PubMed Health⌕ Search

Biomedical subjects

J S Althaus

Publications and source records attributed to J S Althaus.

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

Competitive irreversible inhibition of dopamine uptake by 6-hydroxydopamine.

We examined the effects of 6-hydroxydopamine (6-OHDA) treatment on the human neuroblastoma cell line SK-N-SH-SY5Y (SY5Y) and the rat pheochromocytoma cell line, PC12. Structural and metabolic integrity was tested by measuring the ability of cells to transport the non-metabolizable amino acid analogue [3H]-alpha-aminoisobutyric acid (AIB). We determined that treatment with 6-OHDA at concentrations of 49 microM and 62 microM inhibited 50% of the AIB uptake in SY5Y and PC12 cells, respectively. Inhibition of AIB uptake was prevented by the addition of catalase, but was not influenced by the addition of 1 mM dopamine. This indicated that cell damage resulted from the generation of H2O2 and was independent of the catecholamine uptake system. Effects directly on the catecholamine uptake system were observed by measuring the uptake of 3H-dopamine. In contrast to the effects on amino acid uptake, dopamine uptake was significantly inhibited by 6-OHDA treatment, and this inhibition was not prevented by the addition of catalase. The results indicate a Ki of 430 microM for inhibition of dopamine uptake by 6-OHDA treatment of PC12 cells. The results are consistent with a competitive irreversible inhibition of the dopamine uptake sites by 6-OHDA or one of its metabolites. Thus, the lack of a catecholamine uptake-dependent cellular toxicity appears to result from the direct inactivation of catecholamine uptake sites. Similarly, the inhibition of dopamine uptake in vivo by 6-OHDA may be explained, at least in part, by direct inactivation of dopamine uptake sites rather than exclusively by intracellular transport and action of 6-OHDA.

Adrenal Gland Neoplasms↗
PubMed1992

Dopaminergic and serotonergic activities of imidazoquinolinones and related compounds.

The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.

Aminoquinolines↗
PubMed1992

Kappa agonist-induced reduction in dopamine release: site of action and tolerance.

Kappa opioid agonists are known to inhibit dopamine release. We sought to determine the site of this action and the relationship of tolerance to this effect. Microdialysis perfusion of the nucleus accumbens in unanesthetized rats was used to monitor dopamine release, as well as DOPAC, HVA, and 5-HIAA efflux. Administration of the kappa agonist U-50488H (0.5-10 mg/kg, s.c.) resulted in a dose-related inhibition of basal dopamine release and a delayed reduction in HVA efflux. When added directly to the perfusion medium, U-50488H (10 microM) similarly reduced dopamine release and HVA efflux; however, a much higher concentration (1 mM) produced a transient increase in dopamine release. The more potent kappa agonist, spiradoline mesylate (5 mg/kg, s.c.) caused a more profound and long lasting reduction in dopamine release than that observed with U-50488H. Repeated injections of spiradoline (7 injections over 3 days at 5 and 10 mg/kg, s.c.) resulted in a persistent reduction in dopamine release with no further reduction in release being observed following an acute injection of spiradoline (1 mg/kg, s.c.). We conclude that kappa agonists act to inhibit dopamine release from the nucleus accumbens via a direct effect in that region, and that tolerance does not occur to this neurochemical effect. Thus, kappa agonists may prove useful in chronic conditions resulting from excessive dopamine release.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

The kappa opioid-related anticonvulsants U-50488H and U-54494A attenuate N-methyl-D-aspartate induced brain injury in the neonatal rat.

