MORBID ANATOMICAL CHANGES IN THE LUNGS OF DOGS AFTER INHALATION OF HIGHER OXIDES OF NITROGEN DURING ANAESTHESIA

Twelve dogs were anaesthetized with pentobarbitone and exposedto predetermined concentrations of nitric oxide and nitrogendioxide. Three dogs recovered and were sacrificed, one at 24hours and two at 48 hours. Autopsy was performed and the morbidanatomy of the lungs is described in detail. The changes werefocal, including oedema, hyperinflation, haemorrhage, desquamationof mucosa and bronchopneumonia. The severity of the lesionswas broadly proportional to the duration and concentration ofgaseous exposure and the most severe effects were seen in twoof the survival dogs.     

EFFECTS OF HIGHER OXIDES OF NITROGEN ON THE ANAESTHETIZED DOG

The physiological derangements during and following the administrationof higher oxides of nitrogen have been studied in dogs anaesthetizedwith pentobarbitone. The dogs were exposed to concentrationsof nitric oxide or nitrogen dioxide between 0.1 and 2.0 percent over periods between 5 and 136 minutes. Despite the inhalationof 98 per cent oxygen, death was always associated with a criticalreduction in arterial oxygen content. This was caused by oneor more of the following three factors: methaemoglobinaemia,low arterial Po₂, and acidaemia which caused a shift of theoxyhaemoglobin dissociation curve. The reduction of arterialPo₂ was caused by an outpouring of fluid into the alveoli. ^* In receipt of a Leverhulme Research Fellowship. In receipt of a grant from the Wellcome Foundation. Supported by U.S.P.H.S. Fellowship No. 1-F3-GM-31, 742-01,National Institute of General Medical Sciences. Seconded by the University of Washington, Seattle.     

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.     

CEREBRAL EFFECTS OF SEVOFLURANE IN THE DOG: COMPARISON WITH ISOFLURANE AND ENFLURANE

The cerebral effects of sevoflurane were compared in dogs withthose of enflurane and isoflurane. Initially, the minimum alveolarconcentrations (MAC) of sevoflurane and enflurane were determinedand the electroencephalo-graphic (EEG) responses to increasingdoses of sevoflurane (1.5, 2.0 and 2.5 MAC) or enflurane (1.5and 2.0 MAC) in unparalysed animals were examined. Administrationof sevoflurane was not associated with seizure activity at anyconcentration either during normocapnia (Pa_CO2 5.3 kPa) or hypocapnia(Pa_CO2 2.7 kPa), even in the presence of intense auditory stimuli.All dogs anaesthetized with enflurane demonstrated sustainedEEG and motor evidence of seizure activity induced by auditorystimuli at concentrations of enflurane > 1 MAC, particularlyduring hypocapnia. In a separate group of dogs, the effectsof increasing concentrations of sevoflurane and isoflurane (0.5,1.5 and 2.15 MAC) were compared directly on arterial pressure,cardiac output and heart rate, cerebral blood flow and the cerebralmetabolic rate for oxygen (CMRO₂) using the venous outflow technique.Sevoflurane, in common with isoflurane, had minimal effectson cerebral blood flow at the concentrations studied, but significantlyreduced the CMRO₂ at end-tidal concentrations sufficient toproduce a burst suppression pattern on the EEG (approximately2.15 MAC). Both sevoflurane and isoflurane significantly decreasedarterial pressure in a dose-dependent manner, but neither drugsignificantly altered cardiac output.     

