Role of nitric oxide in regulation of basilar artery tone in vivo

Previous studies have suggested that nitric oxide (NO) may be a major endothelium-derived relaxing factor in peripheral blood vessels. This study tested the hypotheses that 1) formation of NO from L-arginine contributes to basal tone of cerebral arteries in vivo and 2) dilator responses of cerebral arteries to acetylcholine are dependent on formation of NO. Diameter of the basilar artery was measured through a cranial window in anesthetized rats. Under control conditions, topical application of 10 microM NG-monomethyl-L-arginine (L-NMMA, an arginine analogue that inhibits enzymatic formation of NO), constricted the basilar artery by 11 +/- 1% (means +/- SE). L-Arginine (100 microM), which had no effect on baseline diameter, abolished vasoconstriction in response to L-NMMA. L-Arginine did not alter vasodilation during acetylcholine (1 microM) (11 +/- 2 vs. 12 +/- 2%) or vasoconstriction during serotonin (1 nM) (-15 +/- 3 vs. -16 +/- 2%). L-NMMA (5-10 microM) abolished the dilator response of the basilar artery to acetylcholine but did not alter responses to nitroglycerin (0.01 microM) (24 +/- 4 vs. 20 +/- 3%). The inhibitory effect of L-NMMA on the vasodilator response to acetylcholine was prevented by L-arginine. These studies suggest that synthesis of NO from L-arginine influences resting tone of the basilar artery in vivo. Dilatation of the basilar artery to acetylcholine in vivo appears to be dependent on formation of NO from L-arginine.

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Role of ATP-sensitive potassium channels in the basilar artery

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.1.h8 ◽

1993 ◽

Vol 264 (1) ◽

pp. H8-H13 ◽

Cited By ~ 9

Author(s):

F. M. Faraci ◽

D. D. Heistad

Keyword(s):

Potassium Channels ◽

Basilar Artery ◽

Cranial Window ◽

Basal Tone ◽

Dependent Inhibition ◽

Baseline Diameter ◽

Direct Activator ◽

Sustained Increase

This study examined the hypothesis that activation of ATP-sensitive potassium channels produces vasodilation and contributes to dilator responses of the basilar artery to acetylcholine in vivo. Diameter of the basilar artery (baseline diam = 245 +/- 14 microns, means +/- SE) was measured through a cranial window in anesthetized rats. RP52891 (1 microM), a direct activator of ATP-sensitive potassium channels, increased the diameter of the basilar artery by 33 +/- 5%. Glibenclamide (1 microM), an inhibitor of ATP-sensitive potassium channels, did not alter baseline diameter but abolished responses of the basilar artery to RP52891. Topical application of acetylcholine (10 microM) for 3 min produced peak dilatation of 33 +/- 6% at 30 s and produced a sustained increase in diameter of 17 +/- 4%. Glibenclamide did not inhibit dilator responses of the basilar artery to acetylcholine. Nitro-L-arginine methyl ester (10 and 100 microM), which inhibits synthesis of endothelium-derived relaxing factor (EDRF), produced concentration-dependent inhibition of dilatation of the basilar artery in response to acetylcholine. Thus ATP-sensitive potassium channels are functional but do not appear to influence basal tone of the basilar artery. Dilator responses of the basilar artery to acetylcholine are dependent on formation of EDRF but not dependent on activity of glibenclamide-sensitive potassium channels.

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Role of Nitric Oxide in Regulation of Brain Stem Circulation during Hypotension

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199710000-00011 ◽

1997 ◽

Vol 17 (10) ◽

pp. 1089-1096 ◽

Cited By ~ 23

Author(s):

Kazunori Toyoda ◽

Kenichiro Fujii ◽

Setsuro Ibayashi ◽

Tetsuhiko Nagao ◽

Takanari Kitazono ◽

...