The neuroprotective effects of the kappa opioid-related anticonvulsants U-50488H and U-54494A were tested in a model of N-methyl-D-aspartate (NMDA)-induced brain injury in the neonatal rat. Seven-day-old rat pups were injected intracerebrally with 7.5 nmol NMDA. Five days later, the ensuing unilateral hemisphere weight reduction was measured and used to assess the severity of insult. Control animals (n = 85) exhibited a 21.7 +/- 0.5% hemisphere weight reduction. Animals treated with U-54494A in split doses before and after NMDA administration showed significant neuroprotection at 10, 15, and 20 mg/kg, with the maximum effect observed at 15 mg/kg (33.8% protection). Animals treated with U-50488H on a similar dosing schedule showed significant neuroprotection at all doses tested, with peak protection observed at 30 mg/kg (51.8% protection). Both compounds exhibited a neuroprotective effect when hemisphere cross-sectional area and hippocampal histology were assessed. Treatment with U-54494A after NMDA administration also afforded neuroprotection at various doses, as measured by hemisphere weight disparity, with peak protection occurring at a dose of 20 mg/kg (32.4% protection). These data show that both U-50488H and U-54494A afford neuroprotection against NMDA-induced neuronal injury in the neonatal rat brain.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Effects of dopamine agonists on dopamine secretion from PC12 cells: lack of functional autoreceptor activity.

In an effort to determine if PC12 cells have functional dopamine autoreceptors we found that carbachol-stimulated release of dopamine from undifferentiated PC12 cells was inhibited by the dopamine autoreceptor agonists apomorphine and U-68553B. Studies were conducted to determine the mechanism of this effect. The inhibition of dopamine release by apomorphine or U-68553B did not appear to result from effects on dopamine metabolism. When cells were exposed to the dopamine agonists for 2 minutes no changes in dopa, DOPAC or dopamine were observed. Over this same time interval, apomorphine and U68553B at 10 microM inhibited carbachol-stimulated dopamine release by 45.6% and 57.4% respectively. However, these drugs failed to inhibit the potassium dependent release of dopamine from cells suggesting no direct involvement with ion fluxes. Furthermore, haloperidol did not block the inhibitory effects of U-68553B on PC12 cells. This would appear to preclude activation of a dopamine autoreceptor as a possible mechanism. Kinetic analysis revealed that U-68553B is most likely a non-competitive inhibitor (Ki = 2 microM) of the nicotinic acetylcholine receptor. These data do not provide evidence for functional dopamine autoreceptors on undifferentiated PC12 cells but rather indicate that dopamine agonists may alter dopamine release by alternative mechanisms.

Animals↗
PubMed1990

Effects of chronic haloperidol on vitamin E levels and monoamine metabolism in rats fed normal and vitamin E deficient diets.

Experiments were conducted to study the effects of chronic haloperidol treatment on brain catechols and indoles in rats fed vitamin E deficient diets. Rats were fed basal diet or vitamin E deficient diet and injected with saline or haloperidol (1 mg/kg/day x 28 days i.p.). Tissue levels of catechols, indoles and vitamin E were measured using HPLC-EC techniques. Chronic haloperidol reduced striatal vitamin E levels. Activity in the striatal dopaminergic systems was also reduced, as, shown by reduced 3,4-dihydrophenylanine (DOPA), homovanillic acid (HVA), 3-methoxytyramine (3-MT), and dopamine (DA) levels. In addition, serotonergic activity was reduced, as indicated by lowered 5-hydroxytryptophan (5-HTP), 5-hydroxyindoleacetic acid (5-HIAA), and 5-hydroxytryptamine (5-HT) levels. In the substantia nigra, only 5-HIAA levels were reduced by treatment with haloperidol. These effects of haloperidol on monoamine metabolism were noted in both the vitamin E deficient and basal diet treated rats. However, vitamin E deficiency alone resulted in reduced DOPA and dopamine in the striatum. The vitamin E deficient diets resulted in markedly lowered vitamin E levels in the striatum and substantia nigra. All of these effects were more profound in rats that had been maintained on a vitamin E deficient diet for 7 weeks than those that were so treated for 5 weeks. These results suggest that alterations in dopamine metabolism and endogenous antioxidant systems may interact. Neuroleptics such as haloperidol that acutely accelerate dopamine synthesis and metabolism may cause peroxidative stress as indicated by depletions of vitamin E. Such depletions are capable of reducing dopamine levels and synthesis. The possibility that this and the effect of chronic haloperidol are mediated by peroxidative damage to dopamine neurons must be considered.

