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Biomedical subjects

D E Potter

Publications and source records attributed to D E Potter.

At least 37 records · Page 2Linked to original sources

Elevation of intracellular Ca2+ concentration in rabbit nonpigmented ciliary epithelial cells by allicin.

A previous study has shown that allicin produces changes in aqueous humor dynamics, and this study was conducted to examine possible cellular mechanisms. In rabbit nonpigmented ciliary epithelial cells, basal levels of [Ca2+]i were determined to be 164 +/- 34 nM. Allicin, a sulfhydryl-reactive agent, induced Ca2+ transients at 0.01 mM and at 0.2 mM, the Ca2+ transient peaked at 732 +/- 35 nM. Allicin-induced Ca2+ transients were prevented by pretreatment with dithiothreitol which did not affect the basal Ca2+ levels. Allicin had only a slight, insignificant, effect on L-type Ca2+ currents, and allicin-induced Ca2+ transients were also present under extracellular Ca(2+)-free conditions. These data suggest that intracellular Ca2+ stores are the most probable source of allicin's effect. Pretreatment of cells with ryanodine, an inhibitor of Ca(2+)-induced-Ca(2+)-release, inhibited allicin-induced Ca2+ transients, but the basal Ca2+ levels were unaffected by ryanodine. Thus, allicin-induced Ca2+ transients are most likely mediated through ryanodine-sensitive intracellular Ca2+ stores.

Animals↗

Ocular action of an opioid peptide, DPDPE.

This study was performed to examine some ocular actions of an opioid agonist. Experiments were performed to evaluate the effects of a delta opioid agonist, DPDPE ([D-pen2, D-pen5]enkephalin (where pen = penicillamine)), on: 1) intraocular pressure (IOP) in rabbits; 2) cAMP accumulation in rabbit iris ciliary bodies (ICBs). Unilateral, topical administration of DPDPE caused bilateral depression of IOP. Intravitreal injection of DPDPE caused a greater IOP decrease than intravitreal injection of NaH2PO4 (vehicle). Topical administration of naloxone partially inhibited the effect of DPDPE on IOP in normal rabbits. In other experiments, DPDPE suppressed both basal and isoproterenol (ISO)-stimulated cAMP accumulation in ICBs. The presence of naltrindole (NTI), a delta receptor antagonist, did not prevent the suppression of cAMP levels by DPDPE. The conclusions drawn from the findings suggest that the lowering of IOP by DPDPE is mediated, in part, by actions at postjunctional (ciliary body) sites and may involve an atypical opioid receptor.

Administration, Topical↗

Oxymetazoline: potential mechanisms of inhibitory effects on aqueous humor dynamics.

Oxymetazoline, an alpha 2 agonist, was active in lowering intraocular pressure in normal and sympathetically denervated rabbit eyes. Ocular hypotension was accompanied by decreased aqueous humor inflow. Topical pretreatment with rauwolscine, an alpha 2 antagonist, reduced the oxymetazoline-induced hypotensive effect more in contralateral than in ipsilateral eyes indicating the possible involvement of central alpha 2 adrenoceptors. Efaroxan, a relatively selective imidazoline antagonist, and diclofenac, a cyclooxygenase inhibitor, failed to inhibit the oxymetazoline-induced ocular hypotensive response. Oxymetazoline induced mydriasis in treated eyes at all doses. In in vitro studies, oxymetazoline inhibited isoproterenol-stimulated cAMP production in rabbit iris-ciliary bodies and cultured rabbit nonpigmented ciliary epithelial cells. The inhibition of cAMP accumulation induced by oxymetazoline was antagonized by rauwolscine or by BRL-44408, a relatively selective alpha 2A-adrenoceptor antagonist. These data indicate that oxymetazoline lowered intraocular pressure by activating alpha 2A receptors (ciliary epithelium) and that the ocular hypotensive effect was not totally dependent on intact sympathetic nerves. Results suggest that mechanisms involving centrally mediated effects of oxymetazoline are probable and this possibility is currently under investigation.

Adrenergic alpha-Agonists↗

Rilmenidine-induced ocular hypotension: role of imidazoline1 and alpha 2 receptors.

