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.

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.

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 Cardiovascular and Autonomic Responses after a Single Bout of Resistance Exercise in Men with Untreated Stage 2 Hypertension

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Marcus Vinicius Machado ◽  
Thais de Paola Chequer Barbosa ◽  
Thais Camasmine Chrispino ◽  
Fabricia Junqueira das Neves ◽  
Gabriel Dias Rodrigues ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Blood Flow ◽  
Resistance Exercise ◽  
Vascular Reactivity ◽  
Forearm Blood Flow ◽  
Area Under The Curve ◽  
Venous Occlusion ◽  
Antihypertensive Medications ◽  
Single Bout

The aim of this paper is to assess the integrated responses of ambulatory blood pressure (BP), cardiac autonomic modulation, spontaneous baroreflex sensitivity (BRS), and vascular reactivity after a single bout of resistance exercise (RE) in men with stage 2 hypertension who have never been treated before. Ten hypertensive men were subjected to a RE session of three sets of 20 repetitions and an intensity of 40% of the 1-repetition maximum (RM) test in seven different exercises. For the control (CTR) session, the volunteers were positioned on the exercise machines but did not perform any exercise. Forearm blood flow was measured by venous occlusion plethysmography. We also analyzed the heart rate variability (HRV), ambulatory BP, blood pressure variability (BPV), and BRS. All measurements were performed at different timepoints: baseline, 20 min, 80 min, and 24 h after both RE and CTR sessions. There were no differences in ambulatory BP over the 24 h between the RE and CTR sessions. However, the area under the curve of diastolic BP decreased after the RE session. Heart rate (HR) and cardiac output increased for up to 80 and 20 min after RE, respectively. Similarly, forearm blood flow, conductance, and vascular reactivity increased 20 min after RE ( p < 0.05 ). In contrast, HRV and BRS decreased immediately after exercise and remained lower for 20 min after RE. We conclude that a single bout of RE induced an increase in vascular reactivity and reduced the pressure load by attenuating AUC of DBP in hypertensive individuals who had never been treated with antihypertensive medications.

Effects of nitroglycerin on forearm haemodynamics in patients with cirrhosis

1988 ◽  
Vol 74 (4) ◽  
pp. 433-436 ◽  
Author(s):  
M. Isabel Jiron ◽  
Samuel S. Lee ◽  
Raimondo Cerini ◽  
Domenico Pugliese ◽  
Antoine Hadengue ◽  
...  
Keyword(s):  
Blood Flow ◽  
Forearm Blood Flow ◽  
Inverse Correlation ◽  
Venous Occlusion ◽  
Group Iii ◽  
Dilatory Response ◽  
Age Related ◽  
Group I ◽  
Venous Distensibility ◽  
Group Ii

1. Basal forearm haemodynamics were studied by venous occlusion plethysmography in three groups of subjects: group I, healthy controls, group II, patients with cirrhosis age- and sex-matched with group I, and group III, an older group of patients with cirrhosis. Subsequently, responses to sublingual nitroglycerin were measured in group I and II subjects. 2. Controls responded to nitroglycerin with an increase in venous distensibility; group II patients had higher initial venous distensibility but did not respond to nitroglycerin. No other variables in either group were affected by nitroglycerin. 3. Group II and III patients differed in forearm blood flow and vascular resistance and venous distensibility. A significant inverse correlation was found between age and forearm blood flow (r = −0.57, P < 0.001) in all patients with cirrhosis. 4. We conclude that (a) venous tone is reduced in cirrhosis, possibly as a result of chronic venodilatation; (b) this venodilatation impedes further dilatory response to a small dose of nitroglycerin; (c) cirrhosis is also associated with age-related decreases in peripheral haemodynamics.

Increased endothelium-dependent renal vasodilation in cirrhotic rats

1994 ◽  
Vol 267 (2) ◽  
pp. R549-R553 ◽  
Author(s):  
J. Garcia-Estan ◽  
N. M. Atucha ◽  
J. M. Sabio ◽  
F. Vargas ◽  
T. Quesada ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Liver Cirrhosis ◽  
Perfusion Pressure ◽  
Renal Perfusion ◽  
High Dose ◽  
Dependent Manner ◽  
Response Curves ◽  
Renal Perfusion Pressure ◽  
Dose Dependent

We have evaluated the renal blood flow (RBF) response of cirrhotic rats to endothelium-dependent [acetylcholine (ACh)] and -independent [sodium nitroprusside (NP)] vasodilators. In anesthetized rats, ACh dose dependently increased RBF, but the response of the cirrhotic rats (n = 6) was significantly higher than that of the controls (n = 6). NP also increased RBF in a dose-dependent manner, but there were no differences between both groups. NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg i.v.) significantly reduced the responses to ACh in both groups, but those of the cirrhotic rats were still higher than those of the controls. In experiments performed in isolated perfused kidneys, preconstricted with phenylephrine, dose-response curves for ACh and NP were obtained in the presence of indomethacin. Both ACh and NP decreased renal perfusion pressure dose dependently, but only the response of the cirrhotic rats (n = 5) to ACh was significantly higher than that of the controls (n = 5). L-NAME (100 microM) significantly reduced the responses to ACh and increased those of NP and abolished the differences between groups, except at the high dose of ACh. These results demonstrate an elevated endothelium-dependent vasodilator response in the cirrhotic kidney, which is eliminated by combined prostaglandin and nitric oxide (NO) synthesis inhibition and suggest that increased intrarenal activity of NO may be contributing to the renal alterations of liver cirrhosis.

scholarly journals Continuous release of vasodilator prostanoids contributes to regulation of resting forearm blood flow in humans