Animals↗
PubMed1989

Entropy as a factor in the binding of gamma-aminobutyric acid and nipecotic acid to the gamma-aminobutyric acid transport system.

Nipecotic acid is one of the most potent competitive inhibitors and alternative substrates for the high-affinity gamma-aminobutyric acid transport system in neurons, but the structural basis of this potency is unclear. Because gamma-aminobutyrate is a highly flexible molecule in solution, it would be expected to lose rotational entropy upon binding to the transport system, a change which does not favor binding. Nipecotic acid, in contrast, is a much less flexible molecule, and one would expect the loss of conformational entropy upon binding to be smaller thus favoring the binding of nipecotic acid over gamma-aminobutyric acid. To investigate this possibility, the thermodynamic parameters, delta G degrees, delta H degrees, and delta S degrees, were determined for the binding of gamma-aminobutyrate and nipecotic acid to the high affinity GABA transport system in synaptosomes. In keeping with expectations, the apparent entropy change for nipecotic acid binding (112 +/- 13 J.K-1) was more favorable than the apparent entropy change for gamma-aminobutyric acid binding (61.3 +/- 6.6 J.K-1). The results suggest that restricted conformation per se is an important contributory factor to the affinity of nipecotic acid for the high-affinity transport system for gamma-aminobutyric acid.

Animals↗
PubMed1988

Hypoxemia and hypercapnia in conscious dogs: opioid modulation of catecholamines.

The role of endogenous opioids in systemic and renal circulatory changes during combined acute hypoxemia and hypercapnic acidosis was evaluated in seven conscious female mongrel dogs in rigid sodium balance. Animals were studied 2 wk apart in separate protocols of combined acute hypoxemia (arterial O2 tension = 33 +/- 1 mmHg) and hypercapnic acidosis (arterial CO2 tension = 56 +/- 1 mmHg, pH = 7.19 +/- 0.01) of 40 min duration during 1) naloxone, 5 mg/kg iv bolus followed by an intravenous infusion of 5 mg.kg-1.h-1, and 2) vehicle (5% dextrose in water) alone. Systemic circulatory changes during the combined acute blood-gas derangement including increased mean arterial pressure, heart rate, and cardiac output and decreased total peripheral resistance were comparable between naloxone and vehicle treatments. However, in striking contrast to the brief fall in renal hemodynamic function during combined acute hypoxemia and hypercapnic acidosis with vehicle, naloxone administration during the combined acute blood-gas derangement resulted in a sustained decrease in effective renal plasma flow, glomerular filtration rate, and filtered sodium load and enhanced rise in circulating norepinephrine and epinephrine. Changes in plasma renin activity were comparable between vehicle and naloxone protocols except that plasma renin activity increased from the first to the second 20-min periods of combined hypoxemia and hypercapnic acidosis with naloxone. These observations suggest that endogenous opioids may contribute to preservation of renal hemodynamic function during acute blood-gas derangements, possibly through attenuation of sympathetic nervous system and renin-angiotension activation.

Animals↗
PubMed1988

Enhancement of anesthetic effect of halothane by spiradoline, a selective kappa-agonist.

Reduction in the anesthetic requirement of halothane by narcotics has been studied extensively in humans and animals. Problems of respiratory depression, cardiovascular depression, muscle rigidity, and abuse potential make narcotics less than ideal as supplements to general anesthesia with inhalational agents. Spiradoline, a clinical candidate, is a highly potent and selective kappa-agonist. As such it was considered important to study the effects of spiradoline on the minimum anesthetic concentration (MAC) of halothane required to block responses to noxious stimulation. The results of these experiments in rats showed a dose and plasma concentration-dependent reduction in halothane MAC over a wide range of subcutaneous doses of spiradoline (0.03 to 300 mg/kg). A maximum MAC reduction of 70% was obtained. Plasma levels of spiradoline (6 to 1800 ng/ml) were linearly related to dose. Measurement of blood pressure, heart rate, and PCO2 determined over the course of each experiment showed minor variations which would be acceptable if observed in a clinical setting. It is concluded that spiradoline has promise as an anesthetic supplement.

