 +/- 0.2 vs. 4.9 +/- 0.1 mM, NS) infusion. In nondiabetic volunteers, a 6-h cortisol infusion was associated with a 60% increase in palmitate Ra that did not occur with saline infusion. Thus, physiological hypercortisolemia may contribute to the increased rates of lipolysis observed in humans during stress.     

Pharmacology of laudanosine in dogs

The authors determined the pharmacokinetics (including transfer into cerebrospinal fluid [CSF]) and the cardiovascular and central nervous system (CNS) effects of laudanosine, a metabolite of atracurium. Eight dogs were anesthetized with halothane; blood pressure and a fronto-occipital electroencephalographic lead were monitored. Laudanosine (1 mg . kg-1 iv) was administered as a bolus, and its concentrations in plasma, CSF, urine, and bile were determined by liquid chromatography. Three-compartment modeling of plasma laudanosine concentrations yielded an elimination half-life for laudanosine of 113 +/- 24 min (mean +/- SD) and a clearance of 25 +/- 8 ml . kg-1 . min-1. CSF concentrations of laudanosine were highest 5-10 min after iv injection of laudanosine and ranged in concentration from 208 to 572 ng . ml-1 (i.e., 36-87% of the corresponding plasma concentrations). Unchanged laudanosine was found in urine (0.5-12% of injected dose) and bile (less than 0.1%); metabolites of laudanosine were found in both fluids. After a 6-h sampling period, dogs were hyperventilated with halothane (FIO2 = 0.2) to a PaCO2 of 26-28 mmHg. Laudanosine was then administered 2 mg . kg-1 iv every 5 min. With cumulative doses of 2-8 mg . kg-1, all dogs showed signs of "awakening" from anesthesia. Cumulative doses of 14-22 mg . kg-1 produced seizure activity in all animals. Mean arterial blood pressure decreased significantly to 86% of control levels at 1 min following administration of laudanosine (1 mg . kg-1 iv) and returned to control levels 4 min later.(ABSTRACT TRUNCATED AT 250 WORDS)     

Splanchnic amino acid and glucose metabolism during amino acid infusion in dogs

With the organ-balance technique, we studied amino acid and glucose metabolism by hepatic and extrahepatic splanchnic tissues in awake dogs in the postabsorptive state and during a 3-h intravenous amino acid infusion. Dogs received a high (1.4 g/kg body wt, n = 5) or low (0.7 g/kg body wt, n = 8) dose of amino acids. In four of the latter dogs, the dose was delivered into a mesenteric vein. During the basal period there was a net removal of gluconeogenic amino acids (particularly alanine), but not branched-chain amino acids, and a net production of glucose by the liver in all dogs. During this time there was a net removal of glucose and production of alanine by the extrahepatic splanchnic tissues. During either high- or low-dose amino acid infusion, net hepatic glucose release increased; despite this, arterial plasma glucose declined due to an increase in tissue glucose uptake at extrasplanchnic sites. The net amount of glucogenic amino acids removed by the liver during high-dose (9.1 +/- 1.0 mmol.kg-1.3 h-1) and low-dose (4.8 +/- 0.6 mmol.kg-1.3 h-1) infusion equaled or exceeded the infused load of these amino acids. In addition, the liver contributed to the net disposal of branched-chain amino acids during high-dose (536 +/- 147 mumol.kg-1.3 h-1) and low-dose (341 +/- 70 mumol.kg-1.3 h-1) infusion. During high-dose infusion, extrahepatic splanchnic tissues participated in the net removal of branched-chain amino acids (436 +/- 162 mumol.kg-1.3 h-1) but not glucogenic amino acids, and net alanine production continued (410 +/- 91 mumol.kg-1.3 h-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of prolonged pulsatile hyperinsulinemia in humans. Enhancement of insulin sensitivity

