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Biomedical subjects

S M Muldoon

Publications and source records attributed to S M Muldoon.

At least 37 records · Page 2Linked to original sources
PubMed1993

Effects of halothane on EDRF/cGMP-mediated vascular smooth muscle relaxations.

BACKGROUND: Halothane has been reported to inhibit endothelium-dependent relaxation in a variety of vessels. These studies were done to determine whether this inhibition is caused by interference with synthesis, release, or action of endothelium-derived relaxing factor (EDRF) on cyclic guanosine monophosphate (cGMP) levels within the vascular smooth muscle. METHODS: Rat aortic rings were suspended in aerated Krebs solution (37 degrees C) and were contracted to a stable plateau with EC60-70 norepinephrine (NE). Relaxations caused by acetylcholine (ACh; 1 x 10(-8)-1 x 10(-6) M), nitric oxide (NO; 5 x 10(-9)-1 x 10(-6) M), or nitroglycerin (NG; 2 x 10(-9)-3 x 10(-7) M) in rings contracted with NE were compared in the presence and absence of halothane. Tissue cGMP contents were measured using a radioimmunoassay method. RESULTS: In the presence of halothane (0.5, 1.0, and 2.0 MAC), the ACh-induced relaxations were significantly attenuated in a concentration-dependent manner, an effect that was reversible. Halothane (2 MAC) significantly attenuated NO-induced relaxations at all concentrations and NG-induced relaxations at low concentrations (5 x 10(-9)-3 x 10(-8) M) but not at higher concentrations (1 x 10(-9)-3 x 10(-7) M) in denuded vessels. Nitric oxide-stimulated (5 x 10(-8)-5 x 10(-6) M) cGMP content was significantly attenuated by halothane (2 MAC) at NO concentrations between 1 x 10(-7) and 5 x 10(-6) M. CONCLUSIONS: Nitric oxide, either endogenous or exogenous, interacts with the enzyme guanylate cyclase to stimulate the production of cGMP. Halothane interfered with the relaxations caused by NO (in rings without endothelium) and decreased the NO-stimulated cGMP content. These results suggest that the site of action of halothane in attenuating endothelium-dependent relaxation in the rat aorta is within the vascular smooth muscle, rather than on the synthesis, release, or transit of the EDRF from the endothelium and that its action may involve an interference with guanylate cyclase activation.

Animals↗
PubMed1992

Neurovascular effects of reactive oxygen intermediates produced by photoradiation.

These experiments examined the effect of reactive oxygen intermediates, produced by laser illumination of the photosensitizer hematoporphyrin derivative, on the accumulation and release of norepinephrine from sympathetic nerve terminals. Using an isolated, spirally cut, superfused caudal artery of the rat, basal overflow of norepinephrine (NE) was significantly increased both during and after generation of reactive oxygen intermediates. Generation of reactive oxygen intermediates increased overflow of NE in vascular preparations in which release of NE had previously been elevated by the continuous superfusion of Krebs' solution, containing high concentrations of potassium (40 mM). Calcium free solutions did not block the overflow of norepinephrine augmented by reactive oxygen intermediates. This increase in overflow was due both to an increase in release of NE and an inhibition of accumulation of NE.

Animals↗
PubMed1991

Vascular interactions of calcium and reactive oxygen intermediates produced following photoradiation.

This study was designed to examine vascular smooth muscle contractile properties following enhanced production of reactive oxygen intermediates (ROIs), which were produced by pretreating rat caudal arteries and aortas with a photosensitizer, hematoporphyrin derivative, and then illuminating them with red laser light. This treatment produced a long-lasting contraction that was dependent on the presence of extracellular calcium. Reduction in extracellular calcium relaxed the smooth muscle and replacement of calcium 30 min later increased the tension. Oxygen radical scavengers did not block the contractile effect postillumination when calcium was returned to the bathing solution; however, verapamil (5.5 microM) and nifedipine (10 microM) attenuated this contraction. The contractions were dependent on oxygen in the aerating gas mixture. Production of ROIs by isolated blood vessels was supported biochemically by a significant increase in both bath and tissue levels of oxidation products, reactive with thiobarbituric acid, and by a reduction in the tissue stain, nitroblue tetrazolium. These ROI-induced contractions were observed in vitro on large conduit arteries and also in vivo on small ear arteries. The vascular response following this acute production of ROIs may be similar to vascular abnormalities in certain pathological conditions where ROI production is reported to be elevated. Therefore, these results could contribute to a further understanding of mechanisms involved in these ROI-dependent vascular changes.

