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Biomedical subjects

J P Trzeciakowski

Publications and source records attributed to J P Trzeciakowski.

At least 19 recordsLinked to original sources
PubMed1991

Effects of acute and chronic ethanol treatment on pre- and postsynaptic responses to baclofen in rat hippocampus.

Interactions between the GABAB receptor and acute or chronic ethanol treatment were studied using extracellular and intracellular electrophysiological recording techniques. Bath application of the GABAB receptor agonist, (-)-baclofen (0.1-100 microM) induced concentration-dependent inhibition of extracellularly recorded dendritic excitatory postsynaptic potentials (EPSPs) in the CA1 region of hippocampal slices. Responses to baclofen were unchanged relative to control either by simultaneous application of ethanol (10-60 mM) or by previous chronic ethanol exposure. The membrane potential of CA1 pyramidal neurons was reversibly hyperpolarized an average of 5 mV by pressure ejection of baclofen (1 mM). Bath application of ethanol (30 mM) alone occasionally caused a small depolarization of resting membrane potentials in CA1 neurons but failed to increase hyperpolarizing responses to pressure-ejected baclofen. However, in slices from chronic ethanol-treated animals hyperpolarizing responses to bath-applied baclofen (10 microM) were reduced by approximately 30% relative to controls. These results suggest that GABAB-mediated responses in CA1 hippocampal pyramidal neurons are relatively resistant to the acute effects of ethanol, but that continuous exposure to ethanol sufficient to induce physical dependence may evoke an adaptive reduction in some GABAB receptor mediated responses.

Animals↗
PubMed1990

Potentiation by glycine of anticonvulsant drugs in maximal electroshock seizures in rats.

This study evaluated the potentiation by glycine of anticonvulsant drugs in maximal electroshock seizures in rats. Administered alone, glycine (40 mmol/kg, p.o.) induced no anticonvulsant effect or neurotoxicity. Administered together with the anticonvulsants, glycine significantly enhanced the anticonvulsant potency of phenobarbital and carbamazepine. Glycine also potentiated the anticonvulsant actions of MK-801 and diazepam but did not improve the selectivity of the drugs, as effective doses were still associated with neurotoxicity. Glycine did not potentiate phenytoin or sodium divalproate. Administration together with glycine had no significant effect on the concentrations of phenobarbital or carbamazepine in the brain. Administration together with phenobarbital had no relevant effect on the concentration of glycine in the brain but administration of glycine and carbamazepine together resulted in an increased concentration of glycine in the hippocampus and brainstem. These findings indicate a possible glycine-sensitive component in the mechanism of action of phenobarbital, carbamazepine and diazepam in maximal electroshock seizures. Although the mechanism may not be mediated by a glycine-GABA interaction, the evidence does implicate a possible interaction between glycine and anticonvulsant drugs at NMDA receptors.

Animals↗
PubMed1990

Intervertebral disk mineralization in progressive ankylosis mice.

The objective of this study was to quantitate the increasing mineral content of the intervertebral disk of progressive ankylosis mice and to identify changes in serum and bone mineral levels that might occur concurrent with the rapid mineralization of the disk. Serum calcium (8.43 +/- 1.01 mg/dl vs. 7.48 +/- 2.07) and phosphorus (6.66 +/- 1.32 mg/dl vs. 5.53 +/- 2.19) levels were within normal limits. Ankylosing mice had a 5.2% decrease in water content, a 24% increase in calcium content and a 29% decrease in phosphorus content of the intervertebral disks. The magnitude of these changes increased with age. There was no significant difference in mineral or water content of the vertebral bodies. The mineral levels per gram of tissue were much greater in ankylosing disks than in the vertebral bodies. No correlation was identified between ankylosing disks and serum or bone mineral levels.

Aging↗
PubMed1990

Combined effects of autoregulation and vasoconstrictors on hindquarters vascular resistance.

