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M L Cohen

Publications and source records attributed to M L Cohen.

At least 109 records · Page 6Linked to original sources
PubMed1994

Serotonin-induced contraction in canine coronary artery and saphenous vein: role of a 5-HT1D-like receptor.

The identity of the serotonin (5-HT) receptor(s) that mediate(s) contraction in canine coronary artery and saphenous vein remains controversial. Ring segments of endothelium-denuded coronary artery and helical strips of saphenous vein were suspended in organ chambers for measurement of isometric force. 5-HT, alpha Me-5-HT and sumatriptan contracted both coronary artery and saphenous vein and the non-selective 5-HT receptor antagonist 1-naphthylpiperazine (100nM) blocked 5-HT- and sumatriptan-induced contraction in both tissues. The agonist rank order potency for contraction (5-HT > sumatriptan > alpha Me5-HT > 5-MeOT > 5-MeT) was similar in both tissues and was consistent with that for a 5-HT1D receptor. Oligonucleotide primers specific for the 5-HT1D receptor sequence were designed for use in a polymerase chain reaction (PCR). cDNA derived from total RNA or mRNA from canine tissues was used in the PCR. PCR resulted in the amplification of a 632 base pair sequence in both canine coronary artery and saphenous vein; consistent with that expected for the 5-HT1D receptor. Southern blot analysis, with an oligonucleotide probe internal to the sequence amplified by the PCR primers, confirmed that the sequence amplified by PCR was the 5-HT1D receptor. Thus, the 5-HT1D receptor is expressed in canine coronary artery and saphenous vein and taken together with the pharmacological data, supports the possibility that a 5-HT1D-like receptor mediates contraction in these two tissues.

5-Methoxytryptamine↗
PubMed1994

Relationship between 5-HT2A receptor mRNA density and contractility in trachea and aorta from guinea pig and rat.

The present studies document marked differences in contractile responsiveness to serotonin in trachea and aorta between guinea pig and rat. For example, the guinea pig trachea and rat aorta markedly contract in response to serotonin via activation of 5-HT2A receptors. In contrast, the rat trachea and guinea pig aorta only modestly contract to serotonin. The availability of 5-HT2A receptor selective cDNA clones from brain of both guinea pig and rat permitted molecular probes to be designed and PCR amplification studies initiated to identify and quantify 5-HT2A receptor specific mRNA in these tissues. For trachea, 3-fold higher concentrations of 5-HT2A receptor specific mRNA were found in guinea pig relative to rat trachea. These data are consistent with the more profound contractile response to serotonin in guinea pig versus rat trachea and suggest that differences in tracheal contractility to serotonin correlate with the density of 5-HT2A receptor mRNA. In contrast, although rat aorta contracted more dramatically to serotonin than guinea pig aorta, rat aorta possessed a similar concentration of 5-HT2A receptor specific mRNA as compared to guinea pig aorta. Thus, for the aorta, differences in the concentration of 5-HT2A receptor mRNA are not sufficient to explain the observed differences in contractility between tissues from guinea pig and rat. These studies documenting 5-HT2A receptor mRNA in rat trachea and guinea pig aorta, two tissues that do not markedly contract in response to serotonin indicate that 5-HT2A receptor mRNA although present, has not resulted in a receptor capable of mediating a contractile response in these tissues.

Animals↗
PubMed1994

Autoradiographic comparison of [125I]LSD-labeled 5-HT2A receptor distribution in rat and guinea pig brain.

Although the density and distribution of 5-HT2A (5-hydroxytryptamine-2A) receptors is well established for rat brain, the 5-HT2A receptor distribution and density in guinea pig brain has not been extensively studied. In the present in vitro study, we have utilized 125I-lysergic acid diethylamide ([125I]LSD) to quantify and compare 5-HT2A receptor density in coronal sections of rat and guinea pig brain. Spiperone (1 microM) and sulpiride (1 microM) were used to displace [125I]LSD binding from 5-HT2A and D2 binding sites, respectively. Ligand binding was quantified by computer-aided image analysis densitometry (MCID). Similar to the rat, areas of highest specific 5-HT2A receptor binding (fmol/mg protein) in guinea pig brain included the claustrum and Layer 4 of the cerebral cortex. Significant binding was also found in remaining neocortical layers, islands of Calleja, caudate putamen, olfactory bulb, nucleus accumbens, and choroid plexus. While the rat brain exhibited a high level of specific binding in the tenia tecta and mammillary nuclei, little binding was observed in these regions in the guinea pig. In both rat and guinea pig, low specific binding was found in amygdaloid, thalamic, or cerebellar areas. These studies indicate a general similarity between 5-HT2A binding site distribution and relative density in guinea pig and rat brain but point to a few brain regions where significant differences exist.

