Endothelin-1 and endothelin-2 initiate and maintain contractile responses by different mechanisms in rat mesenteric and cerebral arteries

Vasoconstrictor effects of endothelin-1 (ET) were investigated in endothelium-denuded strips of cerebral (basilar and posterior cerebral) and mesenteric arteries of the dog. ET produced a concentration-dependent contraction in these arteries. Contractile responses to lower concentrations (below 3 × 10−10 M) of ET were significantly greater in the cerebral arteries than in the mesenteric artery. Inhibition by nifedipine of the contractile responses to ET was greater in the basilar artery than in the mesenteric artery. After the inhibition by 10−7 M nifedipine, the remaining responses to ET were similar in the two arteries. Cerebral arteries, but not the mesenteric artery, relaxed significantly from the resting level when placed in a Ca2+ -free solution containing 0.1 m M EGTA (0-Ca solution). Readdition of Ca2+ to the cerebral arteries placed in the 0-Ca solution caused a biphasic contraction that was sensitive to nifedipine. When 10−9 M ET was introduced before the Ca2+-induced contraction, this peptide produced only a very small contraction, but enhanced the Ca2+-induced contraction. The extent of the enhancement induced by ET was much greater in the cerebral arteries than in the mesenteric artery. These results indicate that the enhanced responses to ET in the cerebral arteries were dependent to a large extent on Ca2+ influx through voltage-dependent Ca2+ channels (VDCs). It is likely that the VDCs in these arteries are more activated in the resting state than those in the mesenteric artery.

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Contractile and Endothelium-Dependent Dilatory Responses of Cerebral Arteries at Various Extracellular Magnesium Concentrations

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1991.20 ◽

1991 ◽

Vol 11 (1) ◽

pp. 161-164 ◽

Cited By ~ 21

Author(s):

Mária Faragó ◽

Csaba Szabó ◽

Eörs Dóra ◽

Ildikó Horváth ◽

Arisztid G. B. Kovách

Keyword(s):

Smooth Muscle ◽

Vascular Reactivity ◽

Calcium Influx ◽

Cerebral Arteries ◽

Inhibitory Effect ◽

Contractile Responses ◽

Middle Cerebral Arteries ◽

The Right ◽

Endothelial Receptor

To clarify the effect of extracellular magnesium (Mg2+) on the vascular reactivity of feline isolated middle cerebral arteries, the effects of slight alterations in the Mg2+ concentration on the contractile and endothelium-dependent dilatory responses were investigated in vitro. The contractions, induced by 10−8-10−5 M norepinephrine, were significantly potentiated at low Mg2+ (0.8 m M v. the normal, 1.2 m M). High (1.6 and 2.0 m M) Mg2+ exhibited an inhibitory effect on the contractile responses. No significant changes, however, in the EC50 values for norepinephrine were found. The endothelium-dependent relaxations induced by 108–10−5 M acetylcholine were inhibited by high (1.6 and 2.0 m M) Mg2+. Lowering of the Mg2+ concentration to 0.8 m M or total withdrawal of this ion from the medium failed to alter the dilatory potency of acetylcholine. The changes in the dilatory responses also shifted the EC50 values for acetylcholine to the right. The present results show that the contractile responses of the cerebral arteries are extremely susceptible to the changes of Mg2+ concentrations. In response to contractile and endothelium-dependent dilatory agonists, Mg2+ probably affects both the calcium influx into the endothelial and smooth muscle cells as well as the binding of acetylcholine to its endothelial receptor. Since Mg2+ deficiency might facilitate the contractile but not the endothelium-dependent relaxant responses, the present study supports a role for Mg2+ deficiency in the development of the cerebral vasospasm.

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Increased Cerebrovascular Sensitivity to Endothelin-1 in a Rat Model of Obstructive Sleep Apnea: A Role for Endothelin Receptor B

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.214 ◽

2015 ◽

Vol 35 (3) ◽

pp. 402-411 ◽

Cited By ~ 15

Author(s):

David J Durgan ◽

Randy F Crossland ◽

Eric E Lloyd ◽

Sharon C Phillips ◽

Robert M Bryan

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Transient Receptor Potential ◽

Cerebral Arteries ◽

Receptor Potential ◽

Fold Increase ◽

Sleep Cycle ◽

Rock Inhibitor ◽

Endothelin 1 ◽

Obstructive Sleep

Obstructive sleep apnea (OSA) is associated with cerebrovascular diseases. However, little is known regarding the effects of OSA on the cerebrovascular wall. We tested the hypothesis that OSA augments endothelin-1 (ET-1) constrictions of cerebral arteries. Repeated apneas (30 or 60 per hour) were produced in rats during the sleep cycle (8 hours) by remotely inflating a balloon implanted in the trachea. Four weeks of apneas produced a 23-fold increase in ET-1 sensitivity in isolated and pressurized posterior cerebral arteries (PCAs) compared with PCAs from sham-operated rats (EC50=10−9.2 mol/L versus 10−10.6 mol/L; P<0.001). This increased sensitivity was abolished by the ET-B receptor antagonist, BQ-788. Constrictions to the ET-B receptor agonist, IRL-1620, were greater in PCAs from rats after 2 or 4 weeks of apneas compared with that from sham-operated rats ( P=0.013). Increased IRL-1620 constrictions in PCAs from OSA rats were normalized with the transient receptor potential channel (TRPC) blocker, SKF96365, or the Rho kinase (ROCK) inhibitor, Y27632. These data show that OSA increases the sensitivity of PCAs to ET-1 through enhanced ET-B activity, and enhanced activity of TRPCs and ROCK. We conclude that enhanced ET-1 signaling is part of a pathologic mechanism associated with adverse cerebrovascular outcomes of OSA.

