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J E Jumblatt

Publications and source records attributed to J E Jumblatt.

At least 19 recordsLinked to original sources
PubMed1994

M2-type muscarinic receptors mediate prejunctional inhibition of norepinephrine release in the human iris-ciliary body.

Human muscarinic receptors comprise a family of five separate gene products, three of which (designated as M1, M2 and M3 subtypes) can be distinguished pharmacologically. Previous work indicates that sympathetic nerve terminals in the anterior uvea contain prejunctional muscarinic receptors that, upon activation by agonists, inhibit the neural release of norepinephrine. The aim of this study was to characterize the prejunctional effects of muscarinic agents on the electrically-evoked secretion of 3H-norepinephrine in isolated, superfused human iris-ciliary body tissue segments. Stimulation-evoked 3H-norepinephrine release was inhibited > 80% by carbachol and muscarine, but was unaffected by the M1-selective agonist McN A-343. Pilocarpine behaved as a partial agonist in this system, producing less than 40% of the maximum inhibition. The rank order of potency of selective antagonists at prejunctional muscarinic receptors was methoctramine (M2) > AF-DX 116 (M2) > pirenzepine (M1) > or = para-fluoro hexahydro-sila-definidol (M3). These data suggest that prejunctional muscarinic receptors in the human iris-ciliary body correspond to the M2 subtype. No evidence for age-related differences in prejunctional muscarinic receptor activity was seen in tissues obtained from 13 human donors, aged 10-83 years. Prejunctional muscarinic receptors may play a role in mediating the inhibitory effects of parasympathetic nerve stimulation or cholinomimetic drugs on ocular sympathetic neurotransmission in vivo.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1994

Prejunctional alpha 2-adrenoceptors and adenylyl cyclase regulation in the rabbit iris-ciliary body.

Agents that elevate intracellular cyclic AMP (cAMP) have been found to enhance the synaptic discharge of norepinephrine (NE) from sympathetic nerve terminals in the rabbit iris-ciliary body and other peripheral tissues. We explored the hypothesis that prejunctional alpha 2-adrenergic receptors that mediate feedback inhibition of NE release may be coupled to adenylyl cyclase inhibition. To indirectly monitor cAMP changes in sympathetic axon terminals, we analyzed the cAMP-mediated activation of tyrosine hydroxylase, a sympathetic marker protein that undergoes acute phosphorylation and activation by cAMP-dependent protein kinase A. Tyrosine hydroxylase activity was assayed in situ by incubation of rabbit iris-ciliary body tissue segments in buffered Krebs-Ringer solution containing the substrate tyrosine (100 microM) and the DOPA decarboxylase inhibitor brocresine (30 microM). Intraneuronal DOPA accumulation was quantified by HPLC with electrochemical detection. Tyrosine hydroxylase activity was increased approximately 2 fold by incubation with forskolin (10 microM) plus IBMX (0.5 mM) or with 8-Bromo-cAMP (3 mM). Simultaneous addition of the alpha 2-adrenergic agonist clonidine (1 microM) attenuated the response to forskolin/IBMX, but had no effect on the response to 8-Br-cAMP. Clonidine-mediated inhibition of the forskolin/IBMX response was abolished by treatment of tissues with N-ethylmaleimide (NEM), an alkylating agent that inactivates pertussis toxin-sensitive G proteins (Gi) that couple receptors to adenylyl cyclase inhibition. These findings suggest that prejunctional alpha 2-adrenoceptors in the rabbit iris-ciliary body are negatively coupled to adenylyl cyclase. This mechanism may contribute to autofeedback regulation of NE biosynthesis and release.

Adenylyl Cyclases↗
PubMed1993

Prejunctional receptors and second messengers for angiotensin II in the rabbit iris-ciliary body.

