Coronary Vessel Tone Research Articles

Assessing Vessel Tone during Coronary Artery Spasm by Dual-Acquisition Multidetector Computed Tomography Angiography

Background: Diminished vascular tone is an established biomarker of heart damage. Little is known about the extent of coronary vessel tone (CVT) with spasm as assessed by dual-acquisition multidetector computed tomography angiography (MCTA) in patients with vasospastic angina (VSA). Objective: We evaluated the CVT modulated by intravenous nitrate injection (INI) using MCTA imaging in VSA patients. Methods: Twenty-one VSA patients (60 ± 9 years; 76% males) who underwent initial MCTA (without morning vasodilation), followed by an intracoronary ergonovine provocation test were included. Within 3 days after the initial MCTA patients received INI followed by 28-vessel segment spasm analyzed by MCTA 3D software, applying the following formula as the definition of CVT index (CVTI): (CSA_{IV nitrate} - CSA_initial/CSA_{IV nitrate}) ×100 %, where CSA is the cross-sectional area. Results: Compared to the initial MCTA measures, the INI provocation resulted in the significant increase of average diameter and CSA at the spasm site (2.60 mm [2.11-3.16] vs. 1.42 mm [1.13-2.13]; 5.37 mm² [3.67-7.54] vs. 1.62 mm² [1.02-3.02]; p < 0.001). The CVTI at the spastic segments was higher than at the proximal reference segments (41.0% [21.8-52.3] vs. 18.8% [5.9-26.6] for CVTI diameter; 65.1% [38.6-77.0] vs. 33.9% [5.2-48.1] for CVTI CSA, respectively). To predict VSA, the cut-off value for CVTI diameter was 38.6% (AUC 0.777; 95% CI 0.653-0.901) and 62.5% (AUC 0.779; 95% CI 0.657-0.902) for CVTI CSA in a receiver-operating characteristic curve analysis, with 57.1% sensitivity and 92.9% specificity. Conclusions: This novel imaging technique for assessing CVT by dual-acquisition MCTA after applying INI provocation is suitable for the detection of coronary artery spasm in patients with VSA.

Nitrosyl active sites of ferredoxines biomimetics as NO donors for acute coronary syndrome therapy

In studies of the reaction mechanisms of NO intermediates, the synthesis of analogs of cellular nitrosyl adducts has gained increasing importance. It has been reliably established that iron nitrosyl complexes with thiol-containing ligands play important roles in organisms, such as cellular NO storage and transport. Synthesis of synthetic analogs modeling nitrosyl [2Fe-2S] proteins reactivity is an important problem from the point of view practical medicine for the design prodrugs based on natural sources. Recent research in the field of molecular cardiology revealed the key role of NO in the regulation of vascular tone and metabolism of myocardium. The lack of NO results in the development of endothelial disfunction, which in turn is a reason of higher tone of coronary vessels and higher aggregation and adhesion capability of thrombocytes. Ischemic and reperfusion disruption provide the development of the “no reflow” syndrome, which results in the progressive deterioration of blood flow and finally the death of cardiac hystiocytes. Nitrosyl iron complexes with functional sulfur-containing ligands were studied on the models of ischemic and reperfusion heart damage of rats Wistar in vitro and in vivo, and were shown to have a cardioprotective effect. They can be used for the preparation of unique medications in the therapy of acute coronary event. Vasodilatation properties of these compounds affect the restoration of coronary flow; reduction of systolic blood pressure; improvement of restoration, metabolism and heart function after ischemia; reduction of the dimensions of myocardial infarction.

A novel role for endothelial KATP channels in regulating coronary blood vessel tone

ATP-sensitive K+(KATP) channels couple cellular energy status to membrane excitability. Although it is established that KATP channels regulate coronary blood vessel tone, the specific role of endothelial KATP channels is unknown. We transgenically targeted endothelial KATP channels by expressing a dominant-negative Kir6.1 subunit under the control of the Tek promoter. Histologically, the coronary endothelium was preserved in transgenic (TG) mice. Ergonovine did not induce coronary vasospasm and the mean blood pressure was not detectably different in these mice. The nitric oxide pathway was intact since bradykinin decreased the coronary perfusion pressure (CPP). Levcromakalim also decreased the CPP, most likely by acting on smooth muscle KATP channels. In contrast, the CPP of isolated hearts was substantially elevated in TG mice. Pre-treatment of mice with bosentan [an endothelin-1 (ET-1) receptor antagonist] normalized the CPP, suggestive of an enhanced ET-1 release. Indeed, ET-1 levels (measured by RIA) were elevated in the coronary effluent of TG hearts. KATP channel blockers (e.g. tolbutamide) similarly elevated ET-1 release; both from isolated rat hearts and from cultured human coronary artery endothelial cells. In conclusion, our data suggest a novel role for endothelial KATP channels in regulating coronary vessel tone by controlling regulated exocytosis of the vasoconstrictor ET-1.

