scholarly journals Functional contribution of P2Y1receptors to the control of coronary blood flow

2011 ◽  
Vol 111 (6) ◽  
pp. 1744-1750 ◽  
Author(s):  
Shawn B. Bender ◽  
Zachary C. Berwick ◽  
M. Harold Laughlin ◽  
Johnathan D. Tune
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Coronary Blood Flow ◽  
Coronary Vasodilation ◽  
Pressure Flow ◽  
Coronary Pressure ◽  
Mrs 2179 ◽  
Dependent Mechanism

Activation of ADP-sensitive P2Y1receptors has been proposed as an integral step in the putative “nucleotide axis” regulating coronary blood flow. However, the specific mechanism(s) and overall contribution of P2Y1receptors to the control of coronary blood flow have not been clearly defined. Using vertically integrative studies in isolated coronary arterioles and open-chest anesthetized dogs, we examined the hypothesis that P2Y1receptors induce coronary vasodilation via an endothelium-dependent mechanism and contribute to coronary pressure-flow autoregulation and/or ischemic coronary vasodilation. Immunohistochemistry revealed P2Y1receptor expression in coronary arteriolar endothelial and vascular smooth muscle cells. The ADP analog 2-methylthio-ADP induced arteriolar dilation in vitro and in vivo that was abolished by the selective P2Y1antagonist MRS-2179 and the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. MRS-2179 did not alter baseline coronary flow in vivo but significantly attenuated coronary vasodilation to ATP in vitro and in vivo and the nonhydrolyzable ATP analog ATPγS in vitro. Coronary blood flow responses to alterations in coronary perfusion pressure (40–100 mmHg) or to a brief 15-s coronary artery occlusion were unaffected by MRS-2179. Our data reveal that P2Y1receptors are functionally expressed in the coronary circulation and that activation produces coronary vasodilation via an endothelium/nitric oxide-dependent mechanism. Although these receptors represent a critical component of purinergic coronary vasodilation, our findings indicate that P2Y1receptor activation is not required for coronary pressure-flow autoregulation or reactive hyperemia.

Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels

2012 ◽  
Vol 303 (2) ◽  
pp. H216-H223 ◽  
Author(s):  
Giacinta Guarini ◽  
Vahagn A. Ohanyan ◽  
John G. Kmetz ◽  
Daniel J. DelloStritto ◽  
Roslin J. Thoppil ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Coronary Blood Flow ◽  
Cardiac Metabolism ◽  
Bk Channels ◽  
Bk Channel ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Channels ◽  
Channel Dependent

We have previously shown transient receptor potential vanilloid subtype 1 (TRPV1) channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1(−/−)], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1–100 μg·kg−1·min−1) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (l-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1(−/−) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 l-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicin-mediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4–6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1(−/−) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channel-dependent pathway that is corrupted in diabetes.

Coronary smooth muscle reactivity to muscarinic stimulation after ischemia-reperfusion in porcine myocardial infarction

2003 ◽  
Vol 95 (1) ◽  
pp. 81-88 ◽  
Author(s):  
Antonio Rodríguez-Sinovas ◽  
Josep Bis ◽  
Inocencio Anivarro ◽  
Javier de la Torre ◽  
Antoni Bayés-Genís ◽  
...  
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Coronary Blood Flow ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Severe Left Ventricular Dysfunction ◽  
Coronary Smooth Muscle

This study tested whether ischemia-reperfusion alters coronary smooth muscle reactivity to vasoconstrictor stimuli such as those elicited by an adventitial stimulation with methacholine. In vitro studies were performed to assess the reactivity of endothelium-denuded infarct-related coronary arteries to methacholine ( n = 18). In addition, the vasoconstrictor effects of adventitial application of methacholine to left anterior descending (LAD) coronary artery was assessed in vivo in pigs submitted to 2 h of LAD occlusion followed by reperfusion ( n = 12), LAD deendothelization ( n = 11), or a sham operation ( n = 6). Endothelial-dependent vasodilator capacity of infarct-related LAD was assessed by intracoronary injection of bradykinin ( n = 13). In vitro, smooth muscle reactivity to methacholine was unaffected by ischemia-reperfusion. In vivo, baseline methacholine administration induced a transient and reversible drop in coronary blood flow (9.6 ± 4.6 to 1.9 ± 2.6 ml/min, P < 0.01), accompanied by severe left ventricular dysfunction. After ischemia-reperfusion, methacholine induced a prolonged and severe coronary blood flow drop (9.7 ± 7.0 to 3.4 ± 3.9 ml/min), with a significant delay in recovery ( P < 0.001). Endothelial denudation mimics in part the effects of methacholine after ischemia-reperfusion, and intracoronary bradykinin confirmed the existence of endothelial dysfunction. Infarct-related epicardial coronary artery shows a delayed recovery after vasoconstrictor stimuli, because of appropriate smooth muscle reactivity and impairment of endothelial-dependent vasodilator capacity.

