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In vitro toxicity of n-hexane and 2,5-hexanedione using isolated perfused rabbit heart is reported. The hearts were perfused using Langendorf's procedure and modified Anderson's coronary perfusion apparatus. The force of cardiac contraction was significantly reduced following 1 h perfusion with 9.6 mg/l concentration of n-hexane and with 0.35% v/v concentration of 2,5-hexanedione.
The effects of amrinone on pulmonary vascular resistance (PVR) were studied in an isolated, perfused rabbit lung model where all the major determinants of PVR were controlled. In this preparation, the alveolar oxygen and carbon dioxide tensions, vascular pH and vascular oxygen and carbon dioxide tensions, and zonal conditions of the lung and phasic variations of pulmonary artery pressures could be precisely measured and controlled. Measurements of PVR were made by a complete determination of the pulmonary pressure-flow curve and determination of the PVR under identical flow conditions for all studies. This approach allowed a more precise determination of the primary effects of amrinone on normal and elevated PVR than has been previously possible. We found that amrinone in final concentrations of either 4 or 8 micrograms/ml had no effect on basal PVR and no effect on lung water weight to dry ratios. When PVR was elevated by the addition of the thromboxane A2 mimetic U46619, amrinone reduced the PVR by 27% at a final concentration of 4 micrograms/ml and by 74% at a final concentration of 8 micrograms/ml. We conclude that in the doses tested, amrinone has no effects on basal PVR but is able to reduce elevated PVR in a dose-dependent manner. These results are the first to demonstrate clearly that amrinone has the ability to reduce elevated pulmonary vascular tone through a direct mechanism and not through secondary effects on other determinants of PVR such as left atrial pressure (Pla), increased cardiac output with resultant vascular recruitment, or increases in mixed venous oxygen tension. The possible implications for the clinical use of amrinone in situations of elevated PVR are discussed.
This paper reports clinical results of hyperthermal (41.5 degrees C) isolated perfusion of the lower limb for melanoma treatments in association with cytostatic drugs (L-PAM) in 10 consecutive patients. Attention is focussed on the toxicity effects in the search for a possible correlation between the treatment variables and toxicity. Careful heat administration techniques and thorough and accurate temperature monitoring have resulted in a uniform and closely controlled temperature distribution, allowing us to approach the limiting temperature value for possible damage both of the limb tissues and of the perfusate. Care was taken to avoid perfusate overheating (42 degrees C maximum). Local toxicity was observed between grades II and III. Systemic toxicity was of insignificant level. The clinical results show that high-temperature treatments with simultaneous administration of the cytostatic are feasible with acceptable toxicity. Further clinical investigations are recommended to ascertain the efficacy of the method.
Gluconeogenesis was stimulated by glucagon in fed but not fasted isolated perfused guinea pig livers. Both the amount and the rate of incorporation of radioactivity into glucose from L-[U-14C]lactate were increased in fed livers by the addition of glucagon to the perfusate. The glucagon-stimulated increase in gluconeogenesis was accompanied by an increase in oxygen consumption, an increase in the amount of lactate carbon converted to glucose and a decrease in the amount of lactate carbon converted to CO2. The results are interpreted to indicate that glucagon affects gluconeogenesis from lactate in fed livers by redirecting the fate of substrate from other products toward glucose.
1. Vasodilator responses were elicited by field stimulation in isolated perfused segments of rabbit jejunal arteries when noradrenergic and purinergic vasoconstrictor responses had been abolished and the smooth muscle partly contracted by endothelin. 2. The stimulation-induced vasodilator responses were abolished by tetrodotoxin, but were not affected by atropine, propranolol or a nitric oxide synthase inhibitor. 3. After recovery from the vasodilator action of capsaicin, the stimulation-induced vasodilator responses were greatly reduced or abolished. 4. A competitive antagonist of calcitonin gene-related peptide (CGRP) blocked vasodilator responses elicited by field stimulation and exogenously administered CGRP. 5. The findings indicated that the mediator of the stimulation-induced vasodilator responses is neurogenic in origin, and it is not acetylcholine, noradrenaline acting on beta-adrenoceptors, nitric oxide or an endothelium-dependent vasodilator. It appears to be CGRP, presumably released from sensory nerves in the periarterial plexus.
