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BMC Nephrology Jun 2014Tolvaptan is a selective vasopressin receptor antagonist (V2R) that increases free water excretion. We wanted to test the hypotheses that tolvaptan changes both renal... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of vasopressin antagonism on renal handling of sodium and water and central and brachial blood pressure during inhibition of the nitric oxide system in healthy subjects.
BACKGROUND
Tolvaptan is a selective vasopressin receptor antagonist (V2R) that increases free water excretion. We wanted to test the hypotheses that tolvaptan changes both renal handling of water and sodium and systemic hemodynamics during basal conditions and during nitric oxide (NO)-inhibition with L-NG-monomethyl-arginine (L-NMMA).
METHODS
Nineteen healthy subjects were enrolled in a randomized, placebo-controlled, double-blind, crossover study of two examination days. Tolvaptan 15 mg or placebo was given in the morning. L-NMMA was given as a bolus followed by continuous infusion during 60 minutes. We measured urine output(UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP), central and brachial blood pressure(cBP, bBP).
RESULTS
During baseline conditions, tolvaptan caused a significant increase in UO, CH2O and p-AVP, and FENa was unchanged. During L-NMMA infusion, UO and CH2O decreased more pronounced after tolvaptan than after placebo (-54 vs.-42% and -34 vs.-9% respectively). U-AQP2 decreased during both treatments, whereas u-ENaCγ decreased after placebo and increased after tolvaptan. CBP and bBP were unchanged.
CONCLUSION
During baseline conditions, tolvaptan increased renal water excretion. During NO-inhibition, the more pronounced reduction in renal water excretion after tolvaptan indicates that NO promotes water excretion in the principal cells, at least partly, via an AVP-dependent mechanism. The lack of decrease in u-AQP2 by tolvaptan could be explained by a counteracting effect of increased plasma vasopressin. The antagonizing effect of NO-inhibition on u-ENaC suggests that NO interferes with the transport via ENaC by an AVP-dependent mechanism.
Topics: Adolescent; Adult; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Body Water; Brachial Artery; Cross-Over Studies; Double-Blind Method; Female; Humans; Kidney; Male; Nitric Oxide; Placebo Effect; Reference Values; Sodium; Tolvaptan; Vasopressins; Young Adult; omega-N-Methylarginine
PubMed: 24965902
DOI: 10.1186/1471-2369-15-100 -
Circulation. Arrhythmia and... Aug 2016Syncope is a sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). During VVS,...
BACKGROUND
Syncope is a sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). During VVS, gravitational pooling excessively reduces central blood volume and cardiac output. In VVS, as in hemorrhage, impaired adrenergic vasoconstriction and venoconstriction result in hypotension. We hypothesized that impaired adrenergic responsiveness because of excess nitric oxide can be reversed by reducing nitric oxide.
METHODS AND RESULTS
We recorded cardiopulmonary dynamics in supine syncope patients and healthy volunteers (aged 15-27 years) challenged with a dose-response using the α1-agonist phenylephrine (PE), with and without the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine, monoacetate salt (L-NMMA). Systolic and diastolic pressures among control and VVS were the same, although they increased after L-NMMA and saline+PE (volume and pressor control for L-NMMA). Heart rate was significantly reduced by L-NMMA (P<0.05) for control and VVS compared with baseline, but there was no significant difference in heart rate between L-NMMA and saline+PE. Cardiac output and splanchnic blood flow were reduced by L-NMMA for control and VVS (P<0.05) compared with baseline, while total peripheral resistance increased (P<0.05). PE dose-response for splanchnic flow and resistance were blunted for VVS compared with control after saline+PE, but enhanced after L-NMMA (P<0.001). Postsynaptic α1-adrenergic vasoconstrictive impairment was greatest in the splanchnic vasculature, and splanchnic blood flow was unaffected by PE. Forearm and calf α1-adrenergic vasoconstriction were unimpaired in VVS and unaffected by L-NMMA.
CONCLUSIONS
Impaired postsynaptic α1-adrenergic vasoconstriction in young adults with VVS can be corrected by nitric oxide synthase inhibition, demonstrated with our use of L-NMMA.
