A bacteria-induced switch of sympathetic effector mechanisms augments local inhibition of TNF-alpha and IL-6 secretion in the spleen.
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It is believed that an inflammation-induced activation of the CNS leads to an inhibition of overshooting immune responses to prevent extensive local cytokine secretion. However, immunosuppression by the sympathetic nervous system may be unfavorable when bacteria are present locally and when TNF-alpha is necessary to overcome infection. We now report in a superfusion model, using mouse spleen slices, that although local Pseudomonas aeruginosa increased splenic TNF-alpha and IL-6 secretion severalfold over basal levels, electrically released neurotransmitters attenuated cytokine secretion to similar basal level as under bacteria-free conditions. Bacteria reversed noradrenergic inhibitory effector mechanisms: Under bacteria-free conditions, TNF-alpha secretion was very low and IL-6 secretion was mainly inhibited by alpha2-adrenoreceptor ligation. In the presence of bacteria, TNF-alpha and IL-6 secretion were high and IL-6 secretion was mainly inhibited by beta-adrenoreceptor ligation. The alpha- to beta-adrenoswitch of IL-6 inhibition in the presence of bacteria was mediated by the prior adrenergic regulation of TNF-alpha. In vivo, chemical abrogation of sympathetic inhibition reduced accumulation of bacteria in the spleen, which depended at least in part on TNF-alpha. This suggests that activation of the sympathetic nervous system may be a forerunner for accumulation of bacteria in tissue and consecutively sepsis due to intensified inhibition of TNF-alpha secretion. (+info)
Hippocampal noradrenergic neurotransmission in concurrent EEG desynchronization and inhibition of penile erection induced by cocaine in the rat.
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We previously reported that cocaine may induce activation of cortical (cEEG) and hippocampal (hEEG) electroencephalographic signals, concurrent with inhibition of penile erection, via an action on the hippocampal formation. The present study further evaluates the role of noradrenergic neurotransmission at the hippocampal formation in this process, using adult, male Sprague-Dawley rats anaesthetized and maintained by chloral hydrate. Unilateral microinjection of cocaine (100 nmoles) into the hippocampal CA1 or CA3 subfield or dentate gyrus elicited significant activation of both cEEG and hEEG activity. At the same time, the intracavernous pressure (ICP), our experimental index for penile erection, underwent a discernible reduction. Co-administration of equimolar doses (250 pmoles) of prazosin, naftopidil, yohimbine or rauwolscine significantly reversed those effects elicited by cocaine on cEEG, hEEG and ICP. Microinjection unilaterally of equimolar doses (5 nmoles) of norepinephrine, phenylephrine or BHT 933 into the hippocampal formation, similar to cocaine, also induced appreciable cEEG and hEEG excitation, with a simultaneous decrease in ICP. We conclude that cocaine may activate cEEG and hEEG and decrease ICP via noradrenergic neurotransmission, possibly engaging at least alpha(1A/D)-, alpha(2B)- and alpha(2C)-adrenoceptors at the hippocampal formation. (+info)
Multiple receptor activation elicits synergistic IP formation in nonpigmented ciliary body epithelial cells.
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We have examined the interaction between muscarinic and alpha(2)-adrenergic receptor activation on inositol phosphate (IP) formation in the nonpigmented cells of the ciliary body epithelium (NPE cells) of the rabbit. We have compared these changes with those previously observed in the intracellular free Ca(2+) concentration. Whereas muscarinic receptor activation causes an increase in intracellular Ca(2+) and IP formation, activation of alpha(2)-receptors does not significantly increase either intracellular Ca(2+) or IPs over basal levels. However, simultaneous activation of muscarinic and alpha(2)-adrenergic receptors with the specific agonists carbachol and UK-14304 produces massive Ca(2+) increases and results in a synergistic increase in IP formation. This synergistic IP formation is inhibited by both muscarinic and alpha(2)-adrenergic receptor antagonists as well as by pertussis toxin and an inhibitor of phospholipase C. IP formation is predominantly independent of intracellular Ca(2+), because it is decreased but not prevented by blocking the entry of Ca(2+) with LaCl(3) or chelating intracellular Ca(2+) with 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Thus synergistic IP formation underlies, at least in part, the synergistic increase in intracellular Ca(2+) resulting from simultaneous activation of muscarinic and alpha(2)-adrenergic receptors. (+info)
Role of protein kinase C in alpha(1)-adrenergic regulation of a(Na)(i) in guinea pig ventricular myocytes.
