Cytochrome P-450 metabolites but not NO, PGI2, and H2O2 contribute to ACh-induced hyperpolarization of pressurized canine coronary microvessels

2003 ◽  
Vol 285 (5) ◽  
pp. H1939-H1948 ◽  
Author(s):  
Mitsuaki Tanaka ◽  
Hiroshi Kanatsuka ◽  
Boon-Hooi Ong ◽  
Toshinori Tanikawa ◽  
Akira Uruno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Membrane Potential ◽  
Fluorescence Intensity ◽  
Vascular Tone ◽  
Endothelial Damage ◽  
No Synthase ◽  
Internal Diameter ◽  
Physiological Salt Solution ◽  
Cytochrome P 450 ◽  
Large Coronary Arteries

The endothelium-dependent hyperpolarization of cells has a crucial role in regulating vascular tone, especially in microvessels. Nitric oxide (NO) and prostacyclin (PGI2), in addition to endothelium-derived hyperpolarizing factor (EDHF), have been reported to hyperpolarize vascular smooth muscle in several organs. Studies have reported the hyperpolarizing effects of these factors are increased by a stretch in large coronary arteries. EDHF has not yet been identified and cytochrome P-450 metabolites and H2O2 are candidates for EDHF. With the use of the membrane potential-sensitive fluorescent dye bis-(1,3-dibutylbarbituric acid)trimethione oxonol [DiBAC4(3)], we examined whether NO, PGI2, cytochrome P-450 metabolites, and H2O2 contribute to ACh-induced hyperpolarization in pressurized coronary microvessels. Canine coronary arterial microvessels (60–356 μm internal diameter) were cannulated and pressurized at 60 cmH2O in a vessel chamber perfused with physiological salt solution containing DiBAC4(3). Fluorescence intensity and diameter were measured on a computer. There was a linear correlation between changes in the fluorescence intensity and membrane potential. ACh significantly decreased the fluorescence intensity (hyperpolarization) of the microvessels without any inhibitors. Endothelial damage caused by air perfusion abolished the ACh-induced decrease in fluorescence intensity. The inhibitors of NO synthase and cyclooxygenase did not affect the ACh-induced decreases in the fluorescence intensity. The addition of 17-octadecynoic acid, a cytochrome P-450 monooxygenase inhibitor, to those inhibitors significantly attenuated the ACh-induced decreases in fluorescence intensity, whereas catalase, an enzyme that dismutates H2O2 to form water and oxygen, did not. Furthermore, catalase did not affect the vasodilation produced by ACh. These results indicate that NO and PGI2 do not contribute to the ACh-induced hyperpolarization and that the cytochrome P-450 metabolites but not H2O2 are involved in EDHF-mediated hyperpolarization in canine coronary arterial microvessels.

Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction

2002 ◽  
Vol 282 (6) ◽  
pp. H2198-H2209 ◽  
Author(s):  
David B. Haitsma ◽  
Daphne Merkus ◽  
Jefrey Vermeulen ◽  
Pieter D. Verdouw ◽  
Dirk J. Duncker
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Endothelial Dysfunction ◽  
Vascular Tone ◽  
Tissue Perfusion ◽  
Selective Inhibition ◽  
Left Ventricular ◽  
No Synthase ◽  
Lv Dysfunction ◽  
Pulmonary Vasodilator

Left ventricular (LV) dysfunction caused by myocardial infarction (MI) is accompanied by endothelial dysfunction, most notably a loss of nitric oxide (NO) availability. We tested the hypothesis that endothelial dysfunction contributes to impaired tissue perfusion during increased metabolic demands as produced by exercise, and we determined the contribution of NO to regulation of regional systemic, pulmonary, and coronary vasomotor tone in exercising swine with LV dysfunction produced by a 2- to 3-wk-old MI. LV dysfunction resulted in blunted systemic and coronary vasodilator responses to ATP, whereas the responses to nitroprusside were maintained. Exercise resulted in blunted systemic and pulmonary vasodilator responses in MI that resembled the vasodilator responses in normal (N) swine following blockade of NO synthase with N ω-nitro-l-arginine (l-NNA, 20 mg/kg iv). However, l-NNA resulted in similar decreases in systemic (43 ± 3% in N swine and 49 ± 4% in MI swine), pulmonary (45 ± 5% in N swine and 49 ± 4% in MI swine), and coronary (28 ± 4% in N and 35 ± 3% in MI) vascular conductances in N and MI swine under resting conditions; similar effects were observed during treadmill exercise. Selective inhibition of inducible NO synthase with aminoguanidine (20 mg/kg iv) had no effect on vascular tone in MI. These findings indicate that while agonist-induced vasodilation is already blunted early after myocardial infarction, the contribution of endothelial NO synthase-derived NO to regulation of vascular tone under basal conditions and during exercise is maintained.