Pressor responses to bolus injections of noradrenaline (NA) were studied, in the isolated perfused rat mesenteric arterial bed, in the presence of beta-adrenoreceptor agonists and antagonists, in an attempt to identify a possible beta-adrenoreceptor mediated modulation of catecholamine-induced vasoconstrictor effects. NA-induced responses were potentiated in the presence of timolol and (-)propranolol and suppressed in the presence of (-)isoprenaline; (+)isoprenaline was less effective against the NA-induced responses. Timolol attenuated the effects of (-)isoprenaline on NA-induced responses but not those of the stereoisomer (+)isoprenaline. It is concluded that the NA-induced pressor effect in the rat mesenteric vasculature is the net result of vasoconstrictor alpha- and vasodilator beta-adrenoreceptor activation and that the interaction of the two opposing adrenoreceptor-mediated effects represents a 'physiological antagonism'.
1. The effects of histamine on the isolated perfused hearts of guinea-pigs and rabbits were examined. Records of contractile force, heart rate and coronary perfusion pressure were obtained. 2. Histamine exerted positive inotropic and chronotropic effects which were antagonized by burimamide and attributed to stimulation of H2-receptors. 3. The coronary vascular response to histamine differed between guinea-pigs and rabbits. In guinea-pig hearts, three phases were apparent: (a) An initial vasodilatation preceding any effects on heart force and rate was antagonized by mepyramine and therefore mediated by histamine H1-receptors in the coronary circulation. (b) A secondary vasoconstriction was attributed to the increased myocardial compression during the positive inotropic and chronotropic responses. (c) The final, more predominant, component was a prolonged vasodilatation probably associated with the increased metabolic activity of the heart. 4. The latter two components were abolished together with the myocardial responses by burimamide. The remaining coronary vascular response was biphasic, consisting of a vasodilatation immediately followed by vasoconstriction. Both were antagonized by mepyramine and therefore mediated by H1-receptors. 5. The coronary vascular response of rabbit hearts was similar but no direct vasodilatation was observed and it was concluded that histamine receptors in the coronary vasculature involve only vasoconstriction.
1. In the isolated perfused, noradrenaline (NA)-constricted mesenteric arteries of the rat, acetylcholine (0.003-1 nmol), histamine (0.01-10 nmol) and the calcium ionophore A23187 (0.01-1 nmol), caused endothelium-dependent vasodilatation while the vasodilatation by the K+ channel activator BRL 34915 (0.1-1 nmol) was independent of endothelium. 2. The guanylate cyclase inhibitor, methylene blue at 10 microM did not inhibit the action of any of the vasodilators but at 50 microM reduced the vasodilator effect of acetylcholine (ACh), histamine and A23187. 3. Infusion of ouabain or perfusion with K(+)-free or excess K+ (50 mM) Krebs solution reduced the vasodilator effect of ACh, histamine and A23187, suggesting the action of these agents involves, at least in part, activation of Na+/K(+)-ATPase. The vasodilator effect of BRL 34915 was not affected by ouabain, but abolished during perfusion with Krebs solution containing excess K+ or depleted of K+. 4. Five structurally distinct K+ channel blockers (apamin, crude scorpion venom, procaine, quinidine and tetraethylammonium) attenuated the vasodilator effect of ACh, histamine and A23187. The K+ channel blockers, except apamin and crude scorpion venom, also inhibited the vasodilatation produced by BRL 34915. 5. The vasodilator effect of ACh, histamine or A23187 was not altered in mesenteric vessels of pertussis toxin-treated rats, suggesting that the K+ channels associated with the endothelium-dependent vasodilator effect of these agents are either not coupled to G-proteins or are coupled to G-proteins that are insensitive to pertussis toxin. 6. The calcium channel blockers, diltiazem (0.1 or 1 microM), nifedipine (0.01 or 0.1 microM) or nitrendipine (1 nM) attenuated the vasodilatation produced by ACh, histamine, A23187 and also that by BRL 34915. 7. We conclude that endothelium-dependent vasodilatation induced by ACh, histamine and A23187 is mediated via activation of membrane K+ channels and Na+/K+-ATPase. The K+ channels involved in the vasodilator action of these agents are not coupled to pertussis toxin-sensitive G-proteins and appear to be regulated by Ca2 +.