Prolonged near-physiological pulsatile insulin infusion has a greater hypoglycemic effect than continuous insulin infusion. We have previously shown that continuous hyperinsulinemia induces insulin insensitivity. This study examines the mechanisms responsible for the greater hypoglycemic effect of pulsatile insulin administration, in particular, whether prolonged pulsatile hyperinsulinemia induces insulin insensitivity. Basally and 1 h after cessation of a 20-h pulsatile infusion of insulin (0.5 mU.kg-1.min-1), eight nondiabetic human subjects were assessed for 1) glucose turnover with [3-3H]glucose, 2) insulin sensitivity by minimal-model analysis of intravenous glucose tolerance tests, and 3) monocyte insulin-receptor binding. The time-averaged plasma insulin levels were 30 +/- 5 mU/L (mean +/- SE) during the infusion, which was similar to the levels achieved in our previous continuous hyperinsulinemia study. However, the average rate of glucose infusion to maintain euglycemia was 55% greater than in the previous study. Hepatic glucose production was -5.2 +/- 1.4 mumol.kg-1.min-1 during the infusion but returned to preinfusion levels 1 h after the infusion was stopped. Insulin sensitivity (Sl) and glucose tolerance (rate of glucose disappearance, Kg) showed changes opposite in direction to our previous continuous hyperinsulinemia study (pre- vs. postinfusion Kg 1.5 +/- 0.1 vs. 1.7 +/- 0.2 min-1 x 10(2), NS; pre- vs. postinfusion Sl 8.4 +/- 2.3 vs. 11.8 +/- 3.7 min-1.mU-1.L x 10(4), P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo insulin resistance induced by amylin primarily through inhibition of insulin-stimulated glycogen synthesis in skeletal muscle

We examined the in vivo mechanisms of amylin-induced resistance in concious rats (n = 18). During 180-min euglycemic insulin-clamp (21.5 pmol.kg-1.min-1) studies, amylin (50, 200, or 500 pmol.kg-1.min-1; plasma concentration from 3 x 10(-10) to 9 x 10(-9) M) infusion determined a 19-27% reduction in glucose uptake (117.8 +/- 7.0 vs. 145.8 +/- 11.0, 107.1 +/- 9.2 vs. 145.1 +/- 6.7, and 105.0 +/- 7.2 vs. 144.4 +/- 7.0 mumol.kg-1.min-1 at 50, 200, or 500 pmol.kg-1.min-1, respectively, P less than 0.01) versus insulin alone, whereas 10-pmol.kg-1.min-1 amylin infusion (plasma concn 5 x 10(-11) M) failed to affect insulin-mediated glucose disposal. After amylin infusion, the contribution of whole-body glycolysis to overall glucose disposal increased from 43-48 to 62-79%, whereas muscle glycogen synthesis decreased significantly at all peptide concentrations greater than 3 x 10(-10) M, completely accounting for the decrease in glucose uptake. Skeletal muscle glucose-6-phosphate concentration rose from 0.219 +/- 0.038 mumol/g (insulin alone) to 0.350 +/- 0.018, 0.440 +/- 0.020, and 0.505 +/- 0.035 mumol/g (insulin plus amylin at 50, 200, or 500 pmol.kg-1.min-1, P less than 0.01). Suppression of hepatic glucose production by insulin was unaffected by a 50-pmol.kg-1.min-1 amylin infusion (18.5 +/- 4.3 vs. 21.7 +/- 2.9 mumol.kg-1.min-1), whereas it was slightly but significantly impaired by amylin infusion at 200 pmol.kg-1.min-1 (17.8 +/- 3.9 vs. 24.7 +/- 4.5 mumol.kg-1.min-1, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary vascular responses to hypercalcemia and hypocalcemia in the dog

