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M Maze

Publications and source records attributed to M Maze.

At least 109 records · Page 6Linked to original sources
PubMed1988

L-phenylisopropyladenosine (L-PIA) diminishes halothane anesthetic requirements and decreases noradrenergic neurotransmission in rats.

The effect of L-phenylisopropyladenosine (L-PIA), the A1 adenosine agonist, on the depth of anesthesia was investigated in halothane-anesthetized rats. L-PIA treatment reduced the minimum anesthetic concentration (MAC) of halothane that prevented 50% of animals from moving in response to a painful stimulus by 49%. MAC experiments performed with L-PIA given in conjunction with A1 adenosine receptor antagonists which either permeate the blood-brain barrier (8-phenyltheophylline [8-PT] or do not (8-sulphophenyltheophylline [8-So-PT]) indicate that central mechanisms are involved. Noradrenergic neurotransmission was diminished following L-PIA administration in halothane-anesthetized rats in all brain regions. These data suggest that acute L-PIA treatment decreases central noradrenergic neurotransmission and may represent the mechanism for the decrease in halothane dose to achieve an anesthetic endpoint anesthetic response to halothane.

Adenosine↗
PubMed1988

Clonidine and other alpha2 adrenergic agonists: strategies for the rational use of these novel anesthetic agents.

Clonidine and other clinically available alpha-2 adrenergic agonists reduce inhalational and narcotic anesthetic requirements while providing hemodynamic stability during stressful periods of surgery. Like the opiates, the alpha-2 adrenergic agonists are potent analgesics when given systemically, epidurally, or intrathecally. Their effects are reversed by alpha2 adrenergic antagonists. Newer and more selective alpha2 adrenergic agonists are more potent in their anesthetic action than the clinically available opiates. The important difference is that these agents do not appear to be respiratory depressants and do not have an addiction liability of the opioid type. They have anxiolytic properties and therefore can be potentially useful in the preanesthetic period. This drug class has the potential to provide many of the component effects required for perioperative care. For these reasons, the alpha2 adrenergic class of drugs should be important in the future of anesthesia.

Adrenergic alpha-Agonists↗
PubMed1988

Anesthetic and hemodynamic effects of the alpha 2-adrenergic agonist, azepexole, in isoflurane-anesthetized dogs.

The authors studied the reduction in anesthetic requirement (MAC) and the hemodynamic effects of the highly selective alpha 2-adrenergic agonist azepexole in isoflurane-anesthetized dogs. Eleven male beagles were anesthetized with isoflurane in oxygen. After a 2-h equilibration period, they determined isoflurane MAC and baseline hemodynamic function. Azepexole (at 0.1, 0.3, and 1.0 mg/kg) was administered via a right atrial port over 15 min, while each dog was given isoflurane at the MAC dose for that animal. Twenty minutes after the end of infusion, at a time when hemodynamic variables were stable, they reassessed hemodynamic function. They then determined isoflurane MAC again. In other experiments, dogs were pretreated with either idazoxan (the alpha 2-adrenergic antagonist; n = 5) or naloxone (the opiate antagonist; n = 7) prior to the administration of azepexole. Isoflurane MAC was determined before and after each dose of azepexole. Isoflurane MAC decreased as the dose of azepexole increased, to the extent that at the highest dose (1 mg/kg) the decrement in MAC was more than 85%. This reduction of MAC caused by azepexole could be completely prevented by pretreatment with idazoxan, while naloxone was without effect. Azepexole did not change mean arterial blood pressure, but caused heart rate and cardiac output to progressively decrease. The MAC-reducing effect of azepexole appears to be mediated by alpha 2 adrenoreceptors. Given the extent of the reduction of MAC, it is unlikely that inhibition of central noradrenergic neurotransmission through agonism of presynaptic alpha 2 adrenoreceptors is the sole explanation, since complete disruption of central noradrenergic tracts decreases MAC by only 40%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1988

Dexmedetomidine diminishes halothane anesthetic requirements in rats through a postsynaptic alpha 2 adrenergic receptor.

