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B A Berkowitz

Publications and source records attributed to B A Berkowitz.

At least 73 records · Page 4Linked to original sources
PubMed1988

Effects of the novel dopamine beta-hydroxylase inhibitor SK&F 102698 on catecholamines and blood pressure in spontaneously hypertensive rats.

The novel dopamine beta-hydroxylase (D beta H) inhibitor SK&F 102698 was characterized in vitro with soluble enzyme from bovine adrenal medulla and in vivo by measuring the dopamine/norepinephrine (DA/NE) ratio in the mesenteric artery, heart and brains of spontaneously hypertensive rats (SHR). SK&F 102698 was a potent D beta H inhibitor with an IC50 of 1.2 microM on crude enzyme and had a Ki value of 40 nM on purified enzyme. SK&F 102698 produced a dose-dependent fall in NE and a dose-dependent increase in DA in the vasculature of SHR after p.o. administration. Elevation of the vascular DA/NE ratio was observed within 0.5 hr after administration. Peak effects were observed at 12 hr and values were still significantly increased at 18 hr. The rise in the DA/NE ratio of the blood vessels correlated with the fall in blood pressure following the first 4 hr after SK&F 102698. SK&F 102698 inhibited SHR heart D beta H and elevated the myocardial DA/NE ratio approximately 2.4-fold. SK&F 102698 also caused a dose-dependent increase in the whole brain DA/NE ratio of SHR. Catecholamine levels were also studied in six discrete brain regions and SK&F 102698 produced the greatest increase in the DA/NE ratio in the cerebellum, brain stem and midbrain regions, whereas the striatum was the region least affected. No overt sedation was observed in the rats. Further study with SK&F 102698 is warranted to better explore the role of DA and D beta H in pathophysiology, and to determine whether this drug or a congener D beta H inhibitor will be a useful therapeutic agent in humans.

Animals↗
PubMed1987

Pharmacologic characterization of the antiinflammatory properties of a new dual inhibitor of lipoxygenase and cyclooxygenase.

SK&F 86002 [6-(4-fluorophenyl)2,3-dihydro-5-(4-pyridinyl)imidazo (2,1-b)thiazole], a dual inhibitor of arachidonic acid metabolism, administered orally to rats prevented the development of carrageenan-induced edema, immune- and nonimmune-mediated inflammation of adjuvant-induced arthritis (AA) and reduced established inflammation in AA and collagen type II-induced arthritis. A similar profile of activity was observed following treatment with the cyclooxygenase inhibitor, indomethacin. However, unlike other nonsteroidal antiinflammatory drugs, SK&F 86002 exhibited antiinflammatory activity in inflammation models that are insensitive to cyclooxygenase inhibitors such as the established inflammation in carrageenan-induced edema and the edema induced by arachidonic acid and platelet activating factor. Moreover, SK&F 86002, but not indomethacin, inhibited the immune-mediated inflammatory responses evoked in sensitized animals by challenge with purified protein derivative. In addition, SK&F 86002 produced dose-related analgesia in mice, which was not reversed by the narcotic antagonist, naltexone. SK&F 86002 thus represents an orally active antiarthritic and analgesic compound with novel antiinflammatory properties.

Administration, Oral↗
PubMed1987

Proton decoupled fluorine nuclear magnetic resonance spectroscopy in situ.

The efficacy of proton decoupling for enhancing the 19F nuclear magnetic resonance (NMR) signal-to-noise ratio and spectral resolution in the intact subject is demonstrated. A geometrically orthogonal cross-coil antenna configuration (Helmholtz pair, surface coil) is employed to provide 40 dB of isolation between the 19F observe and 1H decouple frequencies of 188 and 200 MHz, respectively. Further isolation is achieved through the use of high-quality notch filters on both observation and decoupling channels. Application of 19F-(1H) NMR spectroscopy to the study of 2-fluoro-2-deoxy-D-glucose metabolism in cerebral tissue in situ is presented. Significant improvements in sensitivity and resolution are obtained and result from both a collapse of the JFH multiple structure and a substantial positive nuclear Overhauser effect (NOE). To our knowledge, this is the first such demonstration of 1H decoupling in conjunction with 19F observation for study of the metabolism of a fluorinated compound in the living subject.