Impaired nitric oxide-mediated vasodilation in transgenic sickle mouse

2000 ◽  
Vol 278 (6) ◽  
pp. H1799-H1806 ◽  
Author(s):  
Dhananjaya K. Kaul ◽  
Xiao-Du Liu ◽  
Mary E. Fabry ◽  
Ronald L. Nagel
Keyword(s):  
Nitric Oxide ◽  
Transgenic Mice ◽  
Endothelial Nitric Oxide Synthase ◽  
Vascular Tone ◽  
Endothelial Damage ◽  
Control Groups ◽  
Lower Blood ◽  
Activating Agent ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Transgenic sickle mice expressing human βS- and βS-Antilles-globins show intravascular sickling, red blood cell adhesion, and attenuated arteriolar constriction in response to oxygen. We hypothesize that these abnormalities and the likely endothelial damage, also reported in sickle cell anemia, alter nitric oxide (NO)-mediated microvascular responses and hemodynamics in this mouse model. Transgenic mice showed a lower mean arterial pressure (MAP) compared with control groups (90 ± 7 vs. 113 ± 8 mmHg, P < 0.00001), accompanied by increased endothelial nitric oxide synthase (eNOS) expression. NG-nitro-l-arginine methyl ester (l-NAME), a nonselective inhibitor of NOS, caused an ∼30% increase in MAP and ∼40% decrease in the diameters of cremaster muscle arterioles (branching orders: A2 and A3) in both control and transgenic mice, confirming NOS activity; these changes were reversible after l-arginine administration. Aminoguanidine, an inhibitor of inducible NOS, had no effect. Transgenic mice showed a decreased ( P < 0.02–0.01) arteriolar dilation in response to NO-mediated vasodilators, i.e., ACh and sodium nitroprusside (SNP). Indomethacin did not alter the responses to ACh and SNP. Forskolin, a cAMP-activating agent, caused a comparable dilation of A2 and A3 vessels (∼44 and 70%) in both groups of mice. Thus in transgenic mice, an increased eNOS/NO activity results in lower blood pressure and diminished arteriolar responses to NO-mediated vasodilators. Although the increased NOS/NO activity may compensate for flow abnormalities, it may also cause pathophysiological alterations in vascular tone.

Acute and chronic NOS inhibition enhances α2- adrenoreceptor-stimulated RhoA and Rho kinase in rat aorta

2002 ◽  
Vol 283 (4) ◽  
pp. H1361-H1369 ◽  
Author(s):  
Rebecca W. Carter ◽  
McKenzie Begaye ◽  
Nancy L. Kanagy
Keyword(s):  
Nitric Oxide ◽  
Drinking Water ◽  
Adrenergic Receptors ◽  
Membrane Fraction ◽  
Vascular Tone ◽  
Rho Kinase ◽  
Rat Aorta ◽  
No Synthase ◽  
Rhoa Activation