Animals↗
PubMed1994

5-HT4 receptors in rat but not guinea pig, rabbit or dog esophageal smooth muscle.

1. Marked heterogeneity among species exists in the esophageal response to pharmacological agents. The present study compared the response to serotonin in esophagus from the rat, guinea pig, rabbit and dog. 2. The esophagus from all four species contracted to carbamylcholine and to PGF2 alpha; responses to serotonin were the most variable among species. 3. Serotonin contracted the guinea pig and rabbit esophagus; an effect blocked by LY53857 (10(-7 M) and ketanserin (10(-7) M), consistent with 5-HT2 receptor activation mediating this contraction. 4. Serotonin neither contracted nor relaxed the canine esophagus and relaxed the rat esophagus via 5-HT4 receptor activation as determined by antagonism with ICS 205-930 (-log KB = 6.4), metoclopramide (-log KB = 6.7) and its ester congener SDZ 205-557 (-log KB = 7.9). Two methylene homologs of SDZ 205-557 also had high 5-HT4 receptor affinity (-log KB = 7.7). 5. Thus, in guinea pig and rabbit esophagus, serotonin induced a contraction mediated by 5-HT2 receptors; and serotonin neither contracted nor relaxed the canine esophagus. In rat esophagus, serotonin induced a relaxation mediated by activation of 5-HT4 receptors.

Animals↗
PubMed1994

Antimicrobial resistance: prognosis for public health.

Antimicrobial resistance poses a significant threat to public health worldwide, with certain infections already being untreatable with antibiotics. Increasing resistance is resulting from antimicrobial use coupled with various epidemiological factors that enhance transmission of drug-resistant organisms, and the problem is likely to worsen. Control of antimicrobial resistance is feasible, but will be difficult.

Community-Acquired Infections↗
PubMed1994

Emerging problems of antimicrobial resistance.

The incidence of organisms resistant to various antimicrobial agents has risen over the last several years, resulting in an increase in morbidity and mortality and overall treatment costs. The emergence of virtually untreatable infections has focused the medical community's attention on this issue. This paper reviews common pathogens (both nosocomial and community-acquired infections) that have become resistant to antimicrobial drugs. Approaches that may prevent or retard the development, of resistance among these organisms are discussed.

Community-Acquired Infections↗
PubMed1994

Disruption of potential alpha-helix in the G loop of the guinea pig 5-hydroxytryptamine2 receptor does not prevent receptor coupling to phosphoinositide hydrolysis.

Heterogeneity of the 5-hydroxytryptamine2 (5-HT2) receptor across species has been implicated in several pharmacological and physiological studies. Although 5-HT2 receptors in the rat have been linked to increases in phosphoinositide (PI) hydrolysis, little evidence exists to support the association of guinea pig 5-HT2 receptors with PI hydrolysis, the second messenger generally linked with 5-HT2 receptors. In the present study, we have taken a molecular and biochemical approach to determining whether species differences in brain 5-HT2 receptors exist between rat and guinea pig. First, we isolated partial cortical 5-HT2 receptor cDNA clones that encompassed the third intracellular loop, a receptor area putatively important in receptor-effector coupling. The amino acid sequences deduced from the cDNA clones for rat and guinea pig brain 5-HT2 receptor were 97% homologous. However, the guinea pig 5-HT2 receptor had two tandem substitutions that disrupted a potential alpha helix in the region of the third cytoplasmic loop, which theoretically could alter the intracellular coupling of the guinea pig cortical 5-HT2 receptor. Because of these molecular differences, we examined further the pharmacological activation of the brain 5-HT2 receptor from guinea pig. 5-HT and the 5-HT2 receptor agonist alpha-methyl-5-HT increased PI hydrolysis in guinea pig cortical slices whereas the 5-HT1C receptor agonist 5-methyltryptamine was significantly less potent. In addition, the 5-HT2 receptor antagonists LY53857, ketanserin, and spiperone blocked 5-HT-stimulated PI hydrolysis. These pharmacological data suggested that activation of the 5-HT2 receptor in guinea pig cortical slices was associated with PI hydrolysis. Thus, although areas of the guinea pig brain 5-HT2 receptor that influence receptor-effector coupling were different from the rat, such differences were not critical to receptor-effector coupling because, as in the rat, guinea pig brain 5-HT2 receptors were also coupled to PI hydrolysis.