The pulmonary artery responses in the isolated whole-blood perfused canine lung to ionized calcium ([Ca++]) were quantified over a range of hypercalcemia and hypocalcemia values ([Ca++] = 0.23-1.88 mM) under conditions of controlled pulmonary blood flow and constant mean aortic and left atrial pressures. Calcium chloride, administered as bolus doses in the clinical range (5-15 mg.kg-1) at initial normocalcemia and without interventions producing vasoconstriction did not influence mean pulmonary artery pressure at constant pulmonary blood flow. Stable hypercalcemia ([Ca++] = 1.88 +/- 0.05 mM) did not influence the slope of the pulmonary artery pressure-flow plot. Because normal pulmonary vasomotor tone is low and cannot readily be lowered further, the possible vasodilator action of hypocalcemia was assessed by its ability to decrease the slope of the mean pulmonary artery pressure-flow plot, which had been first increased by alveolar hypoxia (AHX) or infusion of the prostaglandin endoperoxide analog U46619 (PG). During AHX (n = 5), a graded reduction from normocalcemia ([Ca++] = 1.08 +/- 0.02 mM) to moderate hypocalcemia ([Ca++] = 0.8 and 0.5 mM) did not alter the pulmonary artery pressure-flow plot, but severe hypocalcemia ([Ca++] = 0.26 +/- 0.01 mM) decreased the slope by 13 +/- 0.9 mmHg.l-1.min-1. The comparison of severe hypocalcemia ([Ca++] = 0.23-0.27 mM) versus a high dose of nifedipine (bolus of 10 micrograms/kg followed by continuous infusion at 40 micrograms.kg-1.h-1) on pulmonary vascular tone increased by either AHX or PG infusion indicated that both hypocalcemia and nifedipine decreased the slope of the relationship between mean pulmonary artery pressure and flow (during AHX: -16.1 +/- 1.38 and -23.3 +/- 1.73 mmHg.l-1.min-1, both P = 0.0001 vs. AHX alone, and during PG: -17.05 +/- 1.95 and -8.4 +/- 1.78 mmHg.l-1.min-1, P = 0.0001 vs. PG alone). Two principal conclusions emerge. First, the pulmonary vessels are minimally sensitive to changes in ionized calcium throughout the clinical hypercalcemia and hypocalcemia ranges; extreme hypocalcemia is required to produce vasodilation, which was reversed with calcium infusion. Second, whereas the pulmonary vasodilator effects of extreme hypocalcemia were independent of the intervention inducing pulmonary vasoconstriction (AHX vs. PG), those of nifedipine were much more pronounced with AHX.     

CARDIOVASCULAR ACTIONS OF TRIMETAPHAN NITROPRUSSIDE: Comparison with Sodium Nitroprusside in Greyhounds

Trimetaphan nitroprusside (TNP) is a new potent hypotensiveagent developed to induce and maintain decreases in arterialpressure unaccompanied by resistance. This study investigatedits properties and compared them with those of sodium nitroprusside(SNP) in anaesthetized greyhounds. The mean dose response toTNP was obtained by measuring haemodynamic changes in five dogs.With increasing doses, stepwise decreases in mean arterial pressureand progressive increases in heart rate occurred: cardiac indexdid not change significantly. In a further six greyhounds, SNPand TNP were alternately infused to induce and maintain a 30%reduction in arterial pressure for 30 min. Both drugs were short-acting,decreased systemic vascular resistance and caused tachycardia.Infusion of TNP produced lower plasma and red cell cyanide concentrations;SNP maintained hypotension with significantly less tachycardia.We conclude that there was no outstanding advantage of TNP overSNP when given as a short-term infusion in greyhounds.     

Amelioration of postischaemic acute renal failure in conscious dogs by human atrial natriuretic peptide

We studied the effect of human ANP (alpha-hANP)-99-126 on the course of postischaemic acute renal failure in unilaterally nephrectomised, conscious dogs subjected to 120 min of renal ischaemia. In contrast to a control group A (n = 7), the investigational group B (n = 9) received an intra-aortic bolus injection of 100 micrograms/kg alpha-hANP and an additional continuous infusion of 0.3 micrograms/kg per min x 180 min immediately after ischaemia. On days 1 and 2 after ischaemia, only the bolus injection was repeated. Administration of hANP resulted in a marked restoration of GFR (29 +/- 2 vs 18 +/- 4 ml/min, P less than or equal to 0.01), diuresis (0.8 +/- 0.1 vs 0.5 +/- 0.1 ml/min, P less than or equal to 0.05), and natriuresis (44 +/- 7 vs 25 +/- 4 mumol/min, P less than or equal to 0.05) on the first postischaemic day, which was mirrored by a reduction in nitrogen retention (Purea: 8 +/- 1 vs 12 +/- 2 mmol/l P less than or equal to 0.05, Pcrea: 137 +/- 20 vs 204 +/- 37 mumol/l). Renal perfusion, however, was only slightly improved on day 1 after ischaemia (198 +/- 20 vs 163 +/- 27 ml/min, N.S.). Our data clearly demonstrate that repeated bolus applications of hANP ameliorate postischaemic acute renal failure in conscious dogs. We assume that the observed beneficial effect on GFR might be the consequence of an increase in glomerular capillary pressure rather than an improvement of renal perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma and red blood cell cyanide concentrations during hypotension induced by sodium nitroprusside or by a nitroprusside-trimetaphan mixture in rabbits