Keyword(s):

Nitric Oxide ◽

Brain Stem ◽

Topical Application ◽

Basilar Artery ◽

Group Versus ◽

Control Group ◽

Cranial Window ◽

Severe Hypotension ◽

The Brain

We tested the hypothesis that nitric oxide (NO) plays a role in CBF autoregulation in the brain stem during hypotension. In anesthetized rats, local CBF to the brain stem was determined with laser-Doppler flowmetry, and diameters of the basilar artery and its branches were measured through an open cranial window during stepwise hemorrhagic hypotension. During topical application of 10−5 mol/L and 10−4 mol/L Nω-nitro-L-arginine (L-NNA), a nonselective inhibitor of nitric oxide synthase (NOS), CBF started to decrease at higher steps of mean arterial blood pressure in proportion to the concentration of L-NNA in stepwise hypotension (45 to 60 mm Hg in the 10−5 mol/L and 60 to 75 mm Hg in the 10−4 mol/L L-NNA group versus 30 to 45 mm Hg in the control group). Dilator response of the basilar artery to severe hypotension was significantly attenuated by topical application of L-NNA (maximum dilatation at 30 mm Hg: 16 ± 8% in the 10−5 mol/L and 12 ± 5% in the 10−4 mol/L L-NNA group versus 34 ± 4% in the control group), but that of the branches was similar between the control and L-NNA groups. Topical application of 10−5 mol/L 7-nitro indazole, a selective inhibitor of neuronal NOS, did not affect changes in CBF or vessel diameter through the entire pressure range. Thus, endothelial but not neuronal NO seems to take part in the regulation of CBF to the the brain stem during hypotension around the lower limits of CBF autoregulation. The role of NO in mediating dilatation in response to hypotension appears to be greater in large arteries than in small ones.

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Endothelial L-arginine pathway and relaxations to vasopressin in canine basilar artery

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.2.h413 ◽

1993 ◽

Vol 264 (2) ◽

pp. H413-H418 ◽

Cited By ~ 5

Author(s):

F. Cosentino ◽

J. C. Sill ◽

Z. S. Katusic

Keyword(s):

Nitric Oxide ◽

Basilar Artery ◽

Isometric Tension ◽

Nitric Oxide Donor ◽

Basal Tone ◽

Basilar Arteries ◽

Canine Basilar Artery ◽

Subsequent Activation ◽

Oxide Synthase

Experiments were designed to determine the role of the L-arginine pathway in endothelium-dependent relaxations to vasopressin. The effects of L-arginine analogues NG-nitro-L-arginine (L-NNA), NG-nitro-L-arginine methyl ester (L-NAME), and NG-monomethyl-L-arginine (L-NMMA) on basal and vasopressin-induced activity of nitric oxide synthase were studied in isolated canine basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in Krebs-Ringer bicarbonate solution bubbled with 94% O2-6% CO2 (37 degrees C, pH 7.4). Radioimmunoassay was used to determine the level of guanosine 3',5'-cyclic monophosphate (cGMP). All experiments were performed in the presence of indomethacin, a cyclooxygenase inhibitor. L-NAME and L-NMMA caused endothelium-dependent contractions and inhibited basal production of cGMP. In contrast, L-NNA did not affect basal tone or basal production of cGMP. L-Arginine analogues inhibited relaxations to vasopressin but did not affect relaxations to a nitric oxide donor, molsidomine (SIN-1). The effects of L-NNA, L-NAME, and L-NMMA were reversed in the presence of L-arginine. The relaxations to vasopressin were associated with an increase of cGMP levels in the arterial wall. This effect of vasopressin was inhibited in the presence of L-NNA. These studies suggest that the relaxations to vasopressin are mediated by activation of the endothelial L-arginine pathway, leading to increased production of nitric oxide, with subsequent activation of guanylate cyclase in smooth muscle cells. In canine basilar artery, L-NAME and L-NMMA are nonselective inhibitors of both basal and stimulated production of nitric oxide, whereas L-NNA selectively inhibits vasopressin-induced activation of the L-arginine pathway.