Relative contributions of local autoregulatory tone and vasoconstrictor tone to skeletal muscle vascular resistance were studied in anesthetized rats during hypertension produced by vasoconstrictor infusion. Rats were instrumented with a Doppler flow probe on the sacral aorta (SA) to measure blood flow and to allow calculation of vascular resistance. An occluder was placed on the SA and used to produce stepwise reductions in local perfusion pressure. Pressure-flow curves for the hindquarters were obtained in the absence and presence of elevated mean arterial pressure (MAP) produced by infusion of angiotensin II (ANG II; 50-1,247 ng.kg-1.min-1) or phenylephrine (PE; 2.5-12.4 micrograms.kg-1.min-1). Both ANG II and PE infusion increased MAP. For example, MAP was increased by ANG II from 91 to 134 mmHg and by PE from 89 to 156 mmHg. In addition, infusions of ANG II and PE produced dose-dependent rightward shifts in the hindquarters pressure-flow relationship. To examine the effect of pressure on the dose-response relationships of ANG II or PE, local perfusion pressure was adjusted to remain constant at various pressure levels that were independent of MAP during drug infusions. This produced a series of distinct dose-response curves with each curve defined by a different pressure level and with each characterized by a different maximum change in vascular resistance. If local perfusion pressure was not held constant but was permitted to increase with MAP, a compound dose-response curve was obtained in which the combined effects of the change in local pressure (i.e., autoregulation) and vasoconstrictor dose on vascular resistance could be discerned. These data demonstrate that hindquarters blood flow autoregulation continues to occur in the presence of vasoconstrictors. Consequently, autoregulatory mechanisms may be stimulated by any increase in MAP whether associated with systemic vasoconstrictor infusion or activation of neurohumoral pressor systems. The result is an amplified rise in local vascular resistance.

Angiotensin II↗
PubMed1988

Vasoconstriction is amplified by autoregulation during vasoconstrictor-induced hypertension.

This study investigated the degree to which autoregulation of blood flow interacts with vasoconstrictors to determine vascular resistance. Anesthetized rats were instrumented with a Doppler flow probe on the superior mesenteric artery (SMA) to measure blood flow and for calculation of vascular resistance. An adjustable occluder was placed on the SMA to set local perfusion pressure at values independent of mean arterial pressure (MAP) even when MAP was increased by the vasoconstrictors. Infusion of angiotensin II (ANG II, 50-1,247 ng.kg-1.min-1) produced a dose-dependent rightward shift in the intestinal pressure-flow relationship and elevated MAP from 85 to 127 mmHg. Low doses of phenylephrine (PE, 2.5-12.4 micrograms.kg-1.min-1) failed to shift the pressure-flow curve but did increase arterial pressure from 83 to 102 mmHg. At higher doses (25-62 micrograms.kg-1.min-1), PE also shifted the pressure-flow curve to the right. Maintaining local perfusion pressure at different values during the infusion of ANG II or PE produced a family of dose-response curves, with each exhibiting a different maximum change in resistance. When local pressure was permitted to increase with MAP, the composite dose-response curve for resistance that was obtained reflected the influence of the rise in local pressure (i.e., auto-regulation) and vasoconstrictor dose. At low doses of PE the increase in vascular resistance was attributable solely to an autoregulatory response related to the rise in MAP and not due to the constrictor effects of PE. Thus these data indicate that the rise in MAP accompanying systemic infusion of a vasoconstrictor stimulates autoregulation to amplify the local increase in vascular resistance.

Angiotensin II↗
PubMed1987

Effects of intraventricular histamine and H2 receptor antagonists on intraocular pressure.

Severe ocular hypertension has been reported in a chronic glaucoma patient following use of histamine H2 receptor antagonists for treatment of peptic ulcer. Subsequent studies, however, have failed to demonstrate a significant action of topical or intravenously administered H2 blockers on intraocular pressure (IOP) in humans. In this study, cimetidine and ranitidine were administered into the cerebral ventricles of unanesthetized New Zealand White rabbits. Both drugs caused prolonged increases in IOP at a dose of 1 umol. Maximal elevations of IOP occurred approximately 20 min after drug injections and averaged 5-8 mmHg above pre-drug values. In contrast, histamine (0.3 and 1.0 umol) produced biphasic effects on IOP when given by intracerebroventricular (i.c.v.) injection. These data suggest that central mechanisms may mediate the actions of some histamine receptor agonists and antagonists on IOP.

