In SHR aorta, calcium ionophore A-23187 releases prostacyclin and thromboxane A2 as endothelium-derived contracting factors

2006 ◽  
Vol 291 (5) ◽  
pp. H2255-H2264 ◽  
Author(s):  
Pascale Gluais ◽  
Jerôme Paysant ◽  
Cécile Badier-Commander ◽  
Tony Verbeuren ◽  
Paul M. Vanhoutte ◽  
...  
Keyword(s):  
Calcium Ionophore ◽  
Isometric Tension ◽  
Spontaneously Hypertensive ◽  
A 23187 ◽  
Cyclooxygenase 1 ◽  
Thromboxane Synthase Inhibitor ◽  
Parallel Increase ◽  
Tp Receptors ◽  
Wistar Kyoto ◽  
Synthase Inhibitor

In mature spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), acetylcholine and the calcium ionophore A-23187 release endothelium-derived contracting factors (EDCFs), cyclooxygenase derivatives that activate thromboxane-endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine are most likely prostacyclin and prostaglandin (PG)H2, whereas those released by A-23187 remain to be identified. Isometric tension and the release of PGs were measured in rings of isolated aortas of WKY and SHR. A-23187 evoked the endothelium-dependent release of prostacyclin, thromboxane A2, PGF2α, PGE2, and possibly PGH2 (PGI2 ≫ thromboxane A2 = PGF2α = PGE2). In SHR aortas, the release of prostacyclin and thromboxane A2 was significantly larger in response to A-23187 than to acetylcholine. In response to the calcium ionophore, the release of thromboxane A2 was significantly larger in aortas of SHR than in those of WKY. In both strains of rat, the inhibition of cyclooxygenase-1 prevented the release of PGs and the occurrence of endothelium-dependent contractions. Dazoxiben, the thromboxane synthase inhibitor, abolished the A-23187-dependent production of thromboxane A2 and inhibited by approximately one-half the endothelium-dependent contractions. U-51605, an inhibitor of PGI synthase, reduced the release of prostacyclin elicited by A-23187 but induced a parallel increase in the production of PGE2 and PGF2α, suggestive of a PGH2 spillover, which was associated with the enhancement of the endothelium-dependent contractions. These results indicate that in the aorta of SHR and WKY, the endothelium-dependent contractions elicited by A-23187 involve the release of thromboxane A2 and prostacyclin with a most likely concomitant contribution of PGH2.

Calcium-independent phospholipase A2 plays a key role in the endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat

2010 ◽  
Vol 298 (4) ◽  
pp. H1260-H1266 ◽  
Author(s):  
Michael S. K. Wong ◽  
Ricky Y. K. Man ◽  
Paul M. Vanhoutte
Keyword(s):  
Endothelial Cells ◽  
Mammalian Cells ◽  
Spontaneously Hypertensive Rat ◽  
Calcium Ionophore ◽  
Isometric Tension ◽  
Membrane Phospholipids ◽  
Spontaneously Hypertensive ◽  
A 23187 ◽  
Hypertensive Rat ◽  
Wistar Kyoto

Phospholipase A2 (PLA2), a regulatory enzyme found in most mammalian cells, catalyzes the breakdown of membrane phospholipids to arachidonic acid. There are two major cytosolic types of the enzyme, calcium-dependent (cPLA2) and calcium-independent (iPLA2) PLA2. The present study investigated whether or not iPLA2 plays a role in the endothelium-dependent contractions of the aorta of the spontaneously hypertensive rat and its normotensive counterpart, the Wistar-Kyoto rat. The presence of iPLA2 in the endothelial cells was identified by using immunochemistry and immunoblotting. Aortic rings with and without the endothelium were suspended in organ chambers for isometric tension recording. The production of prostanoids was measured by using enzyme immunoassay kits. iPLA2 was densely distributed in endothelial cells of the aorta of both strains. At 3 × 10−6 M, the selective iPLA2 inhibitor, bromoenol lactone (BEL), abrogated endothelium-dependent contractions induced by acetylcholine but not those evoked by the calcium ionophore A-23187. The effects of BEL were similar in the aortae of Wistar-Kyoto and spontaneously hypertensive rats. The nonselective PLA2 inhibitor quinacrine abolished the contractions triggered by both acetylcholine and A-23187, whereas the store-operated calcium channel inhibitor SKF-96365 prevented only the acetylcholine-induced contraction. The acetylcholine- but not the A-23187-induced release of 6-keto prostaglandin F1α was inhibited by BEL. The release of thromboxane B2 by either acetylcholine or A-23187 was not affected by BEL. In conclusion, iPLA2 plays a substantial role in the generation of endothelium-derived contracting factor evoked by acetylcholine.