Angiotensin II has been shown to act prejunctionally to facilitate sympathetic neutrotransmission in various tissues including the iris-ciliary body. In the present study, we characterized the prejunctional angiotensin II receptor subtype and its signal transduction pathway in the rabbit iris-ciliary body. Angiotensin II caused concentration-dependent facilitation of electrically evoked [3H]-norepinephrine overflow from the isolated, superfused rabbit iris-ciliary body without affecting basal tritium efflux. Responses to angiotensin II were antagonized by saralasin and DuP753 but not by PD123177 indicating that prejunctional angiotensin II receptors of the AT1-subtype mediate the facilitation of evoked [3H]-norepinephrine release. The non-selective cyclic nucleotide phosphodiesterase inhibitor, isobutylmethyl xanthine enhanced the angiotensin II response whereas the cAMP-specific phosphodiesterase inhibitor, RO-20-1724 had no effect. In the presence of 8-bromo-cGMP, responses elicited by angiotensin II were significantly (P < 0.01) greater than that caused in the absence of 8-bromo-cGMP. In contrast, 8-bromo-cAMP had no effect on the angiotensin II-induced response. Guanylate cyclase inhibitors, methylene blue and LY83583 abolished angiotensin II-induced enhancement of [3H]-norepinephrine overflow without affecting basal tritium efflux. Taken together, these results suggest that cGMP could be involved in the angiotensin II response. Neither phospholipase C inhibitors (neomycin, 2-nitro-4-carboxyphenyl-N,N-diphenyl carbamate and phenylmethylsulfonyl fluoride) nor an inhibitor of protein kinase C (staurosporine) had any significant effect on the angiotensin II response, indicating that metabolites of inositol phospholipid metabolism or activation of protein kinase C are not involved in the response to this peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1993

Neuromodulatory effect of sulprostone on the circadian elevation of intraocular pressure in rabbits.

Topical application of sulprostone, a preferential prostaglandin EP3 receptor agonist, caused a dose-dependent reduction of the circadian elevation of intraocular pressure (IOP) in New Zealand albino rabbits which were entrained to 12-hr/12-hr light-dark environment. Corresponding to the effect on IOP, 0.2 micrograms, 2 micrograms, and 20 micrograms sulprostone decreased the norepinephrine (NE) concentration in the aqueous humor in the dark phase. There was no breakdown of the blood-aqueous barrier. Bilateral applications of 2 micrograms and 20 micrograms sulprostone to entrained rabbits that had undergone unilateral, preganglionic transection of the cervical sympathetic trunk reduced the circadian IOP elevation in the intact eye, but caused little IOP change in the decentralized eye. These results indicate that the IOP-lowering effect of topical sulprostone in rabbits is dependent on sympathetic neural activity and that prejunctional inhibition of NE release may be an important mechanism of action.

Animals↗
PubMed1993

Prejunctional modulation of norepinephrine release in the human iris-ciliary body.

PURPOSE: To characterize the prejunctional mechanisms that control the impulse-evoked release of norepinephrine in the isolated, superfused human iris-ciliary body. METHODS: Human iris-ciliary body tissue segments were preincubated with 3H-norepinephrine, superfused and electrically-stimulated in vitro to evoke the discharge of 3H-norepinephrine. The effects of prejunctional modulators on evoked 3H-norepinephrine overflow were evaluated. RESULTS: Stimulation-evoked (but not spontaneous) 3H-norepinephrine release was inhibited by alpha 2-adrenergic, muscarinic, dopaminergic, neuropeptide Y, and prostaglandin agonists and was enhanced by angiotensin II. Agonist-induced effects on 3H-norepinephrine overflow were blocked by selective antagonists, where available. Yohimbine and atropine alone enhanced 3H-norepinephrine output, suggesting that prejunctional alpha 2-adrenergic and muscarinic receptors undergo tonic activation by endogenously released neurotransmitters. CONCLUSIONS: Human ocular sympathetic nerves express inhibitory alpha 2-adrenergic, muscarinic, dopaminergic, prostaglandin, and neuropeptide Y receptors and facilitatory angiotensin II receptors that control the impulse-evoked release of 3H-norepinephrine. These receptors may be useful targets for pharmacologic manipulation of the adrenergic system in vivo.

Adolescent↗
PubMed1991

Prejunctional prostaglandin receptors in the human iris-ciliary body.

Prostaglandins (PGs) of the E series have been shown to modulate sympathetic neurotransmitter release in a variety of peripheral tissues and organs, including the eye. In this study, we evaluated the inhibitory effects of a series of naturally-occurring and synthetic PGs on field stimulation-evoked release of 3H-norepinephrine (3H-NE) from isolated, superfused segments of human iris-ciliary body. Field-stimulated 3H-NE secretion was calcium-dependent, blocked by selective inhibitors of voltage-sensitive calcium and sodium channels, and originated from a desipramine-sensitive transmitter pool. Evoked 3H-NE release was inhibited in a concentration-dependent manner by PGE2 (EC50 = 45 nM) and several closely related compounds with the following rank order of potency: sulprostone greater than 16,16-dimethyl-PGE2 greater than PGE2 greater than 11-deoxy-PGE1. By contrast, PGF2 alpha was relatively inactive (EC50 greater than 10 microM) in this system. None of the above compounds significantly modified spontaneous 3H-NE efflux. PGE2-mediated inhibition was not antagonized by the selective prostanoid EP1-receptor antagonists AH 6809 (10 microM) or SC-19220 (30 microM), nor did these agents alone affect basal or field-stimulated 3H-NE release. The results suggest that human ocular sympathetic nerves possess inhibitory PG receptors which have the pharmacological properties of the EP3 subtype. These receptors may play a role in local feedback regulation of sympathetic transmission in the iris-ciliary body, and may contribute to symptoms of acute ocular inflammation, including vasodilation, miosis and hypotony.