Animals↗
PubMed1991

Effects of bufalin on norepinephrine turnover in canine saphenous vein.

Abundant experimental data suggest that an endogenous digitalislike factor is responsible for some essential hypertension. Some forms of hypertension have also been associated with increased levels of catecholamines. We therefore designed experiments to investigate the role of digitalislike factors in the regulation of norepinephrine turnover in the neurovascular junction. We chose bufalin, an amphibian-derived compound that shares many of the physiological properties postulated as characteristic of digitalislike compounds, as a model of the mammalian compound. In vitro experiments in canine saphenous veins showed that, in addition to inhibiting norepinephrine uptake, bufalin increased norepinephrine overflow by an amount larger than could be explained solely by uptake inhibition. The effect of bufalin on norepinephrine overflow is inhibited by tetrodotoxin, which suggests a dependence of this response on Na+ influx through the neuronal membranes. We propose that Na+,K(+)-ATPase inhibition resulting in neuronal depolarization is responsible for the augmented norepinephrine turnover caused by bufalin and that these indirect effects of norepinephrine on the cardiovascular system may play a role in the etiology of hypertension.

Animals↗
PubMed1990

Evidence that barbiturates inhibit antigen-induced responses through interactions with a GTP-binding protein in rat basophilic leukemia (RBL-2H3) cells.

Little is known about the mechanism of action of anesthetics at the biochemical level. The present work, however, gives evidence that barbiturates inhibit inositol phospholipid hydrolysis in both intact and permeabilized rat basophilic leukemia (RBL-2H3) cells by an effect on GTP-binding proteins (G-proteins). Inhibition of hydrolysis was observed when intact cells were stimulated with antigen (DNP24 BSA) or with oligomers of IgE. The inhibition was dependent on the concentration and type of barbiturate used with an order of inhibitory action of secobarbital less than S(-) pentobarbital less than pentobarbital less than R(+) pentobarbital less than phenobarbital. The relatively inactive analogue, (1'RS, 3'SR) 3-hydroxypentobarbital caused little (less than 30% at 1 mM) or no inhibition (at 0.1-0.5 mM). In permeabilized cells, the hydrolysis induced by DNP24 BSA and the nonhydrolyzable analogue of GTP, GTP gamma S (2-100 microM), was also inhibited by pentobarbital. The inhibition of hydrolysis was decreased as pH increased, and was no longer apparent at pH 7.8, a possible indication that the inhibitory effect was due to the unionized form of the drug. In permeabilized cells, the inhibition by pentobarbital occurred in the presence or absence of Ca2+ and was uncompetitive in nature (Km = 7.1 microM for GTP in controls vs. 1.6 microM in the presence of 0.5 mM pentobarbital). Taken together, the data suggest that barbiturates alter the activity of G-proteins independently of Ca2+, and the inhibition may depend on both the hydrophobic properties and the stereospecific and structural features of the molecule.

Animals↗
PubMed1989

Inhibition of inositol phospholipid hydrolysis in endothelial cells by pentobarbital.

Barbiturates alter cardiovascular function, in part by an effect on vascular cells. However, a biochemical mechanism for the effect is unknown. We have, therefore, studied the effect of barbiturates on inositol phospholipid hydrolysis in cultured rat aortic endothelial cells. Hydrolysis was stimulated by angiotensin II, norepinephrine and phenylephrine. Pentobarbital, and other barbiturates, inhibited hydrolysis at pharmacological and clinical concentrations (0.1-0.5 mM). The inhibition by pentobarbital was concentration-dependent, reversed by washing, and was decreased by high concentrations of angiotensin II. Kinetic studies gave an apparent Km of hydrolysis by angiotensin II of 1.2 nM, which showed mixed inhibition by pentobarbital (Ki = 0.45 mM). Schild analysis of data obtained from pentobarbital inhibition curves also showed a deviation from a competitive type inhibition. [125I]Angiotensin II was bound to a high-affinity receptor (Kd = 1.2 nM), which showed a competitive type inhibition of binding by pentobarbital (0.5 mM). Although inhibition of [125I]angiotensin II binding appeared to be competitively inhibited by pentobarbital, the data, taken together, point to a deviation from a simple competitive type inhibition.