We demonstrated that arteries from rats made hypertensive with chronic nitric oxide (NO) synthase (NOS) inhibition ( N ω-nitro-l-arginine in drinking water, LHR) have enhanced contractile sensitivity to α2-adrenergic receptors (α2-AR) agonist UK-14304 compared with arteries from normotensive rats (NR). NO may regulate vascular tone in part through suppression of RhoA and Rho kinase (ROK). We hypothesized that enhanced RhoA and ROK activity augments α2-AR contraction in LHR aortic rings. Y-27632 eliminated UK-14304 contraction in LHR and NR aortic rings. The order of increasing sensitivity to Y-27632 was the following: endothelium-intact NR, LHR, and endothelium-denuded NR. UK-14304 stimulated RhoA translocation to the membrane fraction in LHR and denuded NR but not in intact NR aorta. Basally, more RhoA was present in the membrane fraction in denuded NR than in intact NR or LHR aorta. Relaxation to S-nitroso- N-acetyl-penicillamine and Y-27632 in denuded ionomycin-permeabilized rings was greater in NR than in LHR. Together these studies indicate α2-AR contraction depends on ROK activity more in NR than LHR aorta. Additionally, endogenous NO may regulate RhoA activation, whereas chronic NOS inhibition appears to cause RhoA desensitization.

Endothelium modulates anion channel-dependent aortic contractions to iodide

2000 ◽  
Vol 278 (5) ◽  
pp. H1527-H1536 ◽  
Author(s):  
Fred S. Lamb ◽  
Thomas J. Barna
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Membrane Potential ◽  
Anion Channel ◽  
Anion Channels ◽  
Anion Substitution ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Channel Dependent ◽  
Cytochrome P 450

Anion currents contribute to vascular smooth muscle (VSM) membrane potential. The substitution of extracellular chloride (Cl) with iodide (I) or bromide (Br) initially inhibited and then potentiated isometric contractile responses of rat aortic rings to norepinephrine. Anion substitution alone produced a small relaxation, which occurred despite a lack of active tone and minimal subsequent contraction of endothelium-intact rings (4.2 ± 1.2% of the response to 90 mM KCl). Endothelium-denuded rings underwent a similar initial relaxation but then contracted vigorously (I > Br). Responses to 130 mM I (93.7 ± 1.9% of 90 mM KCl) were inhibited by nifedipine (10− 6 M), niflumic acid (10− 5 M), tamoxifen (10− 5 M), DIDS (10− 4 M), and[Formula: see text]-free buffer (HEPES 10 mM) but not by bumetanide (10− 5 M). Intact rings treated with N ω-nitro-l-arginine (10− 4 M) responded weakly to I (15.5 ± 2.1% of 90 mM KCl), whereas hemoglobin (10− 5 M), indomethacin (10− 6 M), 17-octadecynoic acid (10− 5 M), and 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10− 6 M) all failed to augment the response of intact rings to I. We hypothesize that VSM takes up I primarily via an anion exchanger. Subsequent I efflux through anion channels having a selectivity of I > Br > Cl produces depolarization. In endothelium-denuded or agonist-stimulated vessels, this current is sufficient to activate voltage-dependent calcium channels and cause contraction. Neither nitric oxide nor prostaglandins are the primary endothelial modulator of these anion channels. If they are regulated by an endothelium-dependent hyperpolarizing factor it is not a cytochrome P-450 metabolite.

scholarly journals Mouse Models of Nitric Oxide Synthase Deficiency

2000 ◽  
Vol 11 (suppl 2) ◽  
pp. S120-S123
Author(s):  
PAUL L. HUANG
Keyword(s):  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Knockout Mice ◽  
Vascular Tone ◽  
Tissue Injury ◽  
No Synthase ◽  
Oxide Synthase ◽  
Pathologic Processes ◽  
Diastolic Cardiac Function ◽  
Inducible Nos

Abstract. Knockout mice for each of the three nitric oxide (NO) synthase (NOS) genes have been generated. Their phenotypes reflect the roles of each NOS isoform in physiologic and pathologic processes. This article reviews how neuronal NOS (nNOS) and endothelial NOS (eNOS) knockout mice have contributed to our knowledge of the roles of NO in cerebral ischemia, cardiovascular processes, and the autonomic nervous system. In some instances, the effects of NO produced by one isoform antagonize the effects of NO produced by another isoform. For example, after cerebral ischemia, the nNOS isoform is involved in tissue injury, whereas the eNOS isoform is important in maintaining blood flow. All three isoforms are expressed in the respiratory tract, but only the nNOS isoform appears to be involved in modulating airway responsiveness and only the inducible NOS isoform appears to respond to antigen stimulation. In the cardiovascular system, endothelial NO is important for vascular tone, systolic and diastolic cardiac function, vascular proliferative responses to injury, platelet aggregation, and hemostasis.