The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the alpha 2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (d-enantiomer) or levomedetomidine (l-enantiomer) 10, 30, and 100 micrograms/kg or vehicle ip. There was a dose-dependent decrease in MAC with the d-, but not the l-, stereoisomer. At the highest dose of dexmedetomidine (100 micrograms/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether alpha 2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg ip, a highly selective alpha 2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg ip, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg ip, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine (DSP-4) or reserpine and alpha-methyl-para-tyrosine and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine depleted rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Mechanism for desensitization of beta-adrenergic receptor-stimulated lipolysis in adipocytes from rats harboring pheochromocytoma.

Prolonged stimulation of beta-adrenergic receptors with catecholamines leads to desensitization of their ability to activate cAMP accumulation. However, little is known about the relationship between these changes and possible alterations in physiological responses. We have used isolated adipocytes prepared from NEDH rats harboring pheochromocytomas, a norepinephrine-secreting tumor, to address this question. As expected, there was a decrease in the ability of isoproterenol to maximally activate cAMP accumulation in adipocytes from rat harboring pheochromocytoma [323 +/- 107 vs. 707 +/- 145 pmol/10(5) cells.min (mean +/- SD) in controls]. This change was associated with an increase in the EC50 of isoproterenol for activation of cAMP-dependent protein kinase (5.8 X 10(-8) vs. 2.4 X 10(-8) M in controls) and a decrease in maximal activation of the kinase (38 +/- 16% vs. 77 +/- 14% in controls). For lipolysis there was a loss in sensitivity to isoproterenol but no change in maximal lipolytic rate in the adipocytes from rats harboring pheochromocytoma. For both groups there was a similar relationship between kinase activation and lipolysis; maximal lipolysis had already occurred for protein kinase-A activity ratios less than 30%. Therefore, the blunted cAMP response in adipocytes from rats harboring pheochromocytoma did not impair the maximal lipolytic rate. These results demonstrate that adipocytes can efficiently maintain maximal lipolysis in a desensitized state because of considerable reserve in the biochemical cascade leading to the lipolytic response. In addition, our findings demonstrate that there are no regulatory changes induced by prolonged exposure to catecholamines that are distal to cAMP accumulation.

Adipose Tissue↗
PubMed1988

Anesthetic and hemodynamic effects of the stereoisomers of medetomidine, an alpha 2-adrenergic agonist, in halothane-anesthetized dogs.

The anesthetic-sparing and hemodynamic effects of the stereoisomers of the highly selective alpha 2-adrenergic agonist medetomidine were studied in halothane-anesthetized dogs. Male beagles were anesthetized with halothane in oxygen. After a 2-hour equilibration period, halothane MAC and baseline hemodynamic functions were determined. DL-(n = 7), D- (n = 5), or L-medetomidine (n = 5) at 1, 3, and 10 micrograms/kg was administered via a right atrial port over 15 minutes while each dog was given halothane at the MAC dose for that animal. Twenty minutes after the end of infusion (when the hemodynamic variables were stable), hemodynamic function was reassessed. Halothane MAC was then redetermined. MAC for halothane significantly decreased after DL-medetomidine administration in a dose-dependent fashion to the extent that at the highest dose (10 micrograms/kg) the halothane MAC was less than 0.1%. This effect could be mimicked by the D-isomer, whereas the L-isomer was without effect. Neither isomer changed the mean arterial pressure, whereas only the D-isomer significantly decreased heart rate and cardiac output. Medetomidine, the highly selective alpha 2-adrenergic agonist, reduces the MAC for volatile anesthesia by a greater degree than with any other physiologic, pharmacologic, or pathologic intervention thus far reported. The fact that this effect is stereospecific suggests a structure activity relation that can be accounted for by a homogeneous receptor population. The role of medetomidine as a supplemental anesthetic agent appears promising and requires further investigation.