Effects of Nitric Oxide on Blood Flow and Mucociliary Activity in the Human Nose

1998 ◽  
Vol 107 (1) ◽  
pp. 40-46 ◽  
Author(s):  
Thomas Runer ◽  
Sven Lindberg
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Maximum Increase ◽  
No Donor ◽  
Doppler Flowmetry ◽  
Human Nose

In an animal model, nitric oxide (NO) has been shown to increase mucociliary activity in vivo and ciliary beat frequency in vitro. The aim of the present study was to investigate the effects of NO on blood flow and mucociliary activity in the human nose. The concentration of NO in nasal air was measured with a chemiluminescence technique after nebulizing the NO donor sodium nitroprusside (SNP) at a dose of 3.0 mg into the nose in six volunteers, and was found to increase by 50.1% ± 10.0% (mean ± SEM; p <.001) after the SNP challenge. Blood flow measured by laser Doppler flowmetry increased by 67.3% ± 15.5% (p <.05) after challenge with SNP at 1.0 mg, and by 75.4% ± 18.5% at 3.0 mg (p <.01; n = 6). The higher dose, which produced no subjective side effects, was then used in the mucociliary experiments. The maximum increase in nasal mucociliary activity was 57.2% ± 6.7% at 3.0 mg of SNP (n = 5). The findings support the view that NO regulates mucociliary activity and blood flow in the human nasal mucosa.

Coronary pressure-flow relationship and exercise: contributions of heart rate, contractility, and alpha 1-adrenergic tone

1994 ◽  
Vol 266 (2) ◽  
pp. H795-H810 ◽  
Author(s):  
D. J. Duncker ◽  
N. S. Van Zon ◽  
M. Crampton ◽  
S. Herrlinger ◽  
D. C. Homans ◽  
...  
Keyword(s):  
Heart Rate ◽  
Blood Flow ◽  
Coronary Blood Flow ◽  
Left Ventricular ◽  
Filling Pressure ◽  
Pressure Flow ◽  
Coronary Pressure ◽  
Ventricular Filling Pressure ◽  
Exercise Induced ◽  
Ventricular Filling

We examined the impeding effects of exercise on coronary blood flow by analyzing exercise-induced changes in the pressure-flow relationship during maximal coronary vasodilation with adenosine in chronically instrumented dogs and assessed the individual contributions produced by heart rate, contractility, and alpha 1-adrenergic vasoconstriction. Treadmill exercise that increased heart rate from 118 +/- 6 beats/min at rest to 213 +/- 8 beats/min (P < 0.01) decreased maximum coronary blood flows by decreasing the slope of the linear part of the pressure-flow relationship for coronary pressures > or = 30 mmHg (slopeP > or = 30) from 12.3 +/- 0.9 to 10.9 +/- 0.9 ml.min-1 x g-1 x mmHg-1 (P < 0.01) and increasing the measured coronary pressure at zero flow (P zf,measured) from 12.6 +/- 1.2 to 23.3 +/- 2.0 mmHg (P < 0.01). Atrial pacing at 200 beats/min caused an increase of P zf,measured from 15.0 +/- 1.6 to 18.3 +/- 2.1 mmHg (P < 0.05) with no change in slopeP > or = 30. While pacing continued, infusion of dobutamine (20 micrograms.kg-1 x min-1 i.v.) increased contractility to levels similar to those during exercise but caused no significant change in coronary blood flow, as a decrease of the slopeP > or = 30 was compensated for by a slight decrease in P zf,measured. alpha 1-Adrenergic blockade with intracoronary prazosin (10 micrograms/kg) did not prevent the exercise-induced increase of P zf,measured but abolished the decrease of the slopeP > or = 30. When the increases in heart rate, contractility, and alpha 1-adrenergic vasoconstriction were prevented, exercise still increased P zf,measured from 15.8 +/- 2.1 to 21.8 +/- 2.6 mmHg (P < 0.05) but had no effect on the slopeP > or = 30. This residual increase in P zf,measured correlated with the concomitant increase in left ventricular filling pressure. In conclusion, exercise-induced decreases of maximum coronary blood flow were explained by increases in heart rate, alpha 1-adrenergic vasoconstriction, and left ventricular filling pressure, with a minimal contribution of contractility.