Angiotensin II↗
PubMed1989

Contractile properties of isolated vascular smooth muscle after photoradiation.

The purpose of this study was to characterize the responses of various types of vascular smooth muscle to conditions that would be encountered during photodynamic therapy, namely laser illumination of photosensitizer-pretreated tissue. Vascular smooth muscle obtained from representative canine, rodent, and rabbit vascular beds was cut into rings and placed in organ baths (37 degrees C, aerated with 95% O2-5% CO2). These vessels were pretreated for 30 min with the photosensitizer hematoporphyrin derivative (HpD, 3-30 micrograms/ml) washed, and then exposed to red laser light (633 nm, 1-3.5 mW) for up to 20 min. Under basal tension conditions laser illumination of HpD-pretreated vessels resulted in an increase in tension, whereas laser illumination of vessels not exposed to HpD did not contract. This sustained contraction was not reversed by washing the tissue with fresh Krebs-Ringer solution. Responses to norepinephrine, transmural electrical stimulation, and elevated concentrations of KCl were reduced in blood vessels tested after HpD laser illumination. Laser-induced contractions of canine carotid arteries did not require the presence of an intact vascular endothelium. Vascular effect of these photosensitizers appears to involve the formation of oxygen-derived radicals. This preparation could provide a good model for examining the effects of free radicals on vascular physiology.

Animals↗
PubMed1988

Adrenergic nerve function and contractile activity of the caudal artery of the streptozotocin diabetic rat.

The adrenergic nerve function and contractile responses of the densely innervated caudal artery of the 8-week streptozotocin (SZ) (65 mg/kg i.p.) diabetic rat were investigated. Segments of this artery were removed from diabetic and control rats, placed in Krebs-filled tissue baths (37 degrees C) and isometric tension recorded. Contractile responses to sympathetic nerve activation by electrical stimulation and to cumulative concentrations of norepinephrine (NE) and tyramine were recorded. In order to determine NE content, the NE was extracted from the caudal artery, isolated by adsorption chromatography, and quantified by HPLC with electrochemical detection. NE accumulation and release were also studied by quantifying the amount of tritiated NE [( 3H]NE) and its metabolites in extracts of the tissue or incubation medium. The responses of the caudal artery of SZ diabetic rats to electrical stimulation (4-16 Hz) and to tyramine (1 X 10(-5)-1 X 10(-4) M) were significantly less than those of arteries from control rats and the NE content reduced by 41%, while sensitivity to NE was unchanged. Diabetic arteries also accumulated and released more [3H]NE than did arteries from control rats. These results establish that neurovascular function of the isolated caudal artery of the 8-week SZ diabetic rat is abnormal and suggest that problems in the ability of adrenergic nerves to store and release NE may contribute to this dysfunction. Such changes may play a role in the cardiovascular disturbances associated with diabetic autonomic neuropathy.

Adrenergic Fibers↗
PubMed1988

Attenuation of endothelium-mediated vasodilation by halothane.

To determine whether halothane alters endothelium-mediated vasodilation of vascular smooth muscle, isolated ring preparations of rabbit aorta and canine femoral and carotid arteries were suspended for isometric tension recordings in Krebs-Ringer bicarbonate solution at 37 degrees C. Acetylcholine and bradykinin have been shown to relax these norepinephrine contracted arteries via an endothelium-dependent process. In this study, these relaxations were reversibly and significantly attenuated by 2% halothane. However, halothane did not affect relaxations caused by nitroglycerin, which, in these vessels, acts by an endothelium independent mechanism. These results suggest that halothane is not interfering with cyclic guanylate-monophosphate mediated relaxation of vascular smooth muscle, but may interfere with the synthesis, release, or transport of the endothelium-derived relaxing factor. In addition, during contractions evoked by norepinephrine, halothane caused significant decreases in tension in both the canine carotid and rabbit aortic preparations, but increased tension in the femoral artery rings. These effects were not altered by mechanical removal of the endothelium. These results suggest a direct action of halothane on the vascular smooth muscle, which can result in either an increase or decrease in tension, depending on the specific vessel. In addition to its direct vascular effect, this study suggests a new action of halothane; it interferes with endothelium-derived relaxing factor-mediated relaxation of vascular smooth muscle. This action may contribute in part to the vascular alterations seen clinically during administration of halothane.