Animals↗
PubMed1987

Inhibition of guinea pig ileum contractions mediated by a class of histamine receptor resembling the H3 subtype.

Segments of guinea pig ileum were isolated and placed on coaxial electrodes in organ baths filled with oxygenated Krebs' solution at 37 degrees C. Twitch responses were produced with rectangular-wave stimuli (0.5 msec; 10 Hz; 4.8-12 V) delivered in 1-sec trains every 10 sec. After addition of pyrilamine to block H1-mediated contractions, histamine and N alpha-methylhistamine (NMH) inhibited the twitch responses with EC50 values of 64 and 1.7 nM, respectively. In contrast, there was no difference in potency between histamine and NMH at contractile H1 receptors in ileum longitudinal muscle or at chronotropic H2 receptors in the atria. Impromidine blocked the inhibitory effect of NMH in a competitive manner with a KB value of 26 nM, whereas inhibition caused by gamma-aminobutyric acid or by adenosine remained unaffected by impromidine. At concentrations that completely prevented the electrically induced twitch, NMH did not alter contractions produced by exogenous acetylcholine. Inhibitory responses to NMH were unaffected by cimetidine, hexamethonium, combined alpha and beta adrenergic receptor blockade, naloxone, 8-phenyltheophylline or gamma-aminobutyric acid receptor desensitization. These data support the presence of inhibitory histamine receptors in the ileum that are pharmacologically similar to the presynaptic H3 autoreceptors found in rat cortex. The distribution of H3 receptors, therefore, may not be confined to the central nervous system and their function, as with alpha-2 adrenergic sites, may not be limited to that of an autoreceptor.

Animals↗
PubMed1986

Pressor responses to central injection of H2 antagonists not caused by GABA blockade.

In awake rats, ranitidine was more effective than cimetidine in elevating blood pressure following intracerebroventricular (i.c.v.) injection, yet neither drug affected the hypotensive response to subsequent injections of muscimol (8.8 nmol i.c.v.). Bicuculline (0.01 nmol) microinjected into the inferior colliculus of rats caused clonic seizures whereas cimetidine (100 nmol) had no effect. The antihistamines did not prevent GABAB receptor-mediated inhibition of twitch responses in transmurally stimulated guinea-pig ileum. Ranitidine potentiated rather than inhibited GABAA receptor-mediated contractions of ileum longitudinal muscle. Cimetidine had no effect on these responses except at high concentrations (3 X 10(-4) M) which caused a slight dextral shift in the contractile response curve for GABA that may be attributed to antimuscarinic actions of cimetidine. Taken together, these data do not support the concept that the centrally mediated pressor effects of H2 antagonists are caused by GABA receptor blockade.

Animals↗
PubMed1986

Ranitidine potentiates ileum contractions caused by GABA and electrical stimulation.

GABA-evoked contractions of the guinea pig ileum were significantly potentiated by the histamine H2-receptor antagonist ranitidine in concentrations above 10 microM. To help define the mechanism of this interaction, the present study compared the effects of ranitidine on contractile responses of the guinea pig ileum to GABA, acetylcholine (A Ch) and electrical stimulation of intrinsic cholinergic neurons. Ranitidine, at concentrations that potentiated responses to GABA, also potentiated contractions induced by transmural electrical stimulation. The ability of ranitidine to amplify these latter responses was antagonized by atropine. Contractile responses to exogenous A Ch, however, were unaffected by ranitidine at any concentration. These results suggest that prejunctional, rather than postjunctional mechanisms, are of primary importance in the interaction between ranitidine and GABA.

Animals↗
PubMed1985

Chronic but not acute treatment with antidepressants enhances the electroconvulsive seizure response in rats.

