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)

Biochemical studies have suggested a voltage-dependent dihydropyridine-sensitive catecholamine release in adrenal chromaffin cells. This release is inhibited by activation of alpha 2-adrenergic and muscarinic receptors; the underlying molecular mechanism is not known. We used undifferentiated PC-12 cells to study the effect of epinephrine and carbachol on transmembranous currents. Applying the patch-clamp technique in the whole cell configuration and using Ba2+ as charge carrier, we identified a high voltage-activated Ca2+ channel current. Both epinephrine (10 microM, in the presence of 1 microM propranolol) and carbachol (10 microM) reversibly inhibited the Ca2+ channel current by 30-40%. Yohimbine abolished and clonidine mimicked the effect of epinephrine. Phenylephrine failed to inhibit the Ca2+ channel current. The effect of carbachol was abolished by atropine. Epinephrine and carbachol did not affect the Ca2+ channel current reduced by the dihydropyridine, PN 200-110 (1 microM), suggesting a selective inhibition of dihydropyridine-sensitive Ca2+ channels. The Ca2+ channel current and its inhibition by receptor agonists were not influenced by intracellularly applied adenosine 3',5'-cyclic monophosphate (cAMP; 100 microM). Pretreatment of cells with pertussis toxin or intracellular infusion of the GDP analogue guanosine-5'-O-(2-thiodiphosphate) was without effects on the control Ca2+ channel current but abolished its hormonal inhibition. Four pertussis toxin-sensitive G proteins were identified in membranes of PC-12 cells: two members of the Gi family, Gi1 and Gi2, and two members of the Go family, Go2 and another Go subtype (possibly Go1). The present data indicate that activated alpha 2-adrenergic and muscarinic receptors inhibit dihydropyridine-sensitive Ca2+ channels via pertussis toxin-sensitive G proteins without the involvement of a cAMP-dependent intermediate step.
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PMID:Inhibition of Ca2+ channels via alpha 2-adrenergic and muscarinic receptors in pheochromocytoma (PC-12) cells. 164 65

We used standard microelectrode techniques to study alpha-1 adrenergic modulation of repolarization in canine Purkinje fibers. Our objectives were to subtype this alpha-1 receptor response pharmacologically, to determine whether alpha-1 adrenergic modulation of repolarization is dependent on the function of a pertussis toxin-sensitive G protein and to identify developmental changes in this alpha-1 response. Phenylephrine (Phe) induced a dose-dependent increase in transmembrane action potential duration at 50% (APD50) and 90% (APD90) repolarization. For the adult fibers, control APD50 and APD90 were 310 +/- 5 and 407 +/- 5 msec; after superfusion with Phe, 1 x 10(-6) M, the values were 350 +/- 6 and 468 +/- 8 msec, respectively (P less than .05). In 2- to 3-week-old dogs, control APD50 and APD90 were 170 +/- 14 and 255 +/- 10 msec; after superfusion with Phe, the values were 228 +/- 10 and 305 +/- 16 msec, respectively (P less than .05). Propranolol, 2 x 10(-7) M, did not affect the response to Phe. The alpha-1 blocker prazosin, 1 x 10(-7) M, and the alpha-1 receptor subtype selective antagonist, WB 4101, 1 x 10(-7) M, suppressed the response to Phe, but no effect on the response to Phe was seen with the subtype selective antagonist, chloroethylclonidine. In vivo pretreatment of dogs with pertussis toxin, 30 micrograms/kg i.v., decreased markedly the amount of G protein substrate available for subsequent in vitro ADP-ribosylation by pertussis toxin and [32P]NAD (from 7039 +/- 713 to 537 +/- 50 fmol/mg of protein in adult fibers and from 1134 to 62 fmol/mg of proteins in pooled young fibers). Pertussis toxin pretreatment increased the Phe-induced prolongation of APD50 and APD90 in the young and adult fibers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A WB 4101-sensitive alpha-1 adrenergic receptor subtype modulates repolarization in canine Purkinje fibers. 167 17

