Mechanisms of endothelial P2Y1- and P2Y2-mediated vasodilatation involve differential [Ca2+]i responses

2001 ◽  
Vol 281 (4) ◽  
pp. H1759-H1766 ◽  
Author(s):  
Sean P. Marrelli
Keyword(s):  
Nitric Oxide ◽  
Simultaneous Measurement ◽  
Cerebral Arteries ◽  
No Synthase ◽  
Fura 2 ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
The Difference ◽  
Stimulation Of

The present study was designed to evaluate the role of endothelial intracellular Ca2+ concentration ([Ca2+]i) in the difference between P2Y1- and P2Y2-mediated vasodilatations in cerebral arteries. Rat middle cerebral arteries were cannulated, pressurized, and luminally perfused. The endothelium was selectively loaded with fura 2, a fluorescent Ca2+indicator, for simultaneous measurement of endothelial [Ca2+]i and diameter. Luminal administration of 2-methylthioadenosine 5′-triphosphate (2-MeS-ATP), an endothelial P2Y1 agonist, resulted in purely nitric oxide (NO)-dependent dilation and [Ca2+]i increases up to ∼300 nM (resting [Ca2+]i = 145 nM). UTP, an endothelial P2Y2 agonist, resulted in dilations that were both endothelium-derived hyperpolarizing factor (EDHF)- and NO-dependent with [Ca2+]iincreases to >400 nM. In the presence of N G-nitro-l-arginine-indomethacin to inhibit NO synthase and cyclooxygenase, UTP resulted in an EDHF-dependent dilation alone. The [Ca2+]ithreshold for NO-dependent dilation was 220 vs. 340 nM for EDHF. In summary, the differences in the mechanism of vasodilatation resulting from stimulation of endothelial P2Y1 and P2Y2purinoceptors result in part from differential [Ca2+]i responses. Consistent with this finding, these studies also demonstrate a higher [Ca2+]i threshold for EDHF-dependent responses compared with NO.

Role of endothelial intermediate conductance KCa channels in cerebral EDHF-mediated dilations

2003 ◽  
Vol 285 (4) ◽  
pp. H1590-H1599 ◽  
Author(s):  
Sean P. Marrelli ◽  
Maxim S. Eckmann ◽  
Michael S. Hunte
Keyword(s):  
Cerebral Arteries ◽  
Cyclooxygenase Inhibitors ◽  
Male Rat ◽  
Direct Stimulation ◽  
Kca Channels ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
Oxide Synthase ◽  
Stimulation Of

The present study evaluated the role of endothelial intermediate conductance calcium-sensitive potassium channels (IKCa) in the mechanism of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilations in pressurized cerebral arteries. Male rat middle cerebral arteries (MCA) were mounted in an isolated vessel chamber, pressurized (85 mmHg), and luminally perfused (100 μl/min). Artery diameter was measured simultaneously with either endothelial intracellular Ca2+ concentration ([Ca2+]i; fura-2) or changes in endothelial membrane potential [4-{2-[6-(dioctylamino)-2-naphthalenyl]ethenyl}1-(3-sulfopropyl)-pyridinium (di-8-ANEPPS)]. Nitric oxide synthase and cyclooxygenase inhibitors were present throughout. Luminal application of UTP produced EDHF-mediated dilations that correlated with significant endothelial hyperpolarization. The dilation and endothelial hyperpolarization were virtually abolished by inhibitors of IKCa channels but not by selective inhibitors of small or large conductance KCa channels (apamin and iberiotoxin, respectively). Additionally, direct stimulation of endothelial IKCa channels with 1-ethyl-2-benzimidazolinone (1-EBIO) produced endothelial hyperpolarization and vasodilatation that were blocked by inhibitors of IKCa channels. 1-EBIO hyperpolarized the endothelium but did not affect endothelial [Ca2+]i. We conclude that the mechanism of EDHF-mediated dilations in cerebral arteries requires stimulation of endothelial IKCa channels to promote endothelial hyperpolarization and subsequent vasodilatation.