Animals↗
PubMed1988

Pressor effect of nalbuphine in hemorrhagic shock is dependent on the sympathoadrenal system.

Nalbuphine, an analgesic with opiate agonist and antagonist properties, increases heart rate, mean arterial pressure (MAP), and cardiac function following a moderate hemorrhage in the rat. The interaction between opiate receptors and the sympathoadrenal system was examined in control, beta receptor-blocked, and adrenal-demedullated animals. MAP and heart rate were measured continuously in chronically instrumented conscious animals. Hemorrhage decreased MAP in the control group by 50%, and nalbuphine (1 mg/kg) returned this to prehemorrhage values within 5 min. MAP remained significantly greater in the nalbuphine-treated animals for 120 min. Heart rate fell with hemorrhage and increased above prehemorrhage values in the nalbuphine-treated animals. The pressor response to nalbuphine was abolished in both beta-blocked and adrenal-demedullated animals. Plasma catecholamines were not significantly elevated in the nalbuphine-treated as compared to control animals, which suggests that nalbuphine effects do not result from an enhancement of central mediated sympathoadrenal discharge. The opiate receptor antagonist naloxone, in a concentration that was not by itself effective in alleviating the hypotensive effects of hemorrhage, prevented the pressor response with nalbuphine. These results suggest that nalbuphine's beneficial effects in hemorrhagic shock depend on an intact sympathoadrenal system and on an interaction with opiate receptor sites, possibly in the heart.

Adrenal Medulla↗
PubMed1987

Calcium uptake in frozen muscle biopsy sections compared with other predictors of malignant hyperthermia susceptibility.

The frozen-section Ca45 uptake procedure of Mabuchi and Sreter has been applied to 51 frozen human muscle biopsies previously tested for halothane and for caffeine contracture responses. In preliminary tests with cat muscle, uptake varied with skeletal muscle fiber type, was absent from smooth muscle, and was blocked by agents which damage or extract sarcoplasmic reticulum. In the human biopsies, however, the calcium uptake values showed no significant correlation with any of the following parameters: time of frozen-biopsy storage up to 5 yr; fiber type distribution; positive versus negative response in the halothane contracture test; positive versus negative response in the caffeine contracture test; positive versus negative response in the combined halothane/caffeine contracture test; and presence of a documented clinical episode of malignant hyperthermia. In contrast, a positive halothane or caffeine contracture test each correlated highly with the presence of a prior clinical episode. We conclude that the evidence fails to support the use of the Ca45 uptake procedure in frozen sections of skeletal muscle biopsies as a valid indicator of malignant hyperthermia susceptibility.

Animals↗
PubMed1987

Plasma histamine and catecholamine levels during hypotension induced by morphine and compound 48/80.

Histamine receptors are present in adrenergic terminals, and histamine is reported to inhibit release of the neurotransmitter norepinephrine (NE) at certain neuroeffector junctions. However, a physiological role for histamine in modifying adrenergic neurotransmission has not been established. To examine the interaction of elevated plasma histamine and catecholamine release, two compounds that release histamine, morphine (3 mg/kg), and compound 48/80 (0.5 mg/kg), were administered intravenously (i.v.). Plasma norepinephrine (NE) levels were used to monitor sympathetic nervous system activity, and plasma epinephrine (Epi) levels were used to monitor adrenal activity. Both morphine and compound 48/80 caused an immediate and marked increase in plasma histamine. Simultaneous with this increase, a marked decrease in mean arterial pressure occurred. Plasma NE levels increased in animals administered compound 48/80, but in morphine-treated animals, plasma NE levels did not change from pretreatment values. Plasma Epi levels increased in both groups, but the magnitude and duration of the responses differed. The results indicate that elevated plasma catecholamines can increase in response to histamine-induced hypotension but this effect can be suppressed by the central actions of morphine.