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.

scholarly journals Involvement of Nitric Oxide in Iodine Deficiency-Induced Microvascular Remodeling in the Thyroid Gland: Role of Nitric Oxide Synthase 3 and Ryanodine Receptors

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 707-720 ◽  
Author(s):  
J. Craps ◽  
C. Wilvers ◽  
V. Joris ◽  
B. De Jongh ◽  
J. Vanderstraeten ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Thyroid Gland ◽  
Mrna Expression ◽  
Iodine Deficiency ◽  
Ryanodine Receptors ◽  
No Production

Iodine deficiency (ID) induces microvascular changes in the thyroid gland via a TSH-independent reactive oxygen species-hypoxia inducible factor (HIF)-1α-vascular endothelial growth factor (VEGF) pathway. The involvement of nitric oxide (NO) in this pathway and the role of calcium (Ca2+) and of ryanodine receptors (RYRs) in NO synthase 3 (NOS3) activation were investigated in a murine model of goitrogenesis and in 3 in vitro models of ID, including primary cultures of human thyrocytes. ID activated NOS3 and the production of NO in thyrocytes in vitro and increased the thyroid blood flow in vivo. Using bevacizumab (a blocking antibody against VEGF-A) in mice, it appeared that NOS3 is activated upstream of VEGF-A. L-nitroarginine methyl ester (a NOS inhibitor) blocked the ID-induced increase in thyroid blood flow in vivo and NO production in vitro, as well as ID-induced VEGF-A mRNA and HIF-1α expression in vitro, whereas S-nitroso-acetyl-penicillamine (a NO donor) did the opposite. Ca2+ is involved in this pathway as intracellular Ca2+ flux increased after ID, and thapsigargin activated NOS3 and increased VEGF-A mRNA expression. Two of the 3 known mammalian RYR isoforms (RYR1 and RYR2) were shown to be expressed in thyrocytes. RYR inhibition using ryanodine at 10μM decreased ID-induced NOS3 activation, HIF-1α, and VEGF-A expression, whereas RYR activation with ryanodine at 1nM increased NOS3 activation and VEGF-A mRNA expression. In conclusion, during the early phase of TSH-independent ID-induced microvascular activation, ID sequentially activates RYRs and NOS3, thereby supporting ID-induced activation of the NO/HIF-1α/VEGF-A pathway in thyrocytes.

Effect of systole on coronary pressure-flow relations in the right ventricle of the dog

1980 ◽  
Vol 238 (4) ◽  
pp. H481-H486 ◽  
Author(s):  
R. F. Bellamy ◽  
H. S. Lowensohn
Keyword(s):  
Blood Flow ◽  
Right Ventricular ◽  
Coronary Blood Flow ◽  
Reactive Hyperemia ◽  
Systolic Pressure ◽  
Aortic Pressure ◽  
Ventricular Pressure ◽  
Pressure Flow ◽  
Ventricular Systole ◽  
Coronary Pressure

Downey and Kirk's hypothesis that ventricular systole inhibits coronary blood flow by forming vascular waterfalls was examined in conscious chronically instrumented dogs by studying the effect of right ventricular systole on right coronary blood flow. Diastolic and systolic pressure-flow relations were constructed at resting-level flow and peak flow reactive hyperemia from phasic pressure and flow tracings recorded in nine dogs with right ventricular pressures ranging between 14 and 154 mmHg. Linear relations were found between aortic pressure and right coronary flow during diastolic and during systole when peak ventricular pressure was less than systemic. At resting-level flow and when peak ventricular pressure was less than one-half systemic, systole translated the diastolic relation to a higher zero-flow-intercept pressure and did not alter the slope of the relation. We interpret the data as showing that ventricular systole inhibits coronary blood flow by augmenting a vascular waterfall mechanism that exists during diastole.

Upregulation of neuronal nitric oxide synthase in skeletal muscle by swim training

2000 ◽  
Vol 279 (4) ◽  
pp. H1757-H1766 ◽  
Author(s):  
Rabelais Tatchum-Talom ◽  
Richard Schulz ◽  
J. Robert McNeill ◽  
Fadi H. Khadour
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Similar Degree ◽  
Mesenteric Arterial Bed ◽  
Neuronal Nos ◽  
Oxide Synthase

Exercise enhances cardiac output and blood flow to working skeletal muscles but decreases visceral perfusion. The alterations in nitric oxide synthase (NOS) activity and/or expression of the cardiopulmonary, skeletal muscle, and visceral organs induced by swim training are unknown. In sedentary and swim-trained rats (60 min twice/day for 3–4 wk), we studied the alterations in NOS in different tissues along with hindquarter vasoreactivity in vivo during rest and mesenteric vascular bed reactivity in vitro. Hindquarter blood flow and conductance were reduced by norepinephrine in both groups to a similar degree, whereas N G-nitro-l-arginine methyl ester reduced both indexes to a greater extent in swim-trained rats. Vasodilator responses to ACh, but not bradykinin or S-nitroso- N-acetyl-penicillamine, were increased in swim-trained rats. Ca2+-dependent NOS activity was enhanced in the hindquarter skeletal muscle, lung, aorta, and atria of swim-trained rats together with increased expression of neuronal NOS in the hindquarter skeletal muscle and endothelial NOS in the cardiopulmonary organs. Mesenteric arterial bed vasoreactivity was unaltered by swim training. Physiological adaptations to swim training are characterized by enhanced hindquarter ACh-induced vasodilation with upregulation of neuronal NOS in skeletal muscle and endothelial NOS in the lung, atria, and aorta.