Functional heterogeneity of endothelial P2 purinoceptors in the cerebrovascular tree of the rat

1999 ◽  
Vol 277 (3) ◽  
pp. H893-H900 ◽  
Author(s):  
Junping You ◽  
T. David Johnson ◽  
Sean P. Marrelli ◽  
Robert M. Bryan
Keyword(s):  
Cerebral Arteries ◽  
No Synthase ◽  
Third Order ◽  
Selective Agonist ◽  
Middle Cerebral Arteries ◽  
Spontaneous Tone ◽  
A Minor ◽  
Calcium Activated Potassium Channel ◽  
Dose Dependent

The effects of stimulating P2Y1 or P2Y2 purinoceptors on the endothelium of isolated middle cerebral arteries (MCAs), third-order branches of the MCA (bMCAs), and penetrating arterioles (PAs) of the rat were studied. After pressurization and development of spontaneous tone (25% contraction), resting diameters for MCAs, bMCAs, and PAs were 203 ± 5 ( n = 50), 99 ± 2 ( n = 42), and 87 ± 2 μm ( n = 53), respectively. Luminal application of the P2Y1-selective agonist 2-methylthioadenosine 5′-triphosphate elicited dose-dependent dilations (or loss of intrinsic tone) in MCAs but not in bMCAs or PAs. The dilation in MCAs was completely blocked by removal of the endothelium or by nitro-l-arginine methyl ester (10−5 M), an inhibitor of NO synthase. Luminal application of the P2Y2-selective agonist ATP elicited dilations in MCAs, bMCAs, and PAs. Removal of the endothelium abolished the dilations in all vessel groups. Dilations in MCAs have been shown to involve both NO and endothelium-derived hyperpolarizing factor (EDHF). The dilations in bMCAs and PAs had a minor NO component and prominent EDHF component; that is, 1) the dilations to ATP were not diminished by the combined inhibition of NO synthase and cyclooxygenase, 2) the dilations were accompanied by significant hyperpolarizations of the vascular smooth muscle (∼15 mV), and 3) the dilations were completely abolished by the calcium-activated potassium channel blocker charybdotoxin. We concluded that the role of NO in purinoceptor-induced dilations diminishes along the cerebrovascular tree in the rat, whereas the role of EDHF becomes more prominent.

Experimental determination of rupture pressure and stress of adventitia of human middle cerebral arteries

2017 ◽  
Vol 12 (6) ◽  
pp. 636-640 ◽  
Author(s):  
Adam Piechna ◽  
Leszek Lombarski ◽  
Bogdan Ciszek ◽  
Krzysztof Cieslicki
Keyword(s):  
Balloon Angioplasty ◽  
Cerebral Arteries ◽  
Biomechanical Properties ◽  
Leading Role ◽  
Middle Cerebral Arteries ◽  
Rupture Pressure ◽  
The Difference ◽  
Age Range

Background Intracranial arterial dissections might be attributed to the particular biomechanical properties of their specific layers. Also, knowledge of adventitia properties would be crucial in the context of intracranial balloon angioplasty. Aims The purpose of this work was to determine the rupture pressure of separated adventitia and compare it to intact cerebral arterial segments. Methods Brain specimens were harvested from 14 autopsy subjects (age range from 23 to 86 years). Pressure-inflation tests were conducted on proximal segments of middle cerebral arteries and separated adventitia layers from contralateral arteries to assess the rupture pressure values. Results The averaged rupture pressure of adventitia layers was 1.41 SD 0.25 atm (1072 SD 190 mmHg), whereas for intact arterial segments it was 2.32 SD 0.70 atm (1763 SD 532 mmHg) and diminished with age according to nonlinear regression trends. The difference beetween the aformentioned rupture pressures was positively correlated with rupture pressure of intact arterial segments ( R2 = 0.88; p < 0.001). Conclusions The obtained experimental results indicate a leading role of adventitia in building arterial strength under supraphysiological pressure conditions. The greater the rupture pressure of complete cerebral arteries, the smaller the contribution of adventitia in overall wall resistance.

