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Biomedical subjects

M L Cohen

Publications and source records attributed to M L Cohen.

At least 19 recordsLinked to original sources
PubMed1995

Role of alpha 1-adrenoceptors and 5-HT2 receptors in serotonin-induced contraction of rat prostate: autoradiographical and functional studies.

Urinary obstruction from benign prostatic hyperplasia is a common clinical problem possibly associated with excessive prostatic constriction around the urethra. These studies compared adrenergic and serotonergic functional activity to specific alpha 1 and serotonin (5-hydroxytryptamine; 5-HT) binding sites in the rat prostate. Isolated, left ventral lobes of the rat prostate were removed and examined for in vitro contraction. Norepinephrine-induced contraction of the rat prostate was competitively blocked by prazosin with an apparent antagonist dissociation constant (pKB) of 8.13. 5-HT also contracted the rat prostate. However, in the presence of prazosin, maximum 5-HT contraction was reduced by half suggesting that high concentrations of 5-HT can activate alpha 1 receptors in the prostate. The concentration-response curve to 5-HT in the presence of 1 microM prazosin was competitively inhibited by the 5-HT2 receptor antagonist LY53857 (6-methyl-1-(1-methylethyl)ergoline-8-carboxylic acid 2-hydroxyl-1-methylpropylester (Z)-2-butenedioate (1:1)) (pKB = 9.02). Autoradiographic studies with [125I]LSD (2-iodo-lysergic acid diethylamide) documented the presence of 5-HT2 receptors since significant displacement of the radioligand occurred with 5-HT and LY53857, but not with prazosin. The alpha 1-adrenoceptor ligand [125I]HEAT ([beta-(4-hydroxy-3-iodophenyl)ethylaminomethyl]-tetralone) confirmed the presence of alpha 1-adrenoceptors in the rat prostate since significant displacement of the radioligand occurred with prazosin, but not 5-HT or LY53857. The inability of prazosin to displace [125I]LSD and the inability of 5-HT to displace [125I]HEAT suggest that 5-HT cannot directly interact with alpha 1-adrenoceptors in the prostate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1995

Hemolytic uremic syndrome with particular involvement of basal ganglia and favorable outcome.

Two children with hemolytic uremic syndrome and extrapyramidal complications are presented. Neuroimaging studies demonstrated bilateral basal ganglia (striatal) involvement with favorable recovery in both patients. The pathophysiology of the neurologic complications in hemolytic uremic syndrome are probably multifactorial. Our patients suggest a reversible process because both patients recovered clinically and radiographically. Neurologic complications do not always portend a poor prognosis and, in general, involvement of the basal ganglia is associated with favorable outcome.

Basal Ganglia↗
PubMed1995

American National Standard for nonautomated sphygmomanometers. Summary report.

The Association for the Advancement of Medical Instrumentation develops voluntary standards for medical devices so that manufacturers might provide information on their product and basic safety and performance criteria that should be considered in qualifying the instrument for clinical use. American National Standards are generated through a consensus process by committees of experts in research, development, and design from user, industry, and government communities. Draft standards are made available for public review and become American National Standards after review by the American National Standards Institute. This report is a summary of the American National Standard that establishes both the safety and performance requirements of pneumatic and other nonautomated sphygmomanometers (especially mercury gravity and aneroid sphygmomanometers) used in the indirect measurement of blood pressure. This standard was developed by a consensus panel from academia, industry, and government; it updates the previous standard approved by the American National Standards Institute in 1986. This summary report does not cover all of the provisions of the revised 1994 American National Standard, thus users, researchers, and instrument designers should refer to the standard for detailed requirements.

Blood Pressure Determination↗
PubMed1995

NF2 gene analysis distinguishes hemangiopericytoma from meningioma.

The histogenesis of dural-based or "central" hemangiopericytomas (cHPCs) remains controversial. Some authors consider these tumors variants of meningiomas while others consider them akin to peripheral hemangiopericytomas (pHPCs). Meningiomas frequently have mutations in the neurofibromatosis 2 (NF2) gene, providing a molecular marker for meningiomas and other NF2-related tumors. We therefore analyzed the NF2 gene in cHPCs, pHPCs, and meningiomas to determine whether cHPCs are more similar at the molecular genetic level to meningiomas or pHPCs. Using paraffin-embedded archival material from 28 cHPCs (including three primary and recurrent tumors), 10 pHPCs, and 26 meningiomas, we scanned all 17 exons of the NF2 gene and flanking intronic sequences for mutations with single strand conformation polymorphism analysis and DNA sequencing. No NF2 mutations were found in either cHPCs or pHPCs, whereas 35% of meningiomas had NF2 gene alterations (P < 0.001). The NF2 gene mutations in meningiomas were all truncating mutations, consistent with previous studies. Our findings suggest that cHPCs are distinct from meningiomas at the molecular genetic level and support prior clinico-pathological data that distinguish these tumor-entities.

Adult↗
PubMed1995

Antagonism of serotonin3 (5-HT3) receptors within the blood-brain barrier prevents cisplatin-induced emesis in dogs.