Topics: Adolescent; Adult; Cardiac Output; Enzyme Inhibitors; Female; Heart Rate; Humans; Male; Nitric Oxide Synthase; Phenylephrine; Splanchnic Circulation; Syncope, Vasovagal; Treatment Outcome; Vascular Resistance; Vasoconstriction; omega-N-Methylarginine
PubMed: 27444639
DOI: 10.1161/CIRCEP.115.003828 -
The Journal of Physiology Jan 2010We tested the hypotheses that (1) nitric oxide (NO) contributes to augmented skeletal muscle vasodilatation during hypoxic exercise and (2) the combined inhibition of NO...
We tested the hypotheses that (1) nitric oxide (NO) contributes to augmented skeletal muscle vasodilatation during hypoxic exercise and (2) the combined inhibition of NO production and adenosine receptor activation would attenuate the augmented vasodilatation during hypoxic exercise more than NO inhibition alone. In separate protocols subjects performed forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O(2) saturation). In protocol 1 (n = 12), subjects received intra-arterial administration of saline (control) and the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). In protocol 2 (n = 10), subjects received intra-arterial saline (control) and combined L-NMMA-aminophylline (adenosine receptor antagonist) administration. Forearm vascular conductance (FVC; ml min(-1) (100 mmHg)(-1)) was calculated from forearm blood flow (ml min(-1)) and blood pressure (mmHg). In protocol 1, the change in FVC (Delta from normoxic baseline) due to hypoxia under resting conditions and during hypoxic exercise was substantially lower with L-NMMA administration compared to saline (control; P < 0.01). In protocol 2, administration of combined L-NMMA-aminophylline reduced the DeltaFVC due to hypoxic exercise compared to saline (control; P < 0.01). However, the relative reduction in DeltaFVC compared to the respective control (saline) conditions was similar between L-NMMA only (protocol 1) and combined L-NMMA-aminophylline (protocol 2) at 10% (-17.5 +/- 3.7 vs. -21.4 +/- 5.2%; P = 0.28) and 20% (-13.4 +/- 3.5 vs. -18.8 +/- 4.5%; P = 0.18) hypoxic exercise. These findings suggest that NO contributes to the augmented vasodilatation observed during hypoxic exercise independent of adenosine.
Topics: Adult; Aminophylline; Analysis of Variance; Blood Pressure; Cardiotonic Agents; Enzyme Inhibitors; Exercise; Female; Forearm; Humans; Hypoxia; Male; Muscle, Skeletal; Nitric Oxide; Regional Blood Flow; Vasodilation; omega-N-Methylarginine
PubMed: 19948661
DOI: 10.1113/jphysiol.2009.180489 -
CNS Neuroscience & Therapeutics Mar 2014Sunitinib is an inhibitor of the multiple receptor tyrosine kinases (RTKs) for cancer therapy. Some sunitinib analogues could prevent neuronal death induced by various...
BACKGROUND
Sunitinib is an inhibitor of the multiple receptor tyrosine kinases (RTKs) for cancer therapy. Some sunitinib analogues could prevent neuronal death induced by various neurotoxins. However, the neuroprotective effects of sunitinib have not been reported.
METHODS
Cerebellar granule neurons (CGNs) and SH-SY5Y cells were exposed to low-potassium and MPP(+) challenges, respectively. MTT assay, FDA/PI staining, Hoechst staining, DAF-FM, colorimetric nitric oxide synthase (NOS) activity assay, and Western blotting were applied to detect cell viability, NO production, NOS activity, and neuronal NOS (nNOS) expression. Short hairpin RNA was used to decrease nNOS expression. In vitro NOS enzyme activity assay was used to determine the direct inhibition of nNOS by sunitinib.
RESULTS
Sunitinib prevented low-potassium-induced neuronal apoptosis in CGNs and MPP(+) -induced neuronal death in SH-SY5Y cells. However, PTK787, another RTK inhibitor, failed to decrease neurotoxicity in the same models. Sunitinib reversed the increase in NO levels, NOS activity, and nNOS expression induced by low potassium or MPP(+) . Knockdown of nNOS expression partially abolished the neuroprotective effects of sunitinib. Moreover, sunitinib directly inhibited nNOS enzyme activity.