PURPOSE: To examine ocular actions by rilmenidine, an imidazoline1 and alpha 2 adrenoceptor agonist. METHODS: Intraocular pressure was measured in normal and sympathetically denervated rabbits by pneumatonometry. Electrically stimulated 3H-norepinephrine release from sympathetic nerves was determined in isolated, perfused rabbit iris-ciliary bodies. cAMP levels were evaluated in rabbit iris-ciliary bodies by radioimmunoassay. Ca2+ concentrations were measured in rabbit transformed nonpigmented ciliary epithelial cells by fluorescence ratio microscopy. RESULTS: Topical, unilateral administration of rilmenidine produced hypotensive responses in normal rabbits which were antagonized by either bilaterally administered efaroxan, an imidazoline receptor antagonist or rauwolscine, an alpha 2 receptor antagonist. Sympathectomy also eliminated the ocular hypotensive response. Rilmenidine (0.001, 0.01, 0.1, 1 microM) caused 5 +/- 1%, 18 +/- 5%, 35 +/- 10%, and 48 +/- 9% inhibition, respectively, of 3H-norepinephrine overflow whereas 10 microM efaroxan or rauwolscine caused enhancement of norepinephrine release by 102 +/- 23% or 86 +/- 25%, respectively. Furthermore, pretreatment with efaroxan or rauwolscine partially antagonized the inhibition of norepinephrine release induced by rilmenidine. In other experiments, rilmenidine (1 microM) inhibited isoproterenol-stimulated cAMP accumulation in rabbit iris-ciliary bodies by 43 +/- 9% which was antagonized by 10 microM efaroxan or rauwolscine. Rilmenidine induced large increases in [Ca2+]i in rabbit nonpigmented ciliary epithelial cells which were effectively antagonized by efaroxan or rauwolscine. CONCLUSIONS: These in vivo and in vitro data suggest that the ocular hypotensive activity induced by rilmenidine is due, in part, to suppression of sympathetic neuroeffector function in the rabbit ciliary body and that alpha 2 adrenergic receptors and/or imidazoline1 receptors are involved.

Adrenergic alpha-Agonists↗

Centrally mediated ocular hypotension: potential role of imidazoline receptors.

These experiments sought to: (1) determine if alpha 2/I1 agonists that are topically active on the eye have similar effects on intraocular pressure when applied to the CNS and (2) ascertain whether these agents lower IOP, in part, via central alpha 2 receptors and/or imidazoline (I1) receptors. New Zealand White rabbits were fitted with chronic indwelling stainless-steel guide cannulas in several brain regions including the lateral ventricle, third ventricle (3V), or medullary intermediate reticular zone. Animals were allowed 5 days' recovery time prior to experiments measuring the effects of drugs on IOP via applanation pneumatonometry. Some animals were also pretreated with 400 micrograms of 6-hydroxydopamine injected into the lateral ventricle to determine the site of action of these alpha 2/I1 agonists. In initial experiments involving microinjection into the lateral ventricle, UK-14,304-18 evoked ocular hypotension that was inhibited by the alpha 2-antagonist rauwolscine but not by the I1-receptor antagonist efaroxan. Conversely, moxonidine and oxymetazoline were preferentially inhibited by efaroxan rather than by rauwolscine. Subsequently, experiments have shown that moxonidine and oxymetazoline, but not UK-14,304-18 will lower intraocular pressure when microinjected into the medullary intermediate reticular zone region and that efaroxan, but not rauwolscine, will inhibit ocular hypotension induced by moxonidine and oxymetazoline. Pretreatment with 6-hydroxydopamine (48 hours) completely eliminated the ocular hypotension induced by moxonidine. These preliminary data demonstrate that alpha 2- and I1-receptors in the brain mediate ocular hypotension induced by UK-14,304-18 and moxonidine/oxymetazoline, respectively. Moreover, the medullary intermediate reticular zone area of the brain stem is the probable presynaptic site mediating ocular hypotension induced by moxonidine and oxymetazoline.

