DEPRESSION OF HYPOXIC PULMONARY VASOCONSTRICTION IN THE DOG BY DOPAMINE AND ISOPRENALINE

The effects of dopamine and isoprenaline on the pulmonary vasoconstrictorresponse to alveolar hypoxia were assessed by measuring theredistribution of blood flow between the lungs in response tounilateral hypoxia. Dose rates of dopamine 25 µg kg^–1min^–1 and isoprenaline 0.25 µg kg^–1 min^–1(which produced equal increments in the contractile force ofthe heart in dogs) produced a similar degree of depression ofthe hypoxic vasoconstrictor response, whereas dopamine 2.5 µgkg ^–1 min^–1 had little effect on the response. Pa_O2during unilateral hypoxia was inversely related to the bloodflow through the hypoxic lung.     

EFFECT OF LOW AND HIGH CONCENTRATIONS OF ALFENTANIL ADMINISTERED INTRATHECALLY ON A{delta} AND C FIBRE MEDIATED SOMATOSYMPATHETIC REFLEXES

We have studied the effects of alfentanil administered intrathecallyon somatosympathetic reflexes evoked by stimulation of radialand tibial nerves in 10 anaesthetized and paralysed dogs. Infive animals, alfentanil was administered in doses of 100, WO,200 and 400 µ in 0.8 ml and 800 µ in 1.6 ml preparedfrom the formulation of 500 µ mt^–1. Five othersreceived alfentanil (high concentration formulation, 5 mg mf^–1)in doses of 500 and 2000 µ in 0.5 ml and 5000 µin 1 ml. C fibre tibial nerve reflexes were depressed by 100µ and abolished with doses of 200–400 µ, butthe A     

DEPRESSION OF NOCICEPTIVE SYMPATHETIC REFLEXES BY THE INTRATHECAL ADMINISTRATION OF MIDAZOLAM

The effect of the intrathecal administration of midazolam 0.5–1.0mg in 1–2 ml of physiological saline solution, has beenobserved on responses evoked in renal sympathetic nerves bysupramaximal electrical stimulation of radial and tibial nerves.In artificially ventilated dogs anaesthetized with a-chloralose,the intrathecal administration of midazolam caused a markeddepression of reflexes evoked from the tibial nerve but hadno effect on either spontaneous sympathetic activity or reflexesevoked by radial nerve stimulation. Neither the small amount(1–2 ulitre) of benzyl alcohol, present as a preservative(administered intrathecally), nor midazolam 1 mg kg^–1i.v. caused any significant depression of the evoked somato-sympatheticreflexes. The effects of intrathecal midazolam were reversedby the benzodiazepine antagonists Ro 15–1788 1 mg kg^–1i.v. and Ro 15–3505 1–2 mg kg^–1 i.v. but notby naloxone 2 mg i.v. It is suggested that the antinociceptiveeffect of locally applied midazolam could be the result of anon-opioid GABA-mediated system which may have implicationsin the management of pain. ^*Present address: Tel-Aviv Medical Centre and Tel-Aviv MedicalSchool, Tel-Aviv, Israel.     

DISSOCIATION BETWEEN THE EFFECTS OF FENTANYL AND ALFENTANIL ON SPONTANEOUS AND REFLEXLY EVOKED CARDIOVASCULAR RESPONSES IN THE DOG

Observations were made for 3 h in 10 anaesthetized dogs on theeffects of alfentanil 500 µg kg ^– andfentanyl 100µg kg^–1 on resting heart rate (HR) and mean arterialpressure (MAP), and on the changes evoked in heart rate andmean arterial pressure ( HR and MAP) by stimulation of a cutaneousnerve. Both drugs caused similar decreases in the resting HR(43%44%) and MAP (28–31%), which returned to baselinewithin lgOmin following alfentanil but not fentanyl. Fentanyldecreased the somato - cardiovascular reflexes by 73% and 82%compared with a significantly smaller reduction of 54% and 55%(P< 0.05) with alfentanil. Following nlffntanilj MAP hadrecovered by 15 min and HR by 70 min compared with 70 and 90nun respectively for fentanyl. In conclusion, there was a dissociationbetween the maximum effect of alfentanil and fentanyl on theresting circulation and on the evoked cardiovascular reflexes.With both drugs a dissociation was observed between the durationsof their effect on the resting cardiovascular system and onthe evoked cardiovascular responses ^*Present address: Department of Anaesthetics, Tzanion Hospital,Piraeus, Greece     

ANTAGONISM OF THE RESPIRATORY EFFECTS OF ALFENTANIL AND FENTANYL BY NALOXONE IN THE CONSCIOUS RABBIT

The ability of naloxone to antagonize the respiratory effectsof alfentanil, a new short-acting analgesic, was studied inthe rabbit. The results were compared with naloxone antagonismof fentanyl. Minute volume and respiratory frequency, and pH,Pco₂ and standard bicarbonate of arterialized venous blood weremeasured. Naloxone was more effective as an antagonist to alfentanilthan as an antagonist to fentanyl.     