Analgesics↗
PubMed1987

Beneficial effects of the kappa opioid receptor agonist U-50488H in experimental acute brain and spinal cord injury.

The effects of the selective kappa opioid receptor agonist U-50488H (trans-3,4-dichloro-N-methyl-N[2-(pyrrolidinyl)-cyclohexyl]- benzeneacetamide) were examined in acute head and spinal injury models. First, in a blinded protocol, male CF-1 mice were treated intravenously with either saline or U-50488H (1, 3 or 10 mg/kg) within 3-5 min following a reproducible and quantifiable moderately severe (900 g/cm) concussive head injury. Using a grip test at 1 h postinjury to evaluate the neurological status of the injured mice, U-50488H produced a dose-related improvement in early recovery compared to the saline-treated mice. The effect was significant (P less than 0.05) after the 3 or 10 mg/kg i.v. doses. A similar concussive injury markedly reduced the % of cardiac output perfusing the forebrain (cerebral blood flow). U-50488H (10 and 20 mg/kg) partially reversed this effect to a significant degree 60 min after a 20 mg/kg dose. Secondly, the effects of U-50488H on the development of progressive post-traumatic spinal cord white matter ischemia after a 500 g/cm contusive injury were studied in pentobarbital-anesthetized cats. In 4 untreated cats, there was a progressive fall in spinal cord and blood flow (SCBF) from a 10-min postinjury level of 10.5 +/- 0.7 ml/100 g/min to 6.1 +/- 0.3 (P less than 0.03 by paired t at 4 h).(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

Effects of U-50488H, a selective kappa-analgesic, on the minimum anesthetic concentration (MAC) of halothane in the rat.

The effects of U-50488H, a selective kappa-analgesic, on the minimum anesthetic concentration (MAC) of an inhalational agent (halothane) were studied in the rat. U-50488H was given subcutaneously in doses of 3, 10, and 30 mg/kg body weight. The maximal MAC reduction was about 60%. The potency ratio of U-50488H to morphine in this model was comparable with potency ratios in other analgesic assays. In separate experiments, the percent reduction in halothane MAC with U-50488H at 30 mg/kg was determined during the infusion of naloxone (5 micrograms X kg-1 X min-1 and 1 mg X kg-1 X min-1) at doses shown to have reversed a 70% reduction in MAC by 10 mg/kg of morphine. Only when naloxone was infused at 1 mg X kg-1 X min-1 was there a significant reversal of the U-50488H-induced reduction in halothane MAC. This observation suggests that the reduction in MAC of halothane with U-50488H was not mediated by a mu-receptor. In conclusion, through the use of a selective pharmacologic tool that stimulates kappa-receptors we have demonstrated potential utility of kappa-analgesics as supplements to general anesthesia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

Effects of dantrolene and verapamil on atrioventricular conduction and cardiovascular performance in dogs.

