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Cardiac excitation, conduction, and refractory parameters of the heart were investigated in 36 pigs (German country breed) to obtain basic values under influence of the following 10 anaesthetic regimes using HIS bundle electrography and programmed stimulation: 1. azaperone/metomidate/chloralose, 2. ditto + nitrous oxide, 3. azaperone/pentobarbital, 4. ditto + nitrous oxide, 5. ketamine/fentanyl/midazolam/pancuronium, 6. ditto + nitrous oxide, 7. ketamine/pentobarbital, 8. ditto + nitrous oxide, 9. ketamine/propofol, 10. ditto + nitrous oxide. Only the effects in the groups 5 and 6 just as 9 and 10 could be compared to former results in dogs under equal anaesthetic conditions. It could be shown that in almost all observed parameters there were differences between both species. This should be considered in experiments with other substances or in cardiovascular results.

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Cardiac excitation, conduction, and refractory parameters of the heart were investigated in 40 beagle dogs to obtain basic values under the influence of the following 9 inhalation anaesthetic regimes using HIS-bundle electrography and programmed stimulation: 1. halothane; 2. enflurane; 3. isoflurane; 4. halothane+nitrous oxide; 4. enflurane+nitrous oxide; 6. isoflurane+nitrous oxide; 7. alfentanil/midazolam/succinylcholine+nitrous oxide; 8. fentanyl/midazolam/pancuronium bromide+nitrous oxide; 9. propofol+nitrous oxide. It could be shown that inhalation anaesthetics under laboratory conditions exert some influences on the observed cardiac parameters, although they are not as strong as those of intravenous anaesthetics. Therefore their effects should be considered in experiments with other substances or in cardiovascular results.

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Cardiac excitation, conduction, and refractory parameters of the heart were investigated in 59 beagle dogs to obtain basic values under the influence of the following 11 intravenous anaesthetic regimes using HIS-bundle electrography and programmed stimulation: 1. Alfentanil/midazolam/succinylcholine; 2. alfentanil/midazolam/succinylcholine/atropine; 3. fentanyl/midazolam/pancuronium bromide; 4. fentanyl-droperidol/chloralose/urethane; 5. ketamine/xylazine; 6. ketamine/xylazine/atropine; 7. propionylpromazine/pentobarbital; 8. propionylpromazine/levomethadon; 9. propofol; 10. propofol/alfentanil; 11. Tiletamine-zolazepam. It could be shown, that some intravenous anaesthetics under laboratory conditions have a strong influence on the observed cardiac parameters that must be considered in experiments with other substances or in cardiovascular results.

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Domestic pigs received single intravenous and oral doses of lorazepam or clonazepam (1 mg/kg), benzodiazepine derivatives biotransformed by glucuronide conjugation and nitroreduction, respectively. Blood samples were simultaneously drawn from portal venous and systemic venous sampling sites during 8 h after dosage. After intravenous dosage with either drug, the area under the serum concentration curve (AUC) for the intact drug, as well as for the principal metabolites (lorazepam glucuronide and 7-aminoclonazepam, respectively), was nearly identical between portal and systemic serum. After oral dosage, absolute systemic availability (relative to intravenous administration) of both lorazepam and clonazepam was incomplete (mean values: 29 and 49%, respectively); however, metabolite levels were also correspondingly lower between oral and intravenous dosages. First-pass hepatic extraction also occurred for both drugs, with mean systemic/portal AUC ratios of 0.60 for lorazepam and 0.74 for clonazepam. Pretreatment with neomycin (1.0 g) had a minimal effect on portal or systemic AUC for intact clonazepam after oral dosage, but 7-aminoclonazepam concentrations were reduced by neomycin pretreatment. Thus incomplete absorption, together with first-pass hepatic biotransformation, appears to explain the incomplete systemic availability of orally administered lorazepam or clonazepam. Biotransformation within the gastrointestinal tract or during absorption through the gastrointestinal mucosa contributes minimally.

