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The direct effect of Escherichia coli endotoxin on the release of norepinephrine (NE) and the contractile response consequent to the release of NE were studied in isolated, superfused segments of dog pulmonary artery and portal vein during resting conditions and during electrical stimulation (ES). High-pressure liquid chromatography with electrochemical detection was used to quantify the endogenous NE released and that remaining in the tissue after stimulation. Endotoxin (1 micrograms/ml and 10 micrograms/ml in superfusate) had no effect on the release of NE from either pulmonary artery or portal vein. Endotoxin also had no effect on vasoactivity in response to ES. Thus, in isolated pulmonary artery and portal vein, endotoxin, in the doses employed, does not directly affect release of NE from adrenergic nerve endings, nor does it affect the sequence of events that starts with transmitter-receptor interaction and ends with contraction of smooth muscle cells.

Neuropeptide Y (NPY), norepinephrine (NE), and 3,4-dihydroxyphenylglycol (DOPEG), the metabolite of NE that arises intraneuronally, were measured in superfusates before, during, and after nerve stimulation and in extracts of dog pulmonary artery after superfusion and electrical stimulation (ES) at 12, 6, and 1 Hz. NE and DOPEG were quantified by high-pressure liquid chromatography with electrochemical detection; peptides were quantified by radioimmunoassay. The rate of overflow of NPY, NE, and DOPEG into superfusate was measured over time. The overflow of DOPEG into superfusate during basal conditions was 3.0 times that of NE. Efflux of DOPEG and NPY increased during ES; peak effluxes were not reached, however, until after cessation of stimulation. NE efflux peaked during ES. Effluxes of NE, NPY, and DOPEG were frequency-dependent at 12 and 6 Hz; at 1 Hz efflux of only NE was greater than basal. Halothane decreased significantly the rates of NPY and DOPEG efflux during and after 12 Hz ES; DOPEG efflux evoked by 6 Hz stimulation was also decreased by halothane. The percentage of the total tissue content of NPY that overflowed was decreased by halothane. Halothane did not affect the molar ratios of NE:DOPEG or NE:NPY during basal conditions or ES. These studies provide evidence that halothane slows efflux of NPY that is released along with NE from dog pulmonary artery during high frequencies of stimulation. Halothane also reduces the metabolism of NE to DOPEG.

Peripheral vascular and direct cardiac effects of calcium chloride were determined in a new animal model, the unanesthetized calf, before and after replacement of its natural heart (NH) with a pneumatically driven artificial heart (AH). Calcium (5 and 10 mg/kg) significantly increased cardiac output (Qt) and reduced systemic vascular resistance (SVR) before and after AH implantation. Increases in Qt in AH calves and reductions in SVR in both NH and AH calves were, however, transient, being present 5 minutes but not 15 minutes after both doses of calcium. Increases in Qt and reductions in SVR were significantly (P less than .05) greater after 10 mg/kg than after 5 mg/kg calcium in NH and AH calves. Both doses of calcium produced greater (P less than .05) increases of Qt in NH than in AH animals but similar reductions in SVR. Pulmonary vascular resitance, heart rate and pulmonary arterial and right atrial pressures were not significantly altered by either dose of calcium in NH or AH calves. Mean aortic pressure was influenced by 10 mg/kg calcium only, being transiently reduced in AH calves and increased in NH animals. Pulmonary shunt (QS/Qt) was increased by both doses of calcium in NH calves but only by 10 mg/kg in AH animals. Correlations of mean change in QS/Qt with mean change in Qt were high both before (r=.99) and after (r=.97) AH implantation. These data demonstrate that calcium significantly reduces SVR in a dose-related manner as well as exerting a positive inotropic effect on the myocardium.