Superoxide anion scavengers restore NO-mediated pulmonary vasodilation after lung transplantation

1999 ◽  
Vol 276 (1) ◽  
pp. H42-H46 ◽  
Author(s):  
Sumihiko Seki ◽  
Nicholas A. Flavahan ◽  
Nicholas G. Smedira ◽  
Paul A. Murray
Keyword(s):  
Xanthine Oxidase ◽  
Dose Response ◽  
Superoxide Anion ◽  
Left Lung ◽  
Calcium Ionophore ◽  
Isometric Tension ◽  
Response Curves ◽  
Superoxide Anion Production ◽  
Pulmonary Vasodilation ◽  
A 23187

Left lung autotransplantation (LLA) results in a chronic attenuation in endothelium-dependent, nitric oxide (NO)-mediated pulmonary vasodilation. We tested the hypothesis that this abnormality involves a decrease in the effective concentration of NO due to inactivation by superoxide anion. Size- and position-matched pulmonary arterial rings were isolated from the right (control) and left (LLA) lungs of seven dogs 1–5 mo post-LLA. The rings were suspended for isometric tension recording and contracted with phenylephrine, and cumulative dose-response curves for ACh or calcium ionophore (A-23187) were generated. Endothelium-dependent relaxation to ACh was inhibited post-LLA, with the maximum vasorelaxation response reduced from 88 ± 5 to 63 ± 5% ( P < 0.01) post-LLA. In contrast, after pretreatment with the superoxide anion scavengers tiron or superoxide dismutase (SOD), the dose-response relationships for ACh were similar in control and LLA rings. Oxypurinol, which inhibits superoxide anion production by endothelial xanthine oxidase, also restored the vasorelaxation response to ACh in LLA rings. The pulmonary vasorelaxant response to A-23187 was also attenuated ( P < 0.01) post-LLA, and this effect was entirely reversed by pretreatment with tiron, SOD, or oxypurinol. These results indicate that the attenuated responses to these pulmonary vasorelaxants post-LLA involve inactivation of NO by superoxide anion generated by endothelial xanthine oxidase.

scholarly journals Acetylcholine and sodium nitroprusside cause long-term inhibition of EDCF-mediated contractions

2005 ◽  
Vol 289 (6) ◽  
pp. H2434-H2440 ◽  
Author(s):  
Eva H. C. Tang ◽  
Michel Feletou ◽  
Yu Huang ◽  
Ricky Y. K. Man ◽  
Paul M. Vanhoutte
Keyword(s):  
Sodium Nitroprusside ◽  
Spontaneously Hypertensive Rat ◽  
Isometric Force ◽  
Calcium Ionophore ◽  
Soluble Guanylyl Cyclase ◽  
Inhibitory Effect ◽  
Previous Exposure ◽  
Spontaneously Hypertensive ◽  
A 23187