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Former experiments with thermal conduction probes showed signs of reductions or increases of myocardial perfusion shortly after injection of microspheres into the left atrium. Because of this, 210 measurements made during experiments on 66 dogs under propionyl-promazine/pentobarbital narcosis were newly analysed to verify a possible influence of microspheres (9 microns phi) injected into the left atrium on microcirculation. Using 20 additional dogs in identically performed experiments, the myocardial perfusion was measured using thermal conductance probes, following injections of isotonic NaCl solution (8 ml each), Ringer's solution, 5% glucose, the subject's blood, and isotonic NaCl solution mixed with the surface-active substance Tween 80. These suspension media were injected both with and without unlabelled microspheres (8.6 microns phi). The results led to the following conclusions: An obligatory decrease in the blood supply as the result of a mechanical blocking of capillaries by microspheres can be ruled out. The particles, the suspension media, and a suspension temperature not sufficiently adjusted to the body temperature induce reactive negative or positive changes in the microcirculation of the myocardium. This was found in approx. 45%-75% of cases. Solutions containing particles cause, in the majority of cases, a decrease. The suspension medium with the smallest effect proved to be isotonic NaCl solution. From the results one can conclude that artefacts may arise from the application of the heat conductance probe method when the temperatures are not perfectly matched. However, the injected solution itself can often lead to various reactions in microcirculation which may last up to 5 min. (ABSTRACT TRUNCATED AT 250 WORDS)

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In an experimental animal study using adolescent pigs we compared the pharmacokinetics and -dynamics of atropine following intravenous injection (0.25 mg, n = 6) or endobronchial instillation (2 mg, n = 6). Results showed that endobronchial atropine is rapidly absorbed by the pulmonary circulation, resulting in a peak plasma concentration of 48.8 +/- 25.9 ng ml-1 (mean +/- SD) after 2 min, compared to 46.3 +/- 16.7 ng ml-1 in the first min after intravenous injection. A first increase in heart rate could be observed within 1 min after both routes of drug administration. Significant changes in heart rate were found 9-30 min after endobronchial and 12-15 min after intravenous medication, with a maximum after 9 min (+57%) and 12 min (+24%), respectively. Mean bioavailability of atropine following the endobronchial route reached only 23% during the first 6 h when compared to intravenous administration. In light of this reduced bioavailability, we suggest an adult dosage in humans of atropine 2 mg diluted in 5-10 ml of saline administered endobronchially to attain a reliable increase in heart rate during a cardiac emergency when, in an intubated individual, no intravenous line is readily available.

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In this study, catecholamine plasma levels and hemodynamic response were measured to compare the effects of endogenously released (group A; n = 8), intravenously injected (group B; 10 micrograms/kg; n = 8), and endobronchially instilled (e.b.) epinephrine (group C; 100 micrograms/kg; n = 8) on resuscitation. Although the endogenous release of epinephrine produced peak plasma concentrations of 214 +/- 86 ng/ml (mean +/- SEM) during cardiac massage, only 5 animals were successfully resuscitated in group A. Mean arterial pressure and cardiac output were significantly lower in the first hour of restored spontaneous circulation compared to groups B and C. Endobronchial and intravenous epinephrine administration proved equally effective with regard to resuscitability and hemodynamic response during cardiac massage. All animals in groups B and C were successfully resuscitated and peak plasma concentrations of epinephrine were achieved with comparable onset times (317 +/- 53 ng/ml after 2.5 min in group B, 634 +/- 202 ng/ml after 3 min in group C). The tenfold epinephrine dose administered endobronchially was able to generate only a twofold increase in peak plasma epinephrine concentrations. The mean bioavailability with this route of administration, however, was 40% (5-71%). The ongoing absorption and therefore significantly longer half life of e.b. epinephrine compared to i.v. administration improved the hemodynamic situation of group C animals during the early postresuscitation period. More extensive use of e.b. epinephrine administration can be recommended, especially in out-of-hospital resuscitation, when intubation is achieved before an intravenous line can be established.(ABSTRACT TRUNCATED AT 250 WORDS)

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In six anesthetized dogs with myocardium partially damaged by ischemia (LAD occlusion), the effect of an i.v. bolus injection of 0.05 mg molsidomine/kg body weight followed by a 6-h i.v. infusion of 0.5 micrograms molsidomine/kg/min on the volume of myocardial ischemia, the relative remaining blood flow in the ischemic area, and the dynamics of the left ventricle were examined by means of computer tomography. The extent of the ischemic volume in the group treated with molsidomine was by far lower than in the control group; this difference was significant if one takes into account the individual heart size. The relative remaining blood flow in the ischemic region was not influenced by molsidomine. The reduction of preload and afterload resulted in corresponding changes in left ventricular areas, segments of these areas, the long axis, thickness of myocardium, ejection fraction and stroke volume. Aortic pressure was lowered insignificantly, heart rate remained nearly unchanged. Plasma analyses of molsidomine. SIN 1 and SIN 1C show that the applied dosage was sufficient to reach a constant concentration over the whole period of observation in the dog.

