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.

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.

scholarly journals EvidenceIn VivoShowing Increase of Baseline Nitric Oxide Generation and Impairment of Endothelium-Dependent Vasodilation in Normotensive Patients on Chronic Hemodialysis

2000 ◽  
Vol 11 (9) ◽  
pp. 1726-1734 ◽  
Author(s):  
JENS PASSAUER ◽  
ECKHART BÜSSEMAKER ◽  
URSULA RANGE ◽  
MARIA PLUG ◽  
PETER GROSS
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Forearm Blood Flow ◽  
Matched Control ◽  
Venous Occlusion ◽  
Chronic Hemodialysis ◽  
Invasive Technique ◽  
Vascular Effects ◽  
Control Subjects ◽  
Pharmacologic Agents

Abstract.Cardiovascular mortality is excessive in hemodialyzed patients. Observations in atherosclerosis suggest that endothelial dysfunction and impaired nitric oxide (NO) may be involved. However, the relation of endothelial NO to its vascular effects has not been studied conclusively in uremia. Therefore, to study these questions an invasive technique was used in normotensive patients who were on hemodialysis (HD;n= 11) and in matched control subjects (n= 11). Pharmacologic agents were infused into the brachial artery to test the chain of events from NO generation to smooth muscle cell relaxation, measuring forearm blood flow by venous occlusion plethysmography. Glyceroltrinitrate (GTN 1:2.2 nmol/min; GTN 2:4.4; GTN 3:8.8), infused to establish the reaction of the vessel wall to defined doses of NO, caused a reduced response in HD patients (control subjects: 183 ± 20 [SEM], 246 ± 26, and 338 ± 29%; HD patients: 161 ± 7, 206 ± 12, and 262 ± 24%; baseline = 100% for each group,P= 0.032 by ANOVA). All subsequent data were corrected for this decreased response to defined doses of NO in HD patients. L-arginine (10 mg/min), given to exclude substrate deficiency of NO synthase (NOS), caused no significant changes (control subjects: 108 ± 4%; HD patients: 103 ± 4%;P= NS). Acetylcholine (ACH 1:55 nmol/min; ACH 2:110; ACH 3:220), infused to stimulate endothelial NOS, had a significantly reduced effect in HD patients (control subjects: 246 ± 32, 340 ± 40, and 465 ± 52%; HD patients: 251 ± 55, 244 ± 36, and 318 ± 50%;P= 0.002).N-monomethyl-L-arginine (LMA 1:1 μmol/min; LMA 2:2; LMA 3:4), given to block baseline NO generation, showed an enhanced response in HD patients (control subjects: 90 ± 2, 83 ± 2, and 74 ± 4%; HD patients: 84 ± 3, 73 ± 3, and 64 ± 4%;P= 0.037). Vascular response to three doses of norepinephrine (60, 120, and 240 pmol/min) was comparable in both groups, which indicated similar endothelium-independent vasoconstriction. In summary, in normotensive HD patients, (1) vasodilation to defined doses of exogenous NO was reduced, (2) there was no evidence of substrate deficiency of NOS, and (3) stimulation of NOS was impaired; however, (4) baseline NO generation was increased. It is concluded that in HD patients, the NO system has a reduced capacity to regulate vascular tone and this impairment is most significant under conditions of NOS stimulation.

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 .

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.

scholarly journals Examination of Potential Mechanisms in the Enhancement of Cerebral Blood Flow by Hypoglycemia and Pharmacological Doses of Deoxyglucose

1997 ◽  
Vol 17 (1) ◽  
pp. 54-63 ◽  
Author(s):  
Naoaki Horinaka ◽  
Nicole Artz ◽  
Jane Jehle ◽  
Shinichi Takahashi ◽  
Charles Kennedy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Glucose Metabolism ◽  
Plasma Glucose ◽  
Plasma Lactate ◽  
Insulin Hypoglycemia ◽  
Glucose Levels ◽  
Arterial Blood ◽  
Arterial Plasma

Cerebral blood flow (CBF) rises when the glucose supply to the brain is limited by hypoglycemia or glucose metabolism is inhibited by pharmacological doses of 2-deoxyglucose (DG). The present studies in unanesthetized rats with insulin-induced hypoglycemia show that the increases in CBF, measured with the [14C]iodoantipyrine method, are relatively small until arterial plasma glucose levels fall to 2.5 to 3.0 m M, at which point CBF rises sharply. A direct effect of insulin on CBF was excluded; insulin administered under euglycemic conditions maintained by glucose injections had no effects on CBF. Insulin administration raised plasma lactate levels and decreased plasma K+ and HCO3– concentrations and arterial pH. These could not, however, be related to the increased CBF because insulin under euglycemic conditions had similar effects without affecting CBF; furthermore, the inhibition of brain glucose metabolism with pharmacological doses (200 mg/kg intravenously) of DG increased CBF, just like insulin hypoglycemia, without altering plasma lactate and K+ levels and arterial blood gas tensions and pH. Nitric oxide also does not appear to mediate the increases in CBF. Chronic blockade of nitric oxide synthase activity by twice daily i.p. injections of NG-nitro-L-arginine methyl ester for 4 days or acutely by a single i.v. injection raised arterial blood pressure and lowered CBF in normoglycemic, hypoglycemic, and DG-treated rats but did not significantly reduce the increases in CBF due to insulin-induced hypoglycemia (arterial plasma glucose levels, 2.5-3 m M) or pharmacological doses of deoxyglucose.