Recently discovered serotonin3 (5-HT3) receptor antagonists are potent antiemetics in cytotoxic drug-induced vomiting. The specific site where 5-HT3 receptor antagonists act to abolish emesis is controversial. The major objective of this study was to determine whether the antiemetic effect of 5-HT3 receptor antagonists is exerted in the brain areas that reside inside or outside of the blood-brain barrier. Tropisetron, zatosetron (LY277359 maleate) and its quaternary analog zatosetron-QUAT were used in this study. Zatosetron and zatosetron-QUAT showed high affinity and selectivity for 5-HT3 receptors in radioligand binding studies. Both compounds antagonized 5-HT-induced bradycardia in rats with an approximate ID50 of 0.7 and 0.2 microgram/kg i.v., respectively. Zatosetron and tropisetron significantly inhibited cisplatin-evoked emesis in dogs (estimated ID50 values of 34.4 +/- 2.3 micrograms/kg and 108.3 +/- 4.8 micrograms/kg i.v., respectively). Zatosetron-QUAT (0.01-1.0 mg/kg i.v.) had no effect. [14C]-zatosetron-QUAT (100 micrograms/kg) was not detected in the brain after i.v. administration to rats, consistent with the inability of charged compounds to achieve significant brain concentrations. However, i.c.v. administration (100 ng/kg) of zatosetron-QUAT reduced emetic episodes significantly (11.6 +/- 1.6 vs. 2.8 +/- 1.2). These studies suggest that, in dogs, antagonism of 5-HT3 receptors located within the blood-brain barrier is important to block cisplatin-induced emesis.

Animals↗
PubMed1995

5-Hydroxytryptamine2B receptor signaling in rat stomach fundus: role of voltage-dependent calcium channels, intracellular calcium release and protein kinase C.

The rat stomach fundus is enriched with the 5-hydroxytryptamine (5-HT)2B receptor, the newest subtype of the 5-HT2 receptor family to be cloned. Although the 5-HT2A and 5-HT2C receptor subtypes couple to phosphatidylinositol hydrolysis, such a coupling has not been established for the 5-HT2B receptor in tissues. Thus, the purpose of this study was to characterize further the signal transduction mechanism of the 5-HT2B receptor in rat stomach fundus. Nitrendipine (1 microM) inhibited the maximal contraction to 5-HT (1 microM) by approximately 50%. Removal of extracellular calcium did not inhibit 5-HT contraction to a greater extent than that produced by nitrendipine, indicating that calcium influx through voltage-dependent calcium channels was predominantly responsible for the dependence of the 5-HT contraction on extracellular calcium. Depletion of both extracellular calcium and intracellular calcium stores abolished 5-HT contraction. Ryanodine (30 microM), a compound which inhibits calcium release from intracellular stores, significantly inhibited the maximal contraction to carbamylcholine (3 microM). In contrast, ryanodine (30 microM) did not inhibit the maximal contraction to 5-HT (1 microM) in the absence of nitrendipine. However, ryanodine (30 microM) did significantly inhibit the nitrendipine-insensitive 5-HT contraction, suggesting that this component of the contraction was due in part to calcium release from a ryanodine-sensitive store. Bisindolylmaleimide (5 microM), a specific inhibitor of protein kinase C (PKC), inhibited 5-HT contraction in either the absence or presence of nitrendipine, suggesting that activation of PKC is also involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Is the "atypical" beta-receptor in the rat stomach fundus the rat beta 3 receptor?

The rat gastric fundus is known to possess an "atypical" beta-adrenergic receptor that mediates relaxation to isoproterenol. The purpose of this study was to characterize the relationship between this "atypical" beta receptor in the rat stomach and the cloned rat beta 3 receptor by taking advantage of highly selective pharmacological and molecular biological probes of the beta 3 receptor. Nuclease protection analysis of RNA from the rat gastric fundus identified beta 3 receptor mRNA whose levels in the stomach were exceeded only by those in adipose tissue. Pharmacological analysis of the recombinant rat beta 3 receptor expressed in Chinese hamster ovary cells indicated low affinity of propranolol with a Ki value of 2.3 microM. Therefore, 0.3 microM propranolol was chosen as a concentration that would completely block beta 1 and beta 2 receptors (Ki = 1-5 nM) but would leave beta 3 receptors largely intact in the rat stomach fundus. In the presence of propranolol, several beta-adrenergic receptor agonists relaxed the rat stomach fundus with a rank potency order of (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3- benzodioxole-2,2-dicarboxylate (CL316,243) > isoproterenol > norepinephrine = epinephrine = dl-4-3[(1,1-dimethylethyl)amino]-2- hydroxylproproy]1,3 dihydro-2H-benzimidazol-2-one hydrochloride (CGP12177) > clenbuterol > terbutaline > pindolol. Isoproterenol, norepinephrine and epinephrine were full agonists, whereas (R,R)-5-[2-[[2-(3-chlorophenyl)-2- hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylate was only a partial agonist with 66% intrinsic activity relative to isoproterenol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1994

Age-related alterations in sensitivity of muscarinic and serotonergic responses of guinea pig trachea to removal of extracellular Ca2+.

Contractile responses to carbamylcholine and 5-hydroxytryptamine (5-HT) in the presence and absence of extracellular Ca2+ were compared in tracheal rings from 3-4-week-old and 7-8-week-old guinea pigs. Contraction to carbamylcholine and 5-HT did not differ in potency or maximal response between age groups in the presence of extracellular Ca2+. However, removal of extracellular Ca2+ inhibited maximal contraction mediated by both agonists to a greater extent in younger versus older guinea pigs. These data suggest that carbamylcholine- and 5-HT-induced contraction of guinea pig trachea from younger animals is more dependent on extracellular Ca2+ as compared to mature animals, and may be related to an age-dependent maturation of sarcoplasmic reticulum function in smooth muscle.

Aging↗
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↗