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Anesthetized dogs received a single 1.0-mg/kg intravenous dose of flurazepam hydrochloride, following which multiple blood and cerebrospinal fluid (CSF) samples were taken over the next 8 h. Concentrations of flurazepam and its metabolite, desalkylflurazepam, were determined by gas chromatography with electron-capture detection. Mean kinetic variables for flurazepam were: volume of distribution 7.9 l/kg, elimination half-life 2.3 h, clearance 37 ml/min/kg, serum free fraction 25% unbound. The metabolic product desalkylflurazepam appeared in serum in low concentrations, and was eliminated with a half-life of 4.9 h. Flurazepam rapidly entered CSF, then was eliminated in parallel with flurazepam in serum. However, the extent of entry into CSF was limited, with the mean ratio of area under the curve for CSF versus serum (0.24) nearly identical to the serum free fraction. Thus, intravenous flurazepam in dogs is characterized by extensive distribution, high clearance, and short half-life. Entry into CSF is rapid, and appears governed by passive diffusion. The extent of CSF entry is limited by protein binding in serum.

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An experimental model was developed to elucidate the site of presystemic extraction of drugs with incomplete bioavailability due to high extraction after p.o. dosage. Domestic pigs received single i.v. or p.o. doses of midazolam (1 mg/kg) or flurazepam (2 mg/kg), two benzodiazepine derivatives with high presystemic extraction after p.o. dosage. Multiple blood samples were simultaneously drawn from the portal vein and from a systemic vein during 8 hr after dosage. After i.v. administration, both drugs had high systemic serum clearance, averaging 24 ml/min/kg. Area under the serum concentration curve (AUC) for systemic vs. portal sites was nearly identical for midazolam (769 vs. 737 ng/ml x hr); for flurazepam, systemic AUC exceeded portal AUC (1035 vs. 778 ng/ml x hr, P less than .01). After p.o. dosage, the systemic/portal AUC ratio averaged 0.15 for midazolam and 0.11 for flurazepam; for both drugs, portal AUC after p.o. dosage did not differ significantly from systemic AUC after i.v. administration. Thus, the extensive presystemic extraction of orally administered midazolam and flurazepam are mainly attributable to hepatic biotransformation rather than metabolism either within the gastrointestinal tract or during absorption into the portal circulation.

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We used a standard animal CPR model to study the effectiveness and hemodynamic response of 100 micrograms/kg epinephrine administered endobronchially and to compare the findings after conventional iv administration. Results showed that the endobronchial and iv epinephrine medication improved the survival rate by 100% compared to that of a control group receiving no medication. Although the hemodynamic conditions during cardiac compression were not significantly different after both routes of drug administration, endobronchial instillation produced a prolonged drug action during the first hour of restored spontaneous circulation. A more extensive use of this type of drug administration, especially in out-of-hospital resuscitation, is suggested.

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The blood supply of end-to-end staple and suture lines in the pig colon was compared. In 15 operated animals there was no anastomotic leak. Sporadic circumscribed areas of restricted circulation could be noticed in hand-sewn anastomoses. This effect was marked on the 7th and 14th postoperative day, when vascularisation of the anastomoses was increased. Such lack of vascular supply was not seen in stapled anastomoses. The intramural arteries passed through the B-shaped staples without hindrance. An unremarkable vascular pattern and a completed healing of the anastomoses were observed after 3 weeks in staple lines and after 4 weeks in suture lines.

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In 11 mongrel dogs in propiophenylpromazine-pentobarbital-anaesthesia the influence of forced respiration on the load of puncture channels of a suture was investigated. For this horizontal suture in the upper abdominal wall, threads No. 3 USP and round needles No. ECT-4 were used. The experiments were carried out in supine position with stretched hindlegs, in supine position with relaxed hindlegs, in lateral position, and in hanging abdominal position. Measurements were performed with a selfconstructed resistance strain gauge element. Rising forced respiration pressure increased the inspiratory load of puncture channels, but there were no significant differences between spontaneous breathing and forced respiration with pressure of 10 cm H2O. In contrary to this there were highly significant differences between spontaneous breathing and forced respiration with pressure of 20 and 30 cm H2O (multiple variance analysis). For instance the load during forced respiration with a pressure of 30 cm H2O in supine position with relaxed hindlegs rose about 67% above pressure values of spontaneous breathing. It could be shown that the expiratory load in the puncture channels was not influenced by forced respiration pressure, but depended on the body position; in dogs it was minimal in side position (45-48 g), higher in supine position with relaxed hindlegs (67-71 g), even higher in supine position with stretched hindlegs (88-92 g), and maximal in hanging abdominal position (109-113 g). By this investigation the increase of load in the puncture channels during forced respiration with pressures of 20 and 30 cm H2O was quantified.

