scholarly journals Endothelin rather than 20-HETE contributes to loss of pial arteriolar dilation during focal cerebral ischemia with and without polymeric hemoglobin transfusion

2009 ◽  
Vol 296 (5) ◽  
pp. R1412-R1418 ◽  
Author(s):  
Suyi Cao ◽  
Liang-Chao Wang ◽  
Herman Kwansa ◽  
Richard J. Roman ◽  
David R. Harder ◽  
...  
Keyword(s):  
Blood Flow ◽  
Receptor Antagonist ◽  
Exchange Transfusion ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Receptor Activation ◽  
Border Region ◽  
Synthesis Inhibitor ◽  
Endothelin A Receptor ◽  
Endothelin A

Partial exchange transfusion with a cell-free hemoglobin (Hb) polymer during transient middle cerebral artery occlusion (MCAO) reduces infarct volume but fails to increase blood flow, as might be expected with the induced decrease in hematocrit. In ischemic brain, endothelin antagonists are known to produce vasodilation. In nonischemic brain, pial arterioles constrict after Hb exchange transfusion, and the constriction is blocked by an inhibitor of 20-HETE synthesis. We tested the hypothesis that a 20-HETE synthesis inhibitor and an endothelin A receptor antagonist increase pial arteriolar dilation after Hb exchange transfusion during MCAO. Pial arteriolar diameter was measured in the ischemic border region of the distal MCA border region through closed cranial windows in anesthetized rats subjected to the filament model of MCAO. During 2 h of MCAO, pial arteriolar dilation gradually subsided from 37 ± 3 to 7 ± 5% (±SE). Compared with residual dilation at 2 h of MCAO with vehicle superfusion (14 ± 3%), loss of dilation was not prevented by superfusion of a 20-HETE synthesis inhibitor (21 ± 5%), partial Hb exchange transfusion (7 ± 5%) that decreased hematocrit to 23%, or a combination of the two (5 ± 5%). However, loss of dilation was prevented by superfusion of an endothelin A receptor antagonist with (35 ± 4%) or without (32 ± 5%) Hb transfusion. Pial artery constriction during reperfusion was attenuated by HET0016 alone and by BQ610 with or without Hb transfusion. Systemic administration of the endothelin antagonist during prolonged MCAO increased blood flow in the border region. Thus loss of pial arteriolar dilation in the ischemic border region during prolonged MCAO depends on endothelin A receptor activation, and this effect was independent of the presence of cell-free Hb polymers in the plasma. In contrast to previous work in nonischemic brain, inhibition of oxygen-dependent 20-HETE synthesis does not significantly influence the pial arteriolar response to polymeric Hb exchange transfusion during focal ischemia.

scholarly journals Effects of endothelin in radiocontrast-induced nephropathy in rats are mediated through endothelin-A receptors.

1996 ◽  
Vol 7 (8) ◽  
pp. 1153-1157
Author(s):  
J E Bird ◽  
M R Giancarli ◽  
J R Megill ◽  
S K Durham
Keyword(s):  
Renal Function ◽  
Receptor Antagonist ◽  
Pressor Response ◽  
Endothelin Receptor Antagonist ◽  
Endothelin Receptor ◽  
Synthesis Inhibitor ◽  
Endothelin A Receptor ◽  
Histopathologic Evaluation ◽  
Endothelin A ◽  
Endothelin B

A role for endothelin in the pathogenesis of radiocontrast-induced nephropathy has been suggested by several studies, but the specific contributions of endothelin-A and endothelin-B receptors to the changes in renal function induced by endothelin in this form of renal failure have not been defined. This study examined the effects of the nonselective endothelin receptor antagonist SB-209,670, and the less potent, but selective, endothelin-A receptor antagonist BMS-182,874 in radiocontrast-induced nephropathy in rats. The doses used in this study were chosen from pressor testing data. BMS-182,874 (100 mumol/kg, iv) and SB-209,670 (30 mumol/kg, iv) maximally inhibited the endothelin-1-induced pressor response in rats. BMS-182,874 had no effect on the endothelin-B-mediated depressor response, whereas SB-209,670 abolished it. These results suggest that this is an endothelin-A selective dose of BMS-182,874, and an endothelin-A/B inhibitory dose of SB-209,670. Radiocontrast-induced nephropathy was produced in anesthetized rats (N = 6/group) by intravenous injection of indomethacin (5.0 mg/kg), the nitric oxide synthesis inhibitor N-nitro-L-arginine methyl ester (10.0 mg/kg), vehicle or antagonist, and the radiocontrast agent lopamidol (2,9 g iodine/kg). GFR was partially protected (P < 0.05) by BMS-182,874 (-43 +/- 3.0% change from baseline) compared with vehicle (-65 +/- 6.0%). The decrease in GFR in SB-209,670-treated rats that received lopamidol was intermediate between the other two groups. The fall in RPF induced by lopamidol was unchanged by either antagonist. The marked diuresis in lopamidol treated rats (630 +/- 125.1%) was reduced (P < 0.01) by BMS-182,874 (176 +/- 77.1%) or SB-209,670 (173 +/- 60.1%). Kidneys were collected for histopathologic evaluation approximately 1 h after lopamidol administration, and the percentage of medullary tubular ascending limbs (mTAL) with morphologic features of necrosis were enumerated by semiquantitative analysis. The percentage of mTAL necrosis was significantly decreased in the BMS-182,874- or SB-209,670-treated rats (P < 0.01) compared with vehicle plus lopamidol-treated animals. In summary, endothelin-A receptor blockade with a highly selective, well-characterized endothelin-A receptor antagonist partly protected GFR, and reduced the marked diuresis and mTAL necrosis in radiocontrast-induced nephropathy in rats. Administration of a nonselective endothelin receptor antagonist provided essentially equivalent ameliorative effects in this model, suggesting that blockade of endothelin-B receptors did not yield any additional protection. These results are consistent with the hypothesis that endothelin-A receptors mediate endothelin-induced changes in renal function and structure in this acute model of radiocontrast-induced nephropathy.