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We investigated the role of protein kinase C (PKC) in alpha(1)-adrenergic regulation of intracellular Na(+) activity (a(Na)(i)) in single guinea pig ventricular myocytes. a(Na)(i) and membrane potentials were measured with the Na(+)-sensitive indicator sodium-binding benzofuran isophthalate and conventional microelectrodes, respectively, at room temperature (24-26 degrees C) while myocytes were stimulated at a rate of 0.25-0.3 Hz. The PKC activator 4beta-phorbol 12-myristate 13-acetate (PMA) decreased a(Na)(i) in a concentration-dependent manner. PMA (100 nM) produced a maximal decrease in a(Na)(i) of 1.5 mM from 6.5 +/- 0.4 to 5.0 +/- 0.4 mM (means +/- SE, n = 12, P < 0.01). The PMA concentration required for a half-maximal decrease in a(Na)(i) was 0.46 +/- 0.13 nM (n = 3, P < 0.01). An inactive phorbol, 4alpha-phorbol 12-myristate 13-acetate, did not decrease a(Na)(i). The decrease caused by PMA could be blocked by the PKC inhibitors staurosporine and bisindolylmaleimide I (GF-109203X). Stimulation of the alpha(1)-adrenoceptor with 50 microM phenylephrine decreased a(Na)(i) from 6.1 +/- 0.3 to 4.6 +/- 0.3 mM (n = 11, P < 0.01). The decrease in a(Na)(i) produced by phenylephrine was blocked by pretreatment with staurosporine, GF-109203X, or PMA. The decrease in a(Na)(i) produced by PMA was not prevented by pretreatment with tetrodotoxin but was blocked by pretreatment with strophanthidin or high extracellular K(+) concentration. The results suggest that alpha(1)-adrenergic receptor activation results in a decrease in a(Na)(i) via PKC-induced stimulation of the Na(+)-K(+) pump in cardiac myocytes. (+info)
Positive inotropic effects of imidazoline derivatives are not mediated via imidazoline binding sites but alpha1-adrenergic receptors.
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Imidazoline-binding sites are non-adrenergic receptors and classified into I11/I2 subtypes. There is strong evidence that I1-binding sites, located in the rostro-ventrolateral medulla, are involved in regulation of blood pressure. However, less is known about the peripheral participation of I1-binding sites in cardiovascular reactions. Therefore, the aim of this study was to investigate whether specific imidazoline derivatives influence myocardial contractility and whether imidazoline binding sites are expressed in rat heart. Agmatine, clonidine and idazoxan failed to alter inotropy in left atria within the whole concentration range tested (1 nM - 100 microM), whereas cirazoline (1- 100 microM) and moxonidine (100 microM) increase inotropy by about 20-30%. After preincubation with the alpha1-adrenoceptor antagonist prazosin, the cirazoline and moxonidine stimulated inotropy was antagonized, indicating more an alpha1-adrenergic and less an imidazoline binding site mediated mechanism. Radioligand-binding studies in membranes of left ventricles using [3H]-clonidine to specify I1-binding yielded KD values of 12.7 microM, confirming the functional results of an absence of I1-binding sites in ventricles of rats. However, the existence of low affinity I2-binding sites determined by [3H]-idazoxan labeling could not be excluded since a KD of 0.5 microM was calculated and since competition studies with guanabenz (Ki = 0.1 microM), clonidine (Ki = 58.1 microM) and moxonidine (Ki = 129 microM) confirmed the specificity of the I2-binding. (+info)
Chronic alpha-adrenergic receptor stimulation modulates the contractile phenotype of cardiac myocytes in vitro.