1998 ◽  
Vol 274 (4) ◽  
pp. H1174-H1183 ◽  
Author(s):  
Stephen J. Duffy ◽  
Binh T. Tran ◽  
Gishel New ◽  
Ronald N. Tudball ◽  
Murray D. Esler ◽  
...  
Keyword(s):  
Blood Flow ◽  
Forearm Blood Flow ◽  
Venous Occlusion ◽  
Continuous Release ◽  
Before And After ◽  
Prostaglandin F ◽  
Resting Tone ◽  
Dose Dependent ◽  
Prostacyclin Production

Continuous release of nitric oxide contributes to the maintenance of resting tone in the human forearm and coronary circulations; however, evidence for a similar role of vasodilator prostanoids such as prostacyclin is lacking. We examined whether continuous release of prostacyclin contributes to basal forearm blood flow. Flow was measured using venous occlusion plethysmography in 38 healthy volunteers [mean age 21.3 ± 2.5 yr (±SD); 13 female, 25 male] at rest, after administration of three incremental intra-arterial infusions of either the cyclooxygenase inhibitor aspirin or placebo, and before and after administration of the endothelium-dependent and -independent dilators acetylcholine (30 μg/min) and nitroprusside (1 μg/min). To assess the effect of aspirin on the production of prostacyclin, plasma 6-keto prostaglandin F1α(6-keto-PGF1α; the stable metabolite of prostacyclin) was measured by simultaneous arterial and venous sampling. Aspirin produced a time- and dose-dependent reduction in forearm blood flow, resulting in a 32% decrease at the highest dose. The effect was maximal after 10 min. Flow at rest and after aspirin doses of 1, 3, and 10 mg/min was 2.6 ± 0.2, 2.3 ± 0.2, 2.1 ± 0.2, and 1.8 ± 0.2 ml ⋅ 100 ml forearm tissue−1 ⋅ min−1, respectively (means ± SE, P< 0.001). Commensurate with these data, the net forearm production of 6-keto-PGF1α was 52.9 ± 16.4, 11.7 ± 8.6, 18.7 ± 8.5, and 12.0 ± 12.5 pg ⋅ 100 ml forearm tissue−1 ⋅ min−1 for the respective doses ( P = 0.04). No time-dependent reduction in flow was seen in subjects with vehicle infusion. Aspirin did not affect the responses to acetylcholine or nitroprusside. These data suggest that continuous release of prostacyclin plays a role in the maintenance of resting forearm blood flow. There appears to be a direct link between the reduction in flow with aspirin and inhibition of prostacyclin production.

Impaired Nitric Oxide-Mediated Vasodilatation and Total Body Nitric Oxide Production in Healthy Old Age

1997 ◽  
Vol 93 (6) ◽  
pp. 519-525 ◽  
Author(s):  
Declan Lyons ◽  
Suzanne Roy ◽  
Mahesh Patel ◽  
Nigel Benjamin ◽  
Cameron G. Swift
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Forearm Blood Flow ◽  
The Elderly ◽  
Elderly Subjects ◽  
Nitric Oxide Production ◽  
Response Curves ◽  
Oxide Production ◽  
The Mean ◽  
Total Body

1. Basal release of nitric oxide from the vascular endothelium maintains a constant vasodilating tone. Impaired nitric oxide-mediated vasodilatation has been described in hypertension and atheromatous disease. Circulatory diseases account for considerable morbidity and almost half of all deaths in people over the age of 75 years. 2. We have therefore compared nitric oxide-dependent vasorelaxation in 12 healthy elderly subjects with 12 young volunteers matched for blood pressure, cholesterol and glucose, using forearm occlusion venous plethysmography combined with brachial artery infusions of the nitric oxide synthase inhibitor, NG-monomethyl-l-arginine (l-NMMA; 1, 2 and 4 μmol/min) with noradrenaline (60, 120 and 240 pmol/min) as a control vasoconstrictor. We also measured urinary nitrate excretion after a controlled 48 h low nitrate diet as an index of total body nitric oxide production and correlated these changes with forearm blood flow responses to l-NMMA and noradrenaline in both groups. 3. The mean age and blood pressure of the elderly subjects was 76 (range 66–82) years and 132/76 (SEM 4/3) mmHg respectively, while in the young these were 27 (20–35) years and 131/72 (4/3) mmHg respectively. l-NMMA and noradrenaline produced dose-dependent reductions in forearm blood flow in both groups. l-NMMA (4 μmol/min) produced less vasoconstriction in the elderly than in the young (−37.7 ± 2.6 versus −48.3 ± 4.2%; P = 0.017). The mean slope of the l-NMMA dose-response curves in the elderly was significantly less than the younger group (−35.2 ± 3.1 versus −63.7 ± 10.6; P = 0.041). Noradrenaline, 240 pmol/min, also produced less vasoconstriction in the elderly compared with the young (−22.8 ± 2.9 versus −35.3 ± 5.0%; P = 0.029) although the slopes of the dose—response curves did not differ significantly. 4. Urinary nitrate adjusted for creatinine clearance was also significantly higher in the younger group (460.6 ± 97.7 versus 205.9 ± 64.8 μmol/day; P = 0.042) and showed a significant correlation with the percentage change in forearm blood flow in response to the maximum dose of l-NMMA (r = 0.5, P = 0.046). 5. We conclude that nitric oxide-mediated vasodilatation in the forearm vascular bed is diminished in old age and this reflects a more generalized reduction in nitric oxide production (as measured by urinary nitrate) in the circulation of older people. The blunted response to noradrenaline points to a more generalized reduction in vascular reactivity in the elderly.

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.

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