Administration, Topical↗

Alpha-2 adrenoceptor mediated changes in aqueous dynamics: effect of pertussis toxin.

Because alpha-2 (alpha 2) adrenoceptor-mediated inhibition of signal transduction mechanisms is regulated, in part, by inhibitory G (Gi) protein, we studied the effects of pertussis toxin (PTX) pretreatment on alpha 2 adrenergic agonist, UK 14,304-18 (UK; brimonidine)-induced: (1) changes in intraocular pressure (IOP) and aqueous flow rate of rabbits; (2) modulation of 3H-norepinephrine (NE) overflow of rabbit iris-ciliary bodies (ICBs) and (3) accumulation of cyclic AMP in rabbit ICBs and cultured non-pigmented ciliary epithelial (NPE) cells. Results showed that UK (50 micrograms) lowered the IOP of normal rabbits by 8 +/- 1 mmHg (n = 8) at 3 hr when treated topically and that the reduction of IOP was accompanied by a decrease in aqueous humor inflow (35%, n = 5). Therefore, it was postulated that these UK-induced effects involve activation of a Gi protein linked to alpha 2 adrenoceptors. In PTX-pretreated (2.5 micrograms kg-1, i.a.) rabbits, hypotensive responses to UK were reduced by 50% and 70% (n = 8) at days 4 and 7 post PTX treatment, respectively. The suppression of aqueous humor inflow induced by UK was also prevented by the PTX treatment. In isolated, perfused rabbit ICBs, UK (1 microM) caused 50% inhibition of 3H-NE overflow from electrical field stimulation. Pretreatment with PTX (150 ng ml-1, 4 hr) partially prevented UK-induced inhibition of NE overflow. In in vitro assays of postjunctional alpha 2 adrenoceptor activity, UK (1 microM) inhibited isoproterenol (ISO, 1 microM)-stimulated cAMP accumulation by 45% and 48% in ICBs and NPE cells, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

The central effects of moxonidine on intraocular pressure and its antagonism by L-659, 066 and L-657, 743 in the rabbit.

1) The imidazoline, moxonidine (MOX), injected icvt into the anterior lateral ventricle of NZW rabbits induced ocular hypotension (> 7.0 mmHg) that persisted for two hrs. 2) L-659, 066 injected i.v. or icvt inhibited MOX-induced ocular hypotension, significantly. 3) L-657, 743, injected icvt at 100-fold lower concentration than icvt L-659, 066, significantly inhibited MOX-induced ocular hypotension. 4) Alpha-2-adrenoceptors, located in the CNS, play a role in MOX-induced ocular hypotension, as evidenced by the ability of the relatively selective alpha-2 antagonists, L-659, 066 and L-657, 743 to inhibit icvt MOX-induced ocular hypotension.

Adrenergic alpha-2 Receptor Antagonists↗

Potential role of imidazoline (I1) receptors in modulating aqueous humor dynamics.

1) Moxonidine (MOX), injected icvt into the anterior lateral ventricle of NZW rabbits, induced bilateral, ocular hypotension (> 7.0 mmHg) that persisted for two hrs. 2) Oxymetazoline (OXY), injected icvt into the anterior lateral ventricle of NZW rabbits, induced bilateral ocular hypotension (> 7.0 mmHg) that peaked at two hrs. 3) Unilateral topical application of OXY induced maximal, bilateral ocular hypotension (> 12 mmHg), at 3 hrs, in both the contralateral and ipsilateral eyes, that persisted more than 12 hrs. 4) The putative imidazoline (I1) antagonist, efaroxan, injected icvt into the anterior lateral ventricle, inhibited significantly the ocular hypotension produced by icvt MOX, icvt OXY, and unilateral topical OXY. 5) Imidazoline (I1) receptors, located in the CNS, play a role in MOX- and OXY-induced ocular hypotension, as suggested by the ability of the putative imidazoline (I1) receptor antagonist efaroxan, to inhibit icvt MOX-, icvt OXY- and topical OXY-induced ocular hypotension.

Administration, Topical↗

Ocular actions of moxonidine: a possible role for imidazoline receptors.