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BACKGROUND: Heart failure is characterized by contractile dysfunction of the myocardium and elevated sympathetic activity. We tested the hypothesis that chronic alpha-adrenergic (alpha-ADR) stimulation modifies the molecular and contractile phenotype of cardiac myocytes. METHODS AND RESULTS: Adult rat ventricular myocytes in culture were exposed to alpha-ADR stimulation (norepinephrine + propranolol) for 48 hours. alpha-ADR stimulation decreased the mRNAs for sarcoplasmic reticulum Ca(2+)-ATPase and Ca(2+) release channel by 56% and 52%, respectively, and increased mRNA and protein for the Na(+)-Ca(2+) exchanger by 70% and 39%, respectively. After washout of the alpha-ADR agonist, simultaneous measurement of [Ca(2+)](i) transients with fura 2 and myocyte shortening by video edge-detection showed that [Ca(2+)](i) amplitude and myocyte shortening were decreased in alpha-ADR-treated myocytes, and the time to peak and time from peak to 80% decline of both [Ca(2+)](i) and myocyte shortening were increased. The concentration-response curve for myocyte shortening by the Na(+) channel activator veratridine was shifted leftward in alpha-ADR-stimulated myocytes (EC(50), 21.6+/-4.6 versus 105.8+/-10.5 nmol/L, P:<0.001). CONCLUSIONS: Chronic alpha-ADR stimulation of cardiac myocytes causes decreases in the expression of sarcoplasmic reticulum Ca(2+)-ATPase and the Ca(2+) release channel that are associated with decreases in [Ca(2+)](i) and contractility. alpha-ADR stimulation simultaneously increases Na(+)-Ca(2+) exchanger expression, thereby increasing sensitivity to intracellular Na(+). (+info)
Cardiovascular effects of medetomidine, detomidine and xylazine in horses.
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The cardiovascular effects of medetomidine, detomidine, and xylazine in horses were studied. Fifteen horses, whose right carotid arteries had previously been surgically raised to a subcutaneous position during general anesthesia were used. Five horses each were given the following 8 treatments: an intravenous injection of 4 doses of medetomidine (3, 5, 7.5, and 10 microg/kg), 3 doses of detomidine (10, 20, and 40 microg/kg), and one dose of xylazine (1 mg/kg). Heart rate decreased, but not statistically significant. Atrio-ventricular block was observed following all treatments and prolonged with detomidine. Cardiac index (CI) and stroke volume (SV) were decreased with all treatments. The CI decreased to about 50% of baseline values for 5 min after 7.5 and 10 microg/kg medetomidine and 1 mg/kg xylazine, for 20 min after 20 microg/kg detomidine, and for 50 min after 40 microg/kg detomidine. All treatments produced an initial hypertension within 2 min of drug administration followed by a significant decrease in arterial blood pressure (ABP) in horses administered 3 to 7.5 microg/kg medetomidine and 1 mg/kg xylazine. Hypertension was significantly prolonged in 20 and 40 microg/kg detomidine. The hypotensive phase was not observed in 10 microg/kg medetomidine or detomidine. The changes in ABP were associated with an increase in peripheral vascular resistance. Respiratory rate was decreased for 40 to 120 min in 5, 7.5, and 10 microg/kg medetomidine and detomidine. The partial pressure of arterial oxygen decreased significantly in 10 microg/kg medetomidine and detomidine, while the partial pressure of arterial carbon dioxide did not change significantly. Medetomidine induced dose-dependent cardiovascular depression similar to detomidine. The cardiovascular effects of medetomidine and xylazine were not as prolonged as that of detomidine. (+info)
Altered adrenergic receptor density in myocardial hibernation in humans: A possible mechanism of depressed myocardial function.
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BACKGROUND: Alterations in adrenergic receptor densities can potentially contribute to myocardial dysfunction. Their relevance to myocardial hibernation in humans is unknown. METHODS AND RESULTS: Accordingly, 22 transmural myocardial biopsies were obtained in 11 patients with ischemic ventricular dysfunction during bypass surgery, guided by transesophageal echocardiography. Patients underwent dobutamine echocardiography (DE) and rest scintigraphic studies before revascularization and DE at 3 to 4 months. alpha- and ss-receptor density (ARD and BRD) and extent of fibrosis were quantified from the myocardial biopsies. Of the 22 segments, 16 had abnormal rest function and 6 were normal. Severely hypokinetic or akinetic segments showed a 2.4-fold increase in ARD with a concomitant 50% decrease in BRD compared with normal segments. An increase in ARD, a decrease in BRD to a lesser extent, and thus an increase in ARD/BRD ratio were seen in dysfunctional segments with contractile reserve compared with normal segments and were most pronounced in those without contractile reserve (P:<0.001). Similar findings were observed if recovery of function or scintigraphic uptake was analyzed as a marker for viability. No significant relation between either ARD or BRD and percent myocardial fibrosis was noted (r=0.37 and -0.39, respectively). CONCLUSIONS: Thus, graded and reciprocal changes in alpha- and ss-adrenergic receptor densities occur in viable, hibernating myocardium and may account in part for the observed depression in resting myocardial function and preserved contractile reserve in this entity. (+info)