Amino Acid Sequence↗
PubMed1994

Referred pain of peripheral nerve origin: an alternative to the "myofascial pain" construct.

The theory of myofascial pain syndrome (MPS) has been constructed around the trigger point (TrP), a region within a muscle from which local and remote pain can be evoked by palpation. Although their pathophysiology is obscure, TrPs have been regarded as the cause of myofascial pain. Spread and chronicity of pain are attributed to the activation of latent, secondary, and satellite TrPs. Although it lacks internal validity, this tautological concept has given rise to a system of empirical treatment that has been uncritically accepted by many. However, not only does the anatomical distribution of pain referred from TrPs bear a close relationship to the course of peripheral nerves, but the pain of MPS is also similar to nerve trunk pain, which is an example of somatic referred pain. Pain of peripheral nerve origin can be present without neurological deficit and with normal findings on conventional electrodiagnostic examination. In contrast to the theory of MPS, which considers the TrPs to be sites of primary hyperalgesia, this article argues that all MPS phenomena are better explained as secondary hyperalgesia of peripheral neural origin.

Humans↗
PubMed1994

Comparative 5-HT2-receptor antagonist activity of amesergide and its active metabolite 4-hydroxyamesergide in rats and rabbits.

Amesergide is an orally active ergoline amide, 5-HT2-receptor antagonist with a long duration of action. Since a major metabolite of amesergide is 4-hydroxyamesergide, we questioned whether the formation of this metabolite might contribute to the pharmacological activity and long duration of action observed after oral administration of amesergide. 4-Hydroxyamesergide was a potent 5-HT2-receptor antagonist with an affinity equal to or greater than amesergide under in-vitro conditions as measured by blockade of vascular 5-HT2 receptors, and 5-hydroxytryptamine (5-HT)-amplified ADP-induced rabbit platelet aggregation. Furthermore, 4-hydroxyamesergide, like amesergide, inhibited the pressor response to 5-HT after its intravenous administration to rats and was about 3-fold more potent than amesergide in this regard. 4-Hydroxyamesergide was also a potent inhibitor of vascular 5-HT2 receptors after oral administration to rats. After oral administration, 4-hydroxyamesergide had a similar or slightly greater duration of activity than the parent molecule. 4-Hydroxyamesergide, again like amesergide, also blocked central 5-HT2 receptors after its in-vivo administration to rats as measured by its ability to inhibit quipazine-induced increases in serum corticosterone. Thus, the formation of 4-hydroxyamesergide after oral administration of amesergide to animals and man may contribute to the potency and long duration of action of amesergide as a 5-HT2-receptor antagonist.

Adenosine Diphosphate↗
PubMed1994

Selective desensitization of 5-hydroxytryptamine 2A receptor mediated contraction in guinea pig trachea.

5-Hydroxytryptamine (serotonin, 5-HT) contracts the guinea pig trachea through stimulation of 5-HT2A receptors, an effect previously reported to rapidly desensitize. The present studies were designed to examine further the putative desensitization to serotonin. In vitro studies investigating functional desensitization of the guinea pig tracheal 5-HT2A receptor documented that 5-HT (3 x 10(-7) M) significantly (50%) but incompletely reduced subsequent tracheal maximal contraction to 5-HT. In contrast, an equieffective concentration of carbamylcholine (3 x 10(-8) M) did not reduce guinea pig tracheal contraction to 5-HT. Furthermore, 5-HT (3 x 10(-7) M) did not diminish tracheal contraction to carbamylcholine. These data indicate that 5-HT can selectively desensitize guinea pig tracheal contraction to 5-HT. In addition, 5-HT-induced contraction but not carbamylcholine-induced contraction in guinea pig trachea declined over time, an effect that was more pronounced at high concentrations of 5-HT (1 x 10(-6) and 1 x 10(-5) M). Inhibitors of mechanisms that oppose contractility to 5-HT (5-HT-induced relaxation, uptake of 5-HT, or metabolism of 5-HT) did not reverse the decline in contraction to 5-HT (1 x 10(-5) M). The decline in 5-HT-induced contraction was most rapid in the guinea pig trachea and less so in the rat jugular vein and rat aorta, two preparations in which 5-HT induced contraction also occurred via activation of 5-HT2A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Transcatheter intrapleural urokinase for loculated pleural effusion.

Two patients who had undergone coronary artery bypass graft surgery in the mid-1980s and who had repeat coronary artery bypass graft procedures in 1992 developed loculated, bloody pleural effusions. Percutaneous catheter drainage and installation of intrapleural urokinase led to resolution of these loculated effusions without morbidity. This procedure should reduce the length of hospitalization and treatment for patients with loculated pleural effusions.