Preliminary studies suggested that previous exposure to acetylcholine (ACh) exerts a delayed inhibition of subsequent contractions mediated by endothelium-derived contracting factor (EDCF). To confirm this long-term inhibitory effect of ACh and to determine whether nitric oxide (NO) mediates the phenomenon, we suspended rings of spontaneously hypertensive rat (SHR) aortas in organ chambers for the recording of isometric force. The rings were incubated in the absence or presence of Nω-nitro-l-arginine methyl ester (l-NAME; inhibitor of NO synthases) or 1 H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one (ODQ; inhibitor of soluble guanylyl cyclase) before exposure to increasing concentrations of ACh or sodium nitroprusside (SNP) during contractions to phenylephrine. Thereafter, EDCF-mediated contractions to ACh or the calcium ionophore A-23187 were elicited. If the rings were preexposed to ACh or SNP, the subsequent ACh-induced EDCF-mediated contractions were reduced compared with those obtained in rings of the same arteries not previously exposed to either agent. ODQ did not affect the inhibition caused by preexposure to ACh but significantly reduced that caused by preexposure to SNP. Previous exposure to SNP reduced, whereas previous exposure to ACh did not affect, endothelium-dependent contractions to A-23187. Previous exposure to either ACh or SNP did not affect the contractions to the thromboxane mimetic U-46619. Thus ACh and SNP exert delayed inhibition of EDCF-mediated contractions via distinct pathways. The effect of ACh is NO independent and upstream of the increase in calcium concentration that triggers the release of EDCF. The effect of SNP is downstream of the calcium rise and is mainly NO dependent.

Inhibitory Effects of Etomidate and Ketamine on Endothelium-dependent Relaxation in Canine Pulmonary Artery

2001 ◽  
Vol 94 (4) ◽  
pp. 668-677 ◽  
Author(s):  
Koji Ogawa ◽  
Satoru Tanaka ◽  
Paul A. Murray
Keyword(s):  
Pulmonary Artery ◽  
Calcium Ionophore ◽  
Receptor Activation ◽  
Isometric Tension ◽  
Calcium Ionophore A23187 ◽  
Ionophore A23187 ◽  
Inhibitory Effects ◽  
Pulmonary Arterial ◽  
Synthase Inhibitor ◽  
Endothelium Dependent Relaxation

Background The authors recently demonstrated that acetylcholine-induced pulmonary vasorelaxation had two primary components, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). The goal was to investigate the effects of etomidate and ketamine on the NO- and EDHF-mediated components of pulmonary vasorelaxation in response to acetylcholine, bradykinin, and the calcium ionophore, A23187. Methods Canine pulmonary arterial rings with an intact endothelium were suspended in organ chambers for isometric tension recording. The effects of etomidate and ketamine (10(-5) M and 10(-4) M) on vasorelaxation responses to acetylcholine, bradykinin, and A23187 were assessed in phenylephrine-contracted rings. The NO- and EDHF-mediated components of relaxation were assessed using a NO synthase inhibitor (N-nitro-L-arginine methylester [L-NAME]: 10(-4) M) and a Ca2+-activated potassium channel inhibitor (tetrabutylammonium hydrogen sulfate [TBA]: 10(-3) M) in rings pretreated with a cyclooxygenase inhibitor (ibuprofen: 10(-5) M). Intracellular calcium concentration ([Ca2+]i) was measured in cultured bovine pulmonary artery endothelial cells loaded with acetoxylmethyl ester of fura-2. Results Etomidate and ketamine attenuated pulmonary vasorelaxation in response to acetylcholine and bradykinin, whereas they had no effect on the response to A23187. The relaxant responses to acetylcholine and bradykinin were attenuated by L-NAME or TBA alone and were abolished by combined inhibition in rings pretreated with ibuprofen. Etomidate and ketamine further attenuated both L-NAME-resistant and TBA-resistant relaxation. These anesthetics also inhibited increases in endothelial [Ca2+]i in response to bradykinin, but not A23187. Conclusion These results indicate that etomidate and ketamine attenuated vasorelaxant responses to acetylcholine and bradykinin by inhibiting both NO- and EDHF-mediated components. Moreover, our results suggest that these anesthetics do not directly suppress NO or EDHF activity, but rather inhibit the endothelial [Ca2+]i transient in response to receptor activation.

Does a general alteration in nitric oxide synthesis system occur in spontaneously hypertensive rats?