Adrenergic alpha-Agonists↗
PubMed1988

Mechanism of halothane-induced inhibition of isoproterenol-stimulated lipolysis in isolated rat adipocytes.

The effect of halothane on isoproterenol-stimulated lipolysis was determined in isolated rat epididymal fat cells. The maximal lipolytic response (Emax) activated by isoproterenol was 350 +/- 61 nmol of glycerol/10(5) cells/hr with an EC50 of 5.1 X 10(-9) M. When the adipocytes were simultaneously bubbled with 2.5% halothane, the Emax decreased to 158 +/- 43 nmol of glycerol/10(5) cells/hr and the dose response curve for isoproterenol was shifted to the right (EC50 3.5 X 10(-8) M, p less than 0.05). When lipolysis was maximally stimulated with (-)-isoproterenol (10(-6)M), the inhibitory effect of halothane was found to be both dose dependent (IC50 approximately 2.5%, v/v) and reversible following washout. Neither the nonhydrolyzable cAMP analog, 8-(4-chlorophenylthio) adenosine 3',5'-cyclic monophosphate (2 X 10(-3)M), nor forskolin (10(-6) M) was able to normalize lipolysis in the presence of halothane. The activation of cAMP-dependent protein kinase (EC 2.7.1.37) activity by isoproterenol was not different in halothane-exposed cells when compared to unexposed cells. When control adipocytes were exposed to isoproterenol (10(-6) M), there was a 2.5-fold increase in the activity of hormone-sensitive lipase (EC 3.1.1.3) from 0.64 +/- 0.13 to 1.53 +/- 0.32 pkat (pmol/sec) per mg (p less than 0.005, n = 10). However, in the presence of halothane (2.5%, v/v) isoproterenol stimulation of hormone-sensitive lipase was attenuated by 50% to values of 1.06 +/- 0.23 pkat/mg (p less than 0.01, n = 10). Halothane had no direct inhibitory effect on hormone-sensitive lipase since this enzyme's activity was unaffected when homogenates of isoproterenol-stimulated control cells were incubated with halothane. These studies suggest that halothane impairs the activation of hormone-sensitive lipase by cAMP-dependent protein kinase and in this manner inhibits beta-adrenergic-stimulated lipolysis.

Adipose Tissue↗
PubMed1987

Halothane hepatotoxicity in Fischer 344 rats pretreated with isoniazid.

Male Fischer 344 rats were used to investigate the hepatic effects of exposure to halothane under normoxic conditions (FIO2 = 0.21) in isoniazid-treated rats. Animals were treated with saline or isoniazid (50 mg/kg) for 7 days and then were exposed to either 1% halothane or air for 2 hr. One-half of the rats from each treatment and exposure group were killed 24 hr postexposure; the remaining were killed 4 days postexposure. Twenty-four hours following halothane exposure, serum transaminase levels were significantly elevated in isoniazid- compared with saline-treated rats (i.e., aspartate aminotransferase = twofold; alanine aminotransferase = seven-fold). Cholesterol levels were significantly depressed by halothane exposure in both saline- and isoniazid-treated rats. Other serum parameters indicative of hepatic and renal function were not different: alkaline phosphatase, total protein, total bilirubin, hematocrit, uric acid, creatinine, urea nitrogen, Na+, K+, Ca2+, and inorganic phosphate. Neither saline-treated nor isoniazid-treated rats exposed to air exhibited histologic evidence of hepatic damage. Halothane-exposed rats, however, showed a circumscribed disruption of cellular morphology. The most severe lesions were observed with isoniazid-treated animals with extensive pericentral hepatocellular necrosis and infiltration by leucocytes and Kupffer cells. Serum concentrations of two products of the oxidative metabolism of halothane, trifluoroacetic acid and bromide, were significantly elevated in isoniazid- compared with saline-treated rats. Serum levels of fluoride, a product of reductive metabolism, were not different. These results strongly suggest that hepatic injury following halothane administration can be produced by intermediates of oxidative metabolism.