The effects of intravenous dantrolene sodium, alone and in combination with verapamil, upon atrioventricular conduction, cardiovascular function, and neuromuscular function were studied in chloralose-urethane anesthetized dogs. Hemodynamic variables (systemic arterial, central venous, and pulmonary arterial pressures and cardiac output) and His-bundle electrograms were monitored, and measurements were made during atrial pacing at 175 beats/min, as well as at the spontaneous heart rate. In one part of the study animals received dantrolene sodium incrementally at 30-min intervals to cumulative doses of 1, 2.5, 5, and 10 mg/kg. Subsequently, verapamil was administered incrementally at 30-min intervals to cumulative doses of 0.1, 0.2, 0.4, and 0.6 mg/kg. In the second part of the study, dogs received identical dosage sequences, but verapamil preceded dantrolene administration. Dantrolene caused no significant depression of atrioventricular conduction or cardiac performance but did increase systemic vascular resistance at doses above 2.5 mg/kg. Verapamil alone (greater than or equal to 0.2 mg/kg) or with dantrolene (greater than or equal to 0.1 mg/kg) increased the atrial-His-bundle conduction interval. In the presence of verapamil, dantrolene (greater than or equal to 2.5 mg/kg) decreased cardiac index and increased pulmonary artery occlusion pressure. Although 0.6 mg/kg verapamil depressed cardiac index and increased pulmonary artery occlusion pressure, this effect was observed at 0.4 mg/kg after prior treatment with dantrolene. Verapamil did not augment the dose-dependent twitch depression observed with dantrolene. Dantrolene alone had no apparent effect on atrioventricular conduction and caused little enhancement of the effects of verapamil. However, each drug appeared to enhance the myocardial depressant effects of the other.

Animals↗
PubMed1985

Application of the median method to the determination of kinetic constants for competitive enzyme inhibition.

A procedure was developed to determine kinetic constants for competitive inhibition (Km, Ki, Vmax) by the median method. Simulated experiments were used to compare the accuracy and precision of kinetic constants determined by the median method with unweighted and weighted least-squares analysis. The median method was superior to unweighted least-squares analysis. The weighted least-squares method was superior to the median method when the error was normally distributed but the median method was superior when two or more outliers were present. The dependence of the accuracy and precision of kinetic constants obtained by the median method on several experimentally important parameters, including the number of experimental points, the number and range of substrate concentrations, and the number and range of inhibitor concentrations, was determined.

Binding, Competitive↗
PubMed1985

Central serotonin depletion: effect on blood pressure during anesthesia.

Serotonin (5-HT) in the central nervous system has been implicated in blood pressure control in both normotensive and hypertensive states. Parachlorophenylalanine (PCPA) depletes 5-HT in the central nervous system. Normotensive Wistar rats, Wistar rats made hypertensive by renal artery clipping (RHR), and spontaneously hypertensive rats (SHR) were depleted of central serotonin by the administration of PCPA. Mean arterial blood pressure (MAP), heart rate (HR), and plasma norepinephrine (NE) levels were measured in rats both before and after they were administered anesthesia with enflurane. Blood pressure was further decreased by the administration of saralasin, a competitive inhibitor of angiotensin II. Principal results are as follows. Central 5-HT was depleted by 70% or more with PCPA. In general, brain catecholamines were not altered by this treatment. No consistent pattern of change in MAP, HR, or plasma NE was observed for Wistar rats, RHR, or SHR during an awake control period in rats treated with PCPA compared with rats treated with vehicle. However, during enflurane anesthesia or enflurane anesthesia with saralasin, MAP, HR, and plasma NE were significantly greater in Wistar rats and RHR treated with PCPA compared to similar groups treated with vehicle. This was not observed in SHR: MAP, HR, and plasma NE were similar to vehicle-treated SHR. Nonsignificant changes in plasma epinephrine, plasma renin activity, or arterial blood gas tensions could not explain the differences seen in Wistar rats, RHR, or SHR. Central serotonin plays an important role in cardiovascular control during anesthesia with enflurane in Wistar rats but does not appear to play a dominant role in SHR.

Analysis of Variance↗
PubMed1985

Analgetic contribution of sufentanil during halothane anesthesia: a mechanism involving serotonin.