Animals↗
PubMed1987

Inhibitors of dopamine beta-hydroxylase. 3. Some 1-(pyridylmethyl)imidazole-2-thiones.

The 1-benzylimidazole-2-thione moiety has been previously shown by Kruse et al. to be broadly associated with dopamine beta-hydroxylase (DBH) inhibitory activity both in vitro and in vivo in spontaneously hypertensive rats (SHR). An extension of structure-activity studies to 1-(pyridylmethyl)- and 1-(oxypyridylmethyl)imidazole-2-thiones is reported here in an attempt to exploit the pH differential that exists across the chromaffin vesicle membrane. We hypothesized that the weakly basic pyridyl compounds would diffuse into the acidic vesicles in their neutral forms where protonation and concentration would occur to enhance their in vivo effectiveness as inhibitors. To test this hypothesis, isomeric 2-, 3- and 4-(1-pyridylmethyl)imidazole-2-thiones were synthesized from the appropriate pyridinecarboxaldehydes by reductive alkylation of aminoacetaldehyde dialkyl acetal followed by imidazole-2-thione formation using acidic potassium thiocyanate. Related oxypyridyl compounds were synthesized by first preparing the appropriate aldehyde intermediate followed by conversion to the imidazole-2-thione by the same procedure. The unsubstituted pyridylmethyl compounds showed modest DBH inhibition in vitro but, consistent with a transport-mediated increase in observed potency, showed significant effects in vivo to increase the vascular ratio of dopamine to norepinephrine and to lower blood pressure.

Animals↗
PubMed1987

Differential selectivity of endothelium-derived relaxing factor and nitric oxide in smooth muscle.

The selectivity of endothelium-derived relaxing factor (EDRF) and nitric oxide (NO) on smooth muscle relaxation was examined and compared. EDRF released from was examined and compared. EDRF released from bovine pulmonary arterial endothelium (BPAE) in culture and NO were superfused over vascular, tracheal, gastrointestinal and uterine smooth muscle. EDRF relaxed vascular smooth muscle but not tracheal, gastrointestinal or uterine smooth muscle. NO relaxed vascular and gastrointestinal smooth muscle but not tracheal or uterine smooth muscle. There was a differential selectivity between the relaxant effect of EDRF and NO on smooth muscle.

Animals↗
PubMed1987

The inhibition of release of endothelium-derived relaxant factor by manoalide, a potent inhibitor of phospholipase A2.

1 The inhibitory action of manoalide on vascular relaxation was characterized. Manoalide was a potent inhibitor of endothelium-dependent relaxations in the isolated aorta of the rabbit. Responses to acetylcholine (ACh), A23187 and substance P were reduced by manoalide in a dose-dependent manner whilst those to nitroglycerin were unaffected. 2 Repeated washing of manoalide-treated tissues did not restore the relaxant response to ACh, indicating an irreversible action of manoalide. Scanning electron microscopic studies revealed that the endothelium remained intact on manoalide-treated tissues. 3 Rabbit aortae from which the endothelium had been removed relaxed in response to perfusion with ACh when delivered via an upstream endothelium-bearing tissue, indicating release of an endothelium-derived relaxant factor (EDRF). Incubation of the tissue without endothelium with manoalide (100 nM; 30 min) or inclusion of manoalide in the superfusate at a point just distal to the endothelium bearing tissue did not reduce the relaxant potency of EDRF. 4 Contractile responses of the guinea-pig isolated ileum to ACh were not affected by manoalide and, furthermore, binding of [3H]-quinuclidinyl benzilate to striatal membranes was not reduced by manoalide except at very high concentrations. 5 Manoalide therefore appears to inhibit vascular relaxation with a selectivity directed towards that mediated by EDRF. A direct antagonism of neither cholinoceptors nor EDRF receptors occurs and it is suggested that manoalide acts at a site within the endothelium to inhibit the synthesis and/or release of EDRF. Based upon these and previous data the possibility that EDRF is lipid-like or controlled by an arachidonic acid metabolite must continue to be considered.

Animals↗
PubMed1987

Stimulation of vascular dopamine receptors: status and future strategies.