Characterizing voltage-dependent Ca2+ channels coupled to VIP release and NO synthesis in enteric synaptosomes

2002 ◽  
Vol 283 (5) ◽  
pp. G1027-G1034 ◽  
Author(s):  
M. Kurjak ◽  
A. Sennefelder ◽  
M. Aigner ◽  
V. Schusdziarra ◽  
H. D. Allescher
Keyword(s):  
Nitric Oxide ◽  
No Synthase ◽  
Channel Blockers ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
P Type ◽  
Ca2 Channels

In enteric synaptosomes of the rat, the role of voltage-dependent Ca2+channels in K+-induced VIP release and nitric oxide (NO) synthesis was investigated. Basal VIP release was 39 ± 4 pg/mg, and cofactor-substituted NO synthase activity was 7.0 ± 0.8 fmol · mg−1 · min−1. K+ depolarization (65 mM) stimulated VIP release Ca2+ dependently (basal, 100%; K+, 172.2 ± 16.2%; P < 0.05, n = 5). K+-stimulated VIP release was reduced by blockers of the P-type (ω-agatoxin-IVA, 3 × 10−8 M) and N-type (ω-conotoxin-GVIA, 10−6 M) Ca2+ channels by ∼50 and 25%, respectively, but not by blockers of the L-type (isradipine, 10−8 M), Q-type (ω-conotoxin-MVIIC, 10−6 M), or T-type (Ni2+, 10−6 M) Ca2+ channels. In contrast, NO synthesis was suppressed by ω-agatoxin-IVA, ω-conotoxin-GVIA, and isradipine by ∼79, 70, and 70%, respectively, whereas Ni2+ and ω-conotoxin-MVIIC had no effect. These findings are suggestive of a coupling of depolarization-induced VIP release primarily to the P- and N-type Ca2+ channels, whereas NO synthesis is presumably dependent on Ca2+ influx not only via the P- and N- but also via the L-type Ca2+ channel. In contrast, none of the Ca2+ channel blockers affected VIP release evoked by exogenous NO, suggesting that NO induces VIP secretion by a different mechanism, presumably involving intracellular Ca2+ stores.

Stimulation of α2Adrenoceptors Dilates the Rat Middle Cerebral Artery

1996 ◽  
Vol 85 (1) ◽  
pp. 82-90 ◽  
Author(s):  
Robert M. Bryan ◽  
M. Y. Eichler ◽  
M. W. G. Swafford ◽  
T. D. Johnson ◽  
M. S. Suresh ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Pertussis Toxin ◽  
Saline Solution ◽  
Cerebral Arteries ◽  
Middle Cerebral Arteries ◽  
Physiologic Saline ◽  
Stimulation Of

Background Because alpha 2 adrenoceptor agonists are used as adjuncts to anesthetics, their effects on the cerebrovascular circulation are of prime importance. We studied changes in the diameter of rat middle cerebral arteries after stimulation of alpha 2 adrenoceptors with UK14,304. Methods Rat middle cerebral arteries were isolated, cannulated at each end with a glass micropipette, and pressurized to 85 mmHg. The middle cerebral arteries were immersed in a bath (37 degrees C) containing physiologic saline solution, and luminally perfused with physiologic saline solution (100 microliters/ min). Changes in vessel diameter were measured after magnification with a microscope. Results Resting diameter of the middle cerebral arteries was 239 +/- 13 microns (n = 8) for the first study. A dose-dependent dilation was produced by addition of UK14,304 to the extraluminal bath; a 10-15% increase in diameter occurred at a concentration of 10(-4)M. The dilations produced by UK14,304 were blocked with selective alpha 2-antagonists, idazoxan and rauwolscine, but not by the selective alpha 1-antagonist, prazosin. The dilations could be blocked by removal of the endothelium, or the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (10(-5) M). The inhibitory effects of N-nitro-L-arginine methyl ester were reversed with the addition of 10(-3) M L-arginine, but not 10(-3) M D-arginine. Furthermore the dilation produced by UK14,304 was completely abolished with pertussis toxin (100 ng/ml). Conclusions It was concluded that the stimulation of alpha 2 adrenoceptors with UK14,304 produced a dilation in the rat middle cerebral artery that (1) was dependent on intact endothelium, (2) involved nitric oxide, and (3) acted via a pertussis toxin-sensitive G protein.

