scholarly journals Agonist-dependent variablity of contributions of nitric oxide and prostaglandins in human skeletal muscle

2005 ◽  
Vol 98 (4) ◽  
pp. 1251-1257 ◽  
Author(s):  
William G. Schrage ◽  
Niki M. Dietz ◽  
John H. Eisenach ◽  
Michael J. Joyner
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Animal Studies ◽  
Forearm Blood Flow ◽  
Feedback Inhibition ◽  
Venous Occlusion ◽  
No Synthase ◽  
Human Forearm ◽  
Independent Mechanism ◽  
Treatment Order

The relative contributions of endothelium-dependent dilators [nitric oxide (NO), prostaglandins (PGs), and endothelium-derived hyperpolarizing factor (EDHF)] in human limbs are poorly understood. We tested the hypothesis that relative contributions of NO and PGs differ between endothelial agonists acetylcholine (ACh; 1, 2, and 4 μg·dl−1·min−1) and bradykinin (BK; 6.25, 25, and 50 ng·dl−1·min−1). We measured forearm blood flow (FBF) using venous occlusion plethysmography in 50 healthy volunteers (27 ± 1 yr) in response to brachial artery infusion of ACh or BK in the absence and presence of inhibitors of NO synthase [NOS; with NG-monomethyl-l-arginine (l-NMMA)] and cyclooxygenase (COX; with ketorolac). Furthermore, we tested the idea that the NOS + COX-independent dilation (in the presence of l-NMMA + ketorolac, presumably EDHF) could be inhibited by exogenous NO administration, as reported in animal studies. FBF increased ∼10-fold in the ACh control; l-NMMA reduced baseline FBF and ACh dilation, whereas addition of ketorolac had no further effect. Ketorolac alone did not alter ACh dilation, but addition of l-NMMA reduced ACh dilation significantly. For BK infusion, FBF increased ∼10-fold in the control condition; l-NMMA tended to reduce BK dilation ( P < 0.1), and addition of ketorolac significantly reduced BK dilation. Similar to ACh, ketorolac alone did not alter BK dilation, but addition of l-NMMA reduced BK dilation. To test the idea that NO can inhibit the NOS + COX-independent portion of dilation, we infused a dose of sodium nitroprusside (NO-clamp technique) during ACh or BK that restored the reduction in baseline blood flow due to l-NMMA. Regardless of treatment order, the NO clamp restored baseline FBF but did not reduce the NOS + COX-independent dilation to ACh or BK. We conclude that the contribution of NO and PGs differs between ACh and BK, with ACh being more dependent on NO and BK being mostly dependent on a NOS + COX-independent mechanism (EDHF) in healthy young adults. The NOS + COX-independent dilation does not appear sensitive to feedback inhibition from NO in the human forearm.

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 .

Vasoconstrictor Sensitivity to Noradrenaline and NG-monomethyl-l-arginine in Men and Women

1997 ◽  
Vol 93 (6) ◽  
pp. 513-518 ◽  
Author(s):  
Barry J. Kneale ◽  
Philip J. Chowienczyk ◽  
John R. Cockcroft ◽  
D. John Coltart ◽  
James M. Ritter
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Animal Studies ◽  
Vascular Tone ◽  
Forearm Blood Flow ◽  
Premenopausal Women ◽  
Relative Sensitivity ◽  
Venous Occlusion ◽  
Men And Women ◽  
Arterial Blood

1. Nitric oxide has potential anti-atherogenic actions as well as regulating vascular tone. Animal studies suggest that there are sex differences in basal nitric oxide biosynthesis, but it is not known whether such differences exist between men and women. 2. We have investigated this question by measuring forearm blood flow responses, using venous occlusion plethysmography, to brachial artery infusion of NG-monomethyl-l-arginine (an inhibitor of NO biosynthesis) and noradrenaline in 40 healthy subjects (20 men and 20 premenopausal women). Mean arterial blood pressure was 89 ± 10 mmHg (mean ± SD) in men and 87 ± 9 mmHg in women, and mean total cholesterol was 4.25 ± 0.99 mmol/l (mean ± SD) and 4.26 ± 0.80 mmol/l respectively. 3. In men, vasoconstrictor responses to NG-monomethyl-l-arginine, 1–4 μmol/min (15–28% mean reduction in blood flow), were consistently less than responses to noradrenaline, 60–240 pmol/min (26–37%), whereas in women, vasoconstrictor responses to NG-monomethyl-l-arginine (19–30%) were consistently greater than those to noradrenaline(11–17%). The sex difference in relative sensitivity to vasoconstrictors was significant (P < 0.001). 4. Our findings are consistent with either greater sensitivity to noradrenaline in men compared with premenopausal women, or a greater basal nitric oxide biosynthesis in premenopausal women compared with men.

Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation

2001 ◽  
Vol 280 (6) ◽  
pp. H2470-H2477 ◽  
Author(s):  
Julian P. J. Halcox ◽  
Suresh Narayanan ◽  
Laura Cramer-Joyce ◽  
Rita Mincemoyer ◽  
Arshed A. Quyyumi
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Sodium Nitroprusside ◽  
Forearm Blood Flow ◽  
Human Subjects ◽  
Epoxyeicosatrienoic Acid ◽  
Healthy Human ◽  
Human Forearm ◽  
Oxide Synthase ◽  
Cytochrome P 450

The identity of endothelium-dependent hyperpolarizing factor (EDHF) in the human circulation remains controversial. We investigated whether EDHF contributes to endothelium-dependent vasomotion in the forearm microvasculature by studying the effect of K+ and miconazole, an inhibitor of cytochrome P-450, on the response to bradykinin in healthy human subjects. Study drugs were infused intra-arterially, and forearm blood flow was measured using strain-gauge plethysmography. Infusion of KCl (0.33 mmol/min) into the brachial artery caused baseline vasodilation and inhibited the vasodilator response to bradykinin, but not to sodium nitroprusside. Thus the incremental vasodilation induced by bradykinin was reduced from 14.3 ± 2 to 7.1 ± 2 ml · min−1 · 100 g−1( P < 0.001) after KCl infusion. A similar inhibition of the bradykinin ( P = 0.014), but not the sodium nitroprusside (not significant), response was observed with KCl after the study was repeated during preconstriction with phenylephrine to restore resting blood flow to basal values after KCl. Miconazole (0.125 mg/min) did not inhibit endothelium-dependent or -independent responses to ACh and sodium nitroprusside, respectively. However, after inhibition of cyclooxygenase and nitric oxide synthase with aspirin and N G-monomethyl-l-arginine, the forearm blood flow response to bradykinin ( P = 0.003), but not to sodium nitroprusside (not significant), was significantly suppressed by miconazole. Thus nitric oxide- and prostaglandin-independent, bradykinin-mediated forearm vasodilation is suppressed by high intravascular K+ concentrations, indicating a contribution of EDHF. In the human forearm microvasculature, EDHF appears to be a cytochrome P-450 derivative, possibly an epoxyeicosatrienoic acid.

Role of Nitric Oxide towards Vasodilator Effects of Substance P and ATP in Human Forearm Vessels

1997 ◽  
Vol 92 (2) ◽  
pp. 123-131 ◽  
Author(s):  
Masanari Shiramoto ◽  
Tsutomu Imaizumi ◽  
Yoshitaka Hirooka ◽  
Toyonari Endo ◽  
Takashi Namba ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Substance P ◽  
Sodium Nitroprusside ◽  
Forearm Blood Flow ◽  
Dependent Manner ◽  
Human Forearm ◽  
Before And After ◽  
Dose Dependent

1. It has been shown in animals that substance P as well as acetylcholine releases endothelium-derived nitric oxide and evokes vasodilatation and that ATP-induced vasodilatation is partially mediated by nitric oxide. The aim of this study was to examine whether vasodilator effects of substance P and ATP are mediated by nitric oxide in humans. 2. In healthy volunteers (n = 35), we measured forearm blood flow by a strain-gauge plethysmograph while infusing graded doses of acetylcholine, substance P, ATP or sodium nitroprusside into the brachial artery before and after infusion of NG-monomethyl-l-arginine (4 or 8 μmol/min for 5 min). In addition, we measured forearm blood flow while infusing substance P before and during infusion of l-arginine (10 mg/min, simultaneously), or before and 1 h after oral administration of indomethacin (75 mg). 3. Acetylcholine, substance P, ATP or sodium nitroprusside increased forearm blood flow in a dose-dependent manner. NG-Monomethyl-l-arginine decreased basal forearm blood flow and inhibited acetylcholine-induced vasodilatation but did not affect substance P-, ATP-, or sodium nitroprusside-induced vasodilatation. Neither supplementation of l-arginine nor pretreatment with indomethacin affected substance P-induced vasodilatation. 4. Our results suggest that, in the human forearm vessels, substance P-induced vasodilatation may not be mediated by either nitric oxide or prostaglandins and that ATP-induced vasodilatation may also not be mediated by nitric oxide.

