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Biomedical subjects

R A Cohen

Publications and source records attributed to R A Cohen.

At least 19 recordsLinked to original sources
PubMed1992

Endothelium-derived nitric oxide and cyclooxygenase products modulate corpus cavernosum smooth muscle tone.

Relaxation of penile corpus cavernosum smooth muscle is controlled by nerve and endothelium derived substances. In this study, endothelium-dependent relaxation of corporal smooth muscle was characterized and the role of arachidonic acid products of cyclooxygenase in endothelium-dependent relaxation was examined. Endothelium removal from rabbit corpora was performed by infusion with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate and was confirmed by transmission electron microscopy. Strips of human and rabbit corporal tissues were studied in the organ chambers for isometric tension measurement. The accumulation of cyclic guanosine monophosphate (cGMP) and the release of eicosanoids from corporal tissue was measured by radioimmunoassay and correlated to smooth muscle relaxation. Our study showed that relaxation of corpus cavernosum tissue to acetylcholine, bradykinin and substance P was endothelium-dependent; potentiated by indomethacin; and inhibited by NG-monomethyl-L-arginine, methylene blue or LY83583. Relaxation to papaverine and sodium nitroprusside was endothelium-independent, and unaffected by NG-monomethyl-L-arginine. Relaxation to vasoactive intestinal polypeptide was partially endothelium-dependent; potentiated by indomethacin; attenuated by NG-monomethyl-L-arginine or methylene blue. The tissue level of cGMP was enhanced by acetylcholine and nitric oxide. Methylene blue inhibited both basal and drug-stimulated levels of cGMP. The release of eicosanoids was enhanced by acetylcholine and blocked by indomethacin. In conclusion, nitric oxide or a closely related substance accounts for the activity of endothelium-derived relaxing factor in the corporal tissue. Inhibition of the release of eicosanoids potentiates the relaxing effect of nitric oxide. Nitric oxide increases tissue cGMP which appears to modulate corporal smooth muscle relaxation.

Acetylcholine↗
PubMed1992

EDTA influences reactivity of isolated aorta from hypercholesterolemic rabbits.

The effects of the trace metal chelator, ethylenediaminetetraacetic acid (EDTA), on endothelium-dependent reactivity of isolated aorta from normal and hypercholesterolemic rabbits were studied. Rings of abdominal aorta were mounted in organ chambers for measurement of isometric force and incubated in physiological salt solution with or without EDTA (26 microM). Aortic rings were obtained from rabbits fed a standard diet or a diet enriched with 0.5% cholesterol and 4% peanut oil for 10 wk. In rabbits fed the standard diet, endothelium-dependent relaxations to acetylcholine and A23187 were not significantly different in rings incubated in physiological salt solution with or without EDTA. In aortic rings from cholesterol-fed rabbits incubated in physiological salt solution with EDTA, the relaxations caused by either acetylcholine or A23187 were not significantly impaired compared with rings from rabbits fed a standard diet. Only in rings incubated in the absence of EDTA did hypercholesterolemia significantly inhibit endothelium-dependent relaxation compared with control rabbits. Relaxations to sodium nitroprusside were not different in rings incubated with or without EDTA in either group. Thus the effect of hypercholesterolemia on endothelium-dependent reactivity of rabbit aorta depends on the in vitro experimental conditions. This study emphasizes the importance of including a metal chelator in physiological solutions used in the in vitro study of blood vessels from hypercholesterolemic animals.

Animals↗
PubMed1992

Role of superoxide anion and endothelium in vasoconstrictor action of prostaglandin endoperoxide.