PHARMACOKINETICS OF THE INFUSION OF ALFENTANIL IN MAN

The pharmacokinetics of alfentanil under the conditions of anempirically derived 1 -h continuous infusion of 3µg kg^–1min^–1, with a bolus of 80 µg kg^–1, both i.v.,were determined in five patients. The distribution half-life(mean±SD) (7.4±3.1 min), elimination half-life(86.7 ± 15.8 min), apparent volume of distribution, V^area(0.44±0.15 litre kg^–1) and elimination clearance(3.33 ± 0.75 ml kg^–1 min^–1) were nimilarto those previously reported for a single bolus of alfentanil.These values for apparent volume of distribution and clearancecan be used to calculate correct bolus and infusion doses tomaintain any desired steady state plasma concentration usingstandard formulae: for example, to maintain a steady state plasmaconcentration of 400 ng ml^–1, a bolus doseof 176 µgkg^–1 and an infusion of 1.3 µg kg^–1min wouldbe required.     

EFFECT OF THE SELECTIVE PHOSPHODIESTERASE TYPE 5 INHIBITOR SILDENAFIL ON ERECTILE FUNCTION IN THE ANESTHETIZED DOG

Purpose

The effects of sildenafil, a highly selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, on erectile function in the anesthetized dog were evaluated.

Materials and Methods

In pentobarbital-anesthetized dogs, increases in intracavernosal pressure in the corpus cavernosum and penile blood flow were induced by pelvic nerve stimulation over a frequency range of 1 to 16 hertz. The effects of increasing doses of sildenafil on electrically stimulated intracavernosal pressure, penile blood flow, blood pressure, and heart-rate were evaluated. In parallel experiments, the effects of the nitric oxide synthase inhibitor N omega-Nitro-L-Arginine (L-NOArg) on these same parameters also were assessed.

Results

The effects of nerve stimulation on intracavernosal pressure and blood flow to the penis were blocked by L-NOArg, 0.1-3 mg./kg., in a dose-related manner, confirming the important role of nitric oxide in producing erections. Sildenafil, 1-100 micro g./kg administered intravenously, had no direct effect on intracavernosal pressure but potentiated the increase in intracavernosal pressure induced by nerve stimulation. This potentiation occurred at sildenafil plasma concentrations consistent with its relaxation effect on isolated human cavernosal tissue and its inhibition of phosphodiesterase type 5 in vitro. Sildenafil had no significant effect on blood pressure or heart rate.

Conclusions

By inhibiting cyclic guanosine monophosphate-specific phosphodiesterase type 5, sildenafil augments the neuronal mechanism responsible for penile erection. This mechanism explains the significant improvements reported in the rigidity and duration of erections seen in patients with erectile dysfunction who have been treated with oral sildenafil.     

MODIFICATION BY FENTANYL AND ALFENTANIL OF THE INTRAOCULAR PRESSURE RESPONSE TO SUXAMETHONIUM AND TRACHEAL INTUBATION

We have measured in a double-blind study the changes in intraocularpressure (IOP) in 40 consecutive patients (pretreated with fentanylor alfentanil) who received suxamethonium and tracheal intubation.Although IOP increased significantly following administrationof suxamethonium, mean IOP in both groups remained significantlyless than control values (P < 0.002). Tracheal intubationcaused a further significant increase in IOP in the fentanyl,but not the alfentanil group. There were no significant differencesin mean IOP between the fentanyl and alfentanil groups. Bothopioids reduced, but did not abolish the haemodynamic responsesto tracheal intubation. ^*Present address: Department of Anaesthesia, Arrowe Park Hospital,Upton, Wirral L49 5LN.     

