Role of pertussis toxin-sensitive G protein in metabolic vasodilation of coronary microcirculation

2000 ◽  
Vol 279 (4) ◽  
pp. H1819-H1829 ◽  
Author(s):  
Toshinori Tanikawa ◽  
Hiroshi Kanatsuka ◽  
Ryohji Koshida ◽  
Mitsuaki Tanaka ◽  
Akihiko Sugimura ◽  
...  
Keyword(s):  
G Protein ◽  
Pertussis Toxin ◽  
Atrial Pacing ◽  
Metabolic Demand ◽  
Before And After ◽  
Vehicle Treatment ◽  
Rapid Pacing ◽  
Metabolic Stimulation ◽  
Metabolic Vasodilation

We have previously demonstrated that pertussis toxin (PTX)-sensitive G protein (GPTX) plays a major role in coronary microvascular vasomotion during hypoperfusion. We aimed to elucidate the role of GPTX during increasing metabolic demand. In 18 mongrel dogs, coronary arteriolar diameters were measured by fluorescence microangiography using a floating objective. Myocardial oxygen consumption (MV˙o 2) was increased by rapid left atrial pacing. In six dogs, PTX (300 ng/ml) was superfused onto the heart surface for 2 h to locally block GPTX. In eight dogs, the vehicle (Krebs solution) was superfused in the same way. Before and after each treatment, the diameters were measured during control (130 beats/min) and rapid pacing (260 beats/min) in each group. Metabolic stimulation before and after the vehicle treatment caused 8.6 ± 1.8 and 16.1 ± 3.6% dilation of coronary arterioles <100 μm in diameter (57 ± 8 μm at control, n = 10), respectively. PTX treatment clearly abolished the dilation of arterioles (12.8 ± 2.5% before and 0.9 ± 1.6% after the treatment, P < 0.001 vs. vehicle; 66 ± 8 μm at control, n = 11) in response to metabolic stimulation. The increases in MV˙o 2 and coronary flow velocity were comparable between the vehicle and PTX groups. In four dogs, 8-phenyltheophylline (10 μM, superfusion for 30 min) did not affect the metabolic dilation of arterioles (15.3 ± 2.0% before and 16.4 ± 3.8% after treatment; 84.3 ± 11.0 μm at control, n = 8). Thus we conclude that GPTXplays a major role in regulating the coronary microvascular tone during active hyperemia, and adenosine does not contribute to metabolic vasodilation via GPTX activation.

Abstract 741: Atrial Fibrillation Begets Atrial Fibrillation: Acute Autonomic Remodeling Leads to Enhanced Inducibility for Atrial Fibrillation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Zhibing Lu ◽  
Benjamin J Scherlag ◽  
Guo-Dong Niu ◽  
Jiaxiong Lin ◽  
Muhammad Ghias ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Pulmonary Veins ◽  
Atrial Pacing ◽  
Time Period ◽  
Before And After ◽  
Rapid Pacing ◽  
Group 2 ◽  
Window Of Vulnerability ◽  
Group 1

Introduction: There have been many forms of remodeling reported to play a role in the concept of “atrial fibrillation (AF) begets atrial fibrillation.” The role of intrinsic cardiac nervous system (ICNS) in this remodeling process was evaluated in this study. Methods: Continuous rapid pacing (1200 bpm, 2× threshold, TH) was performed at the left atrial appendage to maintain AF. Group 1 (N=7): 6-hours of pacing followed by ganglionated plexi (GP) ablation, both left and right side; Group 2 (N=7): GP ablation followed by 6-hours of pacing. At 2x and 10x TH, the effective refractory period (ERP) and window of vulnerability (WOV), i.e., longest-shortest coupling of premature stimulus which induced AF in milliseconds (ms), were measured at the left atrium, right atrium and pulmonary veins (PVs) every hour during the 6-hours of pacing before and after GP ablation. Results: In group 1 (rapid pacing with GP intact) ERP progressively shortened in the first two hours and then stabilized both at 2×TH and 10×TH (Figure 1A ), however, WOV progressively widened throughout the time period (Figure 1B ). After GP ablation, ERP was significantly longer than prior to ablation and AF could not be induced (WOV=0, p<0.01) at any pacing site at either 2×TH or 10×TH (Figure 1B ). In group 2 (initial GP ablation), ERP exhibited a slightly increasing trend as the pacing time increased. AF could not be induced in 6/7 dogs during the 6-hour pacing, and was inducible in 1/7 with a cumulative WOV of only 10 ms. Conclusion: The ICNS is crucial for the process of “AF begets AF” in the acute stages of remodeling by rapid atrial pacing.