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Insulin resistance does not impair contractile responses of cerebral arteries

Life Sciences ◽

10.1016/j.lfs.2005.01.028 ◽

2005 ◽

Vol 77 (18) ◽

pp. 2262-2272 ◽

Cited By ~ 3

Author(s):

Steve A. Simandle ◽

Benedek Erdös ◽

James A. Snipes ◽

Allison W. Miller ◽

David W. Busija

Keyword(s):

Insulin Resistance ◽

Cerebral Arteries ◽

Contractile Responses

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Ca2+sensitization and PKC contribute to exercise training-enhanced contractility in porcine collateral-dependent coronary arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00957.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. H1201-H1209 ◽

Cited By ~ 9

Author(s):

Juan Carlos Robles ◽

Michael Sturek ◽

Janet L. Parker ◽

Cristine L. Heaps

Keyword(s):

Exercise Training ◽

Coronary Arteries ◽

Contractile Function ◽

Rho Kinase ◽

Luminal Diameter ◽

Contractile Responses ◽

Endothelin 1 ◽

Increased Sensitivity ◽

Oxide Synthase ◽

Response Exercise

Exercise training enhances endothelium-dependent coronary vasodilatation, improving perfusion and contractile function of collateral-dependent myocardium. Paradoxically, studies from our laboratory have revealed increased Ca2+-dependent basal active tone in collateral-dependent arteries of exercise-trained pigs. In this study, we tested the hypothesis that exercise training enhances agonist-mediated contractile responses of collateral-dependent arteries by promoting Ca2+sensitization. Ameroid constrictors were surgically placed around the proximal left circumflex coronary (LCX) artery of female Yucatan miniature pigs. Eight weeks postoperatively, pigs were randomized into sedentary (pen confined) or exercise-training (treadmill run; 5 days/wk; 14 wk) groups. Arteries (∼150 μm luminal diameter) were isolated from the collateral-dependent and nonoccluded (left anterior descending artery supplied) myocardial regions, and measures of contractile tension or simultaneous tension and intracellular free Ca2+concentration levels (fura-2) were completed. Exercise training enhanced contractile responses to endothelin-1 in collateral-dependent compared with nonoccluded arteries, an effect that was more pronounced in the presence of nitric oxide synthase inhibition ( Nω-nitro-l-arginine methyl ester; 100 μM). Contractile responses to endothelin-1 were not altered by coronary occlusion alone. Exercise training produced increased tension at comparable levels of intracellular free Ca2+concentration in collateral-dependent compared with nonoccluded arteries, indicative of exercise training-enhanced Ca2+sensitization. Inhibition of PKC (calphostin C; 1 μM), but not Rho-kinase (Y-27632, 10 μM; or hydroxyfasudil, 30 μM), abolished the training-enhanced endothelin-1-mediated contractile response. Exercise training also increased sensitivity to the PKC activator phorbol 12,13-dibutyrate in collateral-dependent compared with nonoccluded arteries. Taken together, these data reveal that exercise training enhances endothelin-1-mediated contractile responses in collateral-dependent coronary arteries likely via increased PKC-mediated Ca2+sensitization.

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Evidence for NO involvement in regulating vascular reactivity in balloon-injured rat carotid artery

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.3.h988 ◽

1995 ◽

Vol 269 (3) ◽

pp. H988-H996 ◽

Cited By ~ 2

Author(s):

T. C. Major ◽

R. W. Overhiser ◽

R. L. Panek

Keyword(s):

Carotid Artery ◽

Factor Viii ◽

Vascular Reactivity ◽

Carotid Arteries ◽

Muscarinic Agonist ◽

Ang Ii ◽

Histomorphometric Analysis ◽

Balloon Injury ◽

Contractile Responses ◽

Endothelin 1

The present study evaluated the influence of this newly formed intima on vascular reactivity in balloon-injured carotid arteries and the regulatory role of the vasodilator, nitric oxide (NO). Balloon injury was performed using a 2-F Fogarty catheter. After 2 and 4 wk, carotid artery segments were removed for both histomorphometric analysis and determination of in vitro contractile responses. Histomorphometric analysis showed a marked intimal thickening with an intima-to-media ratio of 126 +/- 19% (n = 5). The lack of factor VIII staining in injured carotid arteries revealed the absence of endothelium, since factor VIII-related antigen is a glycoprotein synthesized by endothelial cells. Functionally, maximal contractile responses to norepinephrine, angiotensin II (ANG II), endothelin-1, and serotonin were all attenuated in the injured vessels compared with the uninjured carotid arteries [0.38 +/- 0.11 vs. 0.73 +/- 0.10 g (n = 5), norepinephrine; 0.15 +/- 0.06 vs. 0.38 +/- 0.05 g (n = 4), ANG II; 0.60 +/- 0.14 vs. 1.05 +/- 0.12 g (n = 4), endothelin-1; 0.23 +/- 0.07 vs. 0.60 +/- 0.06 g (n = 12), serotonin]. Contractile responses induced by KCl were not affected by the balloon injury (0.62 +/- 0.10 vs. 0.64 +/- 0.09 g, n = 4). Interestingly, carbachol, a muscarinic agonist and vasodilator, caused concentration-dependent relaxations in 2- as well as 4-wk postinjured vessels despite the absence of endothelium. The NO synthase inhibitors, N omega-L-arginine methyl ester (L-NAME) and N omega-nitro-L-arginine (L-NNA), blocked the relaxation responses evoked by carbachol. Exogenously administered L-arginine reversed this blockade of the NOS inhibitors on the carbachol-induced relaxations. In addition, L-NAME partially reversed in a concentration-dependent manner the reduced maximal contractile force elicited by serotonin in the injured carotid artery.(ABSTRACT TRUNCATED AT 250 WORDS)

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