METABOLISM OF SODIUM NITROPRUSSIDE AND CYANIDE IN THE DOG

Blood cyanide (HCN) and thiocyanate (SCN) concentrations weremeasured at intervals in anaesthetized dogs given bolus dosesof sodium nitroprusside (SNP) 1 mg kg^–1 or potassium cyanide1.07 mg kg^–1and in animals infused with SNP 1.5 mg kg^–1for1 h. Cyanide appeared rapidly in the red cells to give peakconcentrations which accounted for more than 90% of the totalblood HCN. A delay between the peak plasma and red cell HCNconcentrations confirmed that some of the SNP was degraded inthe plasma. Comparison of HCN and SCN concentrations with thosemeasured previously in patients receiving an infusion of SNPsuggests that the degradation of SNP and detoxication of HCNmay be more rapid in the dog. The various pathways of HCN detoxicationare discussed in relation to the reduced formation of SCN indogs receiving SNP compared with those receiving KCN. ^*Present addresses: Department of Anaesthesia, Royal Infirmary,Bristol BS2 8HW. Present addresses: Department of Medicine, Charing Cross Hospital,London W6 8RF.     

PROPOFOL INHIBITS ENZYMATIC DEGRADATION OF ALFENTANIL AND SUFENTANIL BY ISOLATED LIVER MICROSOMES IN VITRO

We have studied the effect of propofol on the enzymatic degradationof alfentanii and sufentanii utilizing isolated liver microsomesobtained from pig and human liver. Propofol inhibited dose-dependentlythe oxidative metabolic degradation of alfentanii and sufentaniiby both microsomal preparations. The calculated concentrationof propofol causing 50% inhibition of metabolic degradation(IC₅₀) was 32.6 µmol litre^–1 for alfentanii and22.1 pwnol litre^–1 for sufentanii in pig liver microsomes.Similar values of inhibitory activity of propofol (IC values62.8 and 52.9 µmol litre^–1, respectively) were observedusing human microsomes prepared from liver taken from an organtransplant donor. We suggest that propofol in clinically relevantconcentrations interferes with oxidative metabolic degradationof alfentanii and sufentanii in the microsomal fraction of pigand human liver.     

HAEMODYNAMIC INTERACTIONS OF HIGH-DOSE PROPRANOLOL PRETREATMENT AND ANAESTHESIA IN THE DOG III: THE EFFECTS OF HAEMORRHAGE DURING HALOTHANE AND TRICHLOROETHYLENE ANAESTHESIA

We have examined the haemodynamic effects of 0.8% trichloroethyleneand 1% halothane anaesthesia in a control group of five dogs,chronically implanted with cardiovascular flow- and pressure-measuringapparatus and compared them with a similar group of six dogspretreated for 3 weeks with oral propranolol (20 mg/kg/day).The effects of graded haemorrhage of 25% of the estimated bloodvolume and re-transfusion were studied. Cardiovascular functionwas satisfactory at all stages of the study except during trichloroethyleneanaesthesia in the beta-blocked dogs when the response to bloodloss was impaired severely. Therefore the use of trichloroethylenein the presence of propranolol may not be advisable in clinicalpractice.     

COMPARATIVE HAEMODYNAMIC EFFECTS OF TUBOCURARINE AND METOCURINE IN THE DOG

On account of its histamine releasing and ganglion blockingproperties tubocurarine is known to have significant haemodynamiceffects. Methylation of the compound produces metocurine andshould decrease both histamine release and ganglionic blockade.The haemodynamic effects of these two compounds were comparedin 10 mongrel dogs anaesthetized with chloralose and morphine.Haemodynamic measurements were made 2 min before and 2, 5, 10and 20 min after administration of the drugs. Each animal receivedthree doses of each drug with a 2-h rest period between doses:tubocurarine 0.35 (muscle twitch ED₉₅), 0.7 and l.4mgkg^–1and metocurine 0.2 (2xED₉₅), 0.4 and 0.8 mg kg^–1. Alldoses of tubocurarine produced an increase in heart rate (212,197 and 212% of control respectively). The mean arterial pressuredecreased significantly with 0.7 mg kg^–1 (48% of control;P<0.05). Metocurine produced no significant haemodynamiceffects except for the largest dose (8 x ED₉₅). The data suggestthat the haemodynamic margin of safety with metocurine in thedog is eight times that of tubocurarine.     