Fluoride mobilizes intracellular calcium and promotes Ca2+ influx in rat proximal tubules

1991 ◽  
Vol 261 (2) ◽  
pp. F318-F327 ◽  
Author(s):  
J. H. Dominguez ◽  
J. G. Garcia ◽  
J. K. Rothrock ◽  
D. English ◽  
C. Mann
Keyword(s):  
Signal Transduction ◽  
Parathyroid Hormone ◽  
Proximal Tubule ◽  
G Protein ◽  
Pertussis Toxin ◽  
Time Course ◽  
Proximal Tubules ◽  
Signal Transduction Pathways ◽  
Pi Hydrolysis

In the renal proximal tubule, external Ca2+ ([Ca2+]o) is required for parathyroid hormone to elevate cytosolic Ca2+ ([Ca2+]i). However, other hormones increase [Ca2+]i in the absence of [Ca2+]o. These differences may arise from a diversity of signal transduction pathways acting on external and internal Ca2+ pools. However, Ca2+ influx may be necessary to expedite and maintain the rise of [Ca2+]i for a period after the initial surge. In this study, F- was used to probe the roles of intracellular Ca2+ mobilization, Ca2+ influx, and phosphoinositide (PI) hydrolysis on the surge of [Ca2+]i in rat proximal tubules. In the presence of external Ca2+; 1-20 mM F- evoked incremental rises of [Ca2+]i in tubules loaded with aequorin. Whereas 10 mM F- increased [Ca2+]i in the absence of [Ca2+]o, the time constant for the [Ca2+]i surge was increased. These findings are consistent with a role of Ca2+ influx on the effect of F- on [Ca2+]i. Indeed, 10 mM F- also enhanced the uptake of 45Ca2+, and promoted Ca2+ influx in aequorin- and fura-2-loaded, Ca(2+)-deprived tubules. In tubules, F- also activated PI hydrolysis with a time course that paralleled Ca2+ mobilization. The effect of F- on [Ca2+]i was not altered when the 39-kDa pertussis toxin substrate was inactivated with the toxin. This G protein was most likely Gi, because prostaglandin E2, an activator of Gi in tubules, dissociated the pertussis toxin-sensitive protein. The results support the notion that activation of a signal-transduction complex, the F- substrate, causes Ca2+ influx, mobilizes internal Ca2+, and activates PI hydrolysis in rat proximal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Role of pertussis toxin-sensitive G-protein, K+ channels, and voltage-gated Ca2+ channels in the antinociceptive effect of inosine

2012 ◽  
Vol 9 (1) ◽  
pp. 51-58 ◽  
Author(s):  
Sérgio José Macedo-Junior ◽  
Francisney Pinto Nascimento ◽  
Murilo Luiz-Cerutti ◽  
Adair Roberto Soares Santos
Keyword(s):  
G Protein ◽  
Pertussis Toxin ◽  
Antinociceptive Effect ◽  
K Channels ◽  
Voltage Gated ◽  
Ca2 Channels

scholarly journals Adenosine A1but Not A2aReceptor Agonist Reduces Hyperalgesia Caused by a Surgical Incision in Rats

2007 ◽  
Vol 107 (5) ◽  
pp. 797-806 ◽  
Author(s):  
Peter K. Zahn ◽  
Heidrun Straub ◽  
Manuel Wenk ◽  
Esther M. Pogatzki-Zahn
Keyword(s):  
Pertussis Toxin ◽  
Adenosine Receptors ◽  
Antinociceptive Effect ◽  
Intrathecal Administration ◽  
Pain Behavior ◽  
Spontaneous Pain ◽  
Withdrawal Threshold ◽  
A2a Adenosine Receptors ◽  
Before And After