The vasoconstrictor actions of prostaglandin (PG) endoperoxide, PGH2, were examined in isolated rabbit aortic rings suspended for measurement of isometric tension. In aortic rings with an intact endothelium, PGH2 caused concentration-dependent contractions which were blocked by SQ 29548 (a PGH2-thromboxane A2 receptor blocker) or superoxide dismutase (a superoxide anion scavenger) but not by carbethoxyhexyl imidazole (a thromboxane A2 synthase inhibitor) or catalase (a hydrogen peroxide scavenger). In contrast U 46619, a thromboxane A2 mimic, caused contractions, which were blocked by SQ 29548 but not by superoxide dismutase. PGH2 caused significantly greater contractions in aortic rings without endothelium or in those with intact endothelium treated with NG-nitro-L-arginine, a nitric oxide inhibitor; these contractions were inhibited by SQ 29548 but not by superoxide dismutase. In aortic rings with endothelium contracted with phenylephrine, a subthreshold concentration of PGH2, but not U 46619, impaired relaxations to acetylcholine; the inhibition was prevented by treatment with SQ 29548 or superoxide dismutase, indicating that the abnormality of endothelial cell function was specific for PGH2. These observations indicate that PGH2 causes contractions and inhibits endothelium-dependent relaxation by a mechanism involving formation of superoxide anion, which interacts with endothelium-derived nitric oxide.

Acetylcholine↗
PubMed1992

Free radicals mediate endothelial cell dysfunction caused by elevated glucose.

Impaired endothelium-dependent relaxation occurs in diabetic rabbit aorta and normal aorta exposed to elevated concentrations of glucose and is prevented by cyclooxygenase inhibitors. The role of free radicals in the endothelial cell impairment was examined with free radical scavengers and in aortas from rabbits fed with probucol (1% wt/wt, a lipid-soluble antioxidant). Rings of aorta suspended for measurement of isometric tension were incubated for 6 h in control (5.5 mM) or elevated (44 mM) glucose. Impairment of endothelium-dependent relaxation to acetylcholine caused by exposure to elevated glucose was prevented by superoxide dismutase, catalase, deferoxamine, or allopurinol and did not occur in aortas from probucol-fed rabbits. Similarly, impairment of acetylcholine relaxations in aortas from alloxan-induced diabetic rabbits was restored to normal by superoxide dismutase. Oxygen-derived free radicals generated by xanthine oxidase also caused impaired acetylcholine relaxations. Exposure of aortic segments to elevated glucose or to xanthine oxidase caused a significant increase in release of immunoreactive prostanoids. These data indicate that the endothelial cell dysfunction caused by elevated glucose is mediated by free radicals that are likely generated through the increased cyclooxygenase catalysis occurring in the endothelium. Treatment with antioxidants protects against impaired endothelium-dependent relaxations caused by elevated glucose.

Animals↗
PubMed1992

Platelet-derived growth factor receptors on macrovascular endothelial cells mediate relaxation via nitric oxide in rat aorta.

The effects of platelet-derived growth factor (PDGF) were studied in isolated rings of rat aorta contracted submaximally to phenylephrine. The BB isoform of PDGF elicited relaxation in rings with endothelium and further contraction in rings without endothelium. Both the endothelium-dependent relaxation and endothelium-independent contraction occurred at concentrations known to induce PDGF receptor-mediated responses in cultured cells. Furthermore, the relaxation was isoform specific. This conclusion is supported by the unique ability of PDGF-BB to induce endothelium-dependent relaxations, as well as by studies showing isoform specific, concentration-dependent desensitization of PDGF-BB relaxation. The relaxation induced by PDGF-BB was prevented by N omega-nitro-L-arginine. It was also observed that endothelium-independent contractions to the AB and AA isoforms of PDGF were less than those to PDGF-BB. Contrary to the widely held view that PDGF receptors are not present on the endothelium of macrovessels, these studies provide evidence for an endothelium-dependent, nitric oxide mediated relaxation of rat aorta caused by PDGF via PDGF beta beta-receptors.

Animals↗
PubMed1992

Endothelium-dependent inhibition of Na(+)-K+ ATPase activity in rabbit aorta by hyperglycemia. Possible role of endothelium-derived nitric oxide.