The effects of the chronic administration of antidepressants on threshold electroconvulsive (ECS) seizures were evaluated in rats. Initially, tonic-clonic seizures were induced in 90% of the animals. Of those animals responding with tonic-clonic seizures, 42% had hindlimb extension (extensors); the remainder showed only hindlimb flexion (flexors). No alteration in the pattern of seizures was observed 24 hr after a single oral dose of any of the antidepressant drugs. The rats were then treated with a total of 20 consecutive daily doses of antidepressants and threshold electroconvulsive seizure responses were evaluated 24 hr after the last dose. A significantly greater percentage of rats responded with extensor seizures after chronic treatment with amoxapine, chlorimipramine, parglyine and mianserin. There was no change in the pattern of seizures of the rats treated chronically with desipramine, but the duration of the clonic phase was reduced. After a 7 day period free of drugs a significantly greater percentage of animals had extensor seizures in the groups treated with amoxapine, chlorimipramine, pargyline and desipramine but not mianserin. In the light of evidence that chronic treatment with antidepressants reduces the activity of norepinephrine- or isoproterenol-sensitive adenylate-cyclase, and that the norepinephrine system is an important endogenous anticonvulsant factor in electroconvulsive seizures, these results suggest that the same mechanism may mediate both the therapeutic and proconvulsant effects of the chronic administration of antidepressants.

Amoxapine↗
PubMed1985

Effects of prostaglandins on intraocular pressure recovery rate in rabbits.

The actions of a number of prostaglandins (PGs) were studied in unanesthetized rabbits using an intraocular pressure (IOP) recovery-rate method. In topical doses of 0.1 to 10 micrograms, these compounds accelerated the rate at which IOP returned to control levels after an infusion of hypertonic saline. In general, PGE1 appeared more potent than the other PGs at these doses. Arachidonic acid also increased the IOP recovery rate. The effect of arachidonic acid was completely blocked by the cyclooxygenase inhibitor indomethacin. Recovery rate responses to arachidonic acid were increased further after pretreatment with the lipoxygenase inhibitor phenidone. When administered alone, phenidone itself accelerated IOP recovery; this action was also blocked by indomethacin. The IOP recovery rate method appears to be a useful tool for studying ocular effects of PGs and other products or inhibitors of arachidonic acid metabolism.

Animals↗
PubMed1985

Synergistic interaction between histamine and ouabain on ventricular fibrillation threshold.

The interaction between histamine and ouabain on the ventricular fibrillation threshold (VFT) was studied in the isolated, Langendorff-perfused heart of the guinea-pig. When administered separately, histamine and ouabain each reduced the VFT in a concentration-related manner with ED50 values of 84.3 and 250 nM, respectively. When perfused in combination the effects of these two drugs on VFT were significantly greater than the sum of their individual contributions. Mepyramine and cimetidine both antagonized the fibrillatory effects of the histamine-ouabain combination. Neither antagonist affected the fibrillation concentration-response curve for ouabain. These results suggest that both classes of histamine receptor may participate in the histamine-ouabain interaction.

Animals↗
PubMed1982

Dysrhythmias caused by histamine release in guinea pig and human hearts.

Histamine is released into the systemic circulation during anaphylaxis, by drugs and by surgical procedures. Studies in animal models have conclusively demonstrated that released cardiac histamine is a major mediator of arrhythmias that occur during anaphylaxis and following the administration of histamine-releasing drugs. Several lines of evidence suggest a similar arrhythmogenic role for cardiac histamine in humans: (1) The human heart is rich in histamine; (2) cardiac histamine can be readily released from human heart in vitro by therapeutic concentrations of drugs; (3) histamine has potent arrhythmogenic effects on the human heart in vitro. Arrhythmogenic effects of histamine include enhancement of normal automaticity, induction of abnormal automaticity, induction of triggered tachyarrhythmias, depression of atrioventricular conduction, and increase in the vulnerability of the ventricles to fibrillation. A combination of H1 and H2 antihistamines is needed to block the arrhythmogenic effects of histamine. Certain arrhythmogenic effects of histamine (e.g. induction of slow responses and delayed afterdepolarizations) can also be blocked by drugs which inhibit the influx of cations through slow channels. In contrast, the commonly-used drug digitalis potentiates the arrhythmogenic effects of histamine. We propose that histamine release produced by drugs and surgical procedures may be an overlooked factor in fatal cardiac arrhythmias. Experimental studies suggest that selective pharmacological methods can be developed to block the arrhythmogenic effects of histamine.

Animals↗
PubMed1982

Reduction of ventricular fibrillation threshold by histamine: resolution into separate H1- and H2-mediated components.