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Experiments on phantoms showed very good correlation between flow velocity, as calculated from time-density curves, and theoretical values. After further development using an inter-active computer programme, DSA measurements of flow velocity are now undergoing further experimental investigation, but are also available for routine clinical examination.

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The influence of pentagastrin on gastric blood flow has been investigated using 9 mu-microspheres in dogs. As soon as 6 min after the onset of a pentagastrin infusion blood flow rises in all gastric probes in fasted animals. In dogs, fed two hours previously, such a response can only be seen in the corpus-mucosa areas. Blood flow in the antrum mucosa specimen falls beneath its initial value. This gastric steal-phenomenon takes place at the level of the submucous plexus, as has been shown earlier.

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In an anaesthetized dog model, serum kinetics and CSF entry were determined after i.v. administration of the following 8 drugs: salicylic acid (as acetylsalicylic acid), antipyrine, acetaminophen (paracetamol), lidocaine (lignocaine), trimipramine, amitriptyline, haloperidol, and imipramine. Kinetic variables were evaluated in relation to in-vitro lipophilicity, measured by the reverse-phase high-pressure liquid chromatographic (HPLC) retention index. After correction for individual values of serum binding (determined as the CSF: serum ratio at equilibrium), in-vivo volume of distribution was highly correlated with HPLC retention (r = 0.92). Conversely, the time of peak CSF concentration and the CSF entry half-life were negatively correlated with HPLC retention (r = -0.83 and -0.63, respectively). Thus lipophilicity is a physiochemical property which has an influence on the peripheral distribution of drugs as well as their rate of entry into CSF.

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A CT standard procedure has been developed in six series of experiments, using 62 anaesthetised dogs in order to quantitative relative blood flow through ischaemic heart muscle. Measurements of cardiac dynamics by means of contrast media were less strictly controlled. The use of the standardised procedures with contrast injections is necessary because of the variable perfusion and washout intervals of the contrast in normal and ischaemic myocardium.

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In 8 pentobarbital-anesthetized mongrel dogs the correlation between regional myocardial blood flow (RMBF) and regional cardiac uptake of 15-(p-123I-phenyl)-pentadecanoic acid (IPPA) was determined. Three animals were studied under control conditions, in three dogs an acute ischemia was produced by LAD ligation, and two dogs were paced at 195 beats/min. RMBF values were 20-50 ml/min X 100 g in acutely ischemic myocardium. 90-120 ml/min X 100 g under normal conditions and 200-250 ml/min X 100 g during pacing-induced stimulation. Total cardiac uptake of IPPA was 4.5-6% of the injected dose. In normal and acutely ischemic myocardium a good correlation between RMBF and IPPA uptake was obtained. Under stimulated conditions only a moderate increase of IPPA accumulation was found. At RMBF values above 150-170 ml/min X 100 g an upper limit of IPPA uptake was observed and can be explained by limited diffusion or an increased utilization of alternative substrates.

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Electrical and motor activity of smooth muscle of the canine rectum was registered by transanal recording following low rectum anastomosis. The relaxation reflex of the anal canal had disappeared distal of the anastomosis in the first postoperative week, and electrical slow waves and pressure waves were desynchronized proximal and distal of the anastomosis. The resting pressure of the rectal wall had increased above preoperative values. After wound healing had accomplished the relaxation reflex and the synchronization of electrical and mechanical activity proximal and distal of the anastomosis did occur again. It is concluded that the rectal wall provides the pathways for the relaxation reflex of the anal canal. After wound healing has finished these pathways are restored across the anastomosis.

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On the basis of an experimental model the extent was studied to which even small intramural myocardial ischemia can be demonstrated by SPECT. For this purpose ligature of the Ramus interventricularis anterior (n = 10) or of the Ramus circumflexus (n = 2) of the left coronary artery was performed in 12 dogs to produce myocardial lesions of the anterior and posterior wall. Transmission computed tomography (TCAT) served as a control method in 10 dogs showing that 6 lesions were transmural and 4 intramural. All infarctions could be detected by SPECT with a rotating gamma camera (TCAT: 9/10). TCAT after contrast media enhancement with its morphological advantages (high resolution) should, however, not be used in the acute phase of myocardial infarction because of its hemodynamic side effects. Thus, SPECT with 201T1 remains the method of choice even for the proof of minor intramural (acute) ischemic lesions.

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