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Inhibitory effect of experimental colitis on fluid absorption in rat jejunum: role of the enteric nervous system, VIP, and nitric oxide

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00271.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. G262-G268 ◽

Cited By ~ 24

Author(s):

Fadi H. Mourad ◽

Kassem A. Barada ◽

Nadine A. Bou Rached ◽

Carmen I. Khoury ◽

Nayef E. Saadé ◽

...

Keyword(s):

Nitric Oxide ◽

Nervous System ◽

Enteric Nervous System ◽

Experimental Colitis ◽

Inhibitory Effect ◽

Fluid Absorption ◽

Receptor Antagonism ◽

Chemical Colitis

Impairment of small intestinal absorption has been described in patients with ulcerative colitis and in animal models of experimental colitis. The pathophysiology of this dysfunction has not been elucidated. The aim of this study was to investigate the effect of chemical colitis on jejunal fluid absorption and determine the role of the enteric nervous system and some putative neurotransmitters. In a rat model of iodoacetamide-induced colitis, jejunal net fluid absorption was evaluated by the in vivo single-pass perfusion technique. The effects of 1) tetrodotoxin (TTX), 2) benzylalkonium chloride (BAC), 3) capsaicin, 4) vasoactive intestinal polypeptide (VIP) antagonism, 5) nitric oxide (NO) synthase (NOS) inhibition, and 6) 5-hydroxytryptamine type 3 and 4 (5-HT3 and 5-HT4) receptor antagonism on the changes in fluid movement were investigated. A significant decrease in jejunal net fluid absorption was found 2 and 4 days after colitis induction: 26 (SD 14) and 28 (SD 19) μl·min−1·g dry intestinal wt−1, respectively [ P < 0.0002 compared with sham rats at 61 (SD 6.5) μl·min−1·g dry intestinal wt−1]. No histological changes were evident in jejunal sections. TTX and BAC reversed this decrease in fluid absorption: 54 (SD 13) and 44 (SD 14) μl·min−1·g dry intestinal wt−1 ( P = 0.0005 and P = 0.019, respectively, compared with colitis). Ablation of capsaicin-sensitive primary afferent fibers had a partial effect: 45 (SD 5) μl·min−1·g dry intestinal wt−1 ( P = 0.001 and P = 0.003 compared with colitis and sham, respectively). Constitutive and neuronal NOS inhibition and VIP antagonism returned jejunal net fluid absorption to normal values: 66 (SD 19), 61 (SD 5), and 56 (SD 14) μl·min−1·g dry intestinal wt−1, respectively. 5-HT3 and 5-HT4 receptor antagonism had no effect. Chemical colitis is associated with a significant decrease in jejunal net fluid absorption. This decrease is neurally mediated and involves VIP- and NO-related mechanisms.

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Role of ATP-sensitive K+ channels in CGRP-induced dilatation of basilar artery in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.265.2.h581 ◽

1993 ◽

Vol 265 (2) ◽

pp. H581-H585 ◽

Cited By ~ 15

Author(s):

T. Kitazono ◽

D. D. Heistad ◽

F. M. Faraci

Keyword(s):

