Mechanisms of the inhibitory effect of ketamine on guinea pig isolated main pulmonary artery.

Although ketamine increases pulmonary vascular resistance of patients, an occasional decrease of resistance in animals and humans has been reported. In addition, ketamine has a direct relaxant effect on isolated smooth muscle. The effects of ketamine on the main pulmonary artery rings isolated from the guinea pig were studied to elucidate the underlying mechanism of the reported relaxant effect of this anesthetic on smooth muscle. Ketamine (10-250 micrograms/mL) caused a concentration-dependent shift to the right of CaCl2 concentration-effect curves on artery rings, suggesting an interference with Ca2+ metabolism. In Ca(2+)-free buffer, ketamine (10-250 micrograms/mL) did not affect the magnitude of epinephrine-induced contractions but inhibited dose-dependent BaCl2-induced contractions. These observations suggest that ketamine inhibits transmembrane Ca2+ influx but does not affect its release from intracellular stores or its binding to intracellular receptor sites on the contractile system. Ketamine (25-500 micrograms/mL) also caused equipotent concentration-dependent relaxation of epinephrine-induced contractions in the absence and the presence of monensin, a Na(+)-ionophore that dissipates the Na+ gradient across the cell membrane, and in Na(+)-free, sucrose-substituted buffer. Ketamine (25-500 micrograms/mL) also relaxed ouabain-induced contractions to the baseline, an effect that was significantly attenuated in the presence of ruthenium red, a Ca2+ adenosine triphosphatase (ATPase) inhibitor. The relaxant effect of ketamine (250-750 micrograms/mL) of epinephrine-induced contraction also was attenuated in the presence of 0.1 mM lanthanum chloride (La3+), an inhibitor of adenosine 5'-triphosphate (ATP)-dependent Ca2+ extrusion, and completely inhibited in the presence of 10 mM La3+.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effect of ketamine on cholinergic- and noncholinergic-induced contractions of isolated guinea-pig bronchi.

Ketamine, 3 X 10(-4) M, was found to inhibit transmural electrical stimulation-induced contractile responses of the mainstem and hilar bronchi isolated from reserpine-pretreated guinea-pigs. This concentration of ketamine did not cause direct smooth muscle relaxation in these preparations and a smaller concentration (3 X 10(-5) M) was ineffective in blocking contractions. The pattern of inhibition produced by ketamine was similar to that produced by atropine, 1 X 10(-6) M, in both preparations and was observed at the larger stimulation frequencies employed. When studied in the presence of atropine to optimize noncholinergic-induced contractions, ketamine did not antagonize contractile responses to transmural electrical stimulation. After pretreatment of the isolated tissues with capsaicin, 1 X 10(-6) M, to optimize cholinergic-induced contractions, ketamine produced inhibition of responses to electrical stimulation. Ketamine, 3 X 10(-4) M, produced a shift to the right of the dose-response curve without altering the maximum contractile responses to carbachol, but had no effect on dose-response curves to substance P, the putative noncholinergic transmitter in these bronchial segments. The data suggest that ketamine exerts a selective inhibitory effect on cholinergically mediated contractions in guinea-pig bronchi and that this antagonism is largely exerted post-junctionally, at the level of the smooth muscle muscarinic receptors.

Glutaraldehyde cross-linked collagen (GAX): a new material for therapeutic embolization.

In a search for a better agent for use in therapeutic embolization, a newly available bovine collagen product, glutaraldehyde cross-linked collagen (GAX), was evaluated to determine its effectiveness in causing arterial obstruction, its persistence after embolization, and the acute and chronic pulmonary toxicity resulting from direct pulmonary embolization. GAX is an effective agent for causing arterial obstruction: 3-4 ml caused prompt flow arrest when injected into the internal iliac artery of six dogs. In this canine model, the material persisted within embolized tissue for as long as 2 months, and at follow-up intervals of 2 days, 2 weeks, and 2 months, its presence did not produce any cellular response. Studies of both acute and chronic pulmonary toxicity reveal that when GAX is embolized directly into the pulmonary circulation it causes adverse effects only by mechanical blockage of pulmonary arteries. GAX offers several advantages over other currently available agents and is of sufficient safety that clinical trials in humans can be undertaken.

Domperidone-induced potentiation of ventilatory responses in awake goats.