1994 ◽  
Vol 266 (1) ◽  
pp. H272-H278 ◽  
Author(s):  
J. Xiao ◽  
P. K. Pang
Keyword(s):  
Nitric Oxide ◽  
Spontaneously Hypertensive Rats ◽  
No Synthase ◽  
Hypertensive Rats ◽  
Synthesis System ◽  
Spontaneously Hypertensive ◽  
Proliferation Of Lymphocytes ◽  
General Activation ◽  
Wistar Kyoto ◽  
Synthase Inhibitor

Immune dysfunction has been reported in spontaneously hypertensive rats (SHR). The current study investigated interactions between macrophages or vascular smooth muscle cells (VSMC) and lymphocytes in SHR and examined the role of nitric oxide (NO) in this interaction. SHR macrophages significantly inhibited the proliferation of lymphocytes from SHR and the genetic control, Wistar-Kyoto rats (WKY). This inhibition was reversed by a NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA). SHR VSMC also significantly inhibited the proliferation responses of lymphocytes from SHR and WKY. The inhibition was cell density dependent. In addition, L-NMMA fully reversed the inhibition by SHR VSMC. Upon stimulation, the macrophages and VSMC from SHR produced a significantly higher amount of NO compared with those from WKY. These results suggest that the overproduction of NO was involved in the interaction between macrophages or VSMC and lymphocytes in SHR. Increased NO synthase activity in macrophages and VSMC may indicate a general activation of the NO synthesis system in SHR. The alteration of the NO synthesis system may be an important factor contributing to the lymphocyte depression in hypertension.

Effect of aging and hypertension on contractility of resistance arteries: modulation by endothelial factors

1995 ◽  
Vol 269 (3) ◽  
pp. H837-H844 ◽  
Author(s):  
M. G. Lang ◽  
G. Noll ◽  
T. F. Luscher
Keyword(s):  
Isometric Tension ◽  
No Production ◽  
Ang Ii ◽  
Resistance Arteries ◽  
Spontaneously Hypertensive ◽  
Thromboxane Receptor ◽  
Increased Sensitivity ◽  
Wistar Kyoto ◽  
Thromboxane Receptor Antagonist ◽  
Effects Of Aging

The effects of aging and hypertension on contraction were examined in rat mesenteric resistance arteries of 12- and 74-wk-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). The vessels were suspended in myographs (37 degrees C, 95% O2-5% CO2) filled with modified Krebs-Ringer bicarbonate solution. Isometric tension was measured. Contractions to KCl (100 mM) were similar in adult WKY and SHR; they increased in senescent WKY (P < 0.05) but decreased in senescent SHR (P < 0.05). Responses to norepinephrine (% of KCl) were comparable in all four groups. However, blockade of nitric oxide (NO) production with NG-nitro-L-arginine methyl ester (L-NAME) enhanced the sensitivity to norepinephrine in senescent animals, particularly in SHR. Inhibition of cyclooxygenase with indomethacin prevented increased sensitivity to norepinephrine after NO blockade. Responses to angiotensin (ANG) II were not affected by aging and hypertension, but the thromboxane receptor antagonist SQ-30741 reduced ANG II-induced contractions only in SHR of both ages (P < 0.05). Aging increased responses to ANG I in SHR but decreased it in WKY (P < 0.05). In quiescent rings with endothelium, acetylcholine caused contractions in the presence of L-NAME in adult and senescent SHR but not in WKY (P < 0.05). SQ-30741 prevented these contractions (P < 0.05). Contractions to the thromboxane analogue U-46619 were reduced only in senescent SHR (P < 0.05). Thus aging increases and hypertension decreases contractility of smooth muscle in rat mesenteric resistance arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of gender on control of arterial tone in experimental hypertension