Nitric oxide and cardiac function: ten years after, and continuing.

Nitric oxide (NO) is produced from virtually all cell types composing the myocardium and regulates cardiac function through both vascular-dependent and -independent effects. The former include regulation of coronary vessel tone, thrombogenicity, and proliferative and inflammatory properties as well as cellular cross-talk supporting angiogenesis. The latter comprise the direct effects of NO on several aspects of cardiomyocyte contractility, from the fine regulation of excitation-contraction coupling to modulation of (presynaptic and postsynaptic) autonomic signaling and mitochondrial respiration. This multifaceted involvement of NO in cardiac physiology is supported by a tight molecular regulation of the three NO synthases, from cellular spatial confinement to posttranslational allosteric modulation by specific interacting proteins, acting in concert to restrict the influence of NO to a particular intracellular target in a stimulus-specific manner. Loss of this specificity, such as produced on excessive NO delivery from inflammatory cells (or cytokine-stimulated cardiomyocytes themselves), may result in profound cellular disturbances leading to heart failure. Future therapeutic manipulations of cardiac NO synthesis will necessarily draw on additional characterization of the cellular and molecular determinants for the net effect of this versatile radical on the cardiomyocyte biology.

Differential leukotriene constrictor responses in human atherosclerotic coronary arteries.

Leukotrienes are a class of biologically active lipids that have potent effects on the heart. To assess their role in coronary artery disease, we compared the contractile responses of leukotriene C4 (LTC4) and leukotriene D4 (LTD4) and their binding activity in both atherosclerotic and nonatherosclerotic human coronary arteries. We also studied expression of the enzymes that control their formation to understand how the 5-lipoxygenase (5-LO) pathway is activated in the coronary arteries. The capacity of leukotrienes to affect coronary vessel tone and the influence of atherosclerosis was tested in organ baths. Leukotriene receptors were examined by autoradiography, and antibody binding to the various enzymes responsible for their formation was assessed by use of immunocytochemistry. Nonatherosclerotic coronary artery ring segments were unresponsive to LTC4 and LTD4. In contrast, LTC4 and LTD4 induced concentration-dependent contractions in atherosclerotic coronary arteries. Specific [3H]-LTC4 but not LTD4 binding to atherosclerotic coronary artery was evident, with no evidence of specific binding of [3H]-leukotrienes to nonatherosclerotic coronary artery. High-resolution autoradiography identified specific [3H]-LTC4 binding sites to smooth muscle cell and to regions of intimal proliferation and plaque. Cells showing positive antibody binding to 5-LO, FLAP (5-lipoxygenase activating protein), and leukotriene A4 hydrolase were also present in the coronary arteries and had a similar distribution to macrophages. Atherosclerosis is associated with a specific leukotriene receptor(s) capable of inducing hyperreactivity of human epicardial coronary arteries in response to LTC4 and LTD4.

Nitric oxide and cardiac function.

Nitric oxide (NO) is produced from virtually all cell types composing the myocardium and regulates cardiac function through both vascular-dependent and -independent effects. The former include regulation of coronary vessel tone, thrombogenicity, and proliferative and inflammatory properties as well as cellular cross-talk supporting angiogenesis. The latter comprise the direct effects of NO on several aspects of cardiomyocyte contractility, from the fine regulation of excitation-contraction coupling to modulation of (presynaptic and postsynaptic) autonomic signaling and mitochondrial respiration. This multifaceted involvement of NO in cardiac physiology is supported by a tight molecular regulation of the three NO synthases, from cellular spatial confinement to posttranslational allosteric modulation by specific interacting proteins, acting in concert to restrict the influence of NO to a particular intracellular target in a stimulus-specific manner. Loss of this specificity, such as produced on excessive NO delivery from inflammatory cells (or cytokine-stimulated cardiomyocytes themselves), may result in profound cellular disturbances leading to heart failure. Future therapeutic manipulations of cardiac NO synthesis will necessarily draw on additional characterization of the cellular and molecular determinants for the net effect of this versatile radical on the cardiomyocyte biology.