Aged↗
PubMed1994

Contractile serotonin-2A receptor signal transduction in guinea pig trachea: importance of protein kinase C and extracellular and intracellular calcium but not phosphoinositide hydrolysis.

Serotonin (5-HT) contracts the guinea pig trachea through stimulation of the 5-HT2A receptor, a receptor generally linked with phosphoinositide (PI) hydrolysis. However, previous limited evidence suggested that 5-HT did not increase PI hydrolysis in guinea pig trachea. The present studies confirmed that the 5-HT2A receptor is not coupled to PI hydrolysis and investigated the calcium source and involvement of protein kinase C (PKC) in 5-HT-induced contraction in guinea pig trachea. In vitro experiments, which used an enriched tracheal muscle preparation, confirmed the inability of 5-HT (10(-10) to 10(-2) M) to increase PI hydrolysis. Short incubations (1-60 min) of the trachea with 5-HT (10(-4) M) to minimize possible 5-HT2A receptor desensitization did not increase PI hydrolysis, whereas carbamylcholine (10(-7) to 10(-3) M) and histamine (10(-7) to 10(-4) M) did. These results demonstrate that, unlike most other 5-HT2A receptors, the 5-HT2A receptor in guinea pig trachea is not coupled to PI hydrolysis. The L-type calcium channel antagonists nitrendipine (10(-6) and 10(-5) M) and diltiazem (5 x 10(-5) M) significantly blocked maximal tracheal contraction to 5-HT (45-60%) inhibition) but not to carbamylcholine. The maximal response to 5-HT in calcium-free buffer (0 calcium, 0.05 mM EGTA) was also inhibited by 56%. The residual contraction to 5-HT in the absence of extracellular calcium suggested that at least a portion of the nitrendipine-insensitive 5-HT contraction was due to the release of intracellular calcium. In support of this idea, ryanodine (3 x 10(-5) M), a compound known to deplete intracellular calcium stores, depressed maximal 5-HT contraction in the presence of either nitrendipine or diltiazem. Neither calphostin C (4 x 10(-8) and 10(-6) M) or staurosporine (10(-8) M), both putative PKC inhibitors, affected tracheal contraction to 5-HT. However, the PKC inhibitor bisindolylmaleimide (5 x 10(-6) M), which abolished contraction to phorbol 12,13-dibutyrate (10(-6) M), unlike calphostin C, inhibited contraction to 5-HT in both the absence and presence of nitrendipine. This finding suggests that PKC activation is involved in 5-HT contraction. Thus, the tracheal 5-HT2A receptor is unique in that activation of the receptor does not result in PI hydrolysis but increases calcium influx through L-type voltage-dependent calcium channels, calcium release from the sarcoplasmic reticulum and activation of a bisindolylmaleimide-sensitive PKC.

Alkaloids↗
PubMed1994

Use of the mouse vas deferens to determine mu, delta, and kappa receptor affinities of opioid antagonists.

The present study was designed to identify a single smooth muscle preparation possessing mu, delta, and kappa receptors that can be used in the development of opioid selective antagonists. In vitro studies with the mouse vas deferens indicated that the delta selective agonists, DPLPE and DSLET, had potent agonist activity (ED50 approximately 1 nM) to inhibit the twitch response. The mu selective agonists, normorphine and fentanyl, also inhibited the twitch response in the mouse vas deferens, but were approx 100-fold less potent than the delta selective agonists, consistent with the enrichment of this preparation with delta receptors. U50,488, a kappa selective agonist, also inhibited the twitch response with a potency similar to that of the mu agonists. Naloxone, MR 2266, and WIN 44,441 all antagonized the agonist activity of U50,488 with antagonist dissociation constants distinct from those calculated using mu or delta receptor agonists. To confirm the presence of all three opioid receptors in this preparation, we examined a series of 14 phenylpiperidine opioid antagonists. An excellent correlation was observed between affinities of these piperidine opioid antagonists at mu and kappa receptors determined via radioligand binding studies, and affinities determined by blockade of fentanyl- or U50,488-induced twitch inhibition. Of the piperidine opioid antagonists studied, two possessed relatively high kappa receptor antagonist affinity. Furthermore, the study of an enantiomeric pair of an N-substituted 4-phenylpiperidine derivative demonstrated differences in absolute configuration to be more important for binding at mu and delta than kappa receptors. Thus, we have established the presence of kappa, in addition to the known mu and delta receptors, in the mouse vas deferens, and identified certain piperidines to have high kappa receptor antagonist affinity.