CONCLUSIONS
Sunitinib exerts its neuroprotective effects by inhibiting NO overproduction, possibly via the inhibition of nNOS activity and the decrease in nNOS expression.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Animals, Newborn; Apoptosis; Cells, Cultured; Cerebellum; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation; Humans; Indazoles; Indoles; Neurons; Neuroprotective Agents; Neurotoxins; Nitric Oxide; Pyrroles; Rats; Rats, Sprague-Dawley; Sunitinib; omega-N-Methylarginine
PubMed: 24393200
DOI: 10.1111/cns.12203 -
The Journal of Physiology Mar 2012Passive limb movement elicits a robust increase in limb blood flow (LBF) and limb vascular conductance (LVC), but the peripheral vascular mechanisms associated with this...
Passive limb movement elicits a robust increase in limb blood flow (LBF) and limb vascular conductance (LVC), but the peripheral vascular mechanisms associated with this increase in LBF and LVC are unknown. This study sought to determine the contribution of nitric oxide (NO) to movement-induced LBF and LVC and document the potential for passive-limb movement to assess NO-mediated vasodilatation and therefore NO bioavailability. Six subjects underwent passive knee extension with and without nitric oxide synthase (NOS) inhibition via intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA). LBF was determined second-by-second by Doppler ultrasound, and central haemodynamics were measured by finger photoplethysmography. Although L-NMMA did not alter the immediate increase (initial ∼9 s) in LBF and LVC, NOS blockade attenuated the peak increase in LBF (control: 653 ± 81; L-NMMA: 399 ± 112 ml(−1) min(−1), P = 0.03) and LVC (control: 7.5 ± 0.8; L-NMMA: 4.1 ± 1.1 ml min(−1) mmHg(−1), P = 0.02) and dramatically reduced the overall vasodilatory and hyperaemic response (area under the curve) by nearly 80% (LBF: control: 270 ± 51; L-NMMA: 75 ± 32 ml, P = 0.001; LVC: control: 2.9 ± 0.5; L-NMMA: 0.8 ± 0.3 ml mmHg(−1), P < 0.001). Passive movement in control and L-NMMA trials evoked similar increases in heart rate, stroke volume, cardiac output and a reduction in mean arterial pressure. As movement-induced increases in LBF and LVC are predominantly NO dependent, passive limb movement appears to have significant promise as a new approach to assess NO-mediated vascular function, an important predictor of cardiovascular disease risk.
Topics: Adult; Blood Pressure; Cardiac Output; Enzyme Inhibitors; Femoral Artery; Heart Rate; Humans; Hyperemia; Leg; Male; Movement; Nitric Oxide; Nitric Oxide Synthase Type III; Regional Blood Flow; Vasodilation; Young Adult; omega-N-Methylarginine
PubMed: 22310310
DOI: 10.1113/jphysiol.2011.224741 -
American Journal of Physiology. Heart... Apr 2001The presence of a coronary stenosis results primarily in subendocardial ischemia. Apart from the decrease in coronary perfusion pressure, a stenosis also decreases... (Comparative Study)
Comparative Study
The presence of a coronary stenosis results primarily in subendocardial ischemia. Apart from the decrease in coronary perfusion pressure, a stenosis also decreases coronary flow pulsations. Applying a coronary perfusion system, we compared the autoregulatory response of subendocardial (n = 10) and subepicardial (n = 12) arterioles (<120 microm) after stepwise decreases in coronary arterial pressure from 100 to 70, 50, and 30 mmHg in vivo in dogs (n = 9). Pressure steps were performed with and without stenosis on the perfusion line. Maximal arteriolar diameter during the cardiac cycle was determined and normalized to its value at 100 mmHg. The initial decrease in diameter during reductions in pressure was significantly larger at the subendocardium. Diameters of subendocardial and subepicardial arterioles were similar 10--15 s after the decrease in pressure without stenosis. However, stenosis decreased the dilatory response of the subendocardial arterioles significantly. This decreased dilatory response was also evidenced by a lower coronary inflow at similar average pressure in the presence of a stenosis. Inhibition of nitric oxide production with N(G)-monomethyl-L-arginine abrogated the effect of the stenosis on flow. We conclude that the decrease in pressure caused by a stenosis in vivo results in a larger decrease in diameter of the subendocardial arterioles than in the subepicardial arterioles, and furthermore stenosis selectively decreases the dilatory response of subendocardial arterioles. These two findings expand our understanding of subendocardial vulnerability to ischemia.
