scholarly journals Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs

Endocrinology ◽  
2016 ◽  
Vol 157 (6) ◽  
pp. 2403-2415 ◽  
Author(s):  
Elena Grossini ◽  
Giulia Raina ◽  
Serena Farruggio ◽  
Lara Camillo ◽  
Claudio Molinari ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Endothelial Cells ◽  
Blood Flow ◽  
Coronary Artery ◽  
Coronary Blood Flow ◽  
No Synthase ◽  
Cardiac Perfusion ◽  
No Release ◽  
Acyl Ghrelin

Des-acyl ghrelin (DAG), the most abundant form of ghrelin in humans, has been found to reduce arterial blood pressure and prevent cardiac and endothelial cell apoptosis. Despite this, data regarding its direct effect on cardiac function and coronary blood flow, as well as the related involvement of autonomic nervous system and nitric oxide (NO), are scarce. We therefore examined these issues using both in vivo and in vitro studies. In 20 anesthetized pigs, intracoronary 100 pmol/mL DAG infusion with a constant heart rate and aortic blood pressure, increased coronary blood flow and NO release, whereas reducing coronary vascular resistances (P < .05). Dose responses to DAG were evaluated in five pigs. No effects on cardiac contractility/relaxation or myocardial oxygen consumption were observed. Moreover, whereas the blockade of muscarinic cholinoceptors (n = 5) or α- and β-adrenoceptors (n = 5 each) did not abolish the observed responses, NO synthase inhibition (n = 5) prevented the effects of DAG on coronary blood flow and NO release. In coronary artery endothelial cells, DAG dose dependently increased NO release through cAMP signaling and ERK1/2, Akt, and p38 MAPK involvement as well as the phosphorylation of endothelial NO synthase. In conclusion, in anesthetized pigs, DAG primarily increased cardiac perfusion through the involvement of NO release. Moreover, the phosphorylation of ERK1/2 and Akt appears to play roles in eliciting the observed NO production in coronary artery endothelial cells.

In anesthetized pigs human chorionic gonadotropin increases myocardial perfusion and function through a β-adrenergic-related pathway and nitric oxide

2013 ◽  
Vol 115 (4) ◽  
pp. 422-435 ◽  
Author(s):  
Elena Grossini ◽  
Daniela Surico ◽  
David A. S. G. Mary ◽  
Claudio Molinari ◽  
Nicola Surico ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cardiac Function ◽  
Coronary Blood Flow ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Left Ventricular ◽  
No Synthase ◽  
No Production ◽  
No Release

Human chorionic gonadotropin (hCG) is not only responsible for numerous pregnancy-related processes, but can affect the cardiovascular system as well. So far, however, information about any direct effect elicited by hCG on cardiac function, perfusion, and the mechanisms involved has remained scarce. Therefore, the present study aimed to determine the primary in vivo effect of hCG on cardiac contractility and coronary blood flow and the involvement of autonomic nervous system and nitric oxide (NO). Moreover, in coronary endothelial cells (CEC), the intracellular pathways involved in the effects of hCG on NO release were also examined. In 25 anesthetized pigs, intracoronary 500 mU/ml hCG infusion at constant heart rate and aortic blood pressure increased coronary blood flow, maximum rate of change of left ventricular systolic pressure, segmental shortening, cardiac output, and coronary NO release ( P < 0.0001). These hemodynamic responses were graded in a further five pigs. Moreover, while blockade of muscarinic cholinoceptors ( n = 5) and of α-adrenoceptors ( n = 5) did not abolish the observed responses, β1-adrenoceptors blocker ( n = 5) prevented the effects of hCG on cardiac function. In addition, β2-adrenoceptors ( n = 5) and NO synthase inhibition ( n = 5) abolished the coronary response and the effect of hCG on NO release. In CEC, hCG induced the phosphorylation of endothelial NO synthase through cAMP/PKA signaling and ERK1/2, Akt, p38 MAPK involvement, which were activated as downstream effectors of β2-adrenoceptor stimulation. In conclusion, in anesthetized pigs, hCG primarily increased cardiac function and perfusion through the involvement of β-adrenoceptors and NO release. Moreover, cAMP/PKA-dependent kinases phosphorylation was found to play a role in eliciting the observed NO production in CEC.