scholarly journals Nitric oxide synthase inhibition decreases tolerance to hyperoxia in newborn rats

1995 ◽  
Vol 4 (6) ◽  
pp. 431-436 ◽  
Author(s):  
M. R. Pierce ◽  
C. A. Voelker ◽  
I. R. S. Sosenko ◽  
S. Bustamante ◽  
S. M. Olister ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lung Injury ◽  
Pulmonary Artery ◽  
No Synthase ◽  
Internal Diameter ◽  
Postnatal Exposure ◽  
Newborn Rats ◽  
Pregnant Rats ◽  
Untreated Water ◽  
Oxide Synthase

We evaluated the effects of sustained perinatal inhibition of NO synthase (NOS) on hyperoxia induced lung injury in newborn rats. NG-nitro-Larginine-methyl-ester (L-NAME) or untreated water was administered to pregnant rats for the final 7 days of gestation and during lactation; followed by postnatal exposure to hyperoxia (>95% O2) or room air. The survival rate of L-NAME treated pups when placed in > 95% O2at birth was significantly lower than controls from day 4 (L-NAME, 87%; control pups, 100%, p < 0.05) to 14 (L-NAME, 0%; control pups, 53%, p < 0.05). Foetal pulmonary artery vasoconstriction was induced by L-NAME with a decrease in internal diameter from 0.88 ± 0.03 mm to 0.64 ± 0.01 mm in controlvs. L-NAME groups (p < 0.05), respectively. We conclude that perinatal NOS inhibition results in pulmonary artery vasoconstriction and a decreased tolerance to hyperoxia induced lung injury in newborn rats.

scholarly journals Temperature conditioning of nasal air: effects of vasoactive agents and involvement of nitric oxide

1999 ◽  
Vol 87 (4) ◽  
pp. 1260-1265 ◽  
Author(s):  
William E. Holden ◽  
John P. Wilkins ◽  
Michelle Harris ◽  
Henry A. Milczuk ◽  
George D. Giraud
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Air Temperature ◽  
Vascular Tone ◽  
No Synthase ◽  
Saline Control ◽  
Vasoactive Agents ◽  
Exhaled No ◽  
No Release

Nitric oxide (NO) is released into nasal air, but its function is unknown. We hypothesized that nasal vascular tone and/or flow influences temperature conditioning of nasal air and that NO participates in this process. We measured nasal air temperature (via a thermocouple) and exhaled nasal NO release (by chemiluminescence) in five humans and examined the effects of an aerosolized vasoconstrictor (oxymetazoline), a vasodilator (papaverine), N G-nitro-l-arginine methyl ester, an inhibitor of NO synthase, or saline (control). Compared with saline (which caused no changes in nasal air temperature or exhaled NO release), oxymetazoline (0.05%) reduced nasal air temperature and NO release (130.8 ± 15.1 to 81.3 ± 12.8 nl ⋅ min−1 ⋅ m−2; P < 0.01). Papaverine (0.01 M) increased nasal air temperature and NO release (131.8 ± 13.1 to 157.2 ± 17.4 nl ⋅ min−1 ⋅ m−2; P < 0.03). N G-nitro-l-arginine methyl ester reduced nasal air temperature and NO release (123.7 ± 14.2 to 44.2 ± 23.7 nl ⋅ min−1 ⋅ m−2; P < 0.01). The results suggest that vascular tone and/or flow modulates temperature conditioning and that NO may participate in that function.