Alanine Transaminase↗
PubMed1987

Pulmonary and systemic hemodynamic effects of central venous and left atrial sympathomimetic drug administration in the dog.

Systemic vasopressor or inotropic therapy may exacerbate existing pulmonary hypertension; the optimal agent and route of administration in this situation are unknown. The systemic and pulmonary hemodynamic effects of four sympathomimetic agents (dopamine, epinephrine, norepinephrine, and phenylephrine) during central venous and left atrial administration were investigated in the anesthetized dog. All four drugs increased both systemic and pulmonary artery pressures. Dopamine and epinephrine increased cardiac output and reduced systemic vascular resistance. Phenylephrine decreased cardiac output and increased systemic vascular resistance and left atrial pressure. Norepinephrine did not significantly affect cardiac output, systemic vascular resistance, or left atrial pressure. None of the four drugs affected pulmonary vascular resistance. The ratio of systemic to pulmonary vascular resistance decreased with epinephrine and increased with phenylephrine. There were no hemodynamic differences related to the route of infusion for any of the four drugs. However, pulmonary arterial concentrations of the three drugs measured (dopamine, epinephrine, and norepinephrine) were markedly lower during left atrial compared to central venous drug administration; systemic drug concentrations were similar or increased during left atrial compared to central venous drug administration. It is concluded that the relative effects on the systemic and pulmonary circulations differ for the four drugs; rational choice of a vasopressor will depend upon the hemodynamic situation and the desired effect. Left atrial catecholamine administration is effective in decreasing pulmonary arterial drug concentrations and may decrease adverse pulmonary effects in clinical practice.

Animals↗
PubMed1987

Role of the sympathetic nervous system in the maintenance of hypertension in rats harboring pheochromocytoma.

Hypertension due to pheochromocytoma is generally considered to be a straightforward, direct consequence of the elevated concentrations of circulating catecholamines. However, clonidine, a centrally acting antihypertensive drug, has been reported to lower blood pressure in patients with pheochromocytoma, suggesting the possibility that the sympathetic nervous system is involved in the maintenance of hypertension in this disease. We have investigated this possibility in New England Deaconess Hospital rats harboring a transplantable pheochromocytoma that secretes norepinephrine and dopamine. Both clonidine and chlorisondamine, a ganglionic blocker, markedly decreased blood pressure in tumor-bearing rats. However, in other rats made acutely hypertensive with a norepinephrine infusion, neither clonidine nor chlorisondamine decreased blood pressure. This result indicates that in an acute model of hypertension, where baroreflex mechanisms have likely withdrawn sympathetic tone, neither clonidine nor chlorisondamine had nonspecific antihypertensive effects. A central nervous system site of action for the antihypertensive effect of clonidine in the rats harboring pheochromocytoma was suggested by the observation that the opiate antagonist naloxone both reversed and prevented clonidine's effect on blood pressure. Prazosin and yohimbine were utilized to determine the respective contributions of alpha-1 and alpha-2 adrenergic receptors in the maintenance of hypertension in rats harboring pheochromocytoma. Both drugs markedly lowered blood pressure in these rats. Our data suggest that both the sympathetic nervous system and circulating catecholamines are involved in the maintenance of hypertension due to pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1986

Aminophylline shortens thiopental sleep-time and enhances noradrenergic neurotransmission in rats.

We investigated the effect of aminophylline on thiopental sleep-times and monoamine neurotransmitter turnover rates in discrete brain areas. Aminophylline-treated rats had shorter thiopental sleep-times than saline-treated controls. Noradrenergic neurotransmission was greater following aminophylline treatment in thiopental-anesthetized rats in all brain areas while turnover in other monoaminergic pathways was unchanged. These data suggest that acute aminophylline treatment increases central noradrenergic neurotransmission which pharmacodynamically diminishes the hypnotic response to thiopental.

Aminophylline↗
PubMed1986

Epinephrine arrhythmogenicity is enhanced by acute, but not chronic, aminophylline administration during halothane anesthesia in dogs.