The interaction of agonists with alpha-1 receptor subtypes sensitive and resistant to alkylation by a prazosin analog [1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-bicyclo[2.2.2]octa-2,5- diene-z-carbonyl)-piperazine; SZL-49] has been examined. In rat aortic rings, SZL-49 (0.1-10 nM) shifted the dose-response curves for norepinephrine and phenylephrine to the right. The curves were biphasic, consisting of high and low affinity components. At greater than 10 nM, the curves became monophasic. After SZL-49 treatment, the response to norepinephrine was partially antagonized by diltiazem. Chlorethylclonidine (1-100 microM) also produced biphasic dose-response curves. Phenylephrine bound to high and low affinity sites labeled by [3H]prazosin, and the high affinity site was eliminated by SZL-49. SZL-49 (i.p.) shifted the pressor dose-response curve for phenylephrine to the right but did not decrease the maximal response. Chlorethylclonidine was much less potent than SZL-49 at shifting the pressor dose-response curve. Pertussis toxin, 50 micrograms/kg i.v., shifted the phenylephrine pressor dose-response curve in control and SZL-49-treated animals. SZL-49 inhibited norepinephrine-induced inositol phosphate formation, whereas chlorethylclonidine had no effect on inositol phosphate formation. These data show: 1) both in vitro and in vivo, alpha-1 receptor subtypes sensitive and resistant to alkylation by SZL-49 can mediate the full response of agonists; 2) these subtypes exhibit high and low affinity for agonists; 3) responses mediated by either subtype are partially dependent on calcium channel activity and a pertussis toxin-sensitive G-protein; 4) the SZL-49 sensitive site is able to enhance the formation of inositol phosphates.
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PMID:Agonist interaction with alkylation-sensitive and -resistant alpha-1 adrenoceptor subtypes. 197 27

The pathogenesis of the myopathy occurring in the heart of the cardiomyopathic strain of the Syrian hamster is not well understood but is believed to be associated with abnormal calcium handling by myopathic cells. The purpose of this study was to determine whether the cardiomyopathy occurring in strain BIO 14.6 animals is associated with an enhanced alpha 1-adrenergic receptor-mediated rise in cytosolic calcium, whether a pertussis toxin-sensitive G protein is involved in coupling the alpha 1-adrenergic receptor to changes in intracellular calcium and whether enhanced alpha 1 responsiveness is associated with an increase in the level of expression of the alpha 1-adrenergic receptor or in the pertussis toxin-sensitive G protein or proteins. To test the hypothesis that the cardiomyopathic state is associated with a greater alpha 1-receptor-mediated rise in cytosolic calcium, we studied the effect of phenylephrine (in the presence of propranolol) on time-averaged cytosolic calcium concentration ([Ca2+]i) in isolated cardiac myocytes from cardiomyopathic and age-matched control hamsters. Phenylephrine caused a greater increase both in time-averaged [Ca2+]i (an increase of 48 +/- 8% versus 12 +/- 3%, p less than 0.01) and in contractility (+181 +/- 22% versus +35 +/- 9%, p less than 0.01) in cardiomyopathic than in normal cardiac myocytes. Exposure to pertussis toxin (200 ng/ml for 3 hours) attenuated the alpha 1-adrenergic receptor-mediated increase in contractility and time-averaged [Ca2+]i in both cardiomyopathic and normal cells. The level of pertussis toxin-sensitive G protein, as determined by pertussis toxin-mediated [32P]ADP-ribosylation, was 1.6-fold higher in cardiomyopathic versus normal hamster hearts. The density of alpha 1-adrenergic receptors, as measured by the antagonist radioligand [3H]prazosin and the affinity of the receptor for agonist and antagonist were similar in myopathic and normal heart membranes. Thus, in cardiac myocytes from hamsters, the alpha 1-adrenergic receptor-mediated effects on [Ca2+]i and contractility appear to be mediated by a pertussis toxin-sensitive G protein or proteins. In myocytes from cardiomyopathic hamsters, these alpha 1-adrenergic effects were increased in magnitude, as was the level of pertussis toxin-sensitive G protein, but there was no measurable alteration in the density or ligand binding properties of alpha 1-adrenergic receptors.
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PMID:Enhanced alpha 1-adrenergic responsiveness in cardiomyopathic hamster cardiac myocytes. Relation to the expression of pertussis toxin-sensitive G protein and alpha 1-adrenergic receptors. 217 3

Contractions were induced in rings of rabbit pulmonary artery with the preferential alpha 1-adrenoceptor agonists, phenylephrine, methoxamine and St 587 [2-(2-chloro-trifluoromethyl-phenylimino)imidazolidine and the preferential alpha 2-adrenoceptor agonists, clonidine and B-HT 920 [6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d) azepine] [corrected]. Phenylephrine and methoxamine acted as full agonists whereas St 587, clonidine and B-HT 920 were partial agonists (intrinsic activities 0.62, 0.38 and 0.42, respectively). Experiments with alpha 1- and alpha 2-adrenoceptor antagonists indicated that the receptors involved are of the alpha 1 type only. Removal of extracellular Ca2+ inhibited maximal contractions to phenylephrine and methoxamine by 30% and 49%, respectively. The remaining contraction components of the full agonists were abolished by the "intracellular Ca2+ antagonist" TMB-8 [8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate]. Contractions to St 587, clonidine and B-HT 920 were virtually abolished in Ca2+-free medium. Pretreatment of the donor rabbits with pertussis toxin (2.5 micrograms/kg i.v., 5-6 days before sacrifice) attenuated the efficacies of the full agonists, phenylephrine and methoxamine by only 24% and 17%, respectively, whereas maximal contractions to the partial agonists, St 587, clonidine and B-HT 920, were inhibited by 46%, 61% and 75%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The inhibition of alpha 1-adrenoceptor-mediated contractions of rabbit pulmonary artery by Ca2+-withdrawal, pertussis toxin and N-ethylmaleimide is dependent on agonist intrinsic efficacy. 257 Mar 59

