PubMed Health⌕ Search

Biomedical subjects

J A Nathanson

Publications and source records attributed to J A Nathanson.

At least 19 recordsLinked to original sources
PubMed1992

Epinephrine increases facility of outflow and cyclic AMP content in the human eye in vitro.

The physiologic mechanism that underlies the epinephrine-induced increase in facility of outflow (C) in glaucomatous human eyes and normal primate eyes is not completely understood. In this study, a recently developed in vitro human eye perfusion model was used to simultaneously monitor facility and cyclic adenosine monophosphate (AMP) changes in response to epinephrine (EPI). In this system, EPI (2.5 x 10(-5) mol/l) resulted in a maximal 44% increase in C, with an ED50 occurring at approximately 8 x 10(-6) mol/l. The C-increasing effect of 10(-5) mol/l EPI was unaffected by 10(-6) mol/l phentolamine. However, it was completely blocked in the presence of 10(-6) mol/l timolol or 2 x 10(-7) mol/l ICI118,551, suggesting the involvement of beta-2 adrenergic receptors. In biochemical studies, 10(-5) mol/l EPI induced a 12- to 14-fold increase in cyclic AMP in the perfusate of treated eyes. This increase was blocked by ICI118,551. In isolated intact human trabecular tissue, a 10 min incubation with 10(-5) EPI stimulated cyclic AMP by a factor of 2.7 over control levels. After 90 min, cyclic AMP levels were increased 4.2 fold over control levels. Collectively, these results show that the intraocular pressure lowering effect of EPI in the human eye is mediated, at least in part, by an increase in facility of outflow. Furthermore, the facility increase appears to be mediated by beta-2 adrenergic receptors and is correlated in time with increased cyclic AMP production.

Adrenergic beta-Antagonists↗
PubMed1992

Phosphorylation of DARPP-32 and protein phosphatase inhibitor-1 in rat choroid plexus: regulation by factors other than dopamine.

The molecular mechanisms underlying regulation of fluid production by secretory epithelia such as the choroid plexus are poorly understood. Two cAMP-regulated inhibitors of protein phosphatase-1, inhibitor-1 (I1) and a dopamine- and cAMP-regulated phosphoprotein, M(r) = 32,000 (DARPP-32), are enriched in the choroid plexus. We show here that these two phosphoproteins are colocalized in choroid plexus epithelial cells. We have developed a novel method for studying the phosphorylation state of DARPP-32 and I1 in intact cells, using a phosphorylation state-specific monoclonal antibody. Several drugs and hormones that are known to alter fluid secretion and that increase cAMP levels (forskolin, isoproterenol, vasoactive intestinal peptide) or cGMP levels (atrial natriuretic peptide) or that may use additional second messenger pathways (5-HT), increase the phosphorylation of I1 and DARPP-32 in rat choroid plexus. In contrast, dopamine does not alter cAMP and cGMP levels, or I1 and DARPP-32 phosphorylation. Our results indicate that DARPP-32, known to be regulated by dopamine in a number of tissues, can be phosphorylated in response to non-dopaminergic factors, including hormones acting through non-cAMP-dependent pathways. Our results also raise the possibility that inhibition of phosphatase-1, as a result of I1 and DARPP-32 phosphorylation, might be part of a final common pathway in the action of several factors that are known or thought to alter cerebrospinal fluid production.

Amino Acid Sequence↗
PubMed1992

Nitrovasodilators as a new class of ocular hypotensive agents.