We have investigated the disposition of dapsone (DDS, 1 mg) in the rat isolated perfused liver in the absence and the presence of cimetidine (3 mg). After the addition of DDS alone to the liver there was a monoexponential decline of parent drug concentrations and rapid formation of DDS-NOH (within 10 min) which coincided with methaemoglobin formation (11.7 +/- 3.0%, mean +/- s.d.) which reached a maximum (22.6 +/- 9.2%) at 1 h. The appearance of monoacetyl DDS (MADDS) was not apparent until 30-45 min. Addition of cimetidine resulted in major changes in the pharmacokinetics of DDS and its metabolites. The AUC of DDS in the presence of cimetidine (1018.8 +/- 267.8 micrograms min mL-1) was almost three-fold higher than control (345.0 +/- 68.1 micrograms min mL-1, P less than 0.01). The half-life of DDS was also prolonged by cimetidine compared with control (117.0 +/- 48.2 min vs 51.2 +/- 22.9, P less than 0.05). The clearance of DDS (3.0 +/- 0.55 mL min-1) was greatly reduced in the presence of cimetidine (1.03 +/- 0.26 mL min-1 P less than 0.01). The AUC0-3h for DDS-NOH (28.3 +/- 21.2 micrograms min mL-1) was significantly reduced by cimetidine (8.1 +/- 3.40 micrograms min mL-1, P less than 0.01). In contrast, there was a marked increase in the AUC0-3h for MADDS (32.7 +/- 25.8 micrograms min mL-1) in the presence of cimetidine (166.0 +/- 26.5 micrograms min mL-1 P less than 0.01). The methaemoglobinaemia associated with DDS was reduced to below 5% by cimetidine. Hence, a shift in hepatic metabolism from bioactivation (N-hydroxylation) to detoxication (N-acetylation) caused by cimetidine, was associated with a fall in methaemoglobinaemia. These data suggest that the combination of DDS with a cytochrome P450 inhibitor might reduce the risk to benefit ratio of DDS.
The actions of gastric inhibitory polypeptide (GIP) on insulin release from the isolated perfused rat pancreas were compared with those of pure secretin and cholecystokinin (CCK). At dose levels physiologically achievable for GIP (1 ng/mL perfusate), infusions of CCK stimulated significant insulin release both on a weight (1 ng/mL) and a molar (770 pg/mL) basis. Although 50% as potent as GIP on a weight basis and 43% as potent on a molar basis, the insulin response to CCK was multiphasic and sustained for the duration of the infusion. The action of CCK, like that of GIP, was glucose dependent yielding no significant insulin release at a low perfusate glucose concentration (80 mg/dL). Irrespective of perfusate glucose concentration or dose (1 or 5 ng/mL), secretin failed to stimulate significant release of insulin from the perfused pancreas. It was concluded that secretin is ineffective as an incretin and that a physiological role for CCK in an enteroinsular axis awaits accurate measurement of circulating levels of immunoreactive CCK.
The secretion of somatostatin-like immunoreactivity (SRIF-LI) by the isolated perfused rat stomach was studied in response to stimulation by catecholamines. Gastric SRIF-LI secretion was significantly stimulated in a dose-dependent manner by norepinephrine at 10(-6) and 10(-8) M, and the effect of norepinephrine (10(-8) M) was attenuated by the addition of propranolol (10(-6) M) but not of phentolamine (10(-6) M). SRIF-LI secretion was also stimulated by dopamine at concentrations of 10(-4) and 10(-6) M but not at 10(-8) M. The effect of dopamine (10(-6) M) was not altered by the addition of haloperidol (10(-4) to 10(-7)) or metoclopramide (10(-4) M), and bromocriptine (10(-6) M) was without effect on SRIF-LI secretion. These results suggest that gastric SRIF-LI secretion is stimulated by a beta-adrenergic mechanism and raise the possibility that gastric somatostatin contributes to the inhibitory effect of norepinephrine on gastric acid secretion.
