Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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)
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PMID:Alpha-2 adrenoceptor mediated changes in aqueous dynamics: effect of pertussis toxin. 792 12

After intravitreal injections of cholera or pertussis toxin (CTX or PTX, 0.5 -1 microgram/eye) into the albino rabbit eye, the in vitro responses of ciliary process adenylyl cyclase (AC) to isoproterenol, vasoactive intestinal peptide (VIP), and forskolin (FSK) were increased 21-40% for PTX, but for CTX-injected eyes AC responses to fluoroaluminate, VIP and FSK decreased 70-50%. The increased responses after PTX suggests that this toxin blocked an inhibitory Gi control of AC that is present in the control tissue. However, prolonged (> 24 hr) in vivo exposure to CTX appears to down-regulate the AC enzyme. In contrast to the in vivo findings, AC responsiveness was unaffected by PTX pre-treatment of membranes in vitro, while CTX pre-treatment increased basal activity (+600%), and the FSK response (+30%), but decreased responsiveness to fluoroaluminate, VIP and isoproterenol by 88-56%. Treatment of ciliary process membranes with 32P-NAD and CTX or PTX followed by SDS-PAGE autoradiography of labelled proteins gave two bands for the G-protein alpha-subunits of Gs (45, 56 kDa) and one broad band centered at 40 kDa for Gi-type subunits respectively. Western blots using specific antibodies showed the presence of Gi type I or III, but no detectable Gi type II or Go in rabbit ciliary processes. We conclude that the changes in adenylyl cyclase enzyme responses after intraocular CTX or PTX may not correlate with cAMP levels and intraocular pressure effects. However, the in vitro biochemical data on AC responses and on G-proteins provide evidence for dual regulation of ciliary process AC by activating and inhibitory G-proteins.
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PMID:Role of G-proteins in ciliary process adenylyl cyclase responses of the albino rabbit eye. 803 85

Intravitreal injections of cholera or pertussis toxin (CTX or PTX, 0.5-1 microgram/eye) decreased intraocular pressure (IOP) up to 50% in the albino rabbit eye, which lasted up to six days. Both toxins were active on G-proteins as determined by in vitro and in vivo effects on ciliary process adenylyl cyclase activity and by ADP ribosylation of G-protein alpha-subunits with 32P-NAD. However, forty-two hours after toxin injection aqueous humor proteins increased from control levels of 0.8-1.2 mg/ml to 8-25 mg/ml. Both toxins contained 1-3 parts per thousand endotoxin sufficient to cause the IOP and aqueous humor protein responses observed. We conclude that the in vivo responses to intraocular CTX or PTX obtained from commercial sources may not provide unequivocal evidence for the role(s) of G-proteins in aqueous humor dynamics, and must be interpreted with caution.
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PMID:Endotoxins in cholera and pertussis toxins interfere with in vivo responses to these agents in the albino rabbit eye. 803 92

The effects of pertussis toxin on the intraocular pressure (IOP) lowering effect of clonidine and isoproterenol as well as on the inhibitory effects of clonidine and neuropeptide Y on adenylate cyclase activity of ciliary processes were studied in albino rabbits. I.v. administered pertussis toxin elicited transient changes in IOP which, however, returned to control values during 2-3 days. In the following days the IOP lowering effect of the alpha 2-adrenergic agonist clonidine was abolished and that of the nonselective beta-adrenergic agonist isoproterenol was attenuated. At the same time, the inhibitory effects of clonidine and neuropeptide Y on basal as well as stimulated adenylate cyclase activities in homogenates of ciliary processes were grossly diminished. The effects of pertussis toxin on the IOP lowering action of adrenergic agonists and on the inhibitory action of clonidine and neuropeptide Y on adenylate cyclase activity were ascribed to an impairment of the function of a G protein in ciliary processes, probably G(i) protein. It is suggested that the decrease of IOP induced by clonidine is due to inhibition of adenylate cyclase.
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PMID:Effects of pertussis toxin on intraocular pressure and adenylate cyclase activity of ciliary processes in rabbits. 840 17