Hyperglycemia has been shown to diminish Na(+)-K+ ATPase activity in rabbit aorta. To examine the basis for this effect, aortic rings were incubated for 3 h in Krebs-Henseleit solution containing 5.5 or 44 mM glucose, and Na(+)-K+ ATPase activity was then quantified on the basis of ouabain-sensitive (OS) 86Rb-uptake. Incubation with 44 mM glucose medium caused a 60% decrease in Na(+)-K+ ATPase activity in rings with intact endothelium (from 0.22 +/- 0.01 to 0.091 +/- 0.006 nmol/min per mg dry wt; P less than 0.01). Similar decreases (45%; P less than 0.01) in Na(+)-K+ ATPase activity were seen when rings incubated with 5.5 mM glucose were exposed to NG-monomethyl L-arginine (300 microM), an inhibitor of endothelium-derived nitric oxide (EDNO) synthesis or when the endothelium was removed (43% decrease). The decrease in Na(+)-K+ ATPase activity induced by hyperglycemia was totally reversed upon adding to the medium either L-arginine, a precursor of EDNO biosynthesis or sodium nitroprusside, which bypasses endothelium and directly activates the soluble guanylate cyclase in vascular smooth muscle. A decrease in Na(+)-K+ ATPase activity (42%; P less than 0.05), only seen in the presence of endothelium, was also observed in aortas taken directly from alloxan-induced diabetic rabbits. These studies suggest that the decrease in vascular Na(+)-K+ ATPase activity induced by hyperglycemia is related, at least in part, to a decrease in the basal release of EDNO. They also suggest that alterations in basal EDNO release and possibly Na(+)-K+ ATPase activity contribute to the impairment in vascular relaxation caused by hyperglycemia and diabetes.

Animals↗
PubMed1992

The relationship between disability and memory dysfunction in multiple sclerosis.

We examined the relationship between memory impairment and functional disability in multiple sclerosis. Tests of memory, sensorimotor ability, and functional capacity were administered to fifty-six subjects with chronic-progressive or remitting-relapsing MS. Sensorimotor impairment, functional disability, and chronicity predicted impairment on various measures of memory acquisition, while age and type of diagnosis did not. After accounting for the effects of initial acquisition, delayed-recall performance was weakly-associated with disability. We suggest that: (1) Functional disability is associated with memory loss in MS; (2) MS-forgetting is caused by defective acquisition, rather by a deficit in consolidation or storage; (3) Level of disease activity, rather than type of MS diagnosis, determines the degree of memory impairment; and (4) MS disability needs to be evaluated multidimensionally, to account for both neurologic and functional impairment.

Activities of Daily Living↗
PubMed1992

Aldose reductase and myo-inositol in endothelial cell dysfunction caused by elevated glucose.

A possible relationship between aldose reductase activity and myo-inositol levels and endothelium-dependent relaxations was examined in isolated rabbit aorta incubated with elevated concentrations of glucose (44 mM) for 6 hr to mimic hyperglycemic conditions. Rings of aorta incubated in elevated glucose and contracted submaximally by phenylephrine showed significantly decreased endothelium-dependent relaxations induced by acetylcholine compared with aorta incubated in control (5.5 or 11 mM) glucose. Acetylcholine-induced relaxations of aorta incubated in hyperosmotic mannitol (44 mM) were not different from those incubated in control glucose. Treatment with two structurally unrelated aldose reductase inhibitors, sorbinil or zopolrestat, or supplementation with myo-inositol, prevented the abnormal acetylcholine relaxations of aortic rings caused by elevated glucose. No effects of sorbinil, zopolrestat or myo-inositol were observed on the response to acetylcholine of aorta incubated in control glucose. Neither sorbinil nor myo-inositol affected the increase in release of vasoconstrictor prostanoids caused by elevated glucose. These findings suggest that sorbitol accumulation and myo-inositol depletion contribute to the abnormal endothelial cell function caused by exposure to elevated glucose. The increased release of vasoactive prostanoids is either independent of, or possibly contributes to, the abnormal aldose reductase activity and/or myo-inositol depletion in intact blood vessels exposed to elevated concentrations of glucose.

Acetylcholine↗
PubMed1992

Impaired relaxation of the human mammary artery after temporary clamping.