The ability to stimulate dopamine receptors in the heart and blood vessels with selective receptor agonists, such as fenoldopam, has been an important advance. Fenoldopam is a selective DA1 receptor agonist and is currently in clinical trials for cardiovascular disease therapy. An alternative approach to stimulating dopamine receptors, while at the same time blunting sympathetic nervous system activity, would be by inhibiting the enzyme dopamine beta-hydroxylase (D beta H), thus increasing the cardiovascular and renal ratio of dopamine to norepinephrine. SK&F 102698, (1-[3',5'-difluorobenzyl]-2-mercaptoimidazole), is a potent inhibitor of D beta H with a Ki of 40 nM against D beta H in vitro. In the spontaneously hypertensive rat SK&F 102698 100 mg/kg orally, increases the dopamine/norepinephrine ratio approximately 5-fold and lowers blood pressure approximately 30 mmHg to normotensive levels. Antihypertensive activity can be achieved with single daily oral administration and neither tolerance nor reflex tachycardia occur. Stimulation of dopamine receptors by inhibition of dopamine beta-hydroxylase is a unique approach toward cardiovascular and renal therapeutics.

Cardiovascular System↗
PubMed1987

Endothelium-derived relaxing factor is a selective relaxant of vascular smooth muscle.

The present study examines the relaxant selectivity of endothelium-derived relaxing factor (EDRF) released from cultured endothelial cells. Endothelial cells from bovine pulmonary artery (CCL-209) in culture were grown on Cytodex-3 microcarrier beads, packed into a column and superfused to release EDRF. EDRF response was estimated by its ability to relax phenylephrine-contracted rings of rabbit aorta. Bradykinin and A23187 (10(-10) to 10(-6) M) caused dose-dependent release of EDRF from cultured bovine pulmonary artery endothelial cells. The release was dependent on endothelial cell number. A23187 caused a larger and longer-lasting release of EDRF than bradykinin. EDRF relaxation was selective for blood vessels. EDRF relaxed rabbit aortic rings, but it did not relax histamine-contracted guinea pig tracheal, rabbit taenia coli strips or oxytocin-contracted guinea pig uterine rings. These nonvascular smooth muscles were, however, relaxed by isoproterenol (10(-4) M) and sodium nitroprusside (SNP, 10(-5) M). The sensitivity of guinea pig aortic rings and tracheal strips to SNP were compared. The IC50 values for SNP (10(-9) to 10(-5) M) were 0.07 and 0.3 microM for aortic rings and tracheal strips, respectively. Although the tracheal strips were about 4-fold less sensitive than the aorta toward SNP, a complete relaxation was achieved. These results suggest that EDRF relaxes vascular smooth muscles but not respiratory, Gl or reproductive smooth muscles. Thus, EDRF may be a selective relaxant of vascular smooth muscle.

Animals↗
PubMed1987

Cardiovascular effects of a new potent dopamine beta-hydroxylase inhibitor in spontaneously hypertensive rats.

The cardiovascular effects of a new class of potent inhibitors of dopamine beta-hydroxylase (DBH) were evaluated in spontaneously hypertensive rats (SHR). SK&F 102698 [1-(3,5-difluorobenzyl)imidazole-2-thiol] is the prototype molecule of this class of substituted 1-benzylimidazole-2-thiols and is one of the most potent inhibitors of DBH yet described. After acute p.o. administration in conscious unrestrained SHR, SK&F 102698 elicited a dose-dependent decrease in mean arterial blood pressure. The antihypertensive effect was marked by a gradual onset with long duration of activity. The antihypertensive effect produced by SK&F 102698 was accompanied by bradycardia. SK&F 102698 inhibited DBH in vivo as demonstrated by its ability to increase vascular levels of dopamine (DA) while concomitantly decreasing vascular levels of norepinephrine (NE), thus increasing the overall DA/NE ratio. The chronic cardiovascular effects of SK&F 102698 were evaluated in developing SHR. SHR were administered SK&F 102698 p.o. once daily for 9 weeks beginning when animals were 4 weeks of age. SK&F 102698 (50 mg/kg) significantly attenuated the development of hypertension of these SHR. Tolerance to the chronic effects of DBH inhibition was not observed and blood pressures in drug-treated animals were still reduced significantly 20 hr after drug administration. Vascular catecholamine levels were determined in the mesenteric artery of these chronically treated animals. Vascular DA levels were increased 290%, vascular NE levels were decreased 36% and the DA/NE ratio was increased 520%, as compared to controls. Furthermore, hearts weights of SHR receiving SK&F 102698 were approximately 10% lower than controls. The present study demonstrates that in SHR SK&F 102698 is an effective antihypertensive whose effects are mediated by the novel mechanism of DBH inhibition.