Moxonidine (MOX, 4-chloro-N-[4,5 dihydro-1H-imidazol-2-yl]-6-methoxy-2- methyl-5-pyridinamine), a relatively selective alpha-2 agonist, was investigated for effects on: 1) aqueous humor dynamics in normal and unilaterally sympathectomized rabbits; 2) noradrenergic functions in cat nictitating membrane (CNM); 3) [3H]norepinephrine overflow in rabbit iris-ciliary bodies (ICBs) and 4) cyclic AMP (cAMP) accumulation in rabbit ICBs and nonpigmented ciliary epithelial (NPE) cells. Unilateral, topical administration of MOX to the normal rabbit eyes produced decreases in intraocular pressure, aqueous humor flow rate and ipsilateral increases in pupil diameter. Ocular hypotensive response to MOX was inhibited by bilateral, topical pretreatment with idazoxan, an alpha-2/imidazoline antagonist, and efaroxan, an imidazoline antagonist. In sympathectically denervated rabbit eyes, MOX did not lower intraocular pressure or decrease aqueous humor flow rate. MOX suppressed, dose dependently, contractions of the CNM elicited by electrically stimulating the preganglionic sympathetic trunk, an effect antagonized by rauwolscine, an alpha-2 antagonist. In other experiments, MOX caused a dose-related inhibition of [3H]norepinephrine release from field-stimulated ICBs, an effect antagonized by efaroxan. MOX antagonized isoproterenol-induced cAMP accumulation in rabbit ICBs and NPE cells, an effect inhibited by rauwolscine. These results demonstrate that MOX: 1) produces ocular hypotension in rabbits by suppressing aqueous humor flow; 2) antagonizes electrically induced contractions of the CNM by inhibiting sympathetic neuronal function; 3) suppresses norepinephrine release of rabbit ICBs, an effect that was inhibited by efaroxan and 4) prevents isoproterenol-induced cAMP accumulation in the rabbit ICBs and NPE cells via action on alpha-2 adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

Ocular actions of an octahydrobenzo[f]quinoline: Ha117.

An octahydrobenzo[f]quinoline compound, Ha117, was examined for activity on: (1) intraocular pressure and in normal, sympathectomized and water loaded rabbits and aqueous flow rate in normal and sympathectomized rabbits, respectively; (2) contractions of the cat nictitating membrane elicited by electrical stimulation of cervical sympathetic nerves; (3) cAMP accumulation in the isolated rabbit iris root-ciliary body preparation. Ha117 lowered intraocular pressure and aqueous flow rate in normal but not in sympathectomized rabbits. Elevated intraocular pressure produced by water loading was suppressed by Ha117 and pretreatment with metoclopramide antagonized the inhibitory effect of Ha117. Neuronally mediated contractions of the nictitating membrane were inhibited in a dose-related fashion by Ha117, and inhibitory effects were antagonized by domperidone. Ha117 and an analog, Ha118, did not suppress isoproterenol- and vasoactive intestinal peptide-induced accumulation of cAMP in the rabbit iris root/ciliary body. In vivo results in rabbit and cat models suggest that the ocular hypotensive effect of Ha117 is mediated by an action on prejunctional dopamine (DA2) receptors. In vitro data in the rabbit iris root/ciliary body suggest that Ha117 and Ha118-induced lowering of intraocular pressure does not involve postjunctional suppression of cAMP accumulation.

Animals↗

Comparative effects of alpha-2 and DA-2 agonists on intraocular pressure in pigmented and nonpigmented rabbits.