1998 ◽  
Vol 275 (1) ◽  
pp. H15-H22 ◽  
Author(s):  
Mika Kähönen ◽  
Jari-Petteri Tolvanen ◽  
Kirsimarja Sallinen ◽  
Xiumin Wu ◽  
Ilkka Pörsti
Keyword(s):  
Study Groups ◽  
Experimental Hypertension ◽  
Relative Role ◽  
No Donor ◽  
Spontaneously Hypertensive ◽  
Adrenoceptor Agonist ◽  
Relaxation Responses ◽  
Wistar Kyoto ◽  
Synthase Inhibitor

Endothelial dysfunction has been found to be less severe in female than in male spontaneously hypertensive rats (SHR), which could contribute to the gender differences observed in the extent and rate of progression of hypertension in SHR. However, the influence of gender on the roles of different endothelium-derived mediators in the arterial responses in hypertension have not been evaluated in detail. Therefore, contractile and relaxation responses of mesenteric arterial rings in vitro were studied in female and male SHR, with normotensive female and male Wistar-Kyoto rats (WKY) serving as controls. In norepinephrine (NE)-precontracted arterial rings, endothelium-dependent relaxations to ACh as well as endothelium-independent dilations to sodium nitroprusside were more pronounced in female than in male SHR, whereas relaxations to the β-adrenoceptor agonist isoproterenol remained equally impaired in female and male SHR. The cyclooxygenase inhibitor diclofenac, which reduces the synthesis of dilating and constricting prostanoids, markedly enhanced the relaxations to ACh in male SHR but not in the other groups. The nitric oxide (NO) synthase inhibitor N G-nitro-l-arginine methyl ester attenuated the relaxations to ACh more effectively in female SHR and WKY than in the male groups. However, when endothelium-dependent hyperpolarization was prevented by precontracting the preparations with KCl, no significant differences were found in relaxations to ACh among the study groups. In conclusion, release of cyclooxygenase-derived constricting factors appeared to be more pronounced in male than in female SHR. In addition, the relative role of NO in endothelium-dependent arterial relaxation seemed to be higher in female than in male SHR, and relaxation induced by an NO donor also was more pronounced in female than in male SHR.

Nitric Oxide Modulation of Coronary Artery Myogenic Tone in Spontaneously Hypertensive and Wistar—Kyoto Rats

1998 ◽  
Vol 94 (3) ◽  
pp. 225-229 ◽  
Author(s):  
Susana R. Garcia ◽  
Stuart J. Bund
Keyword(s):  
Nitric Oxide ◽  
Coronary Artery ◽  
Coronary Arteries ◽  
Myogenic Tone ◽  
Internal Diameter ◽  
Nitric Oxide Synthase Inhibitor ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto Rats ◽  
Wistar Kyoto ◽  
Synthase Inhibitor

1. The endothelium contributes substantially to the modulation of myogenic tone in coronary arteries from spontaneously hypertensive rats (SHR) and Wistar—Kyoto rats (WKY). This study has addressed the contributions of endothelium-derived nitric oxide and cyclo-oxygenase products to this modulation in small coronary arteries (approximately 200 μm internal diameter) from 20-week-old SHR and WKY under pressurized, no-flow conditions in an arteriograph. 2. Active pressure—diameter relationships were uninfluenced by the cyclo-oxygenase inhibitor indomethacin (10 μmol/l) in either rat strain. In the presence of indomethacin and the nitric oxide synthase inhibitor Nω-nitro-l-arginine (l-NNA, 0.1 mmol/l), coronary arteries from SHR and WKY generated significantly greater myogenic tone. This increase in tone was similar in both strains. 3. In endothelium-denuded arteries, indomethacin and l-NNA did not influence tone. 4. Therefore, these results demonstrate that endothelium-derived nitric oxide is basally released to attenuate SHR and WKY coronary artery myogenic tone, whereas endothelium-derived cyclo-oxygenase products have no net vasoactive influence. Additionally, these data suggest that basal nitric oxide-mediated relaxation is normal in SHR coronary arteries and is therefore unlikely to be a pathogenic mechanism in this animal model of hypertension.

Sign in / Sign up

Export Citation Format

Share Document