Inhibition of vascular ATP-sensitive K+channels does not affect reactive hyperemia in human forearm

2003 ◽  
Vol 284 (2) ◽  
pp. H711-H718 ◽  
Author(s):  
H. M. Omar Farouque ◽  
Ian T. Meredith
Keyword(s):  
Blood Flow ◽  
Adaptive Response ◽  
Healthy Subjects ◽  
Forearm Blood Flow ◽  
Reactive Hyperemia ◽  
Venous Occlusion ◽  
Channel Inhibition ◽  
Human Forearm ◽  
Hyperemic Response

The extent to which ATP-sensitive K+ channels contribute to reactive hyperemia in humans is unresolved. We examined the role of ATP-sensitive K+channels in regulating reactive hyperemia induced by 5 min of forearm ischemia. Thirty-one healthy subjects had forearm blood flow measured with venous occlusion plethysmography. Reactive hyperemia could be reproducibly induced ( n = 9). The contribution of vascular ATP-sensitive K+ channels to reactive hyperemia was determined by measuring forearm blood flow before and during brachial artery infusion of glibenclamide, an ATP-sensitive K+ channel inhibitor ( n = 12). To document ATP-sensitive K+ channel inhibition with glibenclamide, coinfusion with diazoxide, an ATP-sensitive K+ channel opener, was undertaken ( n = 10). Glibenclamide did not significantly alter resting forearm blood flow or the initial and sustained phases of reactive hyperemia. However, glibenclamide attenuated the hyperemic response induced by diazoxide. These data suggest that ATP-sensitive K+ channels do not play an important role in controlling forearm reactive hyperemia and that other mechanisms are active in this adaptive response.

Ageing is associated with impairment of nitric oxide and prostanoid dilator pathways in the human forearm

2002 ◽  
Vol 102 (5) ◽  
pp. 595-600 ◽  
Author(s):  
Nivedita SINGH ◽  
Sanjay PRASAD ◽  
Donald R.J. SINGER ◽  
Raymond J. Mac ALLISTER
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Forearm Blood Flow ◽  
Area Under The Curve ◽  
Venous Occlusion ◽  
Response Curves ◽  
Age Related ◽  
Older Subjects ◽  
Synthase Inhibitor ◽  
Dose Dependent

Ageing is associated with endothelial dysfunction and increased cardiovascular risk. We assessed the activity of nitric oxide (NO) and prostaglandin pathways in older subjects. Bilateral venous occlusion plethysmography was used to measure forearm blood flow during intra-arterial infusion of the NO synthase inhibitor, NG-monomethyl-l-arginine (l-NMMA; 1, 2 and 4μmol/min), the cyclo-oxygenase inhibitor, aspirin (3, 9 and 30μmol/min), and the smooth muscle constrictor, noradrenaline (60, 120 and 240pmol/min); each dose infused for 5min. Eighteen young and 15 healthy older subjects (mean age±S.E.M., 32±1 and 65±1 years respectively) were studied. Effects of treatment were calculated from the ratio of blood flow in the infused to control arm, expressed as a percentage. Dose-response curves were compared by analysis of the area under the curve (AUC) using independent samples t test. All agents caused dose-dependent decreases in basal forearm blood flow. AUC values for noradrenaline, aspirin and l-NMMA in younger and older subjects were 162±24, 173±24 and 170±17, and 138±22, 70±22 and 89±22 respectively. Effects of aspirin and l-NMMA, but not noradrenaline, were reduced in older subjects (P = 0.004, 0.007 and 0.461 respectively). Our findings suggest a generalized abnormality of basal endothelial function in older people, with similar impairment of NO and prostanoid dilator pathways. Defects in both pathways could contribute to the development of age-related cardiovascular disease.