Adult↗
PubMed1990

Inhibitory effects of neuropeptide Y on sympathetic neurotransmission in the rabbit iris-ciliary body.

Neuropeptide Y (NPY, 1-300 nM) mediated a concentration-dependent inhibition of field stimulation-evoked [3H]norepinephrine (NE) overflow from the isolated, superfused rabbit iris-ciliary body. At equimolar concentrations (100 nM), the homologous neuropeptide peptide YY (PYY) mimicked the effects of NPY, whereas pancreatic polypeptide (PP) and the C-terminal fragment of NPY did not modify [3H]NE release. NPY-induced inhibition of [3H]NE release was unaffected by pretreatment of tissues with atropine (100 nM) plus yohimbine (100 nM) and was non-additive with the maximal prejunctional effects of carbamycholine or clonidine, indicating that NPY acts independently of prejunctional muscarinic or alpha 2-adrenergic receptor activity to reduce [3H]NE overflow. It is concluded that NPY is a specific, potent modulator of adrenergic neurosecretion in the rabbit iris-ciliary body. These findings confirm the role of NPY as a co-transmitter at ocular sympathetic neuroeffector junctions, either mimicking or augmenting the actions of endogenously released norepinephrine.

Animals↗
PubMed1990

Potentiation of norepinephrine secretion by angiotensin II in the isolate rabbit iris-ciliary body.

The prejunctional effects of angiotensin II (AII) on stimulation-evoked secretion of 3H-norepinephrine (3H-NE) were investigated by in vitro methods in isolated, superfused rabbit iris-ciliary body preparations. AII (0.1-10 nM) concentration-dependently enhanced the field- stimulated release of 3H-NE (EC50 = 0.1 nM), nearly doubling evoked neurotransmitter release with no apparent effect on spontaneous 3H-NE efflux. The response to 1 nM AII was abolished by the selective AII receptor antagonist saralasin [( Sar1,Val5, Ala8]-angiotensin II; 500 nM), which alone did not modify 3H-NE overflow. AII-mediated effects on neurosecretion were partially additive to those of forskolin and were not potentiated by phosphodiesterase inhibition, suggesting that AII utilizes a mechanism other than increased cAMP synthesis to facilitate neurotransmitter release. AII also strongly enhanced calcium ionophore (A23187)-induced 3H-NE release in iris-ciliary body segments, indicating that AII can modulate calcium-dependent exocytosis at step(s) distal to calcium influx. These results demonstrate that sympathetic nerves in the rabbit eye contain prejunctional, facilitatory AII receptors, and support the possible involvement of the renin-angiotensin system in regulation of ocular sympathetic neurotransmission in vivo.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Muscarinic cholinergic inhibition of adenylate cyclase in the rabbit iris-ciliary body and ciliary epithelium.

The effects of cholinergic agents on hormone-stimulated cyclic AMP (cAMP) accumulation were investigated in iris-ciliary body segments, excised ciliary processes, and isolated ciliary epithelium from albino rabbit eyes. In all three tissue preparations, the cholinergic agonist carbamylcholine markedly inhibited the stimulation of cAMP biosynthesis by vasoactive intestinal peptide VIP--a potent activator of nonpigmented ciliary epithelial adenylate cyclase. Carbamylcholine also attenuated cAMP increases mediated by isoproterenol, prostaglandin E2, and forskolin. The effects of carbamylcholine on VIP-induced cAMP synthesis were concentration dependent (EC50 = 23 nM), mimicked by selective muscarinic cholinergic agonists (oxotremorine, pilocarpine), and antagonized by atropine. Carbamylcholine- and clonidine-mediated inhibition of VIP-stimulated cAMP accumulation in ciliary processes were nonadditive, indicating that inhibitory muscarinic and alpha 2-adrenergic receptors coexist on VIP-responsive target cells. These findings suggest that the cholinergic system may have a direct role in modulation of ciliary epithelial adenylate cyclase and aqueous humor secretion.

Adenosine Triphosphate↗
PubMed1990

Prejunctional inhibitory effects of prostanoids on sympathetic neurotransmission in the rabbit iris-ciliary body.