Internal mammary artery specimens from 17 patients were each divided into three separate rings. One ring (control) remained in Krebs solution and the other two were clamped for 30 minutes with either a soft or hard jaw clamp. Isometric tensions were measured in an organ chamber by contracting the rings twice with a thromboxane A2 mimetic, U46619, and relaxing the rings first with the endothelium-dependent agent acetylcholine followed by the endothelium-independent agent sodium nitroprusside. Endothelium-dependent maximal relaxation of the rings was impaired from control after both soft (20% versus 91%; p < 0.01) and hard (1% versus 91%; p < 0.01) jaw clamps were used. However, relaxation after use of hard jaw clamps was significantly less than after use of soft jaw clamps (1% versus 20%; p < 0.05). Endothelium-independent maximal relaxation was not impaired from control after soft jaw clamps (89% versus 97%) were applied but was significantly impaired after use of the hard jaw clamps compared with control (73% versus 97%; p < 0.01) and compared with soft jaw clamps (73% versus 89%; p < 0.05). Rings of internal mammary artery specimens from 10 patients from each experimental group were silver stained. The percentage of intact endothelial cells was significantly greater after soft jaw clamping than after hard jaw clamping (39% versus 15%; p < 0.02). These data suggest that soft jaw clamps significantly reduce the degree of vasoactive dysfunction compared with hard jaw clamps. In addition, soft jaw clamps produce fewer morphologic changes in the human mammary artery after temporary occlusion.

Acetylcholine↗
PubMed1992

Analysis of tissue margins of cone biopsy specimens obtained with "cold knife," CO2 and Nd:YAG lasers and a radiofrequency surgical unit.

Analysis of the tissue margins of cone biopsy specimens obtained from 40 patients showed varying degrees of thermal and mechanical artifact at the tissue margins. The least artifact was seen in the tissue margins of specimens obtained with the scalpel ("cold knife"). The amount of thermal damage to biopsies obtained via lasers and the radiofrequency unit varied with the instrument employed. However, the quality of the tissue margins of specimens obtained using a radiofrequency surgical unit equipped with a needle electrode on a "pure cut" setting approached the quality of those obtained with the cold knife in their lack of thermal and mechanical artifact.

Biopsy, Needle↗
PubMed1992

Different mechanisms of relaxation of pig coronary artery to bradykinin and cromakalim are distinguished by potassium channel blockers.

Bradykinin relaxes porcine coronary artery in an endothelium-dependent manner that is not dependent on release of nitric oxide or cyclic GMP accumulation. The mechanism of this relaxation was investigated in rings of porcine coronary artery by comparing bradykinin-induced relaxation with that induced by cromakalim, an agent know to cause hyperpolarization mediated by potassium channels. Relaxation to bradykinin was determined in rings treated with methylene blue, indomethacin and captopril to inhibit cyclic GMP accumulation, prostaglandin formation and bradykinin degradation, respectively. Relaxation to cromakalim was inhibited by the potassium channel blockers glybenclamide (10(-6) M), tetraethylammonium (10(-2) M), quinine (3 x 10(-5) M) and procaine (5 x 10(-3) M), whereas barium (10(-4) M) and 4-amino-pyridine (10(-3) M) were without effect. None of these potassium channel blockers had any effect on the relaxation to bradykinin. These results suggest that relaxation of pig coronary artery to cromakalim is mediated by a mechanism sensitive to potassium channel blockers. Also, the mechanism of nitric oxide-independent relaxation to bradykinin is distinct from that of cromakalim.

4-Aminopyridine↗
PubMed1991

The autobiography of Dr Lilian Lindsay.

Unwillingly, Lilian Lindsay started to commit to paper the story of her professional life, although, sadly, this did not progress further than the early years of her distinguished career. Her autobiography, entrusted to one of us with her personal historical notes and manuscripts in 1950, is published here for the first time, with annotations (in italics) to clarify the text by adding biographical details of persons she mentions and commenting on places and events. For some 40 years Lilian studied the history of dentistry, publishing many important papers as well as a book, Short History of Dentistry, but perhaps her most important contribution to dental history is her translation of Fauchard's Le Chirurgien Dentiste.

Dentists, Women↗
PubMed1991

Two mechanisms mediate relaxation by bradykinin of pig coronary artery: NO-dependent and -independent responses.