In the present study we have examined the effects and mechanisms of endothelin-1 (ET-1) on arachidonic acid (AA) release and prostaglandin (PG) synthesis in human ciliary muscle (HCM) cells. ET-1 stimulated AA release in a time (t1/2=1.5 min) and concentration-dependent (EC50=5 nM) manner, which is primarily mediated through the ETA receptor subtype. The AA liberated by ET-1 appears to derive mainly from the phosphoinositides and phosphatidylcholine. Our data show that phospholipase A2 (PLA2), but not phospholipase C (PLC), plays an important role in ET-1-induced AA release. This conclusion is supported by the following findings: (1) ET-1-evoked AA release was inhibited by the PLA2 inhibitors dexamethasone, mepacrine and manoalide in a concentration-dependent manner. Conversion of AA into PGE2 was inhibited by the cyclooxygenase inhibitors in the following order: Indomethacin>naproxen >ibuprofen>NS-398>aspirin. (2) The phorbol ester, PDBu, an activator of protein kinase C, potentiated ET-1-induced AA release by 39%, but inhibited that of inositol phosphates formation by 62%. (3) Pretreatment of the labeled cells with isoproterenol lowered ET-1-induced inositol phosphates production, but had no effect on AA release. (4) U71322, a PLC inhibitor, inhibited ET-1-induced inositol phosphates production, but had no effect on that of AA release. (5) Pretreatment of the cells with pertussis toxin (0.1 microg ml-1) attenuated the stimulatory effects of ET-1 on AA release and PGE2 formation. These data demonstrate that ET-1 is a potent agonist for AA release and PG synthesis in HCM cells, and that PLA2, but not PLC, plays an important role in ET-1-induced AA release and PG synthesis. In ciliary muscle, AA and its metabolites play important roles in intracellular signalling, modulation of physiological processes, and regulation of intraocular pressure.
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PMID:Endothelin-1 stimulates the release of arachidonic acid and prostaglandins in cultured human ciliary muscle cells: activation of phospholipase A2. 923 67

The effects of the selective alpha2-adrenergic agonist p-aminoclonidine, the nonselective adrenergic agonist epinephrine, the selective beta2-adrenergic agonist fenoterol and the adenosine A1 agonist R-PIA on intraocular pressure were studied in control and pertussis toxin-pretreated rabbits. Pretreatment of rabbits with pertussis toxin decreased the ocular hypotensive effects of p-aminoclonidine and epinephrine, did not influence the same effects of fenoterol or R-PIA and markedly potentiated the initial ocular hypertensive effects of epinephrine and R-PIA. As far as the action on adenylyl cyclase in ciliary processes is concerned, isoproterenol stimulated its activity in control rabbits and epinephrine exerted dual, i.e. stimulatory and inhibitory effects on the activity of this enzyme. The data obtained with epinephrine and p-aminoclonidine confirm the view that their ocular hypotensive effects are associated with their inhibitory action on adenylyl cyclase and contradict the opinion that the hypotensive action of adrenergic drugs depends on adenylyl cyclase activation.
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PMID:Effects of drugs acting on adrenergic and adenosine receptors on the intraocular pressure and the activity of adenylyl cyclase in ciliary processes and their sensitivity to pertussis toxin. 972 8