Effects of prostaglandins on coronary arterial smooth muscle were studied in isolated perfused cat coronary arteries. This preparation was shown to be responsive to known vasoactive agents, including angiotensin II, adenosine, and norepinephrine. Prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha) produced dose-dependent coronary arterial constriction at concentrations of 3 times 10(-9) M or greater. PGE1 produced a biphasic dose-response curve with constriction at low concentrations greater than 10(-7) M.PGI2 dilated coronary arteries at concentrations greater than 10(-8) M. Inhibition of endogenous prostaglandin synthesis with meclofenamate potentiated responses to prostaglandins. The endoperoxide, PGH2, slightly constricted cat coronary arteries. However, in the presence of human platelet microsomes, PGH2 was converted to thromboxane A2(TxA2), which was the most potent coronary artery constrictor among the naturally occurring compounds studied. Analysis of coronary artery perfusate for TxB2 confirmed the thromboxane generation, which was markedly lower in the presence of imidazole. Two synthetic endoperoxide analogs produced potent coronary arterial constriction. Induction of hypoxia to a PO2 of 50 mmHg or increasing basal tome with 30 mM KCl did not diminish coronary artery response to prostaglandins, suggesting that prostaglandins released from ischemic myocardial tissue may influence coronary arterial tone.
There is a sudden release of intracellular constituents upon reoxygenation of isolated perfused hypoxic heart tissue (O2 paradox) or on perfusion with calcium-free medium after a period of hypoxia. Rat hearts were perfused by the method of Langendorff (Pfluegers Arch. 61: 291-332, 1895) with Krebs-Henseleit medium containing 10 mM glucose. Hearts were equilibrated for 30 min, followed by 90 min of hypoxia or 60 min of hypoxia and 30 min of reoxygenation. The massive enzyme release observed upon reoxygenation after 60 min of hypoxia was prevented by infusing 0.5 or 5 mM cyanide 5 min before reoxygenation. Lactate dehydrogenase (LDH) release commenced immediately upon withdrawal of cyanide. Hearts perfused with calcium-free medium throughout hypoxia did not release increased amounts of LDH at reoxygenation. Perfusing heart tissue with medium containing 0 or 25 microM calcium, but not 0.25 or 2.5 mM, after 50 min of hypoxia initiated a release of cardiac LDH, which was not further enhanced by reoxygenation. Enzyme release was significantly inhibited when the calcium-free perfusion medium included 10 mM 2-deoxyglucose (replacing glucose), 0.5 mM dinitrophenol, or 2.5 mM cyanide. Histologically, hearts perfused with calcium-free medium after 50 min of hypoxia showed areas of severe necrosis and contracture without any evidence of the contraction bands that were seen in hearts reoxygenated in the presence of calcium. Cardiac ATP and creatine phosphate (PCr) levels were significantly decreased after 50-60 min of hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
We obtained 202.5-MHz 31P-nuclear magnetic resonance (NMR) spectra of isolated perfused rat lungs, degassed and inflated, and of lung extract. The spectra included those of ATP, ADP, phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters, phosphodiesters, and a broad component due to the membrane phospholipids. The line width at one-half peak height for beta-ATP was 1.0 ppm for the degassed lung and 1.2 ppm for the inflated lung. This suggests that the air-water interfaces in inflated lung, which produce proton NMR line broadening, do not act prominently in 31P-NMR spectroscopy. In a degassed lung, when perfusion was stopped for up to 30 min, PCr and ATP peaks decreased progressively with time while Pi and phosphomonoester peaks increased. On return of flow, these changes reversed. The intracellular pH values calculated from the difference in magnetic field between PCr and Pi peaks of inflated and degassed lungs were 7.16 +/- 0.10 (SD; n = 4) and 6.99 +/- 0.10 (n = 4), respectively. The change of intracellular pH caused by 30 min of ischemia was -0.2 pH units. Our findings indicate that air-water interfaces should not broaden lung 31P peaks in vivo.