Quantitation of peripheral vascular versus direct cardiac effects of isoproterenol (0.002 mg/kg) was attempted in a new pharmacologic animal model, the unanesthetized calf, before and after replacement of its natural heart with a pneumatically driven artificial heart (AH). Isoproterenol significantly increased (rho less then 0.01) cardiac output and pulmonary shunt and decreased aortic blood pressure before and after AH replacment. Elevation of cardiac output and pulmonary shunt was greater (rho less than 0.05) and depression of aortic pressure less (rho less than 0.05) before AH replacement than after. Isoproterenol did not change pulmonary artery (PA) or right atrial (RA) blood pressures before AH implantation but did reduce (rho less than 0.05) PA diastolic and mean pressures and increase mean RA pressures after. Systemic vascular resistance was significantly (rho less than 0.01) reduced by isoproterenol before and after AH implantation. Heart rate, 02 uptake, respiratory rate, tidal volume, and minute volume were all markedly increased before AH implantation but unchanged after. These findings demonstrate that approximately half the increase in output and pulmonary shunt and all changes in 02 uptake and respiratory dynamics after administration of isoproterenol are related to cardiac effects of the drug. Our data also suggest that the unanesthetized bovine before and after AH replacement is a unique model for study of the differential pharmacology of drugs with respiratory, cardiac, and peripheral vascular effects.

The effect of halothane on the release and metabolism of norepinephrine during resting conditions and in response to electrical stimulation at 2 Hz was studied in isolated superfused segments od dog saphenous vein. Liquid chromatography with electrochemical detection was used to measure endogenous norepinephrine overflowing in response to electrical stimulation and the content of norepinephrine remaining in the tissue after stimulation. In other preparations, norepinephrine stores were labeled with [3H]norepinephrine, and measurements were made of [3H]norepinephrine and its metabolites (separated by column chromatography) in superfusates. Radiolabeled metabolites of norepinephrine produced intraneuronally (3,4-dihydroxyphenylglycol) and extraneuronally (O-methylated) were quantitated by liquid scintillation spectrometry. Electrically stimulated release and overflow of endogenous norepinephrine was decreased 11.9% at 0.75% halothane, 17.7% at 1.5% and 19.2% at 2.5% halothane. At each halothane concentration studied, the per cent of tissue NE content released in response to electrical stimulation was less. Halothane decreased the fraction of radioactivity lost during basal conditions and during stimulation. Less oxidative deamination of norepinephrine occurred in the presence of halothane.

The cardiovascular responses of aortic cross-clamping and declamping with normal and high ventricular filling pressures were compared during epidural and nitrous oxide-morphine anesthesia in 32 male patients undergoing reconstructive aortic surgery. The patients were divided into four groups. Groups I and II had lumbar epidural blocks with bupivacaine and received nitrous oxide in oxygen to breathe; groups III and IV were anesthetized with morphine (2 mg/kg) and nitrous oxide. During aortic occlusion groups I and III received Ringer's lactate at a rate which maintained mean pulmonary capillary wedge pressure (PCWP) 3 to 4 torr above pre-anesthetic values whereas groups II and IV were given Ringer's lactate rates which kept PCWP similar to pre-anesthetic values. Prior to cross-clamping mean arterial blood pressure and systemic vascular resistance were lower in groups I and II than in groups III and IV but cardiac output, PCWP, and pulmonary vascular resistance were similar in the four gropus. Cross-clamping of the aorta produced no significant change in any cardiovascular variable measured in any group. Declamping did not significantly alter any variable in groups I and III but produced moderate hypotension in group IV and severe hypotension in group II as well as significant decreases in PCWP in both groups. Our data demonstrate that aortic cross-clamping and release result in little change in cardiovascular dynamics in patients anesthetized with epidural or morphine-nitrous oxide and given balanced salt solutions intravenously in amounts adequate to increase left ventricular filling pressures prior to release of the aortic cross-clamp. Our findings also indicate that hypotension can occur in patients in whom left ventricular filling pressures are maintained at normal levels prior to cross-clamp release, especially in patients given epidural anesthesia.