scholarly journals Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats

2016 ◽  
Vol 310 (6) ◽  
pp. F456-F465 ◽  
Author(s):  
Zhengrong Guan ◽  
Sean T. Singletary ◽  
Haword Cha ◽  
Justin P. Van Beusecum ◽  
Anthony K. Cook ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Receptor Activation ◽  
Pentosan Polysulfate ◽  
Subcutaneous Implantation ◽  
Salt Treatment ◽  
Renal Autoregulation ◽  
Protein Excretion ◽  
Induced Hypertension ◽  
Juxtamedullary Nephron ◽  
Anti Inflammatory

Inflammation contributes to ANG II-associated impairment of renal autoregulation and microvascular P2X1 receptor signaling, but its role in renal autoregulation in mineralocorticoid-induced hypertension is unknown. Autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. Hypertension was induced in uninephrectomized control rats (UNx) by subcutaneous implantation of a DOCA pellet plus administration of 1% NaCl in the drinking water (DOCA-salt) for 3 wk. DOCA-salt rats developed hypertension that was unaltered by anti-inflammatory treatment with pentosan polysulfate (DOCA-salt+PPS) but was suppressed with “triple therapy” (hydrochlorothiazide, hydralazine, and reserpine; DOCA-salt+TTx). Baseline arteriolar diameters were similar across all groups. UNx rats exhibited pressure-dependent vasoconstriction with diameters declining to 69 ± 2% of control at 170 mmHg, indicating intact autoregulation. DOCA-salt treatment significantly blunted this pressure-mediated vasoconstriction. Diameters remained between 91 ± 4 and 98 ± 3% of control over 65–170 mmHg, indicating impaired autoregulation. In contrast, pressure-mediated vasoconstriction was preserved in DOCA-salt+PPS and DOCA-salt+TTx rats, reaching 77 ± 7 and 75 ± 3% of control at 170 mmHg, respectively. ATP is required for autoregulation via P2X1 receptor activation. ATP- and β,γ-methylene ATP (P2X1 receptor agonist)-mediated vasoconstriction were markedly attenuated in DOCA-salt rats compared with UNx ( P < 0.05), but significantly improved by PPS or TTx ( P < 0.05 vs. DOCA-salt) treatment. Arteriolar responses to adenosine and UTP (P2Y2 receptor agonist) were unaffected by DOCA-salt treatment. PPS and TTx significantly reduced MCP-1 and protein excretion in DOCA-salt rats. These results support the hypothesis that hypertension triggers inflammatory cascades but anti-inflammatory treatment preserves renal autoregulation in DOCA-salt rats, most likely by normalizing renal microvascular reactivity to P2X1 receptor activation.

Reciprocal inhibition of voltage-gated potassium currents (IK(V)) by activation of cannabinoid CB1and dopamine D1receptors in ON bipolar cells of goldfish retina

2005 ◽  
Vol 22 (1) ◽  
pp. 55-63 ◽  
Author(s):  
SHIH-FANG FAN ◽  
STEPHEN YAZULLA
Keyword(s):  
G Protein ◽  
Receptor Agonist ◽  
Lucifer Yellow ◽  
Reciprocal Inhibition ◽  
Receptor Activation ◽  
Light Signal ◽  
Bipolar Cells ◽  
Protein G ◽  
Calcium Dependent ◽  
Voltage Dependent

Cannabinoid CB1receptor (viaGs) and dopamine D2receptor (viaGi/o) antagonistically modulate goldfish cone membrane currents. As ON bipolar cells have CB1and D1receptors, but not D2receptors, we focused on whether CB1receptor agonist and dopamine interact to modulate voltage-dependent outward membrane K+currentsIK(V)of the ON mixed rod/cone (Mb) bipolar cells. Whole-cell currents were recorded from Mb bipolar cells in goldfish retinal slices. Mb bipolar cells were identified by intracellular filling with Lucifer yellow. The bath solution was calcium-free and contained 1 mM cobalt to block indirect calcium-dependent effects. Dopamine (10 μM) consistently increasedIK(V)by a factor of 1.57 ± 0.12 (S.E.M.,n= 15). A CB receptor agonist, WIN 55212-2 (0.25–1 μM), had no effect, but 4 μM WIN 55212-2 suppressedIK(V)by 60%. IfIK(V)was first increased by 10 μM dopamine, application of WIN 55212-2 (0.25–1 μM) reversibly blocked the effect of dopamine even though these concentrations of WIN 55212-2 had no effect of their own. If WIN 55212-2 was applied first and dopamine (10 μM) was added to the WIN-containing solution, 0.1 μM WIN 55212-2 blocked the effect of dopamine. All effects of WIN 55212-2 were blocked by coapplication of SR 141716A (CB1antagonist) and pretreatment with pertussis toxin (blocker of Gi/o) indicating actionviaCB1receptor activation of G protein Gi/o. Coactivation of CB1and D1receptors on Mb bipolar cells produces reciprocal effects onIK(V). The CB1-evoked suppression ofIK(V)is mediated by G protein Gi/o, whereas the D1-evoked enhancement is mediated by G protein Gs. As dopamine is a retinal “light” signal, these data support our notion that endocannabinoids function as a “dark” signal, interacting with dopamine to set retinal sensitivity.