Topics: Animals; Arterioles; Blood Pressure; Coronary Circulation; Coronary Disease; Dogs; Endocardium; Heart; Heart Rate; Hemodynamics; Homeostasis; Microscopy, Video; Pacemaker, Artificial; Pericardium; Reference Values; Vascular Resistance; omega-N-Methylarginine
PubMed: 11247779
DOI: 10.1152/ajpheart.2001.280.4.H1674 -
Journal of Applied Physiology... May 2004Our goal was to examine whether exercise training alleviates impaired nitric oxide synthase (NOS)-dependent dilatation of the basilar artery in Type 1 diabetic rats. To...
Our goal was to examine whether exercise training alleviates impaired nitric oxide synthase (NOS)-dependent dilatation of the basilar artery in Type 1 diabetic rats. To test this hypothesis, we measured in vivo diameter of the basilar artery in sedentary and exercised nondiabetic and diabetic rats in response to NOS-dependent (acetylcholine) and -independent (nitroglycerin) agonists. To determine the potential role for nitric oxide in vasodilatation in sedentary and exercised nondiabetic and diabetic rats, we examined responses after NG-monomethyl-l-arginine (l-NMMA). We found that acetylcholine produced dilatation of the basilar artery that was similar in sedentary and exercised nondiabetic rats. Acetylcholine produced only minimal vasodilatation in sedentary diabetic rats. However, exercise alleviated impaired acetylcholine-induced vasodilatation in diabetic rats. Nitroglycerin produced dilatation of the basilar artery that was similar in sedentary and exercised nondiabetic and diabetic rats. l-NMMA produced similar inhibition of acetylcholine-induced dilatation of the basilar artery in sedentary and exercised nondiabetic and diabetic rats. Finally, we found that endothelial NOS (eNOS) protein in the basilar artery was higher in diabetic compared with nondiabetic rats and that exercise increased eNOS protein in the basilar artery of nondiabetic and diabetic rats. We conclude that 1) exercise can alleviate impaired NOS-dependent dilatation of the basilar artery during diabetes mellitus, 2) the synthesis and release of nitric oxide accounts for dilatation of the basilar artery to acetylcholine in sedentary and exercised nondiabetic and diabetic rats, and 3) exercise may exert its affect on cerebrovascular reactivity during diabetes by altering levels of eNOS protein in the basilar artery.
Topics: Acetylcholine; Animals; Basilar Artery; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Male; Motor Activity; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Vasodilation; Vasodilator Agents; omega-N-Methylarginine
PubMed: 14729730
DOI: 10.1152/japplphysiol.01185.2003 -
American Journal of Physiology.... Apr 2005Intermedin (IMD)/adrenomedullin-2 (AM2) is a novel peptide that was independently discovered by two groups. The 47-amino acid peptide is homologous to adrenomedullin...
Intermedin (IMD)/adrenomedullin-2 (AM2) is a novel peptide that was independently discovered by two groups. The 47-amino acid peptide is homologous to adrenomedullin (AM) and can activate both the AM and calcitonin gene-related peptide (CGRP) receptors. IMD should therefore have actions similar to those of AM and CGRP. Indeed, like AM and CGRP, intravenous administration of IMD decreased blood pressure in rats and mice. We demonstrate here that immunoreactive IMD is present in plasma as well as heart, lung, stomach, kidney, pituitary, and brain. Because IMD is present in brain and both AM and CGRP have potent central nervous system (CNS) effects, we examined the ability of IMD within brain to regulate blood pressure and ingestive behaviors. Administration of IMD into the lateral cerebroventricle of rats caused significant, long-lasting elevations in mean arterial pressure and heart rate. These elevations are similar to the effects of CGRP and significantly greater than the effects of AM. IMD-induced elevations in mean arterial pressure were inhibited by intravenous administration of phentolamine, indicating that IMD activates the sympathetic nervous system. Intracerebroventricular administration of IMD also inhibited food and water intake in sated and in food- and water-restricted animals. The effects on feeding are likely related to activation of the CGRP receptor and are independent of the effects on water intake, which are likely through the AM receptor. Our data indicate that IMD has potent actions within the CNS that may be a result of the combined activation of both AM and CGRP receptors.