Intracoronary intermedin 1–47 augments cardiac perfusion and function in anesthetized pigs: role of calcitonin receptors and β-adrenoreceptor-mediated nitric oxide release

2009 ◽  
Vol 107 (4) ◽  
pp. 1037-1050 ◽  
Author(s):  
Elena Grossini ◽  
Claudio Molinari ◽  
David A. S. G. Mary ◽  
Francesca Uberti ◽  
Philippe Primo Caimmi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cardiac Function ◽  
Coronary Blood Flow ◽  
No Synthase ◽  
Cardiac Response ◽  
No Production ◽  
Receptor Complexes ◽  
Arterial Blood

Systemic intermedin (IMD)1–47 administration has been reported to result in vasodilation and marked hypotension through calcitonin-related receptor complexes. However, its effects on the coronary circulation and the heart have not been examined in vivo. The present study was therefore planned to determine the primary in vivo effect of IMD1–47 on coronary blood flow and cardiac function and the involvement of the autonomic nervous system and nitric oxide (NO). In 35 anesthetized pigs, IMD1–47, infused into the left anterior descending coronary artery at doses of 87.2 pmol/min, at constant heart rate and arterial blood pressure, augmented coronary blood flow and cardiac function. These responses were graded in a further five pigs by increasing the infused dose of IMD1–47 between 0.81 and 204.1 pmol/min. In the 35 pigs, the blockade of cholinergic receptors (intravenous atropine, 5 pigs), α-adrenoceptors (intravenous phentolamine, 5 pigs), and β1-adrenoceptors (intravenous atenolol, 5 pigs) did not abolish the cardiac response to IMD1–47, the effects of which were prevented by blockade of β2-adrenoceptors (intravenous butoxamine, 5 pigs), NO synthase (intracoronary Nω-nitro-l-arginine methyl ester, 5 pigs), and calcitonin-related receptors (intracoronary CGRP8–37/AM22–52, 10 pigs). In porcine coronary endothelial cells, IMD1–47 induced the phosphorylation of endothelial NO synthase and NO production through cAMP signaling leading to ERK, Akt, and p38 activation, which was prevented by the inhibition of β2-adrenoceptors, calcitonin-related receptor complexes, and K+ channels. In conclusion, IMD1–47 primarily augmented coronary blood flow and cardiac function through the involvement of calcitonin-related receptor complexes and β2-adrenoreceptor-mediated NO release. The intracellular signaling involved cAMP-dependent activation of kinases and the opening of K+ channels.

Abstract 648: Nebivolol and Valsartan Increase Nitric Oxide Release from Human Endothelial Cells in a Synergistic Fashion

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
R. Preston Mason ◽  
Robert F Jacob ◽  
Tadeusz Malinski
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Endothelial Cells ◽  
Angiotensin Ii ◽  
Adrenergic Receptor ◽  
Calcium Ionophore ◽  
Receptor Activation ◽  
Angiotensin Ii Receptor Blocker ◽  
Human Endothelial Cells ◽  
No Release

Introduction: Nebivolol is a β1-adrenergic receptor antagonist that stimulates endothelial nitric oxide (NO) release through β3-adrenergic receptor activation, ATP-mediated stimulation of purinergic P2Y receptors, and inhibition of membrane lipid oxidation. Valsartan is an angiotensin II receptor blocker (ARB) that selectively inhibits angiotensin II type 1 (AT1) receptors, thereby exerting no direct effect at type 2 (AT2) receptors, which have been shown to stimulate NO synthase activity through a bradykinin-mediated pathway. As NO is a key regulator of blood pressure and these two antihypertensive agents promote NO release through distinct mechanisms, we compared their individual and combined effects on NO release from human endothelial cells. Methods: Human umbilical vein endothelial cells (HUVECs) were incubated for 1 hr with vehicle, nebivolol or valsartan alone (each at 1.0 μM), or nebivolol (1.0 μM) and valsartan (0.5-5.0 μM) combined. The comparative effects of these agents on maximal NO release were measured in individual cells using porphyrinic nanosensors following stimulation with calcium ionophore (1.0 μM). Results: Nebivolol treatment increased HUVEC NO release by 49% (509 ± 18 nM, mean ± SD) as compared to vehicle treatment alone (342 ± 26 nM; p<0.001). Valsartan had a more modest effect, increasing NO release by 13% (385 ± 19 nM) as compared to vehicle-treated controls (p<0.01). Treatment with both agents at 1.0 μM increased HUVEC NO release by 91% (655 ± 19 nM) as compared to vehicle alone (p<0.001) and was 29% (p<0.001) and 70% (p<0.001) greater than the separate effects observed for nebivolol and valsartan, respectively. The additive effect of valsartan was dose-dependent and was also observed at 0.5 and 5.0 μM in combination with nebivolol. Conclusions: These data suggest that nebivolol and valsartan, when applied in combination, increase the ability of endothelial cells to release NO in a synergistic manner. The exact mechanism of this process remains unclear but, considering the importance of NO in regulating blood pressure, merits further study.

scholarly journals The human coronary vasodilatory response to acute mental stress is mediated by neuronal nitric oxide synthase