Basilar Artery ◽

Minor Component ◽

K Channels ◽

Cranial Window ◽

Calcitonin Gene ◽

A Minor ◽

Oxide Synthase ◽

Camp Levels

Stimulation of adenylate cyclase appears to activate ATP-sensitive K+ channels in the basilar artery. We tested the hypothesis that calcitonin gene-related peptide (CGRP), which increases intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels, activates ATP-sensitive K+ channels and thereby causes vasodilatation. Using a cranial window in anesthetized rats, we examined responses of the basilar artery to CGRP in vivo. We also examined responses of the artery to another vasoactive peptide, vasoactive intestinal peptide (VIP). Topical application of CGRP (10(-11) to 10(-8) M) increased diameter of the basilar artery. Responses of the basilar artery to CGRP were almost abolished by a CGRP1 receptor antagonist, CGRP-(8-37). Vasodilatation in response to VIP was much smaller than that produced by CGRP. Dilator responses of the basilar artery to 10(-9) and 10(-8) M CGRP were inhibited by glibenclamide (10(-6) M), a selective inhibitor of ATP-sensitive K+ channels, by 69 +/- 19 and 41 +/- 9%, respectively. NG-nitro-L-arginine methyl ester (10(-5) M), an inhibitor of nitric oxide synthase, did not attenuate dilator response to 10(-8) M CGRP but inhibited responses to 10(-9) M CGRP by 34 +/- 12%. Indomethacin did not alter dilator responses to CGRP. These findings suggest that a minor component of CGRP-induced dilatation of the basilar artery is mediated by endothelium-derived relaxing factor. Vasodilatation in response to CGRP appears to be mediated primarily by direct activation of CGRP1 receptors on vascular muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selective cerebral vascular dysfunction in Mn-SOD-deficient mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.00939.2005 ◽

2006 ◽

Vol 100 (6) ◽

pp. 2089-2093 ◽

Cited By ~ 32

Author(s):

F. M. Faraci ◽

M. L. Modrick ◽

C. M. Lynch ◽

L. A. Didion ◽

P. E. Fegan ◽

...

Keyword(s):

Nitric Oxide ◽

Superoxide Dismutase ◽

Basilar Artery ◽

Manganese Superoxide Dismutase ◽

Cerebral Arteries ◽

Wild Type Littermate ◽

Male And Female ◽

Female Mice ◽

Cranial Window ◽

Basilar Arteries

We tested the hypothesis that the mitochondrial form of superoxide dismutase [manganese superoxide dismutase (Mn-SOD)] protects the cerebral vasculature. Basilar arteries (baseline diameter ∼140 μm) from mice were isolated, cannulated, and pressurized to measure vessel diameter. In arteries from C57BL/6 mice preconstricted with U-46619, acetylcholine (ACh; an endothelium-dependent vasodilator) produced dilation that was similar in male and female mice and abolished by an inhibitor of nitric oxide synthase. Vasodilation to ACh was not altered in heterozygous male or female Mn-SOD-deficient (Mn-SOD+/−) mice compared with wild-type littermate controls (Mn-SOD+/+). Constriction of the basilar artery to arginine vasopressin, but not KCl or U-46619, was increased in Mn-SOD+/− mice ( P < 0.05), and this effect was prevented by tempol, a scavenger of superoxide. We also examined responses of cerebral (pial) arterioles (branches of the middle cerebral artery, control diameter ∼30 μm) to ACh in anesthetized mice using a cranial window. Responses to ACh, but not nitroprusside (an endothelium-independent agonist), were reduced ( P < 0.05) in cerebral arterioles in Mn-SOD+/− mice, and this effect was prevented by tempol. Thus these are the first data on the role of Mn-SOD in cerebral circulation. In the basilar artery, ACh produced nitric oxide-mediated dilation that was similar in male and female mice. Under normal conditions in cerebral arteries, responses to ACh were not altered but constrictor responses were selectively enhanced in Mn-SOD+/− mice. In the cerebral microcirculation, there was superoxide-mediated impairment of responses to ACh.

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Pentobarbital-sensitive EDHF comediates ACh-induced arteriolar dilation in the hamster microcirculation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.276.5.h1527 ◽

1999 ◽

Vol 276 (5) ◽

pp. H1527-H1534 ◽

Cited By ~ 14

Author(s):

Cor de Wit ◽

Norbert Esser ◽

Hans-Anton Lehr ◽

Steffen-Sebastian Bolz ◽

Ulrich Pohl

Keyword(s):