Animals↗
PubMed1986

Neurovascular function in the rat during pregnancy.

Activity of the vascular neuroeffector junction was examined in pregnant (PG) and nonpregnant (NPG) rats to determine whether changes could account for the reported alterations in sympathetic control of the maternal circulation. Caudal and mesenteric arteries were removed from NPG and 19-21 day PG rats and prepared for isometric tension recording. Frequency-response measurements were obtained, followed by norepinephrine (NE) and tyramine concentration-response measurements. The caudal artery developed more tension in response to NE, tyramine, and electrical stimulation than did the mesenteric artery; however, there were no differences between vessels from NPG and PG rats. NE content, [3H]NE accumulation, and effects of plasma on [3H]NE accumulation of NPG and PG caudal arteries were also compared and found to be similar. Therefore, vascular neuroeffector functions of NE release, receptor sensitivity, and NE accumulation are not modified in the rat during pregnancy. Changes in sympathetic control of the maternal circulation are likely to be dependent on alterations at sites other than the neuroeffector junction.

Animals↗
PubMed1986

Verapamil and zero Ca2+ alter responses of cat muscle to halothane and caffeine.

Strips of soleus (slow twitch, oxidative) and gracilis (fast-twitch, glycolytic) muscle were obtained from 27 anesthetized cats and mounted in organ baths filled with oxygenated Krebs-Ringer solution (37 degrees C). The responses to caffeine, halothane (1%), caffeine in the presence of halothane, and electrical stimulation in the presence of halothane were examined in the two fiber types. These responses were compared with those observed in paired strips of muscle that had been treated with verapamil (10 or 28 microM), a slow calcium (Ca2+) channel blocker, with zero Ca2+, or with zero Ca2+ where magnesium (3.7 mM Ca2+) was added to replace the Ca2+. Halothane-induced contractures in the soleus were blocked by verapamil and zero Ca2+. Caffeine-induced contractures and tetanic contractions were attenuated in zero Ca2+ and by verapamil in both fiber types. Halothane overcame verapamil-induced reductions of caffeine contractures and tetanic contractions in both fiber types. In contrast, halothane did not overcome zero Ca2+-induced reductions in caffeine contractures or tetanic contractions in either fiber type. Furthermore, the addition of Mg2+ to the zero Ca2+ did not restore the responses. The findings with verapamil indicate that in cat muscle, both halothane- and caffeine-induced contractures and tetanic contractions are dependent on the influx of extracellular Ca2+. This extracellular Ca2+ may enter through the slow Ca2+ channels. However, because halothane in combination with caffeine or electrical stimulation overcame the effects of verapamil, there may be other sites involved.

Animals↗
PubMed1985

Myoadenylate deaminase deficiency and malignant hyperthermia susceptibility: is there a relationship?

Muscle biopsies from 35 patients referred for possible malignant hyperthermia were subjected to contracture testing with halothane, caffeine, and the combined agents, histopathological and fiber-type-distribution analysis, and quantitative assay of three major muscle enzymes: adenylate deaminase, adenylate kinase, and creatine kinase. Adenylate kinase and creatine kinase were in the normal range in all biopsies and each averaged 92% of expected normal value when corrected for their fiber-type distribution. Of the 14 cases with a positive halothane test, 2 had primary myoadenylate deaminase deficiency, and 5 others had low levels of this enzyme (less than one-third normal). In contrast, only 3 of 21 cases negative to halothane testing had low adenylate deaminase levels, and none were deficient. This association was significant by several statistical tests, although it would not be highly predictive for an individual case. A positive halothane test also correlated with a high type 2 fiber contribution, but this was probably secondary, since cases with low enzyme levels had significantly higher type 2 fiber areas. Caffeine contractures did not correlate with either low enzyme levels or with fiber-type distribution. Sixty percent of the biopsies were entirely normal histologically, and showed a significant correlation with a negative combined contracture test. Data on the one family included in this study suggest separate inheritance of the trait for myoadenylate deaminase deficiency and the trait for positive contracture tests. The present findings suggest that patients with myoadenylate deaminase deficiency (and the carrier state as well) may be at increased risk of malignant hyperthermia when subjected to anesthesia.

AMP Deaminase↗