Both naturally occurring and synthetic prostaglandins (PGs) caused concentration-dependent inhibition of electrically evoked [3H]norepinephrine (NE) overflow from the isolated, superfused rabbit iris-ciliary body without affecting basal tritium efflux. The rank order of potencies of the agonists was: sulprostone greater than 16, 16-dimethyl-PGE2 greater than PGE2 greater than 11-deoxy-PGE1 greater than iloprost (stable PGl2 analog) greater than PGF2 alpha greater than or equal to PGD2. However, the Tx-mimetic, U-46619, was without effect on transmitter release at concentrations up to 1 microM. The selective EP1-receptor antagonists, AH 6809 (30 microM) or SC-19220 (10 microM) had no effect on basal or field-stimulated [3H]NE secretion, nor did they antagonize the PGE2-mediated reduction of evoked [3H]NE overflow. Indomethacin (3 microM) and the 5-lipoxygenase inhibitor, BW A4C (1 microM) were without effect on basal or evoked [3H]NE release, suggesting that endogenously formed arachidonic acid metabolites have no significant modulatory role in this in vitro system. Inhibitory effects of submaximal or maximal concentrations of PGE2 combined with corresponding concentrations of clonidine or carbachol were not additive, suggesting that prejunctional PGE2 receptors coexist with alpha-2 adrenergic and muscarinic receptors at neurotransmitter release sites. In the presence of yohimbine (100 nM) and/or atropine (100 nM), however, the inhibition produced by PGE2 was enhanced markedly, suggesting that tonic activation of prejunctional alpha-2 adrenergic or muscarinic receptors by endogenously released transmitters may impair the response to exogenous PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Benzodiazepine binding sites on PC12 cells: modulation by nerve growth factor and forskolin.

PC12 pheochromocytoma cells show increased binding of the peripheral type benzodiazepine Ro 5-4864 after treatment with nerve growth factor (NGF) in membrane preparations. Forskolin, an activator of adenylate cyclase, acts synergistically with NGF to produce further increases in binding, but by itself produces no effect. The increased binding appears to reflect increases in receptor number, since Kd remains unchanged. Binding shows a trend toward increase by day 6 after NGF treatment, and the increase is significant at days 9 and 12. The physiological roles of benzodiazepine binding sites on PC12 cells are unclear. Treatment of the cells with Ro 5-4864 produces no changes in basal or stimulated release of catecholamines, in activity of adenylate cyclase, or in cell proliferation.

Adenine↗
PubMed1988

Effects of calcium channel antagonists on the depolarization-evoked release of norepinephrine in the rabbit iris-ciliary body.

The effects of several representative calcium channel antagonists on depolarization-evoked release of [3H]-norepinephrine were investigated in isolated, superfused rabbit iris-ciliary bodies. Potassium (50 mM)-evoked neurosecretion was blocked by 5 mM CoCl2 and partially inhibited by 10(-6) M nitrendipine or verapamil. Electrically-evoked neurosecretion was similarly blocked by CoCl2, but was unaffected by nitrendipine or verapamil. It is concluded from these results that sympathetic terminals in the rabbit iris-ciliary body contain dihydropyridine- and verapamil-sensitive calcium channels which contribute, under conditions of prolonged depolarization, to neurotransmitter release.

Action Potentials↗
PubMed1988

Cholinergic inhibition of adrenergic neurosecretion in the rabbit iris-ciliary body.

The prejunctional effects of cholinergic agents on release of norepinephrine from sympathetic nerve endings were investigated in the isolated, superfused rabbit iris-ciliary body. Stimulation-evoked release of 3H-norepinephrine was inhibited by the cholinergic agonists methacholine, oxotremorine, muscarine, carbamylcholine and acetylcholine (plus eserine), but was unmodified by pilocarpine or nicotine. Agonist-induced inhibition was antagonized selectively by atropine, indicating a muscarinic response. Atropine alone markedly enhanced norepinephrine release, revealing considerable tonic activation of prejunctional cholinergic receptors in this system. Prejunctional inhibition by carbamylcholine was found to completely override the facilitative action of forskolin or 8-bromo-cyclic AMP on neurotransmitter release. Cholinergic and alpha 2-adrenergic effects on neurosecretion were non-additive, suggesting that the underlying receptors coexist at neurotransmitter release sites.

Animals↗
PubMed1987

Alpha-2 adrenergic modulation of norepinephrine secretion in the perfused rabbit iris-ciliary body.