Because of recent evidence indicating that hormone regulation of particulate guanylate cyclase in the eye may modulate aqueous humor dynamics, we have investigated the possibility that exogenous activators of soluble guanylate cyclase may be useful in altering intraocular pressure (IOP). A variety of nitrovasodilators known to activate guanylate cyclase were evaluated for their topical effects on IOP, outflow resistance and systemic cardiovascular parameters. In both young and older rabbits, topically applied nitroglycerin (0.003-0.1 g %) rapidly lowered IOP in a dose-dependent fashion, with a peak effect at 1 to 2 hr. Topically applied 0.1% isosorbide dinitrate, sodium nitrite, hydralazine, minoxidil and sodium nitroprusside mimicked the ocular hypotensive actions of nitroglycerin. Ipsilateral effects on IOP were greater than contralateral effects and, at the doses applied, there was little or no alteration in heart rate or systemic blood pressure, or signs of ocular irritation. Higher doses (0.5-2.0 g %) of nitroglycerin, hydralazine and sodium nitroprusside were less effective in lowering IOP. Topically applied molsidomine (0.1%), a prodrug which requires hepatic metabolism to 3-morpholino-sydnonimin hydrochloride for guanylate cyclase stimulatory activity, was ineffective in lowering IOP, whereas topical 0.1% 3-morpholino-sydnonimin hydrochloride was effective. After chronic administration, rabbits receiving nitroglycerin showed diminished ocular response, whereas repeated doses of hydralazine (56 days) did not elicit tolerance. Tonographic studies showed that topically applied nitroglycerin and hydralazine increased the facility (decreased the resistance) of aqueous humor leaving the eye. These data indicate that topically applied nitrovasodilators can effectively lower IOP at doses which have little effect on systemic blood pressure. Because these IOP-lowering effects appear to result, to a significant degree, from local actions on the eye, further investigation of these agents in conditions of elevated intraocular pressure may be warranted.

Administration, Topical↗
PubMed1991

Atrial natriuretic factor and salt wasting after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The causes of volume depletion and hyponatremia after subarachnoid hemorrhage are not fully understood but may be in part due to natriuresis or "cerebral salt wasting." Because previous studies using infrequent hormone sampling have given inconsistent results, we determined if elevations in atrial natriuretic factor concentrations preceded negative sodium and fluid balances. METHODS: We measured diurnal atrial natriuretic factor and vasopressin concentrations and sodium balance for 5 days in 14 consecutive patients after aneurysmal subarachnoid hemorrhage. RESULTS: Plasma concentrations of atrial natriuretic factor on admission were elevated in subarachnoid hemorrhage patients (mean +/- SD 106 +/- 59 pg/ml) compared with acutely ill controls (39 +/- 30 pg/ml). In eight patients, high peak concentrations of atrial natriuretic factor, greater than 300 pg/ml or a twofold increase above baseline, were followed by natriuresis and a negative sodium balance. Three patients, two of whom became hyponatremic, developed cerebral infarcts after natriuresis. Vasopressin concentrations were slightly elevated just after hemorrhage but subsequently declined to normal values. CONCLUSIONS: A markedly increased atrial natriuretic factor concentration precedes natriuresis in some patients and, with other abnormalities of water handling possibly including a relatively diminished vasopressin concentration, may cause volume depletion. Patients with natriuresis appear to be at increased risk for delayed cerebral infarction after subarachnoid hemorrhage.

Adult↗
PubMed1991

Effect of endothelin on outflow facility and accommodation in the monkey eye in vivo.

The effect of the vasoactive peptide, endothelin, on facility of outflow, accommodation, and pupil diameter was measured in the monkey eye in vivo. Endothelin increased the outflow facility 22-71% at approximate anterior chamber concentrations ranging from 10(-10)-10(-7) M. Endothelin-induced accommodation was modest but consistent and statistically significant ranging from 1.61 to a maximum of 2.43 diopters at 10(-9) M and 10(-7) M endothelin, respectively. No change in pupil diameter was noted with any of the administered doses. These data demonstrate an action of endothelin on outflow facility and, together with prior evidence indicating the presence of endothelin receptors on the ciliary muscle, suggest that, like cholinergic agonists, the observed effects of endothelin on outflow facility may be mediated, at least in part, through an action on the ciliary muscle.

Accommodation, Ocular↗
PubMed1989

Isolation and N-terminal amino acid sequence of an octopamine ligand binding protein.

An octopamine receptor photoaffinity probe was used to label membranes from the light organs of Photinus pyralis, a tissue highly enriched in octopamine receptors. Labeling was concentrated in a glycoprotein of 75 +/- 2 kDa with lesser labeling of a 79 +/- 2 kDa component. Labeling could be displaced by prior incubation with octopamine, mianserin, cyproheptadine, phentolamine or propranolol, with a relative potency that correlated with the ability of these same agents to modulate light organ octopamine-sensitive adenylate cyclase. The 75 kDa binding protein was isolated and its N-terminal amino acid sequence was determined.

Affinity Labels↗
PubMed1989

A probe for octopamine receptors: synthesis of 2-[(4-azido-2,6-diethylphenyl)imino]imidazolidine and its tritiated derivative, a potent reversible-irreversible activator of octopamine-sensitive adenylate cyclase.