The authors determined the effect of acute and chronic aminophylline treatment on the arrhythmogenicity of epinephrine during halothane anesthesia. The dose of epinephrine required to achieve an arrhythmia threshold (ADE) was determined in nine unpremedicated dogs anesthetized with halothane (1.5% v/v) in oxygen (A0). Aminophylline was then infused to achieve and sustain a therapeutic theophylline level (mean +/- SD) of 17 +/- 2 micrograms X ml-1 (A1), at which time the ADE was reassessed. The aminophylline infusion regimen was then adjusted to provide a supratherapeutic level of theophylline of 34 micrograms X ml-1 (A2) and the ADE was reassessed. In an additional seven dogs the ADE was assessed before and after 6 weeks of oral aminophylline treatment that yielded a plasma theophylline level of 18 +/- 3 micrograms X ml-1. The ADE was significantly (P less than 0.01) reduced from a basal value (mean +/- SD) of 2.63 +/- 0.97 micrograms X kg X -1 X min-1 to 1.39 +/- 0.47 in the A1 state. There was no further decrement in the ADE at the A2 state (1.17 +/- 0.36). The plasma epinephrine level at the arrhythmia threshold decreased commensurately from 50.7 +/- 40.2 ng X ml-1 (A0) to 20.0 +/- 7.9 and 19.2 +/- 7.6 in the A1 and A2 states, respectively (P less than 0.01). In contrast to these acute treatment experiments, neither the ADE (2.65 +/- 0.95 vs. 2.97 +/- 1.49 micrograms X kg-1 X min-1) nor the plasma epinephrine levels at the arrhythmia threshold (47.2 +/- 13.7 vs. 51.1 +/- 22.0 ng X ml-1) were different after chronic aminophylline treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophylline↗
PubMed1986

Halothane anesthetic requirements are not affected by aminophylline treatment in rats and dogs.

The authors determined the effects of aminophylline on the anesthetic requirements for halothane in rats and dogs. MAC for halothane was determined in rats (n = 24) before and after aminophylline, 100 mg X kg-1 ip, or an equal volume of saline. Because changes in central noradrenergic neurotransmission have been linked to drug-induced changes in the depth of the anesthetic state, we investigated the effect of aminophylline on the turnover of norepinephrine in discrete brain regions of halothane-anesthetized rats. To facilitate testing at steady-state aminophylline conditions and to permit frequent blood sampling, halothane MAC was determined in dogs (n = 7) before and after a therapeutic level of aminophylline (15 +/- 2 micrograms X ml-1) was obtained. Neither in the rats (1.0 vs. 1.0%) nor in the dogs (1.04 +/- 0.14 vs. 1.01 +/- 0.14%) was halothane MAC affected by aminophylline treatment. Commensurate with the lack of change of anesthetic depth, aminophylline treatment did not affect noradrenergic neurotransmission in the brain of halothane-anesthetized rats. Furthermore, the anticipated increase in circulating catecholamines following aminophylline treatment in dogs did not materialize. The authors conclude that halothane anesthetic requirements are not altered by aminophylline treatment, possibly because of the attenuation of the putative sympathomimetic effects of aminophylline by halothane.

Aminophylline↗
PubMed1985

Epinephrine infusion induces hyporesponsiveness of vascular smooth muscle.