Epinephrine and norepinephrine (1-10 microM) stimulated the release of prostacyclin (PGI2) from the rabbit aorta in vitro. The stimulation was maintained for at least 2 h in the continuous presence of epinephrine. Phenylephrine mimicked this effect, whereas the selective alpha 2-agonist UK-14,304 was completely ineffective. The action of epinephrine was abolished by prazosin (1 microM) and was maintained in the presence of yohimbine. Epinephrine or phenylephrine neither increased the basal release of PGI2 from bovine aortic endothelial cells nor potentiated the stimulatory action of adenine nucleotides, which is mediated by P2-purine receptors. The response to epinephrine was lost in freshly deendothelialized strips of rabbit aorta, possibly because of cyclooxygenase self-inactivation. The response recovered however following overnight incubation of these strips in a cell culture medium. The response to epinephrine was mimicked by neither phorbol 12-myristate,13-acetate nor ionophore A23187. It was not inhibited by pretreatment with pertussis toxin. It is concluded that adrenergic agents stimulate the vascular production of PGI2, by activating alpha 1-receptors located on smooth muscle cells.
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PMID:Adrenergic stimulation of vascular prostacyclin: role of alpha 1-receptors in smooth muscle cells. 283 Jan 24

The effects of alpha 1-adrenergic agents on GH release and intracellular free Ca2+ concentration ([Ca2+]i) were investigated in purified rat somatotroph preparations. Phenylephrine (PHE) stimulated in vitro GH release; the maximal effect (2.5-fold stimulation) occurred at 1 microM PHE. The effect was completely blocked by the alpha-adrenergic antagonist phentolamine and partially counteracted by the beta-antagonist propranolol. Experiments with the fluorescent Ca2+ probe fura 2 show that PHE causes [Ca2+]i to rise from 178 +/- 31 nM (mean +/- SE; n = 25) to 370 +/- 55 nM (n = 9). This effect was complete within 20 sec and was maintained for at least 5-10 min. The rise was rapidly interrupted by administration of 1 microM phentolamine. The beta-receptor agonist isoproterenol caused a small [Ca2+]i rise due to action on alpha 1-adrenoreceptors. The PHE-induced [Ca2+]i rise showed two components: an initial peak due to Ca2+ mobilization from intracellular stores and a subsequent rise due to Ca2+ influx from the extracellular space. Somatostatin (SRIF) lowered both resting [Ca2+]i and Ca2+ influx stimulated by PHE. Pertussis toxin pretreatment did not modify PHE-induced [Ca2+]i changes, while it completely prevented the effect of SRIF on both resting and triggered [Ca2+]i, thus suggesting that a GTP-binding protein sensitive to the toxin is involved in the transduction of SRIF action. The increase in cAMP induced by cholera toxin pretreatment modified neither PHE nor SRIF action on [Ca2+]i. In conclusion, in rat somatotrophs Ca2+ mobilization and influx are stimulated by alpha 1-adrenergic agents, and this triggered [Ca2+]i rise results in a stimulation of GH release. In these cells SRIF is able to reduce both resting [Ca2+]i levels and [Ca2+]i increases induced by alpha 1-adrenergic activation.
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PMID:Alpha 1-adrenergic stimulation of in vitro growth hormone release and cytosolic free Ca2+ in rat somatotrophs. 289 97

The role of Ni in mediation of alpha adrenergic stimulated respiration and breakdown of phosphatidylinositol 4,5-P2 in brown adipocytes was examined using pertussis toxin. Phenylephrine stimulation of respiration and breakdown of PtdIns-4,5-P2 was still present in adipocytes harvested from hamsters treated with pertussis toxin although toxin modification of Ni appeared complete as judged from the absence of incorporation of [32P] from [32P]-NAD into a 41 KD protein in membranes. These data suggest that alpha-1 receptors on brown adipocytes are not coupled to inositide hydrolysis through Ni.
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PMID:Pertussis toxin does not prevent alpha adrenergic stimulated breakdown of phosphoinositides or respiration in brown adipocytes. 300 47