THE EFFECT OF FOUR VOLATILE ANAESTHETIC AGENTS ON THE IMPULSE ACTIVITY OF TWO TYPES OF PULMONARY RECEPTOR

The effect of halothane, ether, chloroform and trichloroethyleneon the impulse discharge of two types of pulmonary receptorhas been investigated in cats and dogs under chloralose or barbiturateanaesthesia. Afferent impulses were recorded from pulmonarystretch fibres and also from slowly-conducting vagal fibreswhose pulmonary endings were stimulated by hyperinflation (high-thresholdinflation receptors). Ventilating the lungs with low concentrationsof each agent (e.g. 1–3 per cent halothane) caused sensitizationof the pulmonary stretch receptors but had no effect on thehigh-threshold endings. With high concentrations (e.g. 5–20per cent halothane), pulmonary stretch receptors showed an initialsensitization followed by a reduction or abolition of activity,while the high-threshold receptors showed a marked increasein impulse activity during inflation. The possibility is discussedthat the high-threshold inflation receptors may be involvedin some of the reflex effects that have been observed duringsurgical anaesthesia with high concentrations of halothane.     

THE MATERNAL PLASMA LEVELS AND PLACENTAL TRANSFER OF BUPIVACAINE FOLLOWING EPIDURAL ANALGESIA

The maternal plasma levels of bupivacaine following epiduraladministration of 0.5 per cent solution with 1/200,000 adrenalinewere determined in twelve patients in labour. After 10 ml (50mg) peak concentrations occurred 15–30 min later and rangedfrom 0.22 µg/ml to 0.60 µg/ml. Plasma levels fellgradually with time after the peak until by 3 hours after injectionthey were all well below 0.2 µg/ml. Maternal and umbilicalplasma levels of bupivacaine were determined at delivery. Theratio of the foetal to maternal levels varied from 0.14 to 0.86.The highest foetal plasma level obtained in the series was 0.25µg/ml and the highest maternal level was 0.68 µg/ml.This value was reached after three 10-ml injections of 0.5 percent bupivacaine with 1/200,000 adrenaline. The 1-min Apgarscores ranged from 7 to 10.     

Sevoflurane: a new inhalational anesthetic agent.

Laboratory screening of a series of halogenated methyl isopropyl ethers revealed sevoflurane (fluoromethyl-1,1,1,3,3,3,-hexafluroro-2-propyl ether) as a potent nonexplosive inhalational anesthetic agent. Sevoflurance, a pleasant-smelling liquid, boils at 58.5 degrees C at 760 torr and has a vapor pressure of 200 torr at 25 degrees C. It is nonflammable in air and has lower flammability limits of 11 vols percent in O2 and 10 vols percent in N2O. Sevoflurane exhibits limited chemical reactivity in vitro; it is subject to slight but measurable hydrolysis, and reacts with soda lime to form traces of related ethers. It provides rapid anesthetic induction and recovery consistent with its low distribution coefficients (blood:gas, 0.6; corn oil:gas, 41.6; olive oil:gas, 53.4). In dogs, anesthetic concentrations of sevoflurane did not produce spontaneous cardiac arrhythmias and did not sensitize the heart to epinephrine. Electroencephalographic patterns were similar to those observed during anesthesia with halothane. In rats, small increases in the urinary excretion of inorganic fluoride ion occurred during the first 24 hours after anesthesia. Subacute studies in dogs and rats, using closed-circle absorption with soda lime, revealed no toxicologically significant changes in animals anesthetized frequently for 2 weeks. Sevoflurane appears to be a unique volatile anesthetic agent worthy of further study.     

THE SYSTEMIC ABSORPTION OF LOCAL ANALGESIC DRUGS

Estimations of the plasma concentrations of lignocaine and prilocaineduring epidural block and intercostal regional block show thathigher plasma levels are consistently found with lignocaineprovided comparable solutions are studied; that the site ofinjection is of some importance in determining the absorptionof local analgesic drug; that, within the range 1–2 percent, concentration is not important if a total dose of 400mg of either drug is not exceeded and finally that the additionof adrenaline 1/80,000 is of value with lignocaine but possiblynot with prilocaine.     