Exposure to vasoactive drugs may lead to desensitization of vascular smooth muscle responsiveness. We have explored this phenomenon by infusing epinephrine into awake rabbits for 2h and then assessing smooth muscle contraction, both in vivo and ex vivo. Epinephrine was infused at a rate of 1 microgram X min-1 which resulted in a 15-fold increase in the plasma epinephrine concentration. The dose of phenylephrine required to cause a 25 mmHg increase in mean arterial pressure significantly increased from 109 +/- 56 micrograms prior to the infusion to 261 +/- 143 at the end of the 2h infusion (p less than 0.01). The sensitivity to phenylephrine remained decreased when reassessed 2h later. Untreated rabbits displayed no change in alpha-adrenergic responsiveness when assessed at 2 hourly intervals over the time-course of the experiment. Contraction of aortic rings removed from both epinephrine-treated and control rabbits was determined in vitro in tissue baths. The EC50 of norepinephrine-induced contraction increased from 31 +/- 6 to 210 +/- 20 nM while there was also a 30% decrease in the maximal force of contraction (EMax) in treated vessels. The EC50 only partially recovered after 4h of incubation ex vivo, while the EMax was restored to the control value. The EC50 for histamine in the aortic rings from epinephrine-treated rabbits was not different from controls although there was a 25% reduction in the EMax at 2h. We conclude that desensitization of alpha-adrenergic mediated vascular contractility develops rapidly in vivo and is only slowly reversible after removal of the agonist.

Animals↗
PubMed1985

Halothane anesthesia does not exacerbate hepatic dysfunction in cirrhotic rats.

The authors have refined a model of cirrhosis in the rat and used it to determine whether the administration of halothane anesthesia adversely affects preexisting liver disease. Male Wistar rats were placed on phenobarbital water and were assigned randomly to two groups. Group 1 rats were exposed by inhalation to carbon tetrachloride (CC14) at weekly intervals for 12 exposures while Group 2 rats received only air. All treatment including phenobarbital then was withdrawn for 4 weeks. Rats then were bled for SGOT and SGPT determinations and 24 h later were exposed to 1.8% halothane in oxygen for 3 h (HAL); the remaining rats from each group were exposed to 100% oxygen for 3 h (O2). Twenty-four hours later, rats were killed and blood was obtained for SGOT and SGPT by cardiac puncture. Light microscopic histologic examination was performed blind on liver sections for cirrhosis and scored for superimposed acute focal necrosis. The weekly sublethal CCl4 exposure resulted in histologically demonstrable cirrhosis in all surviving Group 1 animals. The mean (+/- SD) SGOT (128 +/- 32 IU/1) and SGPT (86 +/- 24 IU/1) values for the Group 1 rats were significantly greater (P less than 0.01) than those for Group 2 rats (98 +/- 18 IU/1 and 57 +/- 12 IU/1, respectively). Cirrhotic animals showed neither deterioration in liver function nor acute liver cell necrosis after Hal compared with O2. However, Group 2 rats showed a modest but significant increase in SGOT (P less than 0.05) after HAL, while this change was not noted after O2. Thus, 1.8% halothane anesthesia in oxygen did not result in superimposition of acute liver cell injury in already cirrhotic rats.

Alanine Transaminase↗
PubMed1985

Halothane concentration does not alter the threshold for epinephrine-induced arrhythmias in dogs.

Halothane lessens the dose of epinephrine necessary to induce ventricular arrhythmias. However, results of a previous study in dogs anesthetized at two halothane concentrations suggested, but did not confirm, that at the higher concentration (1.7%) myocardial sensitization to epinephrine was less pronounced. This study was designed to determine the myocardial sensitizing effect of halothane at four concentrations: 0.5, 1.0, 1.5, and 2%. To define the appropriate time interval between repeated epinephrine infusions, plasma epinephrine decay curves were assessed. These data indicated that at 7 min the contribution of the residual epinephrine level to the peak level was negligible. Therefore, 7 min was selected as the interval between epinephrine infusions. The arrhythmogenic dose of epinephrine (ADE) was measured at four concentrations of halothane, 0.5, 1.0, 1.5, and 2.0%. To determine the ADE at the subanesthetic concentration of halothane (0.5%), anesthesia was supplemented with etomidate. In a preliminary study, the authors confirmed that this intravenous hypnotic agent did not affect the halothane-epinephrine arrhythmogenic interaction. By analysis of variance, halothane concentration was shown to have no significant influence on the ADE (P greater than 0.05). The authors' data indicate that, over a clinically appropriate range, halothane concentration does not alter the threshold for the development of epinephrine-induced ventricular arrhythmias.

Animals↗