Background Activation of A1 adenosine receptors (A1Rs) causes antinociception after nerve injury and inflammation. However, the role of A2a adenosine receptors (A2aRs) for pain processing is less clear. In the current study, the authors investigated the role of spinal adenosine A1Rs and A2aRs for the maintenance of mechanical hyperalgesia in an animal model for postoperative pain. Methods Rats with intrathecal catheters were anesthetized and underwent plantar incision. Spontaneous pain behavior and withdrawal threshold to punctuate stimulation were measured before and after administration of intrathecal R-phenylisopropyl-adenosine (R-PIA; A1R agonist), 2-w p-2-carbonyl-ethyl-phenylethylaminox-5X-N-ethylcarboxami-doadenosine (CGS21680; A2aR agonist), or vehicle. In separate groups of animals, the effects of pertussis toxin, forskolin, glibenclamide, 4-aminopyridine, tetraethylammonium, apamin, charybdotoxin, or margatoxin on R-PIA-induced antinociception were examined. Results Intrathecal administration of 5 nmol R-PIA but not 10 nmol CGS21680 decreased nonevoked spontaneous pain behavior. Furthermore, intrathecal administration of R-PIA but not of CGS21680 increased withdrawal thresholds after incision. Pretreatment with pertussis toxin and administration of forskolin, glibenclamide, 4-aminopyridine, and tetraethylammonium inhibited R-PIA-induced antinociception. In addition, intrathecal administration of apamin, charybdotoxin, or margatoxin did not modify mechanical hypoalgesia mediated by R-PIA. Conclusions Spinal A1Rs but not A2aRs play an important role in the maintenance of nonevoked and evoked pain behaviors after an incision. Furthermore, A1R-induced spinal antinociception is mediated by interactions with pertussis toxin-sensitive G proteins. In addition, the opening of adenosine triphosphate-sensitive K channels but not of calcium-activated potassium channels and voltage-gated Kv1.3 or Kv1.6 channels contribute to the antinociceptive effect of A1R agonists.

Localization of G alpha 0 to growth cones in PC12 cells: role of G alpha 0 association with receptors and G beta gamma

1996 ◽  
Vol 109 (1) ◽  
pp. 221-228
Author(s):  
O. Nusse ◽  
E.J. Neer
Keyword(s):  
G Protein ◽  
Pc12 Cells ◽  
Pertussis Toxin ◽  
Growth Cones ◽  
Neonatal Rat ◽  
Gamma Subunit ◽  
Adp Ribosylation ◽  
Gamma Subunits ◽  
Membrane Attachment

The heterotrimeric G protein G0 is highly enriched in the growth cones of neuronal cells and makes up 10% of the membrane protein of growth cones from neonatal rat brain. We have used PC12 cells, a cell line that differentiates to a neuron-like phenotype, as a model with which to study the mechanism of G protein localization. First, the role of the beta gamma-subunit was investigated. The attachment of the beta gamma-subunit to the membrane depends on the isoprenylation of the gamma-subunit. The drug lovastatin blocks isoprenylation by inhibiting a key enzyme in the biosynthetic pathway. After treatment of PC12 cells with 10 microM lovastatin for 48 hours 50% of the beta gamma-subunits were cytosolic compared with 100% membrane bound beta gamma in control cells, as determined by cell fractionation, gel electrophoresis and western blot. Addition of 200 microM mevalonic acid reverses this effect. However, lovastatin affects neither the membrane attachment of alpha 0 nor its localization to the growth cones as determined by immunohistochemistry. This suggests that the localization and retention of alpha 0 are independent of the membrane attachment of the full complement of beta gamma-subunits. Second, pertussis toxin was used to block the interaction between alpha 0 and receptors. PC12 cells were treated with 0.1 microgram/ml pertussis toxin prior to and during nerve growth factor-induced differentiation. In vitro [32P]ADP-ribosylation confirmed that alpha 0 and alpha i were completely ADP-ribosylated by this treatment. The ADP-ribosylation by pertussis toxin did not interfere with neurite outgrowth. The localization of alpha 0 to the growth cones was indistinguishable from that in untreated cells. We conclude that G protein-receptor interaction is not necessary for the distribution of alpha 0 to growth cones.