2017 ◽  
Vol 313 (3) ◽  
pp. H578-H583 ◽  
Author(s):  
Sitara G. Khan ◽  
Narbeh Melikian ◽  
Husain Shabeeh ◽  
Ana R. Cabaco ◽  
Katherine Martin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Coronary Artery ◽  
Nitric Oxide Synthase ◽  
Coronary Blood Flow ◽  
Mental Stress ◽  
Coronary Flow ◽  
Neuronal Nitric Oxide Synthase ◽  
Coronary Artery Diameter ◽  
Oxide Synthase

Mental stress-induced ischemia approximately doubles the risk of cardiac events in patients with coronary artery disease, yet the mechanisms underlying changes in coronary blood flow in response to mental stress are poorly characterized. Neuronal nitric oxide synthase (nNOS) regulates basal coronary blood flow in healthy humans and mediates mental stress-induced vasodilation in the forearm. However, its possible role in mental stress-induced increases in coronary blood flow is unknown. We studied 11 patients (6 men and 5 women, mean age: 58 ± 14 yr) undergoing elective diagnostic cardiac catheterization and assessed the vasodilator response to mental stress elicited by the Stroop color-word test. Intracoronary substance P (20 pmol/min) and isosorbide dinitrate (1 mg) were used to assess endothelium-dependent and -independent vasodilation, respectively. Coronary blood flow was estimated using intracoronary Doppler recordings and quantitative coronary angiography to measure coronary artery diameter. Mental stress increased coronary flow by 34 ± 7.0% over the preceding baseline during saline infusion ( P < 0.01), and this was reduced to 26 ± 7.0% in the presence of the selective nNOS inhibitor S-methyl-l-thiocitrulline (0.625 µmol/min, P < 0.001). Mental stress increased coronary artery diameter by 6.9 ± 3.7% ( P = 0.02) and 0.5 ± 2.8% ( P = 0.51) in the presence of S-methyl-l-thiocitrulline. The response to substance P did not predict the response to mental stress ( r2 = −0.22, P = 0.83). nNOS mediates the human coronary vasodilator response to mental stress, predominantly through actions at the level of coronary resistance vessels. NEW & NOTEWORTHY Acute mental stress induces vasodilation of the coronary microvasculature. Here, we show that this response involves neuronal nitric oxide synthase in the human coronary circulation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/nnos-and-coronary-flow-during-mental-stress/ .

Nitric oxide synthase and cGMP-mediated stimulation of renin secretion

2001 ◽  
Vol 281 (4) ◽  
pp. R1146-R1151 ◽  
Author(s):  
Cecilia M. Sayago ◽  
William H. Beierwaltes
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Renal Blood Flow ◽  
No Synthase ◽  
Renin Secretion ◽  
Hemodynamic Changes ◽  
Oxide Synthase ◽  
Stimulation Of

The interaction between nitric oxide (NO) and renin is controversial. cAMP is a stimulating messenger for renin, which is degraded by phosphodiesterase (PDE)-3. PDE-3 is inhibited by cGMP, whereas PDE-5 degrades cGMP. We hypothesized that if endogenous cGMP was increased by inhibiting PDE-5, it could inhibit PDE-3, increasing endogenous cAMP, and thereby stimulate renin. We used the selective PDE-5 inhibitor zaprinast at 20 mg/kg body wt ip, which we determined would not change blood pressure (BP) or renal blood flow (RBF). In thiobutabarbital (Inactin)-anesthetized rats, renin secretion rate (RSR) was determined before and 75 min after administration of zaprinast or vehicle. Zaprinast increased cGMP excretion from 12.75 ± 1.57 to 18.67 ± 1.87 pmol/min ( P < 0.003), whereas vehicle had no effect. Zaprinast increased RSR sixfold (from 2.95 ± 1.74 to 17.62 ± 5.46 ng ANG I · h−1 · min−1, P< 0.024), while vehicle had no effect (from 4.08 ± 2.02 to 3.87 ± 1.53 ng ANG I · h−1 · min−1). There were no changes in BP or RBF. We then tested whether the increase in cGMP could be partially due to the activity of the neuronal isoform of NO synthase (nNOS). Pretreatment with the nNOS inhibitor 7-nitroindazole (7-NI; 50 mg/kg body wt) did not change BP or RBF but attenuated the renin-stimulating effect of zaprinast by 40% compared with vehicle. In 7-NI-treated animals, zaprinast-stimulated cGMP excretion was attenuated by 48%, from 9.17 ± 1.85 to 13.60 ± 2.15 pmol/min, compared with an increase from 10.94 ± 1.90 to 26.38 ± 3.61 pmol/min with zaprinast without 7-NI ( P < 0.04). This suggests that changes in endogenous cGMP production at levels not associated with renal hemodynamic changes are involved in a renin-stimulatory pathway. One source of this cGMP may be nNOS generation of NO in the kidney.

scholarly journals Magnesium causes nitric oxide independent coronary artery vasodilation in humans