Comparison of Forearm Vasodilatation to Substance P and Acetylcholine: Contribution of Nitric Oxide

1997 ◽  
Vol 92 (2) ◽  
pp. 133-138 ◽  
Author(s):  
David E. Newby ◽  
Nicholas A. Boon ◽  
David J. Webb
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Substance P ◽  
Cell Function ◽  
Forearm Blood Flow ◽  
Venous Occlusion ◽  
Nitric Oxide Synthase Inhibitor ◽  
Endothelial Cell Function ◽  
Synthase Inhibitor ◽  
Oxide Synthase

1. Forearm blood flow responses to incremental challenges of acetylcholine and substance P, administered via the brachial artery, were measured by venous occlusion plethysmography in eight subjects in the presence of saline, the nitric oxide synthase inhibitor, NG-monomethyl-l-arginine, and a control vasoconstrictor, noradrenaline. 2. Substance P and acetylcholine caused dose-dependent increases in forearm blood flow (P < 0.001). When separated by 30 min saline infusions, repeated responses did not undergo tachyphylaxis. 3. Noradrenaline caused a mean reduction in basal blood flow of 34–51% (P < 0.001), and augmented the percentage increases in blood flow with both substance P (P = 0.05) and acetylcholine (P = 0.03) infusions. 4. NG-Monomethyl-l-arginine caused a mean reduction in basal blood flow of 42–45% (P < 0.001) and significantly inhibited the responses to both substance P (P < 0.001) and acetylcholine (P = 0.05). 5. In comparison with saline responses, NG-monomethyl-l-arginine caused a mean inhibition of 69 ± 8% for substance P-induced vasodilatation and 40 ± 5% for acetylcholine-induced vasodilatation. However, comparing responses with those to the control vasoconstrictor noradrenaline, NG-monomethyl-l-arginine caused a mean inhibition of 81 ± 5% for substance P responses and 58 ± 3% for acetylcholine responses. Inhibition by NG-monomethyl-l-arginine of the response to substance P was significantly greater than inhibition of the response to acetylcholine (P = 0.02). 6. Hence, in healthy men, a greater proportion of the forearm vasodilatation to substance P than to acetylcholine appears to be nitric oxide-mediated. Given its greater stability, substance P may be more suitable as a pharmacological tool in the investigation of stimulated nitric oxide production and endothelial cell function.

Is nitric oxide involved in cutaneous vasodilation during body heating in humans?

1994 ◽  
Vol 76 (5) ◽  
pp. 2047-2053 ◽  
Author(s):  
N. M. Dietz ◽  
J. M. Rivera ◽  
D. O. Warner ◽  
M. J. Joyner
Keyword(s):  
Nitric Oxide ◽  
Heart Rate ◽  
Blood Flow ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Forearm Blood Flow ◽  
No Synthase ◽  
Oral Temperature ◽  
Drug Infusion ◽  
Cutaneous Vasodilation

The neurotransmitter responsible for neurogenic vasodilation in human skin during body heating is unknown. We sought to determine whether the vasodilating substance nitric oxide (NO) is involved in this phenomenon. Six subjects were heated for 50 min by use of a water-perfused suit while forearm blood flow (FBF) was measured with plethysmography and skin blood flow (SkBF) was measured by the laser-Doppler method in both arms. In one forearm, NG-monomethyl-L-arginine (L-NMMA), an NO synthase blocker, was infused into the brachial artery. Bolus doses of L-NMMA (< or = 4 mg/min) for 5 min were given to blunt NO-mediated vasodilator responses to acetylcholine (ACh, 64 micrograms/min). A continuous infusion of L-NMMA (< or = 1.0 mg/min) was used during body heating to maintain NO synthase blockade. In the forearm receiving L-NMMA, FBF was 1.8 +/- 0.3 ml.100 ml-1.min-1 before drug infusion and rose to 9.5 +/- 1.3 ml.100 ml-1.min-1 with ACh. After L-NMMA infusion, FBF was 1.3 +/- 0.2 ml.100 ml-1.min-1 and rose to 2.6 +/- 0.4 ml.100 ml-1.min-1 with ACh (both P < 0.05 vs. pre-L-NMMA). Similar changes in SkBF were seen with ACh and L-NMMA, confirming that the drugs reached cutaneous vessels. With body heating, oral temperature increased by 1.2 degrees C, heart rate increased by 34 beats/min, and mean arterial pressure remained constant at approximately 75 mmHg. FBF in the treated forearm rose to 11.5 +/- 2.1 vs. 12.6 +/- 1.7 ml.100 ml-1.min-1 in the control forearm (P > 0.05, control vs. treated response).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Relative contribution of vasodilator prostanoids, NO, and KATP channels to human forearm metabolic vasodilation