Nitric oxide modulates right ventricular flow and oxygen consumption during norepinephrine infusion

2002 ◽  
Vol 282 (2) ◽  
pp. H696-H703 ◽  
Author(s):  
Srinath Setty ◽  
Johnathan D. Tune ◽  
H. Fred Downey
Keyword(s):  
Nitric Oxide ◽  
Heart Rate ◽  
Blood Flow ◽  
Oxygen Consumption ◽  
Right Ventricular ◽  
Ventricular Function ◽  
Coronary Blood Flow ◽  
Right Ventricular Function ◽  
Utilization Efficiency ◽  
Coronary Vasodilation

This study was designed to test if nitric oxide (NO) contributes to norepinephrine-induced right coronary vasodilation and if NO blunts the norepinephrine-induced increase in myocardial oxygen consumption (MV˙o 2) in the right ventricle. In five anesthetized, open-chest dogs, mean aortic pressure, heart rate, right ventricular rate of pressure development over time (dP/d t), right coronary blood flow, and right ventricular MV˙o 2 were measured before and during graded intracoronary infusions of norepinephrine in the absence and presence of a NO synthase blocker, N ω-nitro-l-arginine methyl ester (l-NAME; 150 μg/min ic). During both conditions, right coronary blood flow and right ventricular MV˙o 2 significantly increased with graded infusions of norepinephrine. l-NAME significantly blunted the coronary hyperemic response to norepinephrine, althoughl-NAME did not alter the relationship between right ventricular MV˙o 2 and norepinephrine dose. However, when right ventricular function was indexed by heart rate × right ventricular maximum dP/d t × peak right ventricular systolic pressure, l-NAME significantly increased the oxygen cost of right ventricular function. These results indicate that NO contributes to norepinephrine-induced right coronary vasodilation and improves right ventricular oxygen utilization efficiency.

The coronary and luminal circulations of the myocardium of fishes

1991 ◽  
Vol 69 (7) ◽  
pp. 1993-2001 ◽  
Author(s):  
Peter S. Davie ◽  
Anthony P. Farrell
Keyword(s):  
Blood Flow ◽  
Coronary Blood Flow ◽  
Species Differences ◽  
Coronary Circulation ◽  
Venous Blood ◽  
Coronary Vessels ◽  
Coronary Perfusion ◽  
Environmental Hypoxia

There are two routes to supply oxygen to the myocardium of fishes, an oxygen-poor luminal supply and, in some fishes, an additional oxygen-rich coronary circulation. When present in teleost fishes, coronary vessels penetrate the myocardium to differing degrees. Elasmobranchs have coronary vessels throughout the myocardium. The different distributions of the coronary vessels reflect solutions to the problem of oxygen diffusion from the luminal blood to various parts of the heart, especially the outer layers of large ventricles. By examining cardiovascular data derived from in vivo experimental perturbations, such as exercise and environmental hypoxia, and from in vitro studies with perfused hearts, we discuss the extent to which luminal venous blood obviates the need for a coronary circulation and the extent to which the coronary circulation supplements the luminal oxygen supply. The oxygen content of the venous blood surpasses the maximal demand of the working heart and so the likely limitation of the luminal blood is the venous partial pressure of oxygen [Formula: see text] which in part determines the oxygen gradient to the mitochondria. The threshold venous [Formula: see text] is between 6 and 16 torr. Whether the coronary circulation is perfused in all species of fishes under resting conditions is not clear. Experimental data support the idea that there are species differences in the relative dependence on the coronary circulation. Coronary perfusion becomes relatively more important in situations where venous [Formula: see text] decreases and myocardial oxygen demand stays the same or increases, e.g., sustained aerobic exercise, environmental hypoxia, and the recovery period after exercise. Observations in vivo and in vitro support the idea that the pressure-generating potential of the heart, as opposed to the potential for flow output, is much more sensitive to changes in coronary blood flow. Coronary blood flow is more likely to be controlled through modulation of a large coronary vasodilatory reserve than through variations in perfusion pressure. Studies on coronary vasoactivity in fishes are limited; nonetheless, species differences are apparent.

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