Alpha-2 and DA2 adrenoceptor agonists produce ocular hypotension in cats, rabbits, monkeys and humans. In this study, the effects of topical, unilateral administration of medetomidine (MED), an alpha-2 agonist, and Ha-118 (HA), a DA2 agonist, were compared on intraocular pressure (IOP) in normal, unilaterally sympathectomized (SX), and ocular hypertensive (oral water loaded) Dutch Belted (DB) and New Zealand White (NZW) rabbits. MED (75 micrograms) produced bilateral ocular hypotensive effects in both DB and NZW normal rabbits; however, HA (250 micrograms) lowered IOP unilaterally in NZW rabbits only. MED (25 micrograms) inhibited the rise in IOP caused by oral water loading in both DB and NZW rabbits; HA, on the other hand, was effective only in NZW rabbits. Topical bilateral pretreatment with metoclopramide, a DA2 antagonist, inhibited the ocular antihypertensive effect of HA in NZW rabbits. The IOP lowering effects of MED were absent in the SX eyes of DB and NZW rabbits, but hypotensive responses to MED were present in normal (contralateral) eyes of both strains. In contrast, HA was effective only in the treated, normal eyes of SX NZW rabbits. These data support pharmacodynamic roles for alpha-2 and DA2 receptors in modulating IOP. The lack of activity by HA in DB rabbit eyes suggests a possible absence of DA2 receptors or excessive binding of HA to pigment in the anterior segment of DB rabbit eyes.

Adrenergic alpha-Agonists↗

Allicin-induced hypotension in rabbit eyes.

The intent of this work was to examine the actions of allicin on 1) intraocular pressure (IOP) in normal and unilaterally sympathectomized (SX) rabbits; 2) cAMP accumulation in the rabbit iris-ciliary body (ICB) and cultured nonpigmented epithelial (NPE) ciliary body cells; and 3) 3H-norepinephrine (NE) release by calculating fractional tritium overflow in response to electrical field stimulation (EFS, 5 Hz, 12 V/cm) in isolated, perfused rabbit ICBs. Allicin, one of the active compounds produced by garlic, was evaluated on IOP and it was determined that allicin (1, 2.5, or 10 micrograms), topically, but not the precursor, alliin (10 micrograms), lowered the IOP unilaterally in normal rabbits. Allicin (10 micrograms) reduced the IOP by 6 +/- 1 mmHg (n = 4) in normal rabbits at 2 hrs (maximum response) whereas no change occurred in sympathectomized rabbit eyes. Moreover, allicin (0.01, 0.1, or 1 microM) caused 40, 40, or 52% inhibition, respectively, of 3H-NE overflow in response to EFS. Isoproterenol (ISO, 1 microM) stimulated cAMP accumulation by 3.6 and 9 fold in isolated rabbit ICB and cultured NPE cells, respectively. Allicin (1 microM) had no effect on basal cAMP level while it inhibited ISO-stimulated cAMP accumulation by 40% and 23% in ICB and NPE cells, respectively. This study suggests that allicin lowered IOP, in part, by dual actions at the neuroeffector junction.

Animals↗

Ocular hypotensive action of a dopaminergic (DA2) agonist, 2,10,11-trihydroxy-N-n-propylnoraporphine.

The dopamine (DA2) receptor agonist 2,10,11-trihydroxy-N-n-propylnoraporphine (TNPA) was tested for effects on 1) intraocular pressure (IOP), 2) aqueous humor flow rate, 3) electrically induced contractions of the cat nictitating membrane, 4) 3H-NE release from isolated rabbit iris-ciliary bodies and 5) cAMP accumulation in the isolated rabbit iris-ciliary body. Unilateral, topical administration of TNPA lowered IOP bilaterally in a dose-related fashion and inhibited the bilateral rise in IOP caused by water gavage. Topical pretreatment with metoclopramide, a DA antagonist, inhibited the ocular hypotensive response to TNPA. Subsequently, TNPA was shown to decrease aqueous humor inflow and IOP in normal rabbit eyes but not in surgically sympathectomized rabbit eyes. TNPA caused dose-dependent suppression of contractions of the cat nictitans, which was inhibited competitively by domperidone, a relatively selective DA2 receptor antagonist. In a test of prejunctional activity, TNPA caused dose-related inhibition of 3H-NE release from isolated, field-stimulated rabbit iris-ciliary bodies, which was inhibited by pretreatment with sulpiride, a relatively selective DA2 receptor antagonist. In a test of postjunctional activity, isoproterenol-stimulated cAMP accumulation in the isolated rabbit ciliary body was not affected by TNPA pretreatment. These results indicate that TNPA's suppressive action on aqueous humor flow rate and IOP is exerted predominantly on prejunctional (DA2) receptors of peripheral sympathetic nerves.