5-HT-induced colonic contractions: enteric locus of action and receptor subtypes

1997 ◽  
Vol 273 (1) ◽  
pp. G68-G74 ◽  
Author(s):  
S. Graf ◽  
S. K. Sarna
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Contractile Response ◽  
No Synthase ◽  
Enteric Neurons ◽  
Receptor Subtypes ◽  
Arterial Infusion ◽  
Stimulation Of

The role of 5-hydroxytryptamine (5-HT), its enteric locus of action, and the receptor subtypes involved in the stimulation of in vivo phasic contractions in the colon were investigated by close intra-arterial infusions in conscious dogs. The contractile response to 5-HT was blocked completely by prior close intra-arterial infusion of atropine and reduced significantly by prior close intra-arterial infusions of tetrodotoxin and hexamethonium. The contractile response was, however, enhanced by the inhibition of nitric oxide (NO) synthase by a prior close intra-arterial infusion of N omega-nitro-L-arginine methyl ester. Prior close intra-arterial infusions of 5-HT1A/5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4 receptor antagonists had no significant effect on the contractile response to 5-HT. By contrast, 5-HT3 receptor antagonist significantly and dose dependently inhibited the contractile response to 5-HT. We conclude that the in vivo phasic contractile response to 5-HT in the colon is mediated mainly by 5-HT3 receptors located on pre- and postsynaptic cholinergic enteric neurons. 5-HT receptors may also be localized on nonadrenergic, noncholinergic inhibitory motoneurons that use NO as a neurotransmitter.

scholarly journals Nitric Oxide Mediates the Neurogenic Vasodilation of Bovine Cerebral Arteries

1991 ◽  
Vol 11 (3) ◽  
pp. 366-370 ◽  
Author(s):  
Carmen Gonzalez ◽  
Carmen Estrada
Keyword(s):  
Nitric Oxide ◽  
Superoxide Dismutase ◽  
Nerve Stimulation ◽  
Cerebral Arteries ◽  
Electrical Field Stimulation ◽  
Field Stimulation ◽  
Electrical Field ◽  
Muscarinic Receptor Antagonists ◽  
Stimulation Of

Nitric oxide (NO) is a mediator of the vasodilation induced by a variety of physiological and pharmacological stimuli. The possible role of NO in the relaxation elicited in cerebral arteries by perivascular nerve stimulation has been investigated. Electrical field stimulation of precontracted bovine cerebral arteries induced a relaxation that was blocked by tetrodotoxin, but not by adrenergic or muscarinic receptor antagonists, suggesting the existence of nonadrenergic, noncholinergic dilator nerves, as has been shown in other species. The relaxation was significantly reduced by the inhibitors of NO synthesis, NG-monomethyl-L-arginine and nitro-L-arginine methyl ester, but not by the enantiomer, NG-monomethyl-D-arginine. Such a reduction was reversed by L-arginine. In addition, transmural nerve stimulation (TNS)-induced relaxation was potentiated by superoxide dismutase. No response to TNS was observed in arteries without endothelium. These results suggested that neurogenic relaxation of bovine cerebral arteries is mediated by endothelium-derived NO.

The cerebrovascular response to elevated potassium – role of nitric oxide in the in vitro model of isolated rat middle cerebral arteries

2001 ◽  
Vol 306 (1-2) ◽  
pp. 61-64 ◽  
Author(s):  
Sigrid Schuh-Hofer ◽  
Elmar Lobsien ◽  
Renate Brodowsky ◽  
Johannes Vogt ◽  
Jens Peter Dreier ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
In Vitro Model ◽  
Cerebral Arteries ◽  
Middle Cerebral Arteries ◽  
Vitro Model ◽  
Isolated Rat

Role of endothelium-derived nitric oxide in stimulation of Na(+)-K(+)-ATPase activity by endothelin in rabbit aorta

1994 ◽  
Vol 266 (2) ◽  
pp. H577-H582 ◽  
Author(s):  
S. Gupta ◽  
C. McArthur ◽  
C. Grady ◽  
N. B. Ruderman
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Atpase Activity ◽  
Rabbit Aorta ◽  
No Synthase ◽  
Maximal Increase ◽  
Synthase Inhibitor ◽  
Cgmp Formation ◽  
Stimulation Of