In order to develop an irreversible ligand for octopamine receptors, a highly potent azido-substituted 2-(phenyl-imino)imidazolidine (NC-5Z, 8) and its tritiated derivative (3H-NC-5Z, 11) have been designed and synthesized. Under reversible-binding conditions, NC-5Z is 50-100-fold more potent than octopamine in activating octopamine-sensitive adenylate cyclase in a variety of tissues. After photolysis, 3H-NC-5Z binds irreversibly to cell membranes, and this binding is reduced by preincubation with octopamine agonists and antagonists but not by norepinephrine, dopamine, serotonin, or histamine. NC-5Z should be useful both as a potent reversible octopamine agonist and as an affinity probe for characterizing and isolating octopamine-receptor proteins.

Adenylyl Cyclases↗
PubMed1989

Immunological function of the blood-cerebrospinal fluid barrier.

Because the brain lacks a true lymphatic system, it is unclear how peripheral lymphocytes recognize foreign antigens present in the central nervous system. This report demonstrates that the choroid plexus, which constitutes the blood-cerebrospinal fluid barrier, is able to present foreign antigen to, and stimulate the proliferation of, peripheral helper T lymphocytes through an Ia-dependent, major histocompatibility complex-restricted mechanism. Furthermore, in vivo, choroid plexus epithelial cells have access to, and are capable of taking up, virus-sized particles injected elsewhere into the cerebrospinal fluid. Thus these data suggest that the blood-cerebrospinal fluid barrier may play a role in immunological communication between the central nervous system and periphery, a function relevant to the initiation of immunological responses to central nervous system infections and autoimmune processes and for the surveillance of tumor cells in the cerebrospinal fluid.

Animals↗
PubMed1989

Iso stimulation of GH and cAMP: comparison of beta-adrenergic- to GRF-stimulated GH release and cAMP accumulation in monolayer cultures of anterior pituitary cells in vitro.

Growth hormone (GH) release and cAMP content were measured in monolayer cultures of anterior pituitary cells after beta-adrenergic and GH-releasing factor (GRF) receptor activation. Isoproterenol (Iso, ED50-20 nM) was less potent than GRF (ED50-20 pM) in stimulating GH release. Iso caused a rapid stimulation of GH release that was maximal after 15 min and declined thereafter, while GRF caused a more gradual increase in GH secretion that was maximal after 30 min and remained elevated after 3 h. Both Iso- and GRF-stimulated GH release were preceded by an increase in cAMP content in the pituitary cells. Further, the addition of 3-isobutyl-1-methylxanthine (IBMX) to the medium enhanced the GH-stimulatory and cAMP-accumulating effects of both secretagogues. Experiments performed with native catecholamines and synthetic catecholamine agonists and antagonists indicated that the GH-stimulatory effect of Iso was mediated by a mixed population of beta 1-adrenergic and beta 2-adrenergic receptors. Additionally, experiments performed with cultured GH3 tumor cells, found that incubation with GRF, Iso, vasoactive intestinal polypeptide, forskolin, or cholera toxin caused an increase in cAMP content in the cells. However, compared to the responses observed in primary pituitary cultures the GH secretory response to these agents was comparatively small. Together, these studies suggest that a mixed population of beta 1-adrenergic and beta 2-adrenergic receptors may act, at least in part, on somatotrophs in the anterior pituitary to stimulate GH release. Although both GRF and beta 2-adrenergic receptor agents affect GH release through a common second messenger system, their differing pharmacokinetic properties suggest distinct intracellular mechanisms.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Development of a photoaffinity ligand for octopamine receptors.