scholarly journals Localization and function of dopamine receptors in the subthalamic nucleus of normal and parkinsonian monkeys

2014 ◽  
Vol 112 (2) ◽  
pp. 467-479 ◽  
Author(s):  
Adriana Galvan ◽  
Xing Hu ◽  
Karen S. Rommelfanger ◽  
Jean-Francois Pare ◽  
Zafar U. Khan ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Subthalamic Nucleus ◽  
Receptor Agonist ◽  
Rhesus Macaques ◽  
Extracellular Recording ◽  
Receptor Activation ◽  
D1 Receptors ◽  
Substantia Nigra Pars Compacta ◽  
D1 And D2 Receptors ◽  
And Function

The subthalamic nucleus (STN) receives a dopaminergic innervation from the substantia nigra pars compacta, but the role of this projection remains poorly understood, particularly in primates. To address this issue, we used immuno-electron microscopy to localize D1, D2, and D5 dopamine receptors in the STN of rhesus macaques and studied the electrophysiological effects of activating D1-like or D2-like receptors in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys. Labeling of D1 and D2 receptors was primarily found presynaptically, on preterminal axons and putative glutamatergic and GABAergic terminals, while D5 receptors were more significantly expressed postsynaptically, on dendritic shafts of STN neurons. The electrical spiking activity of STN neurons, recorded with standard extracellular recording methods, was studied before, during, and after intra-STN administration of the dopamine D1-like receptor agonist SKF82958, the D2-like receptor agonist quinpirole, or artificial cerebrospinal fluid (control injections). In normal animals, administration of SKF82958 significantly reduced the spontaneous firing but increased the rate of intraburst firing and the proportion of pause-burst sequences of firing. Quinpirole only increased the proportion of such pause-burst sequences in STN neurons of normal monkeys. In MPTP-treated monkeys, the D1-like receptor agonist also reduced the firing rate and increased the proportion of pause-burst sequences, while the D2-like receptor agonist did not change any of the chosen descriptors of the firing pattern of STN neurons. Our data suggest that dopamine receptor activation can directly modulate the electrical activity of STN neurons by pre- and postsynaptic mechanisms in both normal and parkinsonian states, predominantly via activation of D1 receptors.

scholarly journals CF102 an A3 adenosine receptor agonist mediates anti-tumor and anti-inflammatory effects in the liver

2011 ◽  
Vol 226 (9) ◽  
pp. 2438-2447 ◽  
Author(s):  
S. Cohen ◽  
S.M. Stemmer ◽  
G. Zozulya ◽  
A. Ochaion ◽  
R. Patoka ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Receptor Agonist ◽  
Adenosine Receptor Agonist ◽  
A3 Adenosine Receptor ◽  
Anti Inflammatory

Opioids modulate N-methyl-D-aspartic acid (NMDA)-evoked responses of trigeminothalamic neurons

1996 ◽  
Vol 76 (3) ◽  
pp. 2093-2096 ◽  
Author(s):  
X. M. Wang ◽  
S. S. Mokha
Keyword(s):  
Nmda Receptor ◽  
Dorsal Horn ◽  
Aspartic Acid ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Receptor Activation ◽  
Evoked Responses ◽  
Nociceptive Neurons ◽  
Nociceptive Transmission ◽  
Opioid Receptor Agonist