Nitric oxide contributes to 20-HETE-induced relaxation of pulmonary arteries

2002 ◽  
Vol 93 (4) ◽  
pp. 1391-1399 ◽  
Author(s):  
Ming Yu ◽  
Ryan P. McAndrew ◽  
Rula Al-Saghir ◽  
Kristopher G. Maier ◽  
Meetha Medhora ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Calcium Concentration ◽  
Pulmonary Arteries ◽  
No Synthase ◽  
No Production ◽  
Peripheral Arteries ◽  
Cyclooxygenase Inhibitor ◽  
No Release ◽  
Synthase Inhibitor ◽  
Cytochrome P 450

In contrast to its constrictor effects on peripheral arteries, 20-hydroxyeicosatetraenoic acid (20-HETE) is an endothelial-dependent dilator of pulmonary arteries (PAs). The present study examined the hypothesis that the vasodilator effects of 20-HETE in PAs are due to an elevation of intracellular calcium concentration ([Ca2+]i) and the release of nitric oxide (NO) from bovine PA endothelial cells (BPAECs). BPAECs express cytochrome P-450 4A (CYP4A) protein and produce 20-HETE. 20-HETE dilated PAs preconstricted with U-46619 or norepinephrine and treated with the cytochrome P-450 inhibitor 17-octadecynoic acid and the cyclooxygenase inhibitor indomethacin. The dilator effect of 20-HETE was blocked by the NO synthase inhibitor N ω-nitro-l-arginine methyl ester (l-NAME) or by removal of endothelium. 20-HETE significantly increased [Ca2+]i and NO production in BPAECs. 20-HETE-induced NO release was blunted by removal of extracellular calcium, as well as NO synthase inhibitors (l-NAME). These results suggest that 20-HETE dilates PAs at least in part by increasing [Ca2+]i and NO release in BPAECs.

Abstract 1286: Neuronal Nitric Oxide Synthase Regulates Basal Vascular Tone in the Healthy Human Forearm in vivo.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Mike Seddon ◽  
Phil Chowienczyk ◽  
Barbara Casadei ◽  
Ajay Shah
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Vascular Tone ◽  
Venous Occlusion ◽  
No Synthase ◽  
Healthy Human ◽  
Vasodilator Response ◽  
Nos Inhibitors ◽  
Human Forearm

Nitric oxide (NO) has an established role in the maintenance of vascular tone, generally assumed to be mediated by endothelial NO synthase (eNOS). Previous studies using the non-selective NOS inhibitor N G monomethyl-L-arginine (L-NMMA) in humans confirmed the in vivo importance of NO but the contribution of neuronal NO synthase (nNOS) is unknown due to the lack of available selective NOS inhibitors for human use. In this study, we investigated for the first time in humans the effects of S-methyl-L-thiocitrulline (SMTC), a competitive nNOS-selective inhibitor with 17-fold selectivity over eNOS. SMTC or L-NMMA were infused into the brachial artery of healthy male volunteers and forearm blood flow was measured by venous occlusion plethysmography. SMTC 0.025, 0.05, 0.1 and 0.2 μmol/min caused a dose-dependent reduction in basal blood flow in the infused arm of 9.2±1.9, 16.2±2.9, 22.9±3.9 and 30.1±3.8% respectively (n=10; mean±SE; all P<0.01). Substantially higher doses of L-NMMA of 0.5, 1, 2 and 4 μmol/min were required to reduce basal flow by 11.5±3.0, 25.1±3.0, 33.7±3.0 and 37.4±3.1% respectively (n=10). The highest dose of SMTC (ie, 0.2 μmol/min) tested had no significant effect on the vasodilator response to acetylcholine (ACh): Ach 40 and 80nmol/min increased blood flow by 3.93±0.64 and 5.54±0.69 ml/min/100mls tissue above baseline during saline co-infusion versus 3.95±0.69 and 4.90±0.71 ml/min/100mls tissue during SMTC co-infusion (n=10; P=NS). In contrast, L-NMMA significantly reduced the response to these doses of ACh by 64±9.9 and 60±10% (n=10; both P<0.01). The effect of SMTC on basal blood flow was completely abolished in the presence of the NOS substrate L-arginine (n=6; P<0.001) but was unaffected by the stereoisomer D-arginine (n=6). SMTC had no effect on the vasodilator response to sodium nitroprusside (n=5). In conclusion , SMTC reduced basal blood flow by stereospecific inhibition of the L-arginine:NO pathway but did not affect the eNOS-mediated vasodilator response to ACh. These results indicate that nNOS has a crucial role in the regulation of basal vascular tone in the human forearm in vivo .

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