The effects of histamine and the selective agonists impromidine (H2-agonist) and 2-(2-thiazolyl ethylamine)(H1-agonist) on ventricular fibrillation threshold were tested in the isolated guinea-pig heart. All three compounds produced reversible concentration-dependent decreases in ventricular fibrillation threshold. Ventricular fibrillation threshold reduction was not secondary to the positive chronotropic effect of the three compounds. Computer analysis of the data using appropriate theoretical models suggests that the net effect of histamine on ventricular fibrillation threshold is the resultant of two components: H1 and H2. Pyrilamine inhibited the H1-mediated effects of histamine on ventricular fibrillation threshold with a Kb value of 0.449 nM. H1- and H2-receptors mediating ventricular fibrillation threshold reduction differ in their relative sensitivity to histamine (H1 greater than H2; EC50 for histamine, 53.9 nM at H1- and 311 nM at H2-receptors) and in the maximum response which they are capable of producing (H1 congruent to 1/2 that of H2). The finding that extremely low concentrations of histamine (less than 1 pg/ml) can effectively reduce ventricular fibrillation threshold reinforces the concept that histamine is highly arrhythmogenic.

Animals↗
PubMed1980

The cardiac pharmacology of tiotidine (LCL 125, 211): a new histamine H2-receptor antagonist.

The cardiac pharmacology of tiotidine, a potent and specific antagonist of H2-receptors, was studied in isolated Langendorff-perfused guinea-pig hearts. At a concentration of 2.5 x 10(-6) M, tiotidine caused a slight prolongation of the P-R interval, but had no effect on rate, contractility or coronary function. Tiotidine competitively antagonized the positive chronotropic action of histamine with an apparent dissociation constant of 3.0 x 10(-8) M (2.3 x 10(-8)-3.8 x 10(-8) M). Tiotidine abolished H2-mediated increases in contractile force leaving H2-mediated negative inotropic responses unopposed. The actions of histamine at the A-V node, manifested by lengthening of the P-R interval and A-V block, were attenuated by 2.5 x 10(-7) M tiotidine; nevertheless, higher concentrations of the antagonist did not produce additional inhibition of the negative dromotropic response. As a function of concentration, tiotidine reduced the incidence and duration of histamine-induced idioventricular arrhythmias. Based on its high affinity and specificity for the H2-receptor and relative lack of cardio-depressant effects, tiotidine appears to be a useful new drug for investigating the role of histamine in cardiac function and dysfunction.

Animals↗
PubMedDate not supplied

Effect of ethanol dependence on GABAA antagonist-induced seizures and agonist-stimulated chloride uptake.

The functional state of GABAA receptors during physical dependence on ethanol was evaluated in two ways. First, the ability of ethanol dependence to change the convulsant potency of GABAA antagonists microinjected into the inferior colliculus was examined. A second approach evaluated the effects of ethanol dependence on the ability of muscimol or pentobarbital to stimulate chloride uptake in rat brain vesicles. In the studies examining changes in convulsant potency, bilateral microinfusions of GABAA antagonists, bicuculline methiodide and picrotoxinin, as well as the excitatory amino acid agonist, kainic acid (used as a positive control) induced similar dose-related increases in the frequency of wild-running seizures. Ethanol dependence did not significantly change susceptibility to wild-running seizure induction by an of the convulsants, although susceptibility to the more severe, clonic seizures was significantly increased for each convulsant. This suggested that the receptor-blocking effects of GABAA antagonists responsible for inducing wild-running seizures were not selectively increased by ethanol dependence, but that spread of seizure activity responsible for clonic seizures following the initiation of wild running was generally increased. Finally, in studies examining changes in GABAA receptor-mediated chloride uptake, both muscimol and pentobarbital were found to induce concentration-dependent increases in chloride uptake in rat brain vesicles. However, responses to these drugs were not reduced by ethanol dependence suggesting that a generalized adaptive decrease in GABAA receptor function was unlikely. Together these results do not provide support for the hypothesis that the GABAA receptor-chloride channel complex is down-regulated during the development of physical dependence on ethanol.

Animals↗