Changes in the coronary vessel tone resulting from immobilization stressA

Coronary perfusion pressure at increasing flow of Krebs-Henseleit buffer in the hearts of animals exposed to stress is decreased 23%, a decrease which is eliminated by administering the NO-synthase blocker NG-monomethyl-L-arginine. Stimulated vasodilation of coronary vessels (administration of sodium nitroprusside and acetylcholine) decreases markedly in stressed animals; the concentrations of sodium nitroprusside and acetylcholine inducing a half-maximum coronary response increase.

Adenosine is not the sole vasodilator released on exposure of isolated guinea-pig hearts to histamine and isoprenaline

1. The role of adenosine in the control of coronary vessel tone was studied using two guinea-pig hearts in series. Vasodilatory mediator(s) released by the donor heart were assayed by the recipient heart. 2. Adenosine deaminase reduced the activity of vasodilatory mediator(s) released by histamine and isoprenaline by 58.0 ± 14.4% and 80.5 ± 5.9% respectively; responses to exogenous adenosine were abolished. 3. Adenosine deaminase added to the donor perfusate supplying the recipient heart caused a significant increase in basal perfusion pressure. 4. Our results suggest adenosine is not the sole mediator of vasodilation in stressed hearts and additionally unstressed hearts appear to release a basal vasodilatory level of adenosine.

Interactions between nitric oxide and prostacyclin in myocardial ischemia and endothelial cell cultures.

This study investigates biochemical and functional interactions between NO and PGI2 that generate pathways in two different in vitro assays: porcine aortic endothelial cells (PAEC) and reperfused ischemic Langendorff hearts of rabbits. Using cGMP as an index of NO generation and 6-oxo-PGF1 alpha as an index for PGI2 production in endothelial cells, it is demonstrated that the two metabolic pathways for NO and prostacyclin formation act independent of each other. Moreover, NO appears to have an autocrine function in endothelial cells which does not exist with PGI2, probably because of a lack of PGI2 receptors. Endothelial damage in the course of myocardial ischemia is associated with a marked increase in mediator release whose inhibition has consequences for both myocardial and coronary function: inhibition of NO formation also inhibits PGI2 release and the recovery of coronary vessel tone with only minor if any effect on myocardial contractility. In contrast, inhibition of PGI2-generation results in marked deterioration of myocardial recovery with only minor changes in coronary perfusion. It is concluded from these data that PGI2 in endothelial injury is important for preservation of myocardial function while NO might mainly be involved in control of local vessel tone.

What causes silent myocardial ischemia?

Myocardial ischemia is an imbalance between consumption and production of adenosine triphosphate (ATP) that leads to ATP depletion and a cascade of biochemical events. Why some patients have pain during these events while others do not is unclear, but some studies indicate that a combination of pain threshold and magnitude of ischemia may be at work. Ischemia can occur during vigorous or daily activities or at rest and can be influenced by mental stress. It is most common in the morning hours, possibly because heart rate, blood pressure, and contractility rise rapidly in the morning and factors that increase coronary vessel tone and reduce blood flow also increase during these hours. The specific pathophysiology of an ischemic episode depends on whether the patient also has chronic stable coronary disease, variant angina, or unstable angina, not on whether the episode is silent or symptomatic.

Generation of NO from Molsidomine (SIN-1) in vitro and Its Relationship to Changes in Coronary Vessel Tone

Generation of NO from Molsidomine (SIN-1) in vitro and Its Relationship to Changes in Coronary Vessel Tone

Generation of NO from Molsidomine (SIN-1) in vitro and Its Relationship to Changes in Coronary Vessel Tone