Animals↗
PubMed1986

Multisubstrate inhibitors of dopamine beta-hydroxylase. 1. Some 1-phenyl and 1-phenyl-bridged derivatives of imidazole-2-thione.

The synthesis and characterization of some 1-(phenylalkyl)imidazole-2-thiones as a novel class of "multisubstrate" inhibitors of dopamine beta-hydroxylase (DBH) are described. These inhibitors incorporate structural features that resemble both tyramine and oxygen substrates, and as evidenced by steady-state kinetics, they appear to bind both the phenethylamine binding site and the active site copper atom(s) in DBH. A series of structural congeners that incorporate different bridging chain lengths between the phenyl ring (dopamine mimic) and the imidazole-2-thione group (oxygen mimic) define the optimum distance for inhibitory potency and the likely intersite distance in the DBH active site. Additional bridging analogues were prepared to determine the active site bulk tolerance and the effects of heteroatom replacement.

Animals↗
PubMed1986

Human vascular vasopressin receptors: analysis with selective vasopressin receptor antagonists.

The vascular activity of arginine vasopressin (AVP) and selective AVP receptor antagonists was investigated in isolated arterial ring segments from human superior mesenteric arteries. AVP elicited a potent and concentration-dependent contraction in human mesenteric arterial rings with an EC50 value of 2.01 X 10(-9) M. The presence or absence of the vascular endothelium did not affect significantly AVP-induced contraction. AVP induced slight, although significant, tachyphylaxis in human mesenteric arteries. The selective vascular (V1) receptor antagonist [d(CH2)5 1Tyr(Me)2]AVP (SK&F 100273) shifted the concentration-response curves for AVP-induced vascular contraction to the right in a parallel manner (KB = 2.23 X 10(-9) M). A mixed V1/V2 receptor antagonist, [d(CH2)5 1D-Tyr(Et)2Val4desGly9]AVP (SK&F 101926), was also a potent antagonist of AVP-mediated vascular contraction; however, inhibition was marked by a nonparallel shift of the concentration-response curves with depression of maximum contraction. Furthermore, a relatively renal (V2) selective receptor antagonist [d(CH2)5 1D-Ile2Val4]AVP (SK&F 101485) was approximately 100-fold less potent at inhibiting AVP-induced vascular contraction (KB = 1.37 X 10(-7) M). These studies illustrate for the first time the in vitro effects of selective vasopressin receptor antagonists in isolated human blood vessels. Studies of other blood vessels and the design of therapeutically useful antagonists should proceed with the hypothesis that the vasopressin receptors mediating vascular contraction in human mesenteric arteries are of the V1 subtype.

Arginine Vasopressin↗
PubMed1985

The DA1 receptor agonist fenoldopam (SK & F 82526) is also an alpha 2-adrenoceptor antagonist.

The alpha-adrenoceptor activity of fenoldopam was evaluated in three different in vitro tissue preparations. In rabbit isolated aortic rings fenoldopam displayed weak alpha 1-adrenoceptor antagonist activity (-log KB = 5.41) and displayed no alpha 1-adrenoceptor agonist activity. In contrast, fenoldopam demonstrated moderately potent antagonist properties at the alpha 2-adrenoceptor in two other tissue preparations. In in vitro model systems used for the characterization of alpha 2-adrenoceptors, fenoldopam competitively antagonized the effects of the alpha 2-adrenoceptor agonist B-HT 920. In the dog isolated saphenous vein and in the isolated field-stimulated guinea-pig ileum, fenoldopam antagonized the effects of B-HT 920 with -log KB values of 7.78 and 7.60, respectively. These data indicate that in addition to being an agonist at DA1 receptors, fenoldopam is also a relatively selective antagonist at alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1985

SCH 23390 and SK&F 83566 are antagonists at vascular dopamine and serotonin receptors.