Dopamine has been implicated in maintaining tonic inhibition of carotid body activity. We tested this hypothesis by assessing the ventilatory effects of a peripheral dopamine antagonist, domperidone. The effects of this agent on the ventilatory responses to hypoxia and hypercapnia were also examined. The study was performed in awake carotid body intact and carotid body denervated goats. Resting minute ventilation increased while PaCO2 decreased (4 Torr) following domperidone administration (0.5 mg/kg, I.V.) in carotid body intact goats. This response did not occur in carotid body denervated goats supporting the hypothesis that endogenous dopamine provides tonic inhibition in the carotid body. Hypoxic and hypercapnic ventilatory responses were significantly augmented following domperidone administration in the carotid body intact goats. This supports the concept of dopaminergic modulation of the response of the carotid body to stimuli. Domperidone allows study of carotid chemoreceptor dopaminergic activity in awake animals because of its high affinity for carotid body D2 dopamine receptors and its lack of CNS effects.

Pharmacological evidence that human intralobar airways do not contain different receptors that mediate contractions to leukotriene C4 and leukotriene D4.

Contractile responses to leukotriene (LT)C4, LTD4 and LTE4 were examined in intralobar airways from human lung obtained after surgical resection. In addition, the ability of the LT receptor antagonist FPL55712 to antagonize responses to LTC4 and LTD4 was quantified (by calculating -log molar KB values) under experimental conditions designed to minimize metabolic transformation of the LTs. In the absence of drug pretreatment, the three peptide LTs were approximately equipotent and produced similar maximum degrees of contraction. L-Serine borate complex, 45 mM, used as an inhibitor of the degradation of LTC4 to LTD4 by the enzyme gamma-glutamyl transpeptidase, in paired airway segments (adjacent segments from the same branch), produced a small degree (about 3-fold) of shift to the right of the dose-response curve and reduction of the maximum response to LTC4. L-Cysteine, 3 mM, used as an inhibitor of the degradation of LTD4 to LTE4 by the enzyme aminopeptidase, in paired segments, did not alter the dose-response effects of LTD4 or appear to further alter the dose-response effects of LTC4 when applied together with L-serine borate complex in unpaired (nonadjacent) segments. The -log molar KB value for FPL55712 (about 6) was similar for antagonism of responses to both LTC4 and LTD4 in the absence or presence of treatment with the metabolic inhibitors L-serine borate complex, L-cysteine or a combination of the two treatments. The results suggest that inhibition of the enzymes involved in the pathway from LTC4 to LTE4 has little consequence in human airways because the three peptide LTs are approximately equipotent.(ABSTRACT TRUNCATED AT 250 WORDS)

Relaxation of isolated guinea pig trachea, bronchi and pulmonary arteries produced by vasoactive intestinal peptide (VIP).

Vasoactive intestinal peptide (VIP) relaxed isolated guinea pig airways contracted with carbamylcholine and isolated pulmonary arteries contracted with prostaglandin F2 alpha. VIP was more potent as a relaxant agonist on trachea than on bronchi but was equipotent on the main and branch pulmonary artery. The VIP-induced relaxation of either airway or artery segments was not altered by pretreatment of animals with reserpine or pretreatment of isolated tissues with propranolol, metiamide, indomethacin or theophylline. These results are consistent with a direct relaxant effect by VIP in guinea pig lung.

Changes in lung membrane diffusing capacity for oxygen produced by halothane.

The effect of halothane on membrane diffusing capacity for O2 (DMO2) was measured in isolated left lower lobes of dog lungs using the sodium dithionite method. At 25 degrees C, halothane reduced DMO2 according to the regression equation: per cent control DMO2 = -4.85(per cent halothane) + 97.5 (r = -0.55, P = 0.0007). Although DMO2 was reduced from control by halothane administration, lung volume (VL) increased at higher halothane concentrations and tended to restore DMO2 by increasing surface area. There was a better correlation between the DMO2/VL ratios and per cent halothane: per cent (DMO2/VL) = -5.76 (per cent halothane) + 95.6 (r = -0.65, P = 0.00003). Effects of halothane on DMO2 and VL were reversible and were not influenced by gas mixing efficiency since argon dilution half-times over two decades were unchanged by halothane. It is unlikely that altered vascular recruitment affected the measured DMO2 since resistance to blood flow was unchanged. We conclude that halothane decreases DMO2 by either decreasing the physical diffusion coefficient (D') for O2 or decreasing the effective O2 solubility (alpha), or both, in the alveolar-capillary membrane.