Animals↗

Pharmacological evidence for heterogeneity of ocular alpha 2 adrenoceptors.

Previous studies have shown that ocular alpha 2 adrenoceptors are located prejunctionally on sympathetic neurons and postjunctionally on cells in the iris/ciliary body. While the activation of alpha 2 adrenoceptors at each site has been postulated to alter aqueous humor dynamics, little is known about the pharmacological characteristics of these receptors or their role in the modulation of anterior segment function. The purpose of the current study was to determine the possible heterogeneity of ocular alpha 2 adrenoceptors using relatively selective alpha 2 adrenoceptor agonists and antagonists to examine ocular pre- and postjunctional alpha 2 adrenoceptors. Prejunctional alpha 2 effects were evaluated by means of the cat nictitating membrane (CNM) preparation. Postjunctional alpha 2 effects were evaluated by means of the cAMP assay in rabbit iris root/ciliary body. In the CNM, the administration of UK-14, 304 (UK) produced a dose-related inhibition of neuronally mediated contractions. Pretreatment with the alpha 2 antagonist rauwolscine caused a 1 to 2 log unit right shift in the dose-response curve of UK in the CNM. However, pretreatment with alpha 2 antagonist SKF 104078 had no demonstrable effect on UK-induced inhibition of neuronally mediated contractions of the CNM. In the rabbit iris root/ciliary body, UK produced a concentration-dependent inhibition of cAMP accumulation on isoproterenol- and VIP-induced cAMP production. Pretreatment of iris root/ciliary bodies with SKF 104078 or rauwolscine reversed the inhibitory effect of UK on isoproterenol- and VIP-induced accumulation of cAMP. These data provide the first evidence that the pre- and postjunctional alpha 2 adrenoceptors represent pharmacologically distinct subpopulations of receptors in the eye.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

Are blood transfusions beneficial in the cyclosporine era?

In patients treated with conventional immunosuppression (azathioprine and prednisone) after renal transplantation, there is a beneficial effect of pre-transplant blood transfusions on graft survival; in patients treated with cyclosporine, this effect may be lost. In 66 children who received living-related donor transplants after donor-specific transfusions (DST) and were treated with azathioprine-prednisone in our center, 1- and 5-year graft survival rates were 99% and 77% respectively. These rates were similar to those reported for children who did not receive DST but were treated with cyclosporine in other centers. There were 634 adult and pediatric recipients of cadaver transplants in our center who were treated with cyclosporine and prednisone (non-sequential therapy, n = 89) or antilymphoblast globulin, azathioprine preduisone, and cyclosporin (sequential therapy, n = 545). When all patients were considered, graft survival rates were higher in transfused than in non-transfused patients at 3-5 years, but in the sequential therapy group, there were no differences in graft survival rates between transfused and non-transfused patients. The results suggest that transfusions do not improve cadaver graft survival in patients receiving optimal cyclosporine therapy and that equally good related donor graft survival can be achieved with DST and conventional immunosuppression or no DST and cyclosporine.

Blood Transfusion↗

Long-term results of renal transplantation in children.

The results of renal transplantation in 37 children, 3 through 16 years of age, who received transplants prior to June, 1970 in our center, were examined. Twenty-three received kidneys from living-related donors and 14 received kidneys from cadaver donors. Patient survival rates were 78% at 10 years and 68% at 20 to 26 years. Graft survival rates were 56% at 10 years, 31% at 20 years, and 23% at 22 to 26 years. Twenty children received on or more retransplants. At follow-up, 23 (62%) of the patients had functioning grafts and two (5%) were undergoing dialysis. Cataracts, hypertension, and aseptic necrosis of bone were the most common medical complications and most of the patients were more than two standard deviations below average height. Most enjoyed good rehabilitation, however: more than 70% were employed or performing full time housework, more than 50% were married, 24% had children, and all had normal activity at least part of the time. These results, achieved with immunosuppressive methods now considered obsolete, indicate that renal transplantation is a satisfactory long-term treatment for children with renal failure.

Adolescent↗