SCH 23390 and SK&F 83566 have been utilized as selective antagonists at postjunctional dopamine receptors. However, in the isolated rabbit thoracic aorta evidence for competitive antagonism of serotonin was obtained. The KB values were 11 and 34 nM for SK&F R-83566 and SCH 23390, respectively. The S-enantiomer of SK&F 83566 was a weaker antagonist at the vascular serotonin receptor (KB = 1.5 microM). Thus, these results indicate that SCH 23390 and SK&F 83566 are not totally specific for the dopamine DA-1 receptor because they can also be potent antagonists at the vascular serotonin receptor.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1984

Phosphorus-31 NMR of rat brain in vivo with bloodless perfluorocarbon perfused rat.

Rat brain in vivo has been examined by 31P NMR under conditions of normal blood perfusion (hematocrit 38%) and under conditions in which a perfluorocarbon blood substitute, devoid of any phosphorus containing compounds, largely replaced the animal's normal blood supply (hematocrit 7%). These studies demonstrate that 2,3-diphosphoglycerate does not - as has been suggested - contribute to, and thus does not interfere with, the 31P NMR analysis of rat brain in vivo. However, low intensity 31P resonances assigned to choline phosphate, glycerol 3-phosphorylethanolamine, and glycerol 3-phosphorylcholine are observed. "High energy phosphorus" metabolite levels show no marked change over two hours with perfluorocarbon blood substitution from those of the normal blood perfused animal. This supports use of perfluorocarbon media for tissue perfusion in vitro and for 19F NMR vascular imaging in vivo.

Animals↗
PubMed1984

Studies on vascular dopamine receptors with the dopamine receptor agonist: SK&F 82526.

The vascular effects of a new dopamine receptor agonist, SK&F 82526, were evaluated in isolated rabbit splenic arterial ring segments. In this preparation, previously shown to possess dopamine receptors, SK&F 82526 produced a stereoselective relaxation with the R-enantiomer more active (ED50 1 X 10(-6) M) than the S-enantiomer (ED50 7 X 10(-6) M). Because SK&F 82526 lacks alpha agonist adrenoreceptor activity, a unique feature of these studies was the ability to examine the relaxant action of a dopamine receptor agonist using norepinephrine to contract the tissue in the absence of phenoxybenzamine which is required to antagonize the alpha adrenoreceptor agonist activity of other dopamine receptor agonists. Dopamine receptor antagonists inhibited SK&F 82526-mediated vascular relaxation with the following pA2 values: metoclopramide, 5.20; R-sulpiride, 4.96; and bulbocapnine, 4.62. Initial studies on the location of the receptors, and possible biochemical mechanisms, involved in the relaxation were undertaken. The relaxant effect of SK&F 82526 was decreased when the vascular endothelium was removed. However, removal of the endothelium did not produce a generalized inability to inhibit vascular relaxation because nitroglycerin relaxation of this tissue was not reduced. Phosphodiesterase inhibitors potentiated the vascular relaxant effects of SK&F 82526 only when the endothelium was present. This evidence suggests that a cyclic nucleotide-mediated process may be involved. In summary, direct physiologic evidence for the vascular relaxant effects of SK&F 82526 being mediated on postjunctional dopamine receptors is presented. This drug is a useful agent for the study and characterization of dopamine receptors.

Animals↗
PubMed1984

Cardiovascular dopamine receptors: recent advances in agonists and antagonists of the DA1-receptor.

Until recently, the key pharmacologic tools necessary for major advances in understanding and studying cardiovascular and renal dopamine receptors have been lacking. This communication describes new advances in the pharmacology of dopamine receptors as studied with a series of newly synthetized benzazepines. Fenoldopam (SK&F 82526) is a selective (DA1) dopamine-receptor agonist. Initial studies with fenoldopam on splenic arterial ring segments of the rabbit have suggested that the endothelium as well as vascular smooth muscle may possess hemodynamically important dopamine receptors, and that cyclic adenosine monophosphate can be a second messenger mediating dopaminomimetic vasodilatation. Significant advances in DA1-selective antagonists have also recently been made. SK&F 83566 is a potent antagonist of both dopamine and fenoldopam in the vasculature. Dopamine-receptor selective agonists and antagonists represent an emerging strategy for the treatment of several cardiovascular diseases, including hypertension and edema. Moreover, these compounds are important tools for the characterization and study of dopamine receptors.

Animals↗