1. The present study investigated opioid-mediated modulation of N-methyl-D-aspartic acid (NMDA)-evoked responses of trigeminothalamic neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in rats anesthetized with urethane. 2. Microiontophoretic application of NMDA activated 18/19 trigeminothalamic neurons. Administration of [D-Ala2, N-Me-Phe4,Gly5-ol]-Enkephalin, a selective mu-opioid receptor agonist, reduced the NMDA-evoked responses in 77% of trigeminothalamic neurons. [D-Pen2,5]-Enkephalin, a selective delta-opioid receptor agonist, produced inhibition of NMDA-evoked responses in 36% of neurons. 3. We suggest that 1) NMDA-receptor activation excites trigeminothalamic nociceptive neurons and may, therefore, mediate nociceptive transmission in the medullary dorsal horn; and 2) the predominantly inhibitory modulation of NMDA-receptor-mediated responses of nociceptive trigeminothalamic neurons by activation of mu- and delta-opioid receptors may provide a neural mechanism for the antinociceptive actions of opioids.

ANG II AT2 receptor modulates AT1receptor-mediated descending vasa recta endothelial Ca2+ signaling

2003 ◽  
Vol 284 (3) ◽  
pp. H779-H789 ◽  
Author(s):  
Kristie Rhinehart ◽  
Corey A. Handelsman ◽  
Erik P. Silldorff ◽  
Thomas L. Pallone
Keyword(s):  
Receptor Agonist ◽  
Calcium Concentration ◽  
Cyclopiazonic Acid ◽  
Receptor Activation ◽  
Receptor Subtype ◽  
Ang Ii ◽  
Receptor Stimulation ◽  
Vasa Recta ◽  
Stimulation Of

We tested whether the respective angiotensin type 1 (AT1) and 2 (AT2) receptor subtype antagonists losartan and PD-123319 could block the descending vasa recta (DVR) endothelial intracellular calcium concentration ([Ca2+]i) suppression induced by ANG II. ANG II partially reversed the increase in [Ca2+]igenerated by cyclopiazonic acid (CPA; 10−5 M), acetylcholine (ACh; 10−5 M), or bradykinin (BK; 10−7 M). Losartan (10−5 M) blocked that effect. When vessels were treated with ANG II before stimulation with BK and ACh, concomitant AT2 receptor blockade with PD-123319 (10−8 M) augmented the suppression of endothelial [Ca2+]i responses. Similarly, preactivation with the AT2 receptor agonist CGP-42112A (10−8 M) prevented AT1 receptor stimulation with ANG II + PD-123319 from suppressing endothelial [Ca2+]i. In contrast to endothelial [Ca2+]i suppression by ANG II, pericyte [Ca2+]i exhibited typical peak and plateau [Ca2+]i responses that were blocked by losartan but not PD-123319. DVR vasoconstriction by ANG II was augmented when AT2 receptors were blocked with PD-123319. Similarly, AT2 receptor stimulation with CGP-42112A delayed the onset of ANG II-induced constriction. PD-123319 alone (10−5 M) showed no AT1-like action to constrict microperfused DVR or increase pericyte [Ca2+]i. We conclude that ANG II suppression of endothelial [Ca2+]i and stimulation of pericyte [Ca2+]i is mediated by AT1 or AT1-like receptors. Furthermore, AT2 receptor activation opposes ANG II-induced endothelial [Ca2+]i suppression and abrogates ANG II-induced DVR vasoconstriction.

scholarly journals Adenosine A1receptor-mediated antiadrenergic effects are modulated by A2a receptor activation in rat heart

1999 ◽  
Vol 276 (2) ◽  
pp. H341-H349 ◽  
Author(s):  
Gavin R. Norton ◽  
Angela J. Woodiwiss ◽  
Robert J. McGinn ◽  
Mojca Lorbar ◽  
Eugene S. Chung ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Ventricular Myocytes ◽  
Physiological Role ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Receptor Antagonists ◽  
Rat Hearts ◽  
Intracellular Ca ◽  
Perfused Rat Hearts