Plasma and red blood cells cyanide concentrations during hypotension induced by sodium nitroprusside and a nitroprusside-trimetaphan mixture were studied in 29 male rabbits under halothane anesthesia. They were randomly divided into three groups; Nitroprusside (group N; n = 10), A nitroprusside-trimetaphan mixture (group M; n = 10), Controls (group C; n = 9). No changes were noted in plasma and red blood cells cyanide concentrations in group C throughout the experiment. During and after induced hypotension, in group N, plasma cyanide concentration was significantly higher than the control value. The maximum increase occurred 60min after induction of hypotension and the highest concentration of plasma cyanide was six times the control value. In contrast, in group M, plasma cyanide concentration was unchanged from the control value. However, during and after induced hypotension, red blood cells cyanide concentrations of group N and group M were significantly higher compared with the control values. Red blood cells concentrations of cyanide increased for 30 and 60 min during induced hypotension in group N (27.11 +/- 3.9 micrograms.ml-1, P less than 0.001, 46, 73 +/- 4.7 micrograms.ml-1, P less than 0.001, respectively) and in group M (0.31 +/- 0.05 micrograms.ml-1, P less than 0.05, 0.29 +/- 0.03 micrograms.ml-1, P less than 0.05, respectively). In conclusion, the data suggest that a nitroprusside-trimetaphan mixture is a safe method for hypotensive anesthesia.     

Contribution of alpha- and beta-receptors to ketogenic and lipolytic effects of norepinephrine in humans

To assess the effects of alpha- and beta-adrenergic-receptor activation on ketone body kinetics and lipolysis in humans, five groups of overnight-fasted subjects were studied. Group 1 (n = 7) received norepinephrine (NE) to activate alpha- and beta-receptors, resulting in plasma NE concentrations of 1.5 +/- 0.19 ng/ml; group 2 (n = 7) received NE plus beta-blockade; group 3 (n = 7) NE plus alpha-blockade; group 4 (n = 6) NE plus alpha- and beta-blockade; and group 5 (n = 6) saline. Plasma insulin and glucagon concentrations were maintained constant by infusion of somatostatin with insulin and glucagon replacements. Infusion of NE for 170 min resulted in an increase in total ketone body production ([3-14C]acetoacetate infusions) to 8.5 +/- 1.3 vs. 3.9 +/- 0.6 mumol.kg-1.min-1 (P less than .01) in saline controls and in an increase in plasma free fatty acids (FFAs) to 1120 +/- 102 vs. 526 +/- 115 microM (P less than .01) in controls. alpha-Blockade during NE infusion enhanced the lipolytic effect of NE, because plasma FFA increased to 1981 +/- 204 vs. 1301 +/- 146 microM after 45 min (P less than .002), and the ketogenic effect was augmented (14.3 +/- 1.7 vs. 5.6 +/- 0.9 mumol.kg-1.min-1) after 60 min (P less than .001). In contrast, beta-blockade abolished the ketogenic and lipolytic effects of NE to those observed in saline controls. Combined alpha- and beta-blockade during NE infusion was without significant effect on ketone body kinetics and plasma FFA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Esmolol prevents and suppresses arrhythmias during halothane anaesthesia in dogs

The antiarrhythmic effect of esmolol, a selective beta 1 adrenoreceptor blocker, was evaluated in the presence of epinephrine induced arrhythmias in dogs (n = 6). The arrhythmogenic dose of epinephrine (ADE) during 1.2 MAC halothane in dogs was increased from 3.23 +/- 0.25 (mean +/- SD) to 30.90 +/- 3.56 micrograms.kg-1.min-1 (P less than 0.001) by the prior administration of esmolol 0.5 microgram.kg-1 bolus followed by an infusion at the rate of 150 micrograms.kg-1.min-1. Higher esmolol infusion doses of 200 micrograms.kg-1.min-1 further increased ADE to 99.0 +/- 2.92 micrograms.kg-1.min-1 (P less than 0.001). After discontinuation of esmolol and during continued halothane anaesthesia, ventricular tachycardia was induced by increasing the infusion rate of the 100 micrograms.ml-1 solution of epinephrine. In all dogs ventricular tachycardia was restored to sinus rhythm by a bolus dose of esmolol (1 microgram.kg-1). We conclude that esmolol pretreatment increases the ADE during halothane anaesthesia in dogs. Our data suggest that esmolol may be useful as an antiarrhythmic agent in the management of epinephrine-related ventricular arrhythmias during anaesthesia in man.