INVESTIGATION OF RESPIRATORY AND CIRCULATORY EFFECTS OF ETHAMIVAN IN THE DOG AND CAT

Intravenous injections of ethamivan caused apnoea, bradycardiaand hypotension in anaesthetized dogs whilst a similar circulatoryresponse without apnoea was seen in anaesthetized cats. Apnoeaand bradycardia were abolished and hypotension was reduced bybilateral vagotomy. Premedication with atropine abolished bradycardiabut did not modify the other responses to ethamivan. The effectof intravenous injection of ethamivan was not altered by premedicationwith mepyramine or hexamethonium. Ethamivan did not cause apnoeawhen injected into the left auricle, the carotid artery or theposterior aorta. The effect on heart rate and blood pressurewhen injection was made at these sites was variable. It wasconcluded that ethamivan stimulated a chemo-reflex having receptorsin the pulmonary circulation. The reflex was not, however, inhibitedby intravenous infusions of procaine.     

AUTONOMIC REFLEXES AND THE CARDIOVASCULAR EFFECTS OF PROPYLENE GLYCOL

The effect of i.v. propylene glycol in doses of 160–800mg kg^–1. on heart rate, arterial pressure and efferentsympathetic activity were observed in anaesthetized paralysed,artificially ventilated dogs. Within 3–5 s of the commencementof the injection of propylene glycol there was an immediatemean decrease in heart rate of 22.7 and 72.1 beat min^–1and in arterial pressure of 27.2 and 58.8 mm Hg at doses of400 mg kg^–1 and 800 mg kg^–1, respectively, togetherwith a gross reduction of sympathetic activity and a subsequentincrease in heart rate above control values. All these effectswere transient and at a dose of propylene glycol 800 mg kg^–1,heart rate and arterial pressure returned to control valuesby 1 min, and sympathetic activity by 2 min. Blocking the vagusnerves with atropine prevented the observed changes in heartrate and arterial pressure, whereas sympathetic blockade withbretylium tosylate had little effect. It was concluded thatpropylene glycol causes powerful reflex stimulation of the cardiomotorvagus and transient inhibition of efferent sympathetic activitywithin 5 s of injection, and that the origin of the reflex islikely to be intrathoracic.     

PHARMACOKINETICS OF HALOTHANE IN THE DOG

After surgical preparation under pentobarbitone anaesthesiaseven dogs of mean body weight 31 kg were ventilated with 1% halothane for 80 min. At 1, 2, 5, 10, 20, 40 and 80 min afterthe start of the halothane administration blood samples weretaken from the femoral artery and pulmonary artery and froma cerebral, a renal and a femoral vein. At 80 min a biopsy sampleof skeletal muscle (psoas) was taken. The halothane tensionin all samples was determined by extraction into carbon tetrachloridefollowed by gas chromatographic analysis using chloroform asan internal standard. The measured tensions were compared withtensions computed from a multi-compartment model of the uptakeand distribution of halothane in the body. The model was quantifiedby measurements, in each individual, of total body mass, themasses of the major organs and the solubility of halothane inthe major organs and tissues; by measurements of blood volumeand solubility in blood at the start and finish of the halothaneadministration and by repeated measurements of alveolar ventilation,cardiac output and body temperature. For the original versionof the model, the computed tensions deviated from the measuredtensions to an extent greater than could be attributed to experimentalerror and in a manner which could be attributed to metabolismof halothane and probably to direct diffusion of halothane fromwell-perfused organs and lean tissues into fat. Direct experimentalevidence of diffusion into perirenal fat was obtained in supplementaryexperiments. With the quantitation of the model distorted tomimic the processes of metabolism and diffusion, measured arterialtensions could be predicted with a mean error of — 0.2mm Hg (SD 0.6 mm Hg). The mean measured arterial tension was3.5 mm Hg. ^*Computer Unit, University of Essex, Wivenhoe Park, Colchester,Essex CO4 3SQ. Department of Drug Metabolism, Hoechst Pharmaceuticals ResearchLtd, Walton Manor, Walton, Milton Keynes, Bucks MK7 7AJ.     