The objective of this study was to examine the ocular hydrodynamic effects of topically and centrally administered naphazoline, alone and following pretreatment with pertussis toxin (PTX) and alpha(2)/I(1)receptor antagonists. Topically and intracisternally administered naphazoline was examined for its ability to alter intraocular pressure (IOP) of rabbits in the absence and presence of receptor antagonists (rauwolscine, efaroxan) and a G(i/o)ribosylating agent PTX. In addition, the topical effects of naphazoline on pupil diameter and aqueous humor flow rate were evaluated. Topical unilateral application of naphazoline (7.5, 25 and 75 micro g; 25 micro l) elicited an ipsilateral dose-dependent mydriasis (2, 4 and 5.5 mm) that peaked at 2 hr with a duration of up to 5 hr. The IOP decreases induced by naphazoline were bilateral and dose-dependent (3, 6 and 10 mmHg); the response peaked at 1 hr and lasted for up to 5 hr. Pretreatment with efaroxan (250 micro g) elicited significantly greater antagonism of the ocular hypotensive response to naphazoline than did rauwolscine (250 micro g) suggesting an involvement of imidazoline (I(1)) receptors. Intracisternal application of naphazoline (3.3 micro g) also produced bilateral reductions (6 mmHg) of IOP that were immediate (10 min post drug) and lasted for approximately 2 hr. In PTX-pretreated (2.5 micro g kg(-1), i.a.) rabbits, the ocular hypotensive effects of naphazoline by both routes (topically and centrally) were attenuated by 50--65%. In addition to producing ocular hypotension, topical application of naphazoline (75 micro g; 25 micro l) caused significant reduction, from 2.8 to 1.5 micro l min(-1), in aqueous humor flow. These in vivo data indicate that, regardless of route of administration, alteration of aqueous humor flow by naphazoline was induced by the activation of alpha(2)and I(1)receptors. The ocular hypotensive effects produced by central administration did not result in sedation, therefore, there is the suggestion that central alpha(2)adrenergic receptors were stimulated minimally by naphazoline. Thus, these data suggest that ocular hypotensive effects and suppression of aqueous humor flow rate by naphazoline are mediated, in part, by alpha(2)and/or central I(1)at both central (brain) and peripheral (eye) sites. Moreover, these data indicate that the receptors are linked to PTX-sensitive G((i/o))proteins.
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PMID:Naphazoline-induced suppression of aqueous humor pressure and flow: involvement of central and peripheral alpha(2)/I(1) receptors. 1118 Sep 82

Kappa-opioid receptor agonists have been shown to reduce intraocular pressure in rabbits and monkeys. This study was designed to investigate mechanisms in the iris-ciliary body (ICB) that may be involved in bremazocine (BRE)-induced ocular hypotension in New Zealand White rabbits. Using ICBs, BRE and norbinaltorphimine (nor-BNI), relatively selective kappa-opioid receptor agonist and antagonist, respectively, along with pertussis toxin (PTX), were used to evaluate the effect of 1) kappa-opioid receptors on [(3)H]norepinephrine (NE) release from postganglionic sympathetic neurons, and 2) cAMP accumulation. BRE caused dose-related (0.1, 1, and 10 microM) inhibition of electrically stimulated [(3)H]NE release from ICBs to 77, 57, and 36% of the control, respectively. Nor-BNI antagonized the inhibition of [(3)H]NE release by BRE, while PTX pretreatment limited the suppressive effect of BRE (1 and 10 microM). When used alone, BRE (0.01, 0.1, 1, and 10 microM) caused stimulation of cAMP levels in ICBs, however, similar concentrations caused inhibition of isoproterenol (ISO)-stimulated cAMP production. Pretreatment of ICBs with nor-BNI (10 microM) or PTX (150 ng/ml) antagonized BRE-induced suppression of ISO-stimulated cAMP. These data demonstrate that BRE acts at multiple [prejunctional (neuronal) and postjunctional] sites in the ICB. BRE had a biphasic effect on ISO-stimulated adenylyl cyclase activity; enhancing cAMP levels at low concentrations and inhibiting cAMP production at high concentrations. Based on the modifications induced by PTX pretreatment, the kappa-opioid receptors involved in some of the ocular actions of BRE are linked to a G(i/o) protein.
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PMID:Biphasic alterations of cAMP levels and inhibition of norepinephrine release in iris-ciliary body by bremazocine. 1150 88