Octapamine receptors are widely distributed in invertebrate species, yet little is known about their biochemical structure or tissue localization, in part because there exist no high affinity or irreversible ligands for these receptors. This paper characterizes 2-(2,6-diethyl-4-azidophenylimino)imidazolidine (NC-5Z), a new, high affinity octopamine receptor probe that binds reversibly and, under photolyzing conditions, irreversibly to membrane-associated octopamine receptors. Under reversible conditions NC-5Z is a full agonist, 50-100 times more potent than octopamine in activating the highly enriched and specific octopamine-sensitive adenylate cyclase of the firefly light organ. NC-5Z shows a similar potency in cockroach muscle and thoracic ganglia and in tobacco hornworm nerve cord. Activation of light organ adenylate cyclase by NC-5Z is nonadditive to that caused by octopamine and can be blocked by antagonists, including mainserin (Ki = 0.9 microM), cyproheptadine (Ki = 5 microM), phentolamine (Ki = 20 microM), and propranolol (Ki = 75 microM). These constants agree well with those for the same antagonists in inhibiting stimulation due to octopamine. In physiological studies, NC-5Z mimics the action of, but is more potent than, octopamine in stimulating light emission in intact firefly tails and in disrupting motor behavior and feeding of tobacco hornworms. Under reversible conditions, [3H]NC-5Z, the tritiated derivative of NC-5Z, binds to light organ membranes with an apparent affinity (0.59-0.7 microM) similar to that (0.35-0.7 microM) for NC-5Z in activating adenylate cyclase. Under photolyzing conditions, NC-5Z irreversibly activates light organ adenylate cyclase, and this can be blocked by an excess of octopamine. Under similar conditions, [3H]NC-5Z binds irreversibly to light organ membranes and to membranes from tobacco hornworm nerve ganglia, fat body, and gut. This binding is reduced by prior incubation with octopamine agonists, including octopamine, demethyl-chlordimeform, and 2-(phenylimino)imidazolidines, but not by norepinephrine, dopamine, serotonin, or histamine. Irreversible binding is also reduced by prior incubation with antagonists, most effectively (55% of total binding) by mianserin. The apparent affinity of [3H]NC-5Z for membrane binding, as reflected by its ability to be displaced by mianserin, is altered by GTP. In autoradiographic studies of whole tissue, [3H]NC-5Z shows irreversible, mianserin-displaceable labeling of intact firefly light organs. Taken together, these data indicate that NC-5Z and [3H]NC-5Z are potent and selective agonists of octopamine receptors in a variety of tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed1988

Galanin stimulates rat pituitary growth hormone secretion in vitro.

The effect of galanin on growth hormone (GH) secretion was investigated in monolayer cultures of rat anterior pituitary cells. Galanin caused a gradual increase in GH concentrations into the culture medium that was maximal at 90 minutes and sustained after 180 minutes. The ED50 for galanin-stimulated GH secretion was approximately 200 nM compared to an ED50 for rat GH-releasing factor (rGRF)-stimulated GH secretion of 10pM. Galanin and rGRF were additive in increasing GH release into the incubation medium. These data indicate that porcine-derived galanin has a direct effect on pituitary GH secretion in vitro.

Animals↗
PubMed1988

Selective beta 2-adrenoceptor antagonists: derivatives of ICI 118,551 and a binary aryloxypropanolamine.

Recent studies indicate that selective beta 2-adrenoceptor antagonists may be of use in the treatment of glaucoma. ICI 118,551, its desmethyl-, didesmethyl-, and ethyl- analogues, and a putative highly beta 2-selective binary aryloxypropanolamine (4d) have been evaluated for their ability to inhibit beta-adrenergic-stimulated adenylate cyclase activity in rabbit ciliary process and heart. Potency ratios (Ki heart/Ki ciliary process) were 440 for ICI 118,551; 9.3 for the desmethyl analogue; 8.2 for the didesmethyl analogue; 720 for the ethyl analogue; and 11 for the binary aryloxypropanolamine. The values for the ethyl derivative of ICI 118,551 indicate that it is the most oculoselective beta-adrenoceptor antagonist yet reported.

Adrenergic beta-Antagonists↗
PubMed1988

Stereospecificity of beta adrenergic antagonists: R-enantiomers show increased selectivity for beta-2 receptors in ciliary process.