Pharmacology and use of muscle relaxants in infants and children.

Succinylcholine is a short-acting depolarizing neuromuscular blocker used to facilitate intubation; pancuronium is a longer-acting, nondepolarizing agent commonly employed to control ventilation in pediatric patients. The neuromuscular block produced by both drugs may be modified by patient age, acid-base and electrolyte status, body temperature, and drugs such as aminoglycoside antibiotics; adjustment in dose or in technique of administration may be required. Cardiovascular side-effects, primarily arrhythmias, are occasionally associated with the use of either agent. In contrast to that of succinylcholine, the paralysis from pancuronium is pharmacologically reversible with the combination of atropine and neostigmine.

Left ventricular function during aortic surgery.

Fourteen patients undergoing surgery for aneurysm or occlusive disease of the abdominal aorta were studied. Thirteen patients had a history of hypertension or myocardial infarction; two patients had chronic obstructive pulmonary disease. Tachycardia, hypertension, and elevated pulmonary artery occluded. (PAo) pressure occurred in response to laryngoscopy and intubation in two patients; elevation of PAo pressure in response to aortic cross-clamping occurred in two patients. In three of these four patients, electrocardiographic evidence of myocardial ischemia appeared. These events are important in a consideration of the occurence of myocardial infarction in patients undergoing abdominal aortic surgery. Satisfactory treatment of myocardial ischemia has been accomplished with the use of propranolol hydrochloride and sodium nitroprusside.

Distribution of ventilation-perfusion ratios in dogs with normal and abnormal lungs.

We have recently described a new method for measuring distributions of ventilation-perfusion ratios (VA/Q) based on inert gas elimination. Here we report the initial application of the method in normal dogs and in dogs with pulmonary embolism, pulmonary edema, and pneumonia. Characteristic distributions appropriate to the known effects of each lesion were observed. Comparison with traditional indices of gas exchange revealed that the arterial PO2 calculated from the distributions agreed well with measured values, as did the shunts indicated by the method and by the arterial PO2 while breathing 100 per cent 02. Also the Bohr dead space closely matched the dispersion of ventilation in realtion to VA/Q. Assumptions made in the method were critically evaluated and appear justified. These include the existence of a steady state of gas exchange, an alveolar-end-capillary diffusion equilibration, and the fact that all of the observered VA/Q inequality occurs between gas exchange units in parallel. However, theoretical analysis suggests that the method can detect failure of diffusion equilbration across the blood-gas barrier should it exist. These results suggest that the method is well-suited to clinical investigation of patients with pulmonary disease.

Continuous distributions of ventilation-perfusion ratios in normal subjects breathing air and 100 per cent O2.

A new method has been developed for measuring virtually continuous distributions of ventilation-perfusion ratios (V(A)/Q) based on the steadystate elimination of six gases of different solubilities. The method is applied here to 12 normal subjects, aged 21-60. In nine, the distributions were compared breathing air and 100% oxygen, while in the remaining three, effects of changes in posture were examined. In four young semirecumbent subjects (ages 21-24) the distributions of blood flow and ventilation with respect to V(A)/Q were virtually log-normal with little dispersion (mean log standard deviations 0.43 and 0.35, respectively). The 95.5% range of both blood flow and ventilation was from V(A)/Q ratios of 0.3-2.1, and there was no intrapulmonary shunt (V(A)/Q of 0). On breathing oxygen, a shunt developed in three of these subjects, the mean value being 0.5% of the cardiac output. The five older subjects (ages 39-60) had broader distributions (mean log standard deviations, 0.76 and 0.44) containing areas with V(A)/Q ratios in the range 0.01-0.1 in three subjects. As for the young subjects, there was no shunt breathing air, but all five developed a shunt breathing oxygen (mean value 3.2%), and in one the value was 10.7%. Postural changes were generally those expected from the known effects of gravity, with more ventilation to high V(A)/Q areas when the subjects were erect than supine. Measurements of the shunt while breathing oxygen, the Bohr CO(2) dead space, and the alveolar-arterial oxygen difference were all consistent with the observed distributions. Since the method involves only a short infusion of dissolved inert gases, sampling of arterial blood and expired gas, and measurement of cardiac output and minute ventilation, we conclude that it is well suited to the investigation of pulmonary gas exchange in man.