Presently, the physiological significance of myocardial adenosine A2a receptor stimulation is unclear. In this study, the influence of adenosine A2a receptor activation on A1 receptor-mediated antiadrenergic actions was studied using constant-flow perfused rat hearts and isolated rat ventricular myocytes. In isolated perfused hearts, the selective A2a receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385) potentiated adenosine-mediated decreases in isoproterenol (Iso; 10−8 M)-elicited contractile responses (+dP/d t max) in a dose-dependent manner. The effect of ZM-241385 on adenosine-induced antiadrenergic actions was abolished by the selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10−7 M), but not the selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191, 10−7 M). The A2a receptor agonist carboxyethylphenethyl-aminoethyl-carboxyamido-adenosine (CGS-21680) at 10−5 M attenuated the antiadrenergic effect of the selective A1 receptor agonist 2-chloro- N 6-cyclopentyladenosine (CCPA), whereas CSC did not influence the antiadrenergic action of this agonist. In isolated ventricular myocytes, CSC potentiated the inhibitory action of adenosine on Iso (2 × 10−7 M)-elicited increases in intracellular Ca2+concentration ([Ca2+]i) transients but did not influence Iso-induced changes in [Ca2+]itransients in the absence of exogenous adenosine. These results indicate that adenosine A2areceptor antagonists enhance A1-receptor-induced antiadrenergic responses and that A2a receptor agonists attenuate (albeit to a modest degree) the antiadrenergic actions of A1 receptor activation. In conclusion, the data in this study support the notion that an important physiological role of A2a receptors in the normal mammalian myocardium is to reduce A1 receptor-mediated antiadrenergic actions.

scholarly journals Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Hiroshi Yamaguchi ◽  
Toshihiko Maruyama ◽  
Yoshihiro Urade ◽  
Shigekazu Nagata
Keyword(s):  
Adenosine Receptor ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Adenosine Monophosphate ◽  
Receptor Activation ◽  
Death Process ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
A2a Adenosine Receptor ◽  
Anti Inflammatory

Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a ‘calm down’ signal.

Abstract 277: Elevated C-Reactive Protein Contributes to Preeclampsia via Kinin Signaling Pathways

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Nicholas Parchim ◽  
Wei Wang ◽  
Takayuki Iriyama ◽  
Chen Liu ◽  
Athar H Siddiqui ◽  
...  
Keyword(s):  
Acute Phase Reactant ◽  
Receptor Activation ◽  
C Reactive Protein ◽  
Direct Role ◽  
Human Trophoblast ◽  
Reactive Protein ◽  
Induced Hypertension ◽  
Pregnant Mice

Preeclampsia (PE) is a serious pregnancy disease characterized by hypertension and proteinuria. Despite intensive research efforts, the underlying cause of PE remains a mystery. PE is, however, associated with abnormalities of the immune system. Here we report that the levels of C-reactive protein (CRP), an important acute phase reactant, were significantly elevated in the plasma of human with PE at the third trimester. Next, we found that CRP protein levels in the placentas of PE patients were also significantly increased compared to controls. In an effort to determine the exact role of elevated CRP in PE, we infused CRP into pregnant mice. We found that injection of CRP into pregnant mice induced hypertension (170 mmHg mean systolic vs. 125 mmHg mean systolic control; p<0.05) and proteinuria (25 mg/ug vs 12 mg/ug vehicle; p<0.05), indicating the direct role of CRP in PE. CRP is known to bind with phosphocholine on damaged cell membranes. Recent studies identified that neurokinin B (NKB), a placental enriched neuropeptide and known pathogenic molecule for PE, is phosphocholinated. This posttranslational modification increases its stability and enhances NKB-mediated receptor activation. These findings raise an intriguing hypothesis that CRP may bind with NKB coupled to NK3R activation and contribute to PE. To test this hypothesis, we conducted a pulldown assay, and we found that CRP bound with NKB. Next, using a cellular invasion assay, we revealed that CRP decreased invasion of human trophoblast cells (0.7 to 0.07 invasion index, p<0.05), while treatment with an NK3R selective antagonist, SB222200, ameliorated this shallow invasion. Finally, we provided in vivo evidence that inhibition of NK3R by SB222200 or knockdown of NK3R by specific siRNA in a potent nanoparticle delivery system significantly reduced CRP-induced hypertension and proteinuria in pregnant mice (170 mmHg mean systolic CRP-injected vs. 130 mmHg mean systolic siRNA NK3R; p<0.05 and proteinuria 25 mg/ug vs. 15 mg/ug; p<0.05). Overall, our findings demonstrate that elevated CRP contributes to PE and NKB/NK3R is a novel mechanism underlying CRP-mediated shallow invasion and disease development. These studies suggest novel pathogenic biomarkers and innovative therapeutic targets for PE.

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