Animals↗
PubMed1994

Serotonin-induced pulmonary responses are mediated by the 5-HT2 receptor in the mouse.

C57BL/6 mice exhibit acute transient decreases in lung conductance (GL) and dynamic compliance (Cdyn) after intravenous administration of serotonin (5-HT). To identify the specific agonist receptor subtypes responsible for this bronchoconstriction, we measured changes in pulmonary function in C57BL/6 mice in response to intravenous infusion of 5-HT receptor subtype-selective agonists and to 5-HT in the presence of antagonists selective for the 5-HT2 or 5-HT3 receptor subtypes. Agonists selective for the 5-HT1A/1B/1D or 5-HT3 receptor subtypes induced minimal or undetectable pulmonary responses, whereas infusion of alpha-methyl-5-hydroxytryptamine, a 5-HT2 receptor-selective agonist, led to dose-related decreases in Cdyn and GL. The selective 5-HT3 receptor antagonist, LY278584 maleate, (1.0 mg/kg i.v.) caused no detectable reduction in the response to 100 micrograms/kg of 5-HT. In contrast, treatment with the 5-HT2 receptor antagonist LY53857 (10 micrograms/kg i.v.) resulted in a significant diminution of the pulmonary response observed after infusion of 100 micrograms/kg of 5-HT. Dose-response relationships were established for 5-HT in experiments in which each mouse was treated with a single dose of 5-HT without antagonist or after LY53857. Compared with responses to doses of 5-HT of more than 100 micrograms/kg in the absence of antagonist, pulmonary responses to 5-HT after infusion of 10 micrograms/kg of LY53857 were significantly reduced; 100 micrograms/kg of LY53857 nearly abolished the responses to all doses of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Fibromyalgia syndrome, a problem of tautology.

Fibromyalgia syndrome is generally taken to denote a clinical state of widespread musculoskeletal pain, stiffness, and fatigue but its pathophysiology, physical and psychological, is unknown, and the nature of the diagnostically mandatory "tender points" remains obscure. Diagnostic criteria convey no pathophysiological insight and they have been "validated" via a circular argument in which the evidence on which the construct is based is taken as proof of its veracity. The concept of fibromyalgia syndrome is valid only in the sense that it includes all possibilities. An alternative approach to this very real clinical presentation is via secondary hyperalgesia.

Fibromyalgia↗
PubMed1993

Amesergide and structurally related nor-D-ergolines: 5HT2 receptor interactions in the rat.

A series of tricyclic (nor-D) partial ergolines were synthesized via a highly convergent enantiospecific strategy, ultimately arising from a racemic tricyclic ketone. Michael addition to an acrylamide, followed by reductive methylation, afforded the key intermediate. Selective deprotection and oxidation provided the tricyclic ergoline. Vascular 5HT2 receptor interactions for the partial ergolines were dramatically reduced compared to the parent ergoline, amesergide, as determined in vivo by activation of a pressor response or blockade of 5HT-induced pressor responses in pithed rats. The desisopropyl tricyclic ergolines possessed some modest pressor activity that was unlikely to be related to 5HT2 receptor activation since these compounds did not inhibit the pressor response to serotonin. In contrast, the isopropyl tricyclic ergolines exhibited no agonist activity, but inhibited the pressor response to serotonin at 1 mg/kg i.v. The ergoline amesergide inhibited the pressor response to serotonin in doses of 0.01-0.1 mg/kg i.v. The homochiral isopropyl tricyclic ergoline was more potent as a 5HT2 receptor antagonist than the epimeric (unnatural stereochemistry) analogue. Thus, the isopropyl moiety on the indole nitrogen is important for vascular 5HT2 receptor affinity in the rat. Most importantly, these data suggest that conformational rigidity of the ergoline D-ring is required for optimal 5HT2 receptor interactions in the rat.

Animals↗
PubMed1993

Improvement of yellow nail syndrome with oral zinc supplementation.

An unusual case of yellow nail syndrome (YNS) is reported. Total resolution of yellow nails and lymphoedema was observed following oral zinc supplementation for 2 years. A few years later, the patient developed a classical seropositive rheumatoid arthritis (RA). YNS, alone or associated with RA remains a rare clinical condition. The reported beneficial effects of zinc supplementation in YNS, as well as in several other pathological conditions, raise interest about the role of this trace element and its potential therapeutic implications and suggest further investigations are necessary.

Administration, Oral↗