VENTILATORY EFFECTS PRODUCED BY THE I.V. ADMINISTRATION OF INCREMENTAL DOSES OF THIOPENTONE IN THE DOG

Ventilation, ventilatory pattern and ventiflatory drive werestudied in five dogs during the administration of increasingblood concentrations of thiopentone. Ventilation (Ve, RR, Vt)and blood-gas tensions (pHa, Paco₂, Pao₂) were measured. Ventilatorypattern (VT, TI, TE, T_tot) and ventilatory drive (VT/TI) andocclusion pressure) were analysed. Occlusions of the airwaywere performed at end-inspiration and at end-expiration. Thiopentoneproduced a biphasic action on respiratory rate, ranging fromtachypnoea during light anaesthesia to a progressive slowingof respiration with deepening anaesthesia. The Hering-Breuerreflex did not seem to be modified by the level of anaesthesia,whereas the central mechanisms which modulate the duration ofinspiration and of expiration, were perturbed.     

THE CARDIORESPIRATORY EFFECTS OF INTRAVENOUS ISOPRENALINE IN MECHANICALLY VENTILATED DOGS

The cardiorespiratory effects of intravenous infusions of isoprenaline(3 and 12 µg/min) were studied in eighteen mechanicallyventilated dogs. Isoprenaline produced an increase in cardiacoutput, carbon dioxide output and oxygen consumption and a non-respiratoryacidosis. In six dogs minute volume was kept constant so thatarterial Pco₂ increased. These dogs developed a marked increasein total venous admixture, most of which was due to an increasein ventilation/perfusion inequality, In tyhe remaining two groupsof dogs arterial Pco₂ was kept constant by increasing titalvolume or respiratory frequency. Isoprenaline produced a smallerincrease in total venous admixture in these dogs but the increasein right-to-left shunt was approximately the same in all threegroups of dogs. In another six dogs the addition of carbon dioxideto the inspired gas produced no change in venous admixture. ^*Present address: Western Infirmary, Glasgow.     

Quantitative effects of antiplatelet therapy on healing of the endarterectomized canine aorta

This study was designed to quantitatively evaluate the effects of an antiplatelet agent, ibuprofen, on mural thrombus formation and pseudointimal development in the endarterectomized canine aorta. A 3 cm segment of abdominal aorta was endarterectomized in 18 dogs. Nine dogs served as controls and nine dogs were treated with ibuprofen (12.5 mg/kg) given intravenously 1 hour preoperatively and orally (7.5 mg/kg) three times a day in the postoperative period. Three dogs were killed from each group at 7, 14, and 21 days. Healing of the endarterectomized aortic segment was assessed by means of computerassisted surface morphometry, light microscopy, and both scanning and transmission electron microscopy. One week postoperatively, the thrombus-free surface in the treated dogs was 75 percent, compared with 20 percent in control animals; at 2 weeks 97 percent, compared with 38 percent and at 3 weeks 98 percent, compared with 38 percent (p < 0.01 for each group). The thickness of the pseudointima was 9 percent of the aortic wall thickness in treated dogs compared with 60 percent in control animals 1 week postoperatively (p < 0.001); at 2 weeks 24 percent in treated animals and 64 percent in control animals (p < 0.001); and at 3 weeks 31 percent in treated animals and 55 percent in control animals (p < 0.05). Partial reendothelialization was observed 1 week postoperatively and complete reendothelialization at 3 weeks in both the control and treated animals. These data suggest that administration of preoperative and maintenance therapy with ibuprofen significantly reduces mural thrombus formation and pseudointimal thickness in the endarterectomized canine aorta.     

THE EFFECTS OF EXPERIMENTAL DIVISION OF THE VASCULAR PEDICLE OF A TRANSPOSED SUBCUTANEOUS ILEAL LOOP

The effects of immediate division of the neurovascular pedicles of ileal loops implanted in the subcutaneous tissues for four weeks were studied In eight mongrel dogs. The structural and functional changes were studied by examining sections under light and electron microscopy and by comparing D-xylose absorption and motility patterns. Arteriograms were done to show the new subcutaneous collaterals supplying the loops. Of the eight dogs, four had loops showing normal histological appearances and D-xylose absorptive functions after division of the pedicles. In the remaining four dogs, the loops showed evidence of pseudomembranous changes in some areas, resulting in patching necrosis possibly due to inadequate collaterals. The absorption of D-xylose was impaired in these dogs. Perhaps a longer period of transposition and a gradual division of the vascular pedicle would improve the results. The motility pattern did not change after division of the pedicle, though the response to intravenous carbachol was significantly delayed.     