We previously have shown that alpha-adrenergic stimulation of canine Purkinje fibers and rat ventricle decreases automaticity. Experiments on rat ventricular myocytes in tissue culture have suggested that the decrease in automaticity induced by alpha-adrenergic stimulation depends on the development of sympathetic innervation and the presence of a pertussis toxin-sensitive, 41-kDa guanosine triphosphate (GTP)-regulatory protein. In the present study, microelectrode and biochemical techniques were used to test the role of the pertussis toxin-sensitive protein and sympathetic innervation in modulating automaticity of adult canine Purkinje fibers. Fibers were incubated in Tyrode's solution alone or in Tyrode's solution plus pertussis toxin (0.1-0.5 microgram/ml) for 24 hours and were then superfused with phenylephrine. Phenylephrine in the 5 x 10(-9)-5 x 10(-8) M range induced a decrease in automaticity in 63% of the 16 fibers not treated with pertussis toxin and an increase in automaticity in 37%. The former group had a higher level of pertussis toxin-sensitive substrate by the [32P]nicotinamide adenine dinucleotide adenosine diphosphate (ADP)-ribosylation assay than the latter. In contrast, all fibers treated with pertussis toxin (0.5 microgram/ml) showed increased automaticity in response to phenylephrine and had no detectable pertussis toxin-sensitive substrate. Over the range of pertussis toxin concentrations studied, there was a smooth concentration-response relation between the substrate levels measured and the automatic response to phenylephrine. As ADP-ribosylatable substrate levels decreased, the percent of fibers showing an increase in automaticity increased.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of a pertussis toxin-sensitive protein in the modulation of canine Purkinje fiber automaticity. 312 90

alpha-Adrenergic stimulation is known to play a role in cardiac arrhythmogenesis and to modulate a variety of cardiac K+ currents. The effects of alpha-adrenergic stimulation on Cl- currents are largely unknown. Many cardiac cell types show a volume-sensitive Cl- current induced by cell swelling (ICl.swell). The present experiments were designed to assess the potential alpha-adrenergic modulation of ICl.swell in rabbit atrial myocytes. ICl.swell was induced with the use of a hypotonic superfusate, under conditions designed to prevent currents carried by K+, Na+, and Ca2+ ions. A basal Cl- current (ICl.b) was observed under isotonic conditions in 128 of 150 cells (85%), had the same dependency on [Cl-]o as ICl.swell, and was reduced by cell shrinkage induced by hypertonic superfusion, suggesting that ICl.b is carried by the same volume-sensitive Cl- conductance as ICl.swell. Phenylephrine produced a concentration-dependent and near-complete inhibition of ICl.b and ICl.swell, with EC50 values of 86 +/- 5 and 72 +/- 7 (mean +/- SEM) mumol/L, respectively, at +20 mV. Norepinephrine (administered in the presence of 1 mumol/L propranolol) also inhibited ICl.b and ICl.swell, with EC50 values of 2.6 +/- 0.1 and 2.8 +/- 0.4 mumol/L, respectively. The concentration-response curve for phenylephrine was shifted significantly (P < .001) to the right by the alpha 1-adrenoceptor antagonist prazosin and by the alpha 1A-receptor antagonists (+)-niguldipine and 5-methylurapidil but was unaltered by the alpha 1B-receptor antagonist chloroethylclonidine (100 mumol/L). Inhibition of protein kinase C (PKC) with staurosporine, H-7, or 18-hour preincubation with the phorbol ester 4 beta-phorbol 12-myristate 13-acetate (PMA, 500 nmol/L) blocked the effects of phenylephrine on ICl.swell, and the highly selective PKC inhibitor bisindolylmaleimide blocked the effects of norepinephrine on ICl.swell and ICl.b. Both PMA and 1-oleoyl-2-acetylglycerol inhibited ICl.swell in a concentration-dependent fashion. In blinded studies, the phorbol ester phorbol 12,13-didecanoate (PDD) reduced ICl.swell by 91 +/- 3%; its inactive analogue 4 alpha-PDD had no effect (mean change, 3 +/- 1%). Preincubation with pertussis toxin (PTX) prevented the actions of phenylephrine on ICl.swell, indicating a role for a PTX-sensitive guanine nucleotide-binding (G) protein. We conclude that alpha-adrenergic agonists inhibit volume-sensitive Cl- currents in rabbit atrial cells by interacting with an alpha 1A-adrenoceptor mechanism that is coupled to PKC via a PTX-sensitive G protein.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alpha-adrenergic control of volume-regulated Cl- currents in rabbit atrial myocytes. Characterization of a novel ionic regulatory mechanism. 754 83


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