2003 ◽  
Vol 284 (6) ◽  
pp. H2405-H2411 ◽  
Author(s):  
H. M. Omar Farouque ◽  
Ian T. Meredith
Keyword(s):  
Blood Flow ◽  
Forearm Blood Flow ◽  
Katp Channels ◽  
Venous Occlusion ◽  
Channel Blockade ◽  
Relative Contribution ◽  
Channel Inhibition ◽  
Human Forearm ◽  
Exercise Induced ◽  
Metabolic Vasodilation

Isolated ATP-sensitive K+(KATP) channel inhibition with glibenclamide does not alter exercise-induced forearm metabolic vasodilation. Whether forearm metabolic vasodilation would be influenced by KATP channel inhibition in the setting of impaired nitric oxide (NO)- and prostanoid-mediated vasodilation is unknown. Thirty-seven healthy subjects were recruited. Forearm blood flow (FBF) was assessed using venous occlusion plethysmography, and functional hyperemic blood flow (FHBF) was induced by isotonic wrist exercise. Infusion of N G-monomethyl-l-arginine(l-NMMA), aspirin, or the combination reduced resting FBF compared with vehicle ( P < 0.05). Addition of glibenclamide to l-NMMA, aspirin, or the combination did not further reduce resting FBF. l-NMMA decreased peak FHBF by 26%, and volume was restored after 5 min ( P < 0.05). Aspirin reduced peak FHBF by 13%, and volume repaid after 5 min ( P < 0.05). Coinfusion of l-NMMA and aspirin reduced peak FHBF by 21% ( P < 0.01), and volume was restored after 5 min ( P < 0.05). Addition of glibenclamide to l-NMMA and aspirin did not further decrease FHBF. Vascular KATP channel blockade with glibenclamide does not affect resting FBF or FHBF in the setting of NO and vasodilator prostanoid inhibition.

Baseline blood flow and bradykinin-induced vasodilator responses in the human forearm are insensitive to the cytochrome P450 2C9 (CYP2C9) inhibitor sulphaphenazole

2003 ◽  
Vol 105 (4) ◽  
pp. 513-518 ◽  
Author(s):  
Jens PASSAUER ◽  
Eckhart BÜSSEMAKER ◽  
Grit LÄSSIG ◽  
Frank PISTROSCH ◽  
Joachim FAULER ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cytochrome P450 ◽  
Forearm Blood Flow ◽  
Potent Inhibitor ◽  
Venous Occlusion ◽  
Controlled Study ◽  
Cytochrome P450 2C9 ◽  
Pathological Conditions ◽  
Human Forearm ◽  
Study Test

A substantial portion of the vasodilator response elicited by bradykinin in the human forearm is unaffected by the combined inhibition of nitric oxide (NO) synthases and cyclo-oxygenases. The cytochrome P450 (CYP) 2C9 inhibitor sulphaphenazole was recently identified as a potent inhibitor of NO- and prostacyclin (PGI2)-independent relaxation in porcine coronary arteries. The aim of the present study was to determine the effect of sulphaphenazole on basal and bradykinin-induced NO/PGI2-independent changes in the forearm blood flow (FBF) of healthy subjects. Eleven healthy male volunteers participated in this placebo-controlled study. Test agents were infused into the brachial artery and FBF was measured by bilateral venous occlusion plethysmography. Sulphaphenazole (0.02–2 mg/min) alone did not affect basal blood flow. Inhibition of the NO synthases by NG-monomethyl-L-arginine (L-NMMA; 4 μmol/min) and cyclo-oxygenases by ibuprofen (1200 mg, orally) reduced FBF to 48±7% in the absence and 50±8% in the presence of sulphaphenazole (2 mg/min; P=not significant). After pretreatment with L-NMMA (16 μmol/min) and ibuprofen (1200 mg, orally), sulphaphenazole (6 mg/min) did not substantially inhibit bradykinin-induced vasodilation. We conclude that CYP2C9-derived metabolites (i) are not involved in the regulation of baseline blood flow, and (ii) do not mediate bradykinin-induced NO/PGI2-independent vasorelaxation in the human forearm. However, determining the contribution of this enzyme to regulation of blood flow in pathological conditions associated with endothelial dysfunction requires further studies.

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