scholarly journals Endothelin a receptor antagonist BQ-123 provokes coronary vasodilation and blood flow increase in humans

1998 ◽  
Vol 31 ◽  
pp. 359 ◽  
Author(s):  
Z.S. Kyriakides ◽  
E. Bofilis ◽  
O. Tousoulis ◽  
A. Antoniadis ◽  
D.Th. Kremastinos ◽  
...  
Keyword(s):  
Blood Flow ◽  
Receptor Antagonist ◽  
Coronary Vasodilation ◽  
Endothelin A Receptor ◽  
Blood Flow Increase ◽  
Endothelin A

The Selective Endothelin-A-Receptor Antagonist LU 135.252 Inhibits the Direct Arrhythmogenic Action of Endothelin-1

2000 ◽  
Vol 36 ◽  
pp. S314-S316 ◽  
Author(s):  
Béla Merkely ◽  
Tamás Szabó ◽  
László Gellér ◽  
Orsolya Kiss ◽  
Ferenc Horkay ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Endothelin 1 ◽  
Endothelin A Receptor ◽  
Endothelin A

scholarly journals Minimal role for H1 and H2 histamine receptors in cutaneous thermal hyperemia to local heating in humans

2006 ◽  
Vol 100 (2) ◽  
pp. 535-540 ◽  
Author(s):  
Brett J. Wong ◽  
Sarah J. Williams ◽  
Christopher T. Minson
Keyword(s):  
Blood Flow ◽  
Receptor Antagonist ◽  
Skin Blood Flow ◽  
Local Heating ◽  
Histamine Receptor ◽  
Receptor Activation ◽  
Control Site ◽  
Doppler Flowmetry ◽  
Histamine Receptor Antagonist ◽  
And Control

The precise mechanism(s) underlying the thermal hyperemic response to local heating of human skin are not fully understood. The purpose of this study was to investigate a potential role for H1 and H2 histamine-receptor activation in this response. Two groups of six subjects participated in two separate protocols and were instrumented with three microdialysis fibers on the ventral forearm. In both protocols, sites were randomly assigned to receive one of three treatments. In protocol 1, sites received 1) 500 μM pyrilamine maleate (H1-receptor antagonist), 2) 10 mM l-NAME to inhibit nitric oxide synthase, and 3) 500 μM pyrilamine with 10 mM NG-nitro-l-arginine methyl ester (l-NAME). In protocol 2, sites received 1) 2 mM cimetidine (H2 antagonist), 2) 10 mM l-NAME, and 3) 2 mM cimetidine with 10 mM l-NAME. A fourth site served as a control site (no microdialysis fiber). Skin sites were locally heated from a baseline of 33 to 42°C at a rate of 0.5°C/5 s, and skin blood flow was monitored using laser-Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated as LDF/mean arterial pressure. To normalize skin blood flow to maximal vasodilation, microdialysis sites were perfused with 28 mM sodium nitroprusside, and control sites were heated to 43°C. In both H1 and H2 antagonist studies, no differences in initial peak or secondary plateau phase were observed between control and histamine-receptor antagonist only sites or between l-NAME and l-NAME with histamine receptor antagonist. There were no differences in nadir response between l-NAME and l-NAME with histamine-receptor antagonist. However, the nadir response in H1 antagonist sites was significantly reduced compared with control sites, but there was no effect of H2 antagonist on the nadir response. These data suggest only a modest role for H1-receptor activation in the cutaneous response to local heating as evidenced by a diminished nadir response and no role for H2-receptor activation.

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