ALFENTANIL AND PROPOFOL INFUSIONS FOR SURGERY IN THE BURNED PATIENT

We have studied combinations of alfentanil and propofol fortotal i.v. anaesthesia in 24 severely burned patients. No inhalationagents were used. After a loading dose of alfentanil 100 µgkg^–1, the intraoperative requirement was 1.24 (SEM 0.7)µg kg^–1 min^–1, and after a propofol inductiondose of 2 mg kg^–1 the maintenance rate was 100 µgkg^–1 min^–1. Initial hypotension occurred after inductionof anaesthesia, but during the operation, cardiovascular variableswere stable. After adequate antagonism of neuromuscular block,respiratory depression persisted in three patients when thetwo agents were discontinued simultaneously; this was not seenwhen alfentanil was discontinued 15 min before propofol. Qualityof recovery was good, and satisfactory postoperative analgesiawas present in the majority of patients 2 h after operation.This study indicates that total i.v. anaesthesia with a combinationof alfentanil and propofol appears to be satisfactory in burnedpatients.     

PULMONARY KINETICS OF FENTANYL AND ALFENTANIL IN SURGICAL PATIENTS

The pulmonary kinetics of fentanyl and alfentanil were studiedquantitatively in two groups of five and six surgical patients,respectively, after the induction of anaesthesia. A mixtureof one of the opioids and indocyanine green was administeredas a bolus. From measurements of the concentrations of the dyein plasma and the opioids in blood, central blood volume andthe amount of drug which passed through the pulmonary circulationwere calculated. The pulmonary release of fentanyl and alfentanilwas calculated from the arterial-mixed venous blood concentrationdifferences. Fentanyl 43.0–86.9% (median 70.9%) and 35.9–79.8%of alfentanil (median 58.6%) were sequestered by the lung onfirst passage of the opioid- containing blood through the pulmonarycapillaries. During the following 14 min, fentanyl was released,apparently from two binding sites (: 0.22 (0.16–0.27) min; : 5.78 (3.65–13.86) min). Initially, there was a rapid releaseof alfentanil (: 0.28 (0.08–0.51) min). However, 1–3 min after injection, the arterial-mixedvenous blood concentration difference of alfentanil disappeared,although considerable amounts of drug were still present inthe lung of five of the six patients studied. It may be expectedthat a temporary pulmonary sequestration of fentanyl and alfentanilhas considerable impact on the time course of their pharmacologicaleffects, on the time necessary to reach their maximum effectand on the intensity and (in case of fentanyl) the durationof these effects.     

ATTENUATION OF THE PRESSOR RESPONSE TO TRACHEAL INTUBATION IN HYPERTENSIVE PROTEINURIC PREGNANT PATIENTS BY LIGNOCAINE, ALFENTANIL AND MAGNESIUM SULPHATE

The pressor response to intubation is known to be exaggeratedin patients with gestational proteinuric hypertension (GPH).The effect of pretreatment with lignocaine 1.5 mg kg^–1,magnesium sulphate 40 mg kg^–1 or alfentanil 10 µgkg^–1 on this pressor response was studied in 69 patientswith moderate to severe GPH. Systolic arterial pressure exceededbaseline values for the first 5 min after tracheal intubationin the lignocaine group, with a peak increase of 31.6 (SEM 3.6)mm Hg at 2 min after intubation, but no mean increase in pressureoccurred in the two other groups. Following intubation, sixof 24 mothers in the alfentanil group, six of 21 in the lignocainegroup and one of 24 in the magnesium group (P < 0.05) exhibiteda systolic arterial pressure (SAP) greater than 180 mm Hg sustainedfor 2 min or more. Alfentanil caused the least change in heartrate, but resulted in significant fetal depression.     

SOME PHYSIOLOGICAL AND METABOLIC EFFECTS OF SODIUM NITROPRUSSIDE AND CYANIDE IN THE DOG

The cardiovascular and acid-base changes following equivalenti.v. bolus doses of sodium nitro-prusside (SNP) and potassiumcyanide (KCN) have been studied in two groups of anaesthetizeddogs. In a third group, the metabolic changes produced by i.v.infusion of SNP 1.5 mg kg^–1 at a constant rate over 1h have been studied. In contrast to a decrease in arterial pressurefollowing SNP, hypertension and tachycardia occurred after theadministration of KCN, with hyperventilation and an increasein packed cell volume. During infusion of SNP, increases inplasma cyanide concentrations were associated with an increasein arterial base deficit, plasma lactate and excess lactateand a decrease in oxygen consumption. The occurrence of lacticacidosis with SNP 1.5 mg kg^–1 suggests that this may bethe maximum safe dose for short term infusion. However, allthese changes reversed spontaneously following discontinuationof SNP, indicating that base deficit is an adequate metabolicmonitor during administration of SNP.