Topics: Adrenomedullin; Animals; Area Under Curve; Blood Pressure; Calcitonin Gene-Related Peptide; Central Nervous System; Dose-Response Relationship, Drug; Drinking; Eating; Enzyme Inhibitors; Heart Rate; Injections, Intravenous; Injections, Intraventricular; Male; Neuropeptides; Nitric Oxide; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Calcitonin; Receptors, Calcitonin Gene-Related Peptide; Reverse Transcriptase Polymerase Chain Reaction; omega-N-Methylarginine
PubMed: 15576658
DOI: 10.1152/ajpregu.00744.2004 -
Swiss Medical Weekly 2012Nitric oxide (NO) regulates arterial pressure by modulating peripheral vascular tone and sympathetic vasoconstrictor outflow. NO synthesis is impaired in several major...
OBJECTIVE
Nitric oxide (NO) regulates arterial pressure by modulating peripheral vascular tone and sympathetic vasoconstrictor outflow. NO synthesis is impaired in several major cardiovascular disease states. Loss of NO-induced vasodilator tone and restraint on sympathetic outflow could result in exaggerated pressor responses to mental stress.
METHODS
We, therefore, compared the sympathetic (muscle sympathetic nerve activity) and haemodynamic responses to mental stress performed during saline infusion and systemic inhibition of NO-synthase by NG-monomethyl-L-arginine (L-NMMA) infusion.
RESULTS
The major finding was that mental stress which during saline infusion increased sympathetic nerve activity by ~50 percent and mean arterial pressure by ~15 percent had no detectable sympathoexcitatory and pressor effect during L-NMMA infusion. These findings were not related to a generalised impairment of the haemodynamic and/or sympathetic responsiveness by L-NMMA, since the pressor and sympathetic nerve responses to immersion of the hand in ice water were preserved during L-NMMA infusion.
CONCLUSION
Mental stress causes pressor and sympathoexcitatory effects in humans that are mediated by NO. These findings are consistent with the new concept that, in contrast to what has been generally assumed, under some circumstances, NO has a blood pressure raising action in vivo.
Topics: Adult; Analysis of Variance; Blood Pressure; Epinephrine; Forearm; Heart Rate; Humans; Leg; Male; Nitric Oxide; Nitric Oxide Synthase; Regional Blood Flow; Stress, Psychological; Vascular Resistance; Vasomotor System; omega-N-Methylarginine
PubMed: 22786663
DOI: 10.4414/smw.2012.13627 -
Hypertension (Dallas, Tex. : 1979) Mar 2011Aging has been recently associated with increased retrograde and oscillatory shear in peripheral conduit arteries, a hemodynamic environment that favors a proatherogenic...
Aging has been recently associated with increased retrograde and oscillatory shear in peripheral conduit arteries, a hemodynamic environment that favors a proatherogenic endothelial cell phenotype. We evaluated whether nitric oxide (NO) bioavailability in resistance vessels contributes to age-related differences in shear rate patterns in upstream conduit arteries at rest and during rhythmic muscle contraction. Younger (n=11, age 26 ± 2 years) and older (n=11, age 61 ± 2 years) healthy subjects received intra-arterial saline (control) and the NO synthase inhibitor N(G)-Monomethyl-L-arginine. Brachial artery diameter and velocities were measured via Doppler ultrasound at rest and during a 5-minute bout of rhythmic forearm exercise. At rest, older subjects exhibited greater brachial artery retrograde and oscillatory shear (-13.2 ± 3.0 s(-1) and 0.11 ± .0.02 arbitrary units, respectively) compared with young subjects (-4.8 ± 2.3 s(-1) and 0.04 ± 0.02 arbitrary units, respectively; both P<0.05). NO synthase inhibition in the forearm circulation of young, but not of older, subjects increased retrograde and oscillatory shear (both P<0.05), such that differences between young and old at rest were abolished (both P>0.05). From rest to steady-state exercise, older subjects decreased retrograde and oscillatory shear (both P<0.05) to the extent that no exercise-related differences were found between groups (both P>0.05). Inhibition of NO synthase in the forearm circulation did not affect retrograde and oscillatory shear during exercise in either group (all P>0.05). These data demonstrate for the first time that reduced NO bioavailability in the resistance vessels contributes, in part, to age-related discrepancies in resting shear patterns, thus identifying a potential mechanism for increased risk of atherosclerotic disease in conduit arteries.
Topics: Adult; Age Factors; Aged; Aging; Analysis of Variance; Blood Flow Velocity; Brachial Artery; Enzyme Inhibitors; Exercise; Humans; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Regional Blood Flow; Ultrasonography; omega-N-Methylarginine
PubMed: 21263118
DOI: 10.1161/HYPERTENSIONAHA.110.165365