The (+)-stereoisomers of arylethanolamine beta adrenergic agonists and antagonists are usually much less active in biological systems than their corresponding (-)-forms. In the eye, however, prior physiological studies have shown that these (+)-stereoisomers are unexpectedly potent in altering intraocular pressure, results which could be due to a difference in distribution and metabolism or to a difference in receptor interaction. The present experiments evaluated six stereoisomeric pairs of beta adrenergic antagonists for their ability to block rabbit ciliary process and cardiac beta adrenergic receptors activating adenylate cyclase, in vitro, under conditions in which the effects of drug metabolism, distribution and membrane lipid solubility were minimized. In the heart, all six pairs of antagonists demonstrated the expected increased potency of (-)-forms, with isomeric activity ratios of: 33 for metoprolol, 44 for timolol; 48 for bunitrolol; 76 for t-butyl-betaxolol; 100 for t-butyl-didesmethyl-ICI-118,551; and 530 for betaxolol. Under identical assay conditions in the ciliary process, (+)-enantiomers were much more potent relative to (-)-forms, with isomeric activity ratios of: 0.82 for timolol; 3.3 for bunitrolol; 7.4 for t-butyl-didesmethyl-ICI-118,551; 10 for metoprolol; 16 for t-butyl-betaxolol; and 190 for betaxolol. With the exception of metoprolol, all (+)-enantiomers demonstrated a substantially higher absolute affinity for ciliary process receptors (known to be almost exclusively of the beta-2 subtype) than for cardiac receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1987

Brain barrier tissues: end organs for atriopeptins.

Little is known about the pathophysiology of cerebral edema and other disturbances of water balance that involve the barrier tissues at the interface of blood and brain. The present experiments show that these barrier tissues contain receptors and second messenger systems for atriopeptins, recently identified cardiac peptides involved in peripheral water regulation. They also show that atriopeptins can alter the rate of cerebrospinal fluid production. Because the blood-brain and blood-cerebrospinal fluid barriers are involved in normal water movements in the central nervous system, these studies suggest that brain barrier tissues may be important end organs for the atriopeptins and that atriopeptins could have therapeutic application to disorders of water balance in the central nervous system. An isolated, purified population of atriopeptin receptor cells, obtained from choroid epithelium, was used in these experiments. This cell population may provide a valuable model system for investigating the intracellular biochemical mechanisms through which atriopeptins exert their actions.

Adenylyl Cyclases↗
PubMed1987

Atriopeptin-activated guanylate cyclase in the anterior segment. Identification, localization, and effects of atriopeptins on IOP.

Atriopeptins are a recently-discovered group of polypeptides secreted from cardiac myocytes in response to fluid overload. The present studies demonstrate that atriopeptin receptors, coupled to the activation of guanylate cyclase, are present in rabbit ciliary process. Rat atrial natriuretic peptide 1-28 (rANP) activated ciliary process guanylate cyclase activity with a Vmax of from 24-337% and with a Ka of from 0.4-4 nM, similar to that for atriopeptin receptors present in rabbit kidney. Activation was greater for the intact peptide than for rANP fragments 1-11 or 13-28, and stimulated activity was greater in isolated ciliary processes than in ciliary muscle or iris. Intravitreal injection of the complete peptide into living rabbits caused a marked decrease in IOP in the ipsilateral eye which persisted for more than 48 hr and occurred without evidence of an inflammatory response. There was a smaller decrease in IOP in the contralateral eye. Following intravitreal injection of rANP 1-28, atriopeptin levels in aqueous humor remained elevated for at least 44 hr. Injection of the biochemically less active rANP fragments 1-11 and 13-28 caused no decrease in IOP. These physiological data, together with the biochemical identification of atriopeptin receptors and second messenger systems in the ciliary process, suggest that certain tissues of the anterior segment may be atriopeptin end-organs and that agents acting at atriopeptin receptors may be able to regulate IOP.

Animals↗
PubMed1985

Characterization of octopamine-sensitive adenylate cyclase: elucidation of a class of potent and selective octopamine-2 receptor agonists with toxic effects in insects.

Octopamine-2 receptors, associated with activation of adenylate cyclase, mediate a number of the important hormonal and neurotransmitter functions of octopamine in invertebrates. By utilizing the highly enriched octopamine-sensitive adenylate cyclase present in the firefly light organ, it has been possible to pharmacologically characterize octopamine-2 receptors and to define a new class of highly potent and selective octopamine-2 agonists. At low concentrations, these substituted phenyliminoimidazolidines stimulate light emission when injected into fireflies. At somewhat higher concentrations, these compounds, when ingested by tobacco hornworms, cause disruption of motor and feeding behavior, leading to insect death. The effects of these compounds are markedly potentiated by phosphodiesterase inhibitors and mimicked by other activators of octopamine-sensitive adenylate cyclase, including octopamine itself. Because octopamine-2 receptors appear to be present primarily in invertebrates, these findings, together with other data, raise the possibility that potent and selective octopamine agonists could be useful as insect toxins with low toxicity in vertebrates.

Adenylyl Cyclases↗