THE INFLUENCE OF ADRENALINE ON THE MATERNAL PLASMA LEVELS AND PLACENTAL TRANSFER OF LIGNOCAINE FOLLOWING LUMBAR EPIDURAL ADMINSTRATION

The maternal and cord plasma concentrations of lignocaine havebeen determined following the administration of 20 ml 2 percent lignocaine solution both with and without the additionof adrenaline 1/250,000. Forty-two patients were examined, 24with adrenaline (Group 1) and 18 with adrenaline (Group 2).A significant difference (P>0.001) was found between Groups1 and 2 in the maternal concentrations for those patients whowere delivered either 11–22 min after injection or 23–30min after injection but not for those patients delivered morethan 30 min after injection. The effect of added adrenalineon the cord plasma lignocaine levels was much less than on thematernal plasma levels. Adrenaline had no effect on the ratioof cord venous plasma concentration at delivery and maternalplasma concetration, the mean value in the two groups beingapproximately 0.5. The addition of adrenaline 1/250,000 to lignocainesolutions administered epidurally increases the safety of themethod for the mother but does not increase it for the neonateto the same extent.     

CARDIOVASCULAR EFFECTS OF PROPOFOL IN THE ANAESTHETIZED DOG

This study was designed to investigate if propofol producedcardiovascular effects by indirect actions or by indirect actionssecondary to depression of the central nervous system. Experimentswere performed on chloralose anaesthetized dogs in which allneurogenic cardiovascular reflexes were abolished by bilateralvagotomy and common carotid ligatures, in combination with i.v. bretylium and propranolol. Bolus doses of propofol followedby infusions at rates up to 160 mg kg^–1 h^–1 producedblood concentrations of propofol from 1.99 to 112 µg ml–1.Infusions of hydroxyethyl starch given to maintain central venouspressures and pulmonary artery occlusion pressures at controlvalues were used as an index of changes in capacitance. Bloodconcentrations of propofol less than 10 µg ml^–1caused an increase in mean capacitance of 8.0 (SEM 1) ml kg^–1with no significant changes in systemic vascular resistance,pulmonary vascular resistance or intropic state of the heart.We conclude that anaesthesia with propofol may be accompainedby decreased cardiac output secondary to reduction in preloadby a direct venodilator effect. Our experiments indicate thatcardiac output and arterial pressure are preserved well at normalanaesthetic blood concentrations of propofol if the preloadis maintained.     

THE EFFECT OF EXTREME HYPOCAPNIA ON THE ANAESTHETIC REQUIREMENT (MAC) OF DOGS

The effect on the minimum alveolar concentration of halothane(MAC) during extreme hypocapnia with oxygen, and with air, wasdetermined in nine dogs. MAC was unaffected by hypocapina withhalothane-oxygen. Changing halothane-oxygen to halothane-airreduced the MAC significantly in only five of nine dogs. Theaverage decrease in this group of nine dogs was 11 per cent,only slightly more than the possible error of the method. Amild metabolic acidosis remained constant throughout the twoor three hours of hypocapnia.     

THE EFFECTS OF CLINICAL CONCENTRATIONS OF HALOTHANE ON THE BLOOD FLOW AND OXYGEN UPTAKE OF THE CEREBRAL CORTEX

Clinical concentrations of halothane vaporized in nitrous oxide-oxygencaused vasodilatation in the cerebral cortex of anaesthetizeddogs at constant arterial carbon dioxide tension. The vasodilatoryaction on the cerebral circulation was greater the higher theconcentration of halothane. Consequently 2 per cent halothaneincreased blood flow through the cerebral cortex more than did0.5 per cent halothane. However, the administration of 4 percent halothane reduced mean blood pressure so markedly thatblood flow was not elevated above the control value. The oxygenuptake of the cerebral cortex was depressed by halothane andthis depression was greater with 2 per cent halothane than with0.5 per cent. These results are discussed with reference tothe effects of halothane on intracranial pressure and on theoxygenation of the brain.     