Catecholamine and serotonin concentrations in the cord, medulla, and hypothalamus were measured in rats after saline, after sufentanil sufficient to reduce the minimum alveolar concentration (MAC) of halothane by 30% or less, or after sufentanil sufficient to reduce the MAC of halothane by 80% or more. In the cord, high doses of sufentanil resulted in a 13.4% reduction (P less than 0.05) in serotonin concentration compared to saline control and a 17.4% reduction (P less than 0.05) in serotonin concentration compared to low dosages of sufentanil. A 12.8% reduction (P less than 0.05) in medullary serotonin also was observed with high sufentanil compared to low sufentanil. Epinephrine decreased significantly in the hypothalamus at the high sufentanil dose. No other significant differences were found in catecholamine content. The experimental results support the hypothesis that sufentanil may contribute to an analgetic component of general anesthesia by modulating nociception via the release of 5-HT.

Analgesics↗
PubMed1985

Hormonal and hemodynamic responses to halothane and enflurane in spontaneously hypertensive rats.

Forty-two spontaneously hypertensive rats (SHR) and 42 normotensive Wistar-Kyoto rats (WKY) were anesthetized with either halothane or enflurane. Blood pressure, heart rate, cardiac output, distribution of blood flow, plasma renin activity, and plasma catecholamines were measured to determine in what manner the hypertensive animal responded to these two anesthetics. Major findings of the study were that plasma renin activity did not increase in the SHR despite a 25% reduction in MAP. The infusion of saralasin, an angiotensin II antagonist, resulted in a further decrease in blood pressure in SHR anesthetized with halothane but not with enflurane. Plasma catecholamine concentrations were elevated in the awake SHR and were decreased in SHR anesthetized with enflurane. Both halothane and enflurane anesthesia resulted in similar alterations in blood flow in the SHR. The normotensive WKY responded to halothane and enflurane in a different manner than the SHR. Plasma renin activity increased with the decrease in blood pressure with both agents. A further decrease in blood pressure occurred with saralasin infusion in WKY anesthetized with halothane or enflurane. Significant blood flow alterations occurred in the WKY anesthetized with both agents, but enflurane caused the greatest changes. The SHR may prove useful in examining the effects of anesthetic agents and other drugs so that we may have a better understanding of the perioperative management of the patients with essential hypertension.

Anesthesia, Inhalation↗
PubMed1984

Central depletion of catecholamines--importance of hypertension and anesthesia.

The importance of the brain noradrenergic sympathetic nervous system in blood pressure control during anesthesia with halothane and enflurane was investigated in normotensive and hypertensive rats. Central noradrenergic neurons were destroyed by instillation of 6-hydroxydopamine (6-OHDA) into the cerebral ventricle of both normotensive Wistar rats and spontaneously hypertensive rats (SHR). One week later, arterial and venous lines were placed in the rats under anesthesia; the rats were allowed to recover; and blood pressure and plasma renin activity were measured while the rats were awake. Anesthesia then was induced with 1.3 vol% halothane (Wistar n = 8, Wistar 6-OHDA n = 10, SHR n = 8, SHR 6-OHDA n = 6) or 2.2 vol% enflurane (Wistar n = 6, Wistar 6-OHDA n = 10, SHR n = 8, SHR 6-OHDA n = 6). A control group (Wistar n = 10, Wistar 6-OHDA n = 6, SHR n = 8, SHR 6-OHDA n = 6) was treated identically, but remained unanesthetized throughout the experiment. The untreated normotensive and hypertensive rats received no intraventricular injections. After 1 hr of stable anesthesia, plasma renin activity was measured again, and saralasin, a competitive inhibitor of angiotensin II, was infused to determine the importance of the renin--angiotensin system in blood pressure control. Treatment with 6-OHDA resulted in a 60-90% depletion of norepinephrine in the medulla and hypothalamus. Normotensive Wistar rats treated with 6-OHDA responded to halothane and enflurane anesthesia in a manner similar to untreated normotensive rats. In contrast, hypertensive animals treated with 6-OHDA and then anesthetized with halothane had a significantly greater decrease in blood pressure than untreated hypertensive rats (100 +/- 4 mm Hg vs 125 +/- 4 mm Hg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