Heart ◽  
2001 ◽  
Vol 86 (2) ◽  
pp. 212-216
Author(s):  
H Teragawa ◽  
M Kato ◽  
T Yamagata ◽  
H Matsuura ◽  
G Kajiyama
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Coronary Artery ◽  
Coronary Blood Flow ◽  
Coronary Arteries ◽  
Quantitative Coronary Angiography ◽  
University Hospital ◽  
Nitric Oxide Synthase Inhibitor ◽  
Before And After ◽  
Synthase Inhibitor

OBJECTIVETo determine how magnesium affects human coronary arteries and whether endothelium derived nitric oxide (EDNO) is involved in the coronary arterial response to magnesium.DESIGNQuantitative coronary angiography and Doppler flow velocity measurements were used to determine the effects of the nitric oxide synthase inhibitorNG-monomethyl-L-arginine (L-NMMA) on magnesium induced dilation of the epicardial and resistance coronary arteries.SETTINGHiroshima University Hospital a tertiary cardiology centre.PATIENTS17 patients with angiographically normal coronary arteries.INTERVENTIONSMagnesium sulfate (MgSO4) (0.02 mmol/min and 0.2 mmol/min) was infused for two minutes into the left coronary ostium before and after intracoronary infusion of L-NMMA.MAIN OUTCOME MEASURESDiameter of the proximal and distal segments of the epicardial coronary arteries and coronary blood flow.RESULTSAt a dose of 0.02 mmol/min, MgSO4 did not affect the coronary arteries. At a dose of 0.2 mmol/min, MgSO4 caused coronary artery dilation (mean (SEM) proximal diameter 3.00 (0.09) to 3.11 (0.09) mm; distal 1.64 (0.06) to 1.77 (0.07) mm) and increased coronary blood flow (79.3 (7.5) to 101.4 (9.9) ml/min, p < 0.001 vbaseline for all). MgSO4 increased the changes in these parameters after the infusion of L-NMMA (p < 0.001v baseline).CONCLUSIONSMagnesium dilates both the epicardial and resistance coronary arteries in humans. Furthermore, the coronary arterial response to magnesium is dose dependent and independent of EDNO.

Abstract 447: Sonic Hedgehog Carried By Microparticles Corrects Endothelial Injury Through Nitric Oxide Release

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Abdelali Agouni ◽  
Hadj A Mostefai ◽  
Chiarra Porro ◽  
Nunzia Carusio ◽  
Julie Favre ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Sonic Hedgehog ◽  
Ischemia Reperfusion ◽  
Pi3 Kinase ◽  
Endothelial Injury ◽  
No Release

Microparticles (MPs) are small fragments generated from the plasma membrane of cells upon stimulation. Among the candidate proteins harboured by MPs, we have recently shown that Sonic Hedgehog (Shh) is present in MPs generated from activated/apoptotic human T CEM lymphocytes. MPs were isolated following serial centrifugations. Eahy 926 endothelial cells were grown for 24h in the absence or presence of 10 μg/mL MPs pre-incubated (or not) either with inhibitors of PI3-kinase (LY294002, 20 μM), MEK 1/2 (U0126, 10 μM), cyclopamine (30 μM), a specific antagonist of the Sonic Hedgehog receptor (Patched), or siRNA of Patched. Cell lysates were analyzed by Western blot. Cells were used for direct measurement of nitric oxide (NO), and oxidative stress was determined by flow cytometry. In other experiments, after 24h of intravenous injection of MPs to mice, endothelium-dependent relaxation was determined in aortic rings. In addition, ischemia/reperfusion was induced in mice by ligating the left anterior descending coronary artery proximal to its origin and endothelial function of the distal coronary artery was assessed. We show that Shh carried by MPs: a) induces NO release from endothelial cells under basal (2.5 fold) and after a bradykinin-stimulation (20 μM) conditions (2.6 fold) b) increases both the expression and the phosphorylation of enzymes related to the NO pathway, and c) decreases the production of reactive oxygen species (38.6 ± 1.4 % of positive cells in treated vs. 51.4 ± 0.2 % in control). Inhibition of PI3-kinase and ERK signalling reversed the effects of MPs. Injection of MPs to mice improved endothelial function in aorta (EC 50 ; 8.5 x 10 −8 M of acetylcholine in control vs. 7.05 x 10 −8 M in treated mice) and elevated NO release in blood, heart and lungs (1.4, 1.9 and 2.6-fold, respectively). Mice treated with Shh MPs had reduced coronary endothelial dysfunction after ischaemia/reperfusion. Silencing Shh with either cyclopamine or siRNA of Patched caused a 35 % reduction of NO release elicited by MPs. Based on our findings, we propose that the cardiovascular effects of MPs harbouring Shh may represent a new therapeutic approach against endothelial dysfunction caused by endothelial injury e.g. during cardiac ischemia.

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