Potential Role ◽

Inhibitory Effect ◽

Cellular Effects ◽

Basal Tone ◽

Direct Inhibitory Effect ◽

Isolated Arteries ◽

Conscious Animals ◽

Cytochrome P 450

It is unclear to what extent the endothelium-derived hyperpolarizing factor (EDHF) contributes to the control of microcirculatory blood flow in vivo. We analyzed, by intravital microscopy in hamster muscles, the potential role of EDHF along the vascular tree under stimulated (ACh) or basal conditions. Experiments were performed in conscious as well as anesthetized (pentobarbital, urethan) animals. Additionally, cellular effects of the potential EDHF were studied in isolated small arteries. In pentobarbital-anesthetized animals, treatment with N ω-nitro-l-arginine (l-NNA; 30 μmol/l) and indomethacin (3 μmol/l) reduced the dilation in response to 10 μmol/l ACh from 60 ± 6 to 20 ± 4%. This nitric oxide/prostaglandin-independent dilation (NPID), which was of a similar magnitude in large and small arterioles, was abolished by potassium depolarization or charybdotoxin (ChTX, 1 μmol/l) but not by glibenclamide. In conscious animals, NPID amounted to 33 ± 3%. The inhibitor of the P-450 monooxygenase 17-octadecynoic acid (ODYA) reduced NPID further to 9 ± 4%. ChTX abolished the NPID and also reduced basal diameters (by −11 ± 3%). The induction of anesthesia with pentobarbital reduced NPID (to 12 ± 6%), whereas urethan anesthesia was without effect. Pentobarbital also reduced the ACh-induced hyperpolarization of vascular smooth muscle in isolated arteries, whereas ChTX abolished it. This study suggests that a considerable part of the ACh dilation in the microcirculation is mediated by EDHF, which also contributes to the control of basal tone in conscious animals. The direct inhibitory effect of pentobarbital and ODYA supports the idea that “microcirculatory” EDHF is a product of the cytochrome P-450 pathway. The role of EDHF might be underestimated in pentobarbital-anesthetized animals.

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Subarachnoid Hemorrhage and the Role of Potassium Channels in Relaxations of Canine Basilar Artery to Nitrovasodilators

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199802000-00010 ◽

1998 ◽

Vol 18 (2) ◽

pp. 186-195 ◽

Cited By ~ 18

Author(s):

Hisashi Onoue ◽

Zvonimir S. Katusic

Keyword(s):

Nitric Oxide ◽

Subarachnoid Hemorrhage ◽

Sodium Nitroprusside ◽

Basilar Artery ◽

Cyclic Gmp ◽

Cerebral Arteries ◽

Basilar Arteries ◽

Canine Basilar Artery ◽

Gmp Production

This study was designed to determine the effect of subarachnoid hemorrhage (SAH) on potassium (K+) channels involved in relaxations of cerebral arteries to nitrovasodilators. The effects of K+ channel inhibitors on relaxations to 3-morpholinosydnonimine (SIN-1) and sodium nitroprusside (SNP) were studied in rings of basilar arteries obtained from untreated dogs and dogs exposed to SAH. The levels of cyclic GMP were measured by radioimmunoassay. In rings without endothelium, concentration-dependent relaxations to SIN-1 (10−9 − 10−4 mol/L) and SNP (10−9 − 10−4 mol/L) were not affected by SAH, whereas increase in cyclic GMP production stimulated by SIN-1 (10−6 mol/L) was significantly suppressed after SAH. The relaxations to SIN-1 and SNP were reduced by charybdotoxin (CTX; 10−7 mol/L), a selective Ca2+-activated K+ channel inhibitor, in both normal and SAH arteries; however, the reduction of relaxations by CTX was significantly greater in SAH arteries. By contrast, the relaxations to these nitrovasodilators were not affected by glyburide (10−5 mol/L), an ATP-sensitive K+ channel inhibitor, in both normal and SAH arteries. These findings suggest that in cerebral arteries exposed to SAH, Ca2+-activated K+ channels may play a compensatory role in mediation of relaxations to nitric oxide. This may help to explain mechanisms of relaxations to nitrovasodilators in arteries with impaired production of cyclic GMP.

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