Clonidine and other selective alpha-2 adrenergic agonists have been found to lower intraocular pressure in the eyes of rabbits and primates, including humans. It has been suggested that the ocular hypotensive response to alpha-2 agonists may be mediated, in part, by prejunctional inhibition of norepinephrine secretion at intraocular synapses. In this study, we have investigated the effects of adrenergic agonists and antagonists on field-stimulated, Ca++-dependent release of 3H-norepinephrine (3H-NE) from isolated, perfused rabbit iris-ciliary bodies and have utilized radioligand binding methods to identify prejunctional adrenoceptors in this tissue. Clonidine (10(-9)-10(-5) M) produced a dosage-dependent inhibition of stimulation-evoked 3H-NE secretion (EC50 approximately equal to 3 X 10(-8) M), but did not alter basal secretion. Other adrenergic agonists capable of activating alpha-2 adrenoceptors (e.g., epinephrine, norepinephrine and xylazine) also significantly depressed 3H-NE secretion, whereas selective alpha-1 adrenergic or beta adrenergic agonists were without effect. Clonidine-mediated inhibition of 3H-NE release was reversed by the selective alpha-2 antagonist yohimbine (10(-7) M), but was unaffected by prazosin or timolol. Yohimbine alone markedly enhanced 3H-NE secretion, indicating tonic activation of prejunctional alpha-2 adrenoceptors by endogenous released norepinephrine. Forskolin or 8-bromo-cAMP, which alone enhanced norepinephrine secretion, failed to attenuate the inhibitory responses to alpha-2 agonists. 3H-rauwolscine binding measurements showed a small decrease in alpha-2 receptor sites in iris-ciliary body membranes following surgical sympathetic denervation. It is concluded that the rabbit iris-ciliary body contains functional, prejunctional alpha-2 adrenoceptors which may play an autoregulatory role in vivo and contribute to the ocular effects of adrenergic drugs.

Animals↗
PubMed1986

Potentiation of sympathetic neurosecretion by forskolin and cyclic AMP in the rabbit iris-ciliary body.

Forskolin has been reported to stimulate cAMP formation and reduce intraocular pressure in rabbit and primate eyes. In view of recent evidence for the involvement of cAMP in modulation of transmitter release at adrenergic synapses, we have investigated the presynaptic effects of forskolin and other cAMP activators on field-stimulated secretion of 3H-norepinephrine (3H-NE) in the isolated, perfused rabbit iris-ciliary body. Forskolin (10(-7)-10(-5) M) was found to markedly enhance stimulation-evoked 3H-NE release without affecting basal (spontaneous) release. The response to forskolin was potentiated by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX; 0.5 mM) and was mimicked by the cell-permeant cyclic nucleotide analog 8-bromo-cAMP. 8-bromo-cGMP also produce a small enhancement of stimulus-evoked 3H-NE secretion, whereas IBMX alone had little effect on either stimulated or basal secretion. These results suggest that cAMP may play an important neuromodulatory role in regulation of norepinephrine release at intraocular synapses, and raise the possibility that the ocular hypotensive response to forskolin in rabbit eyes may be mediated, in part, by enhanced adrenergic neurosecretion.

Animals↗
PubMed1982

Cell binding fragments from a sponge proteoglycan-like aggregation factor.

The marine sponge Microciona prolifera aggregation factor (MAF) is a 2 X 10(7) dalton proteoglycan. MAF mediates species-specific cell-cell recognition through two functionally different sites: a Ca2+-independent species-specific cell binding site and a Ca2+-dependent MAF-MAF binding site. Dissociation procedures combined with protease treatment were used to produce cell-binding pieces from the large complex. The seven different sized fragments produced were all uronic acid-rich glycoproteins of the apparent molecular weights: 15 X 10(6), 2.5 X 10(5), 1.2 X 10(5), 7 X 10(4), 2.7 X 10(4), 5 X 10(3), and 3.6 X 10(3). Each of the fragments retained species-specific binding to Microciona cells and was also capable of inhibiting MAF-promoted cell aggregation. However, the fragments were unable to bind to MAF-conjugated agarose beads in the presence or absence of CA2+ ions. These three properties are those expected for the cell binding site of MAF. Since the binding affinity decreased linearly with decreasing molecular weight of the fragments, we believe that the cell binding sites in MAF may be highly polyvalent, although to fully support such a concept, a detailed chemical characterization of each of the fragments is needed. A high valency of cell binding sites would overcome a relatively low Ka for the single site and would thereby not only guarantee specificity but also explain the need for the large size of the proteoglycan complex found to mediate species-specific sponge aggregation.

Animals↗