THE EFFECT OF HALOTHANE ON BACTERIAL GROWTH RATE

The growth rate of four species of non-pathogenic bacteria inbroth was estimated spectrophotometrically. Exposure to halothane(1–10 per cent) vaporized in air produced a dose-dependentdepression of growth rate, but for all species the effect wasnegligible at clinical concentrations of halothane. The ED₅₀was within the range 7–8 per cent halothane for threespecies: 50 per cent inhibition was not obtained with 10 percent halothane in the fourth species. Inhibition of divisionwith 10 per cent halothane was delayed by 20–25 minuteswhich was close to the mean generation time. The effect wasfully reversible although there was again a lag of about 20minutes before division was resumed after withdrawal of halothane.     

The effect of nitric oxide on the pressure of the acutely obstructed ureter

Acute ureteral obstruction leads to changes in pressure inside the ureter, interrupting ureter function. The aim of our study is to explore the relationship between nitric oxide (NO) concentration and pressure in the ureter and to observe the effects of nitric oxide on the revival of renal function. We created the animal models by embedding balloons in the lower ureters of anesthetized dogs and expanding them to simulate acute ureteral obstruction. First, the test animals were pre-treated intravenously with different doses of L-NAME (non-selective nitric oxide synthase inhibitor) to inhibit nitric oxide synthase (NOS), and 10 min later, each subject was administered an intravenous dose of isoproterenol (10 μg/kg). We measured ureter pressure (UP), total and peak concentrations of NO (using an NO monitor, model inNO-T) in ureteral urine, and the volume of the urine (UFV) leaking from the balloon edge. After a certain amount of time had elapsed, it became clear that the dose of L-NAME was inversely related to the total and peak concentrations of NO, the rate of change in UP, and the volume of urine produced. We conclude that L-NAME prevents the NOS from inhibiting the release of NO, then inhibits the effect of isoproterenol reducing the pressure of the acute obstructive ureter. Inversely, we think that NO can reduce the pressure of the acute obstructive ureter and make the obstructive ureter recanalization. And when more the concentration of nitric oxide, the more the pressure will be reduced, and more urine will be collected.     

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.     

COMPLEX RELATIONS BETWEEN CORTICOSTEROIDS AND THE ADHESIVE STATE OF THE WHITE BLOOD CELLS IN THE PERIPHERAL BLOOD: FURTHER ANALYSIS OF THE STATE OF LEUKOCYTE/ADHESIVENESS AGGREGATION IN THE PERIPHERAL BLOOD AS A MARKER OF STRESS

Stress is associated with an increment in the concentration of cortisol, a leukocytotic response and increased state of leukocyte adhesiveness/aggregation (LAA) in the peripheral blood. We investigated the interrelationship between these three parameters in individuals under various conditions of stress. These included 123 emergency room patients with chest pain who were also classified in regard to the presence or absence of heart failure; 15 men in the fertility clinic donating semen and 16 women in the operating room before induction of anaesthesia for dilatation and curettage. A low (r=0.35) but significant (p<0.001) correlation was noted between cortisol level, leukocyte count, and per cent of aggregated leukocytes in the peripheral blood in the first group (ischaemic heart disease) but not the fertility clinic or operating room patients. A complementary study in dogs which received an intravenous hydrocortisone injection revealed neither an increased leukocyte number in the peripheral blood nor an increment in the adhesive state. In vitro studies confirmed the depressant effect of high concentrations of hydrocortisone on cell adhesiveness despite an increment in the expression of various adhesive proteins on the surface of the peripheral blood leukocytes. We concluded that the increased state of leukocyte adhesiveness noted by us in the past in patients under stress is not necessarily related to the presence of an increased cortisol concentration, and that factors other than corticosteroid level should be explored as possible triggers of the LAA response during stress. © 1997 by John Wiley & Sons, Ltd.