An endothelium-derived factor with the properties of nitric oxide (NO) has recently been implicated in the regulation of basal Na(+)-K(+)-adenosinetriphosphatase (ATPase) activity in vascular smooth muscle. To determine whether this factor also plays a role in the stimulation of ouabain-sensitive (OS) 86Rb uptake by specific agonists, studies were carried out using rabbit aortic rings. In endothelium-intact rings incubated for 3 h with Krebs-Henseleit solution containing 5.5 mM glucose, endothelin (ET) caused a concentration-dependent increase in OS 86Rb uptake (maximal increase = 205%, with 100 nM ET). Incubation with phenylephrine (Phe; 0.1 and 1 microM) or phorbol 12,13-dibutyrate (PDBu; 0.1 microM), under the same conditions, increased OS 86Rb uptake by 128, 144, and 140%, respectively. Removal of endothelium before incubation decreased the ability of ET to stimulate OS 86Rb uptake by 38–45%, but it did not diminish the stimulation of OS 86Rb uptake by Phe or PDBu. An increase in the concentration of glucose from 5.5 to 44 mM diminished ET-stimulated OS 86Rb uptake by 50% in endothelium-intact rings but had no effect on Phe- or PDBu-induced increases in OS 86Rb uptake. Addition of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 0.3 mM) to the medium decreased ET-stimulated OS 86Rb uptake by 40%. Guanosine 3',5'-cyclic monophophate (cGMP) formation in endothelium-intact rings was also increased (65%) by ET but not by Phe or PDBu. The increase in cGMP by ET was totally inhibited by L-NMMA or endothelium denudation.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of cGMP contribution to the vasodilator response to NO in rat middle cerebral arteries

2002 ◽  
Vol 282 (5) ◽  
pp. H1724-H1731 ◽  
Author(s):  
Ming Yu ◽  
Cheng-Wen Sun ◽  
Kristopher G. Maier ◽  
David R. Harder ◽  
Richard J. Roman
Keyword(s):  
Nitric Oxide ◽  
Contractile Response ◽  
Cerebral Arteries ◽  
Inhibitory Effect ◽  
No Donor ◽  
Vasodilator Response ◽  
Vasoconstrictor Response ◽  
High K ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca

This study examined the mechanism by which cGMP contributes to the vasodilator response to nitric oxide (NO) in rat middle cerebral arteries (MCA). Administration of a NO donor, diethylaminodiazen-1-ium-1,2-dioate (DEA-NONOate), or 8-bromo-cGMP (8-BrcGMP) increased the diameter of serotonin-preconstricted MCA by 79 ± 3%. The response to DEA-NONOate, but not 8-BrcGMP, was attenuated by iberiotoxin (10−7 M) or a 80 mM high-K+ media, suggesting that activation of K+channels contributes to the vasodilator response to NO but not 8-BrcGMP. The effects of NO and cGMP on the vasoconstrictor response to Ca2+ were also studied in MCA that were permeabilized with α-toxin and ionomycin. Elevations in bath Ca2+ from 10−8 to 10−5 M decreased the diameter of permeabilized MCA by 76 ± 5%. DEA-NONOate (10−6 M) and 8-BrcGMP (10−4 M) blunted this response by 60%. Inhibition of guanylyl cyclase with 1 H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one (10−5 M) blocked the inhibitory effect of the NO donor, but not 8-BrcGMP, on Ca2+-induced vasoconstriction. 8-BrcGMP (10−4 M) had no effect on intracellular Ca2+ concentration ([Ca2+]i) in control, serotonin-stimulated, or α-toxin- and ionomycin-permeabilized vascular smooth muscle cells isolated from the MCA. These results indicate that the vasodilator response to NO in rat MCA is mediated by activation of Ca2+-activated K+ channels via a cGMP-independent pathway and that cGMP also contributes to the vasodilator response to NO by decreasing the contractile response to elevations in [Ca2+]i.

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