It has been demonstrated that natriuretic peptides lower intraocular pressure, however, the underlying cellular mechanism(s) mediating this response remain(s) to be determined. The purpose of this study was to investigate the effects of C-type natriuretic peptide (CNP) on pH(i), cGMP/cAMP and expression of atrial natriuretic peptide receptor (NPR-A), brain natriuretic peptide receptor (NPR-B) and C-type natriuretic peptide receptor (NPR-C), in HTM cells. At concentrations of 10(-7) M, CNP caused an acidification of pH(i). In addition, CNP caused a dose-dependent increase in cGMP formation and inhibition of forskolin-stimulated cAMP accumulation. These changes were not significantly altered in the absence of 10(-3) M isobutylmethylxanthine (IBMX). Treatment with the NPR-A antagonist, anantin, produced no influence on basal cGMP/cAMP levels, the CNP-stimulated cGMP accumulation and CNP-induced inhibition of forskolin-stimulated cAMP accumulation. However, CNP-induced reduction of forskolin-stimulated cAMP accumulation was inhibited by pretreatment with pertussis toxin (PTX). Furthermore, NPRB receptors were predominantly expressed and pretreatment with CNP (10(-7) M, 24hr) enhanced all NPR mRNAs expression which was not altered by higher concentrations or longer incubation. Results demonstrate that NPR-A, NPR-B and NPR-C receptors' expression can be up-regulated by CNP treatment. CNP activates NPR-B receptors preferentially to increase cGMP accumulation and acts through the PTX-sensitive cAMP-signaling pathway leading to a decrease in pH(i).
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PMID:CNP-induced changes in pHi, cGMP/cAMP and mRNA expression of natriuretic peptide receptors in human trabecular meshwork cells. 1458 35

Our laboratory has previously demonstrated the ability of kappa- and delta-opioid agonists to decrease aqueous flow rates and intraocular pressure of rabbits. The mechanisms by which these agents act in the ciliary body of the rabbit could involve inhibition of cAMP production, as well as increased generation of inositol phosphates (IPs). With regard to enhanced production of IPs, it has been suggested that their levels can be augmented by stimulation of phospholipase C via opioid receptors linked to either Galpha-subunits derived from Gq proteins or Gbetagamma-subunits derived from G(i/o)-proteins. The aim of the current study is to investigate the role of pertussis toxin (PTX)-sensitive G-proteins and Gbetagamma-subunits in delta-opioid agonist-mediated changes in IP production in the isolated, rabbit iris-ciliary body (ICB). In one set of experiments, ICB segments were treated with the delta agonist, SNC80 (10(-12)-10(-7) mol/l) alone. Other experiments were conducted utilizing SNC80 following pretreatment with either phosducin (Gbetagamma-subunit scavenger), PTX, or the delta antagonist, naltrindole. IP production was measured by ion exchange chromatography. Basal levels of IPs in the rabbit ICB were 58,287 +/- 2162, 15,218 +/- 969 and 2083 +/- 367 dpm/mg protein for IP1, IP2 and IP3, respectively. The highly selective delta-opioid receptor agonist, SNC80, produced concentration-dependent increases in the levels of the IPs in the ICB, which were diminished in the presence of the delta antagonist, naltrindole, indicating the effect was mediated via activation of delta-opioid receptors. Pretreatment of tissues with PTX (75 ng/ml), completely abolished the concentration-dependent production of IPs generated by SNC80 (10(-11)-10(-7) mol/l). In addition, pretreatment with phosducin (1 nmol/l) ablated the SNC80 (1 nmol/l)-induced increase in the formation of all three inositol phosphates. Results from this study indicate that the delta-opioid receptor-mediated increase in IP production is a PTX-sensitive G(i/o) response that involves participation of Gbetagamma-subunits. Thus, delta-opioid receptor activation by SNC80 in the ICB could be responsible, in part, for suppression of aqueous humor dynamics.
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PMID:Delta-opioid agonist-stimulated inositol phosphate formation in isolated, rabbit iris-ciliary bodies: role of G(i/o) proteins and Gbetagamma-subunits. 1460 52


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