Forearm and finger blood flow responses to passive body tilts

1979 ◽  
Vol 46 (2) ◽  
pp. 288-292 ◽  
Author(s):  
Y. A. Mengesha ◽  
G. H. Bell
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Arterial Blood Pressure ◽  
Vascular Resistance ◽  
Pulse Rate ◽  
Forearm Blood Flow ◽  
Body Tilt ◽  
Finger Blood Flow ◽  
Arterial Blood ◽  
Forearm Vascular Resistance

Ten to fifteen healthy subjects, ages 18--30 yr, were used to assess the correlation of forearm blood flow with graded passive body tilts and vascular resistance and also to discern the relative effects of body tilts on finger blood flow. In the head-up tilts forearm blood flow and arterial blood pressure fell progressively, whereas forearm vascular resistance and pulse rate increased. In the head-down tilts the forearm blood flow and the arterial blood pressure increased, whereas the forearm vascular resistance and pulse rate decreased. These changes were found to be significantly correlated with the different tilt angles and with one another. In a preliminary study it was found that infrared heating of the carpometacarpal region produced finger vasodilatation similar to the forearm vasodilatation observed by Crockford and Hellon (6). However, unlike forearm blood flow, finger blood flow showed no appreciable response to either the head-up or head-down tilts. This indicates that the sympathetic tone and the volume of blood in the finger are not appreciably altered by this test procedure at least 1 min after the body tilt is assumed.

scholarly journals Effects of acetylcholine and nitric oxide on forearm blood flow at rest and after a single muscle contraction

1998 ◽  
Vol 85 (6) ◽  
pp. 2249-2254 ◽  
Author(s):  
R. W. Brock ◽  
M. E. Tschakovsky ◽  
J. K. Shoemaker ◽  
J. R. Halliwill ◽  
M. J. Joyner ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Muscle Contraction ◽  
Forearm Blood Flow ◽  
Mechanical Effect ◽  
Voluntary Contraction ◽  
Single Muscle ◽  
Cuff Inflation ◽  
S Period ◽  
Echo Doppler Ultrasound

We tested the hypothesis that ACh or nitric oxide (NO) might be involved in the vasodilation that accompanies a single contraction of the forearm. Eight adults (3 women and 5 men) completed single 1-s-duration contractions of the forearm to raise and lower a weight equivalent to ∼20% maximal voluntary contraction through a distance of 5 cm. In a second protocol, each subject had a cuff, placed completely about the forearm, inflated to 120 mmHg for a 1-s period, then released as a simulation of the mechanical effect of muscle contraction. Three conditions were studied, always in this order: 1) control, with intra-arterial infusion of saline; 2) after muscarinic blockade with atropine; and 3) after NO synthase inhibition with N G-monomethyl-l-arginine (l-NMMA) plus atropine. Forearm blood flow (FBF), measured by combined pulsed and echo Doppler ultrasound, was reduced at rest with l-NMMA-atropine compared with the other two conditions. After the single contraction, there were no effects of atropine, butl-NMMA reduced the peak FBF and the total postcontraction hyperemia. After the single cuff inflation, atropine had no effects, whereasl-NMMA caused changes similar to those seen after contraction, reducing the peak FBF and the total hyperemia. The observation thatl-NMMA reduced FBF in response to both cuff inflation and a brief contraction indicates that NO from the vascular endothelium might modulate the basal level of vascular tone and the mechanical component of the hyperemia with exercise. It is unlikely that ACh and NO from the endothelium are involved in the dilator response to a single muscle contraction.

Dilator actions of arginine in human peripheral vasculature

1991 ◽  
Vol 81 (5) ◽  
pp. 695-700 ◽  
Author(s):  
Alison Calver ◽  
Joe Collier ◽  
Patrick Vallance
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Forearm Blood Flow ◽  
Hypotensive Effect ◽  
Linear Displacement ◽  
High Dose ◽  
Free Base ◽  
Peripheral Vasculature ◽  
Arginine Hydrochloride

1. l-Arginine is the physiological precursor for the formation of endothelium-derived nitric oxide. The synthesis of nitric oxide is stereospecific: d-arginine is not a substrate for nitric oxide synthase. It is possible that the provision of excess l-arginine substrate might increase the vascular synthesis of nitric oxide. We have examined this possibility by studying the effects of local infusion of l-and d-arginine in the forearm resistance bed and the superficial dorsal hand veins of healthy subjects. 2. Drugs were either infused locally into a vein on the back of the hand and then the vein diameter was measured using a linear displacement technique, or into the brachial artery and then the forearm blood flow was measured by venous occlusion plethysmography. 3. In the superficial hand veins, l- and d-arginine free base and l- and d-arginine hydrochloride (all four preparations at a dose of 5 μmol/min) all caused a significant increase in venous diameter. The responses of the l-and d-enantiomers did not differ significantly from one another. 4. In the forearm resistance bed, l- and d-arginine free base and l-arginine hydrochloride were without effect at doses of 10 and 40 μmol/min. However, at doses of 160 μmol/min all three preparations of arginine caused a significant increase in forearm blood flow compared with control values. The responses to the three preparations of arginine did not differ significantly from one another. 5. These results show that arginine in high dose is a vasodilator in both human resistance vessels and superficial veins in vivo. The response to arginine was not stereospecific: both the l- and d-enantiomers had the same effect. The dilator effect of high-dose arginine showed neither arterio-nor veno-selectivity. 6. This suggests that the hypotensive effect of systemic infusions of l-arginine in man is mediated by peripheral vasodilatation. It is not possible to ascribe the actions of arginine supplementation in this study to activation of the l-arginine/nitric oxide pathway through the provision of excess substrate.

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