Metabolic regulation of coronary vascular tone: role of endothelin-1

2002 ◽  
Vol 283 (5) ◽  
pp. H1915-H1921 ◽  
Author(s):  
Daphne Merkus ◽  
Dirk J. Duncker ◽  
William M. Chilian
Keyword(s):  
Metabolic Regulation ◽  
Vascular Tone ◽  
Metabolic Demand ◽  
Coronary Vasodilation ◽  
Coronary Vascular Tone ◽  
Before And After ◽  
Rat Myocytes ◽  
Coronary Tone

Coronary tone is determined by a balance between endogenously produced endothelin and metabolic dilators. We hypothesized that coronary vasodilation during augmented metabolism is the net result of decreased endothelin production and increased production of vasodilators. Isolated rat myocytes were stimulated at 0, 200, and 400 beats/min to modify metabolism. Supernatant from these preparations was added to isolated coronary arterioles with and without blocking vasoactive pathways (adenosine, bradykinin, and endothelin). Chronically instrumented swine were studied while resting and running on a treadmill before and after endothelin type A (ETA) receptor blockade. The vasodilatory properties of the supernatant increased with increased stimulation frequencies. Combined blockade of adenosine and bradykinin receptors abolished vasodilation in response to supernatant of stimulated myocytes. ETA blockade increased vasodilation to supernatant of unstimulated myocytes but did not affect dilation to supernatant of myocytes stimulated at 400 beats/min. In vivo, ETA blockade resulted in coronary vasodilation at rest, which waned during exercise. Thus endothelin has a tonic constrictor influence through the ETA receptor at low myocardial metabolic demand but its influence decreased during increased metabolism.

scholarly journals PTX-sensitive G proteins and permissive action of prostacyclin in newborn pig cerebral circulation

1998 ◽  
Vol 275 (1) ◽  
pp. H259-H263
Author(s):  
Boruch Zucker ◽  
Charles W. Leffler
Keyword(s):  
G Protein ◽  
Cerebral Circulation ◽  
Epoxyeicosatrienoic Acid ◽  
Kinase C ◽  
Artificial Cerebrospinal Fluid ◽  
Before And After ◽  
Pial Arterioles ◽  
Camp Elevation

The present study of newborn pig cerebral circulation investigated the role of pertussis toxin (PTX)-sensitive GTP binding proteins in the permissive action of prostacyclin in specific dilator responses. Pial arterioles of anesthetized piglets were observed through closed cranial windows. The piglets were treated topically with PTX and intravenously with indomethacin. The effects of hypercapnia (10% CO2ventilation) and topical 5,6-epoxyeicosatrienoic acid (5,6-EET) on pial arteriolar diameter were noted before and after the intervention. Samples of the artificial cerebrospinal fluid (aCSF) were collected from beneath the cranial windows for determination of the cAMP concentration. After administration of PTX, indomethacin still abolished pial arteriolar dilation to both hypercapnia and 5,6-EET and also inhibited the cAMP elevation caused by hypercapnia. The addition of phorbol 12-myristate 13-acetate (PMA), but not iloprost, restored the increase in cAMP and vascular responses to hypercapnia and 5,6-EET. Therefore, in the newborn pig cerebral microvasculature, PTX appears to inhibit a G protein involved in the permissive action of prostacyclin. However, the protein kinase C (PKC) activator PMA appears to act downstream from the block, and, therefore, the permissive action of PMA is not affected by PTX. We suggest that the prostacyclin IP receptor may be coupled to phospholipase C via a PTX-sensitive G protein that normally permits vasodilation to specific stimuli via activation of a PKC, resulting in phosphorylation of a component of the adenylyl cyclase pathway.

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