The role of nitric oxide and guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in the endothelium-dependent relaxation of the porcine coronary artery to bradykinin was investigated by comparing relaxation and cGMP accumulation in the presence or absence of NG-monomethyl-L-arginine (L-NMMA) and methylene blue. Rings were treated with indomethacin to eliminate the effects of prostaglandins. Relaxation to bradykinin of rings contracted with the thromboxane A2 mimetic U-46619 was not affected by L-NMMA and was only minimally inhibited by methylene blue. Rings contracted with elevated potassium (25 mM) also relaxed completely to bradykinin. However, L-NMMA or methylene blue effectively inhibited relaxation to bradykinin in rings contracted with potassium. cGMP accumulation was stimulated by bradykinin and inhibited by L-NMMA or methylene blue in rings contracted with either U-46619 or potassium. These results suggest that in the absence of nitric oxide-induced cGMP accumulation, a nonprostanoid mechanism exists that is capable of completely relaxing U-46619-contracted coronary artery. This mechanism is either inhibited in or unable to relax potassium-contracted rings. These results also demonstrate that nitric oxide mediates the bradykinin-induced cGMP accumulation that is largely responsible for the relaxation during contraction with potassium.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C.

A possible relationship between protein kinase C activation and impaired receptor-mediated endothelium-dependent relaxation in diabetes mellitus was examined in isolated aorta from normal rabbit exposed to elevated glucose. Aorta treated for 10 min with 4-phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, showed decreased relaxations to the endothelium-dependent vasodilator, acetylcholine, similar to normal aorta exposed to elevated glucose (22 and 44 mM) for 6 h. Relaxations to the receptor-independent endothelium-dependent vasodilator, A23187, and those caused by the direct smooth muscle vasodilator, sodium nitroprusside, were unaffected by treatment with PMA or exposure to elevated glucose. Indomethacin increased relaxations to acetylcholine of aorta treated with PMA indicating a role for vasoconstrictor prostanoids. PMA caused a significant increase in basal and acetylcholine-stimulated release of vasoconstrictor prostanoids including thromboxane A2 from aortic segments with, but not without endothelium. Protein kinase C inhibitors, H-7 or sphingosine, restored the abnormal acetylcholine-induced relaxations as well as suppressed the abnormal release of prostanoids in aorta exposed to elevated glucose. These findings suggest that the dysfunction of receptor-mediated endothelium-dependent relaxation associated with exposure to elevated glucose is due to increased production of vasoconstrictor prostanoids by the endothelium as a consequence of protein kinase C activation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

A 21-aminosteroid inhibits stimulated monocyte hydrogen peroxide and chemiluminescence measurements from MS patients and controls.

Monocytes are recruited to active sites of multiple sclerosis (MS) demyelination and may promote local tissue injury by generating an inflammatory response, mediated in part by the production of toxic oxygen metabolites. Corticosteroids are frequently and effectively used to ameliorate MS exacerbations, despite inadequate knowledge about the mechanism. We assessed the effects of a 21-aminosteroid, U74500A, a new class of steroid derivatives without glucocorticoid or mineralocorticoid effects, on the production of hydrogen peroxide (H2O2) and chemiluminescence by stimulated monocytes harvested from 8 stable MS patients and age- and sex-matched controls. H2O2 measurements and chemiluminescence were significantly reduced in both groups by U74500A. These results demonstrate that 21-aminosteroids reduce production of toxic oxygen metabolites by monocytes and thus their inflammatory potential, suggesting that these agents may be potentially effective and safe treatment for MS exacerbations.

Adult↗
PubMed1991

Disruption of human circadian and cognitive regulation following a discrete hypothalamic lesion: a case study.

We report a patient with rostral hypothalamic damage that significantly disrupted temporal patterning of the sleep-wake cycle, body temperature, and cognitive and behavioral functioning. The findings suggest that the suprachiasmatic region of the hypothalamus is important for the circadian control of human behavior, and that circadian organization may be essential for normal cognitive functioning.

Adult↗