Dimethylacetamide (DMAc) is a skin-penetrating solvent able to induce hepatic damage after chronic exposure. Previous research has indicated that metabolism may be saturated at its present TLV/TWA (10 ppm). Biological monitoring of monomethylacetamide (MMAc), the primary metabolite of DMAc, might therefore underestimate exposure to DMAc and related health hazards. We used the recirculating perfusion technique in isolated rat liver to evaluate DMAc metabolism. Medium concentrations starting at about 30, 50, 100 and 275 microM, respectively, were tested. Perfusate samples were taken regularly and analysed for DMAc; pharmacokinetic parameters (extraction ratio and clearance) were calculated for each perfusion. Inlet DMAc concentrations were calculated and concentration groups divided in 16, 36, 70, 160, 225 microM. The extraction ratio of the 16 microM group differed significantly from the other concentration groups tested. DMAc metabolism was saturated at a DMAc concentration of 36 microM. Extraction ratios were unaffected when cimetidine, an inhibitor of cytochrome P450 activity, was added to the perfusion medium or when cimetidine-pretreated animals were used. DMAc clearance was 2.20 ml min-1 at a medium concentration of about 36 microM. Extrapolation of the observed (rat) liver clearance to man showed that airborne concentrations of 18 ppm would, under the presumptions used, lead to saturated metabolism of DMAc; however, saturation at even lower concentrations could not be excluded.
Neuromedin B and neuromedin C are novel decapeptides that have recently been isolated from porcine spinal cord and canine intestinal mucosa. We have studied the effects of neuromedin B and neuromedin C on insulin release from the isolated perfused rat pancreas. The effect of neuromedin B was detectable at a concentration of 10mM, and that of neuromedin C was detectable at a concentration of 1nM. Further increase in the concentration of neuromedin B and neuromedin C resulted in dose-dependent increases in insulin secretion. The effectiveness of neuromedin B and neuromedin C as insulinotropic agents depended on the glucose concentration; both were more effective at a higher concentration of glucose. However, insulinotropic effects of these peptides in the presence of 8.3mM glucose were limited to the first 3 min of a 20-min perfusion. These results, coupled with a recent study demonstrating bombesin-like immunoreactivity in nerves in the pancreas, suggest that neuromedin B and neuromedin C exert a direct local action on insulin secretion in the pancreas.
Two novel calpain inhibitors (A-705239 and A-705253) were studied in isolated perfused rabbit hearts subjected to 60-min occlusion of the ramus interventricularis of the left coronary artery (below the origin of the first diagonal branch), followed by 120 min of reperfusion. The inhibitors were added to the perfusion fluid in various final concentrations from the beginning of the experiments before the coronary artery was blocked. Hemodynamic monitoring and biochemical analysis of perfusion fluid from the coronary outflow were carried out. Myocardial infarct size and the area at risk (transiently non-perfused myocardium) were determined from left ventricular slices after a special staining procedure with Evans blue and 2,3,5-triphenyltetrazolium chloride. The infarcted area (dead myocardium) was 77.9+/-2.3% of the area at risk in untreated controls ( n =12). The infarct size was significantly reduced in the presence of both calpain inhibitors. The best effect was achieved with 10 -8 M A-705253 ( n =8), which reduced ( p <0.001) the infarcted area to 49.3+/-3.9% of the area at risk, corresponding to an infarct reduction of 61.8%. No statistical difference was observed between the experimental groups in coronary perfusion, left ventricular pressure, and in the release of lactate dehydrogenase and creatine kinase from heart muscle.
The generation of somatomedin activity by isolated perfused livers was examined in protein-malnourished (4% casein diet) and well-nourished (controls, 20% casein diet) rats. There was significantly less somatomedin activity (measured by the porcine costal cartilage bioassay), after perfusion for 2 h, in the perfusates from the livers of malnourished rats both in hormone-free perfusates and perfusates containing hormones (10 microgram GH/ml, 1000 microunits insulin/ml or a combination of the two). A reduction in the somatomedin activity generated by the liver may be the mechanism responsible for the low serum level of somatomedin (in spite of raised or normal levels of growth hormone) in human or experimental protein malnutrition.