The release of NO from SIN-1, the active metabolite of molsidomine, was measured in vitro in Langendorff-perfused rabbit hearts. NO in the coronary effluent was determined on-line using the oxyhemoglobin technique. Left ventricular and coronary perfusion pressure were also recorded continuously. Glyceryl trinitrate and iloprost were used as reference compounds. Infusion of SIN-1 or glyceryl trinitrate into the coronary inflow resulted in a significant and dose-dependent NO release. An apparently identical response was seen when SIN-1 was infused into the coronary effluent while the response to glyceryl trinitrate was greatly reduced or abolished. The glyceryl trinitrate-induced coronary vasodilation was only slightly diminished in presence of oxyhemoglobin whereas the response to SIN-1 was abolished. This is explained by complete scavenging of NO by oxyhemoglobin within the vessel lumen. In isolated porcine aortic endothelial cells, SIN-1 induced a significant and dose-dependent increase in cyclic GMP, whereas glyceryl trinitrate was ineffective. This would argue against biotransformation of glyceryl trinitrate to NO by endothelial cells. Finally, glyceryl trinitrate-tolerant heart preparations exhibited a considerably reduced or even undetectable release of NO, whereas the response to SIN-1 was unchanged.

The Effects of Molsidomine and Its Metabolite SIN-1 on Coronary Vessel Tone, Platelet Aggregation, and Eicosanoid Formation In Vitro???Inhibition of 12-HPETE Biosynthesis

We studied the action of the biologically active metabolite of molsidomine, N-morpholino-N-nitrosoamino-acetonitrile (SIN), on eicosanoid formation and functional behavior of bovine coronary arteries and human platelets in vitro. Glyceryltrinitrate (GTN) and prostaglandin (PG) I2 were used as reference compounds. SIN dose-dependently inhibited the thrombin-, collagen-, and primary ADP-induced platelet aggregation. The IC50 was in the range of 0.1-0.8 mumol/L. At these concentrations SIN also inhibited thromboxane formation, but did not influence the PGI2 biosynthesis of coronary vessels. Molsidomine itself was inactive. GTN stimulated vascular PGI2 formation, but did not modify the platelet aggregation at comparable concentrations. A particularly interesting finding was the dose-dependent and apparently complete inhibition of formation of the hydroperoxide of 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) in human platelets by SIN. The IC50 amounted to 1.7 +/- 0.4 mumol/L and was in the same range as with 5,8,11,14-eicosatetraynoic acid (2.0 +/- 0.3 mumol/L). Although the results may not suggest a common mechanism of the antiaggregatory action of GTN and SIN, they provide no evidence of a similar or dissimilar mechanism of action in vascular smooth muscle.

The effects of periarterial nerve activation on coronary vessel tone in an isolated and perfused slab of beef ventricle

The direct effects of extrinsic nerve stimulation on coronary artery tone are unclear because of the complications arising from alterations in myocardial dynamics which themselves alter flow. An isolated and perfused nonbeating slab of beef ventricle was utilized in the present experiments to eliminate secondary complications and the efects of periarterial nerve activation on coronary perfusion pressure were examined. It was found that stimulation induced vasoconstrictor responses which were enhanced by physostigmine, a cholinesterase inhibitor, and blocked by atropine. These responses were duplicated by exogenous acetylcholine both in the perfused preparation and in isolated strips of coronary artery. Although added noradrenaline gave vasodilatation, no response attributable to the release of noradrenaline from nerves was obtained. It is concluded that the coronary vasculature of the beef receives a cholinergic innervation and that its activation, especially under conditions of reduced transmitter degradation, may induce considerable coronary vessel constriction.

The effect of potassium on the coronary circulation

The influence of potassium on the coronary circulation was studied. Experiments were carried out on dogs under morphine-urethane anesthesia with the use of thermoelectric recording of the coronary circulation volume velocity, and with the resistography method with perfusion through the coronary artery at constant blood volume. Intracoronary and intravenous injections of different doses of potassium chloride caused coronary dilatation. Large doses led to cardiac arrest. In most of the cases there was a reduction of the cardiac blood supply after application of concentrated potassium chloride solution to the epicardium. However, it·increased in rare cases when the blood pressure was greatly elevated, thus compensating a slight rise of the coronary vessel tone. The coronary tone rose to a greater degree at the place of K application than in the remote zone. In these experiments the EKG changes seen were similar to those observed in myocardial infraction. They did not correlate with changes of coronary circulation.

The effect of analgesics on the coronary circulation

The author studied the effect of analgesics (morphine, thecodin, phenadon and promedol) on the blood output from the coronary sinus and the tone of the coronary blood vessels in cats. Of the analgesics mentioned only morphine increases the cardiac blood supply. In the majority of cases the introduction of promedol and phenadon leads to a decrease of the volume velocity of the coronary blood flow, increasing the tone of coronary vessels. Thecodin exerts no material effect on the coronary circulation.