[Endothelial control of coronary circulation].
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Coronary Circulation↗
Biomedical subjects
G Losano
Publications and source records attributed to G Losano.
The Gaboon viper, Bitis gabonica: hemorrhagic, metabolic, cardiovascular and clinical effects of the venom.
The effects of Bitis gabonica venom have been studied in several animal species, including the monkey, dog, rabbit, rat and guinea pig. Further information has been provided by observations on the effects of snake bite in man. Bitis gabonica venom exerts a number of cytotoxic and cardiovascular effects: cytotoxic effects include widespread hemorrhage, caused by the presence of two hemorrhagic proteins. These hemorrhagins bring about separation of vascular endothelial cells and extravasation of blood into the tissue spaces. Metabolic alterations include decreased oxygen utilization by tissues and increased plasma glucose and lactate concentrations. Metabolic non-compensated acidosis has also been seen in the rat as a consequence of the cytotoxicity of the venom. Cardiovascular effects include disturbances in atrio-ventricular conduction and reduction in amplitude and duration of the action potential brought about by a decreased calcium membrane conductance. A progressive decrease in myocardial contractility can also be attributed to the decreased calcium conductance, which together with the severe acidosis may cause death in experimental animals. A severe, though reversible, vasodilatation was observed after envenomation due to unidentified compounds in the venom. In man, envenomation causes a variable clinical picture depending on the time course and severity of envenomation. Frequently seen effects include hypotension, hemorrhage at the site of the bite and elsewhere and disseminated intravascular coagulation. Envenomation can be satisfactorily treated with antivenom.
Animals↗
[Mechanisms of ischemic preconditioning: relation with ischemia-reperfusion injury].
If a coronary occlusion long enough to produce a myocardial infarction is preceded by one or more brief periods of occlusion, the infarct size is reduced with respect to the area at risk. Also the ischaemia reperfusion injury is remarkably reduced. Such effects form the ischaemic preconditioning. Ischaemia-reperfusion injury is attributed to a Ca2+ overload of the myocardial fibres together with an inadequate resynthesis of ATP, a loss of membrane phospholipids and a release of free oxygen radicals. The inadequate resynthesis of ATP is responsible for an increased concentration of nucleosides and purinic bases with swelling of the myocardial fibres. The cell Ca2+ overload depends on a reduced activity of the ionic pumps caused by the oxygen lack during ischaemia. During reperfusion the vascular endothelial cells of the previously ischaemic area release free oxygen radicals in response to the activity of the xanthine-oxidase on hypoxanthine produced by the ischaemic myocardium. This initial release of oxygen radicals is responsible for the adhesion of neutrophils to the endothelium. After adhesion also the neutrophils release free radicals due to the activity of NADPH-oxidase on molecular oxygen. Myocardial, neural and endothelial mechanisms account for the protective effect of preconditioning. Myocardial mechanisms include the release of adenosine as well as of antioxidant enzymes. Adenosine, which activates protein-kinase C, favours the phosphorylation of a protective protein, whereas the antioxidant enzymes impair the activity of the free oxygen radicals. Preconditioning may also involve the synthesis of a heat shock protein. Neural mechanisms are represented by a reduced release of noradrenaline from the sympathetic nerve endings and a reduced sensitivity of myocardium to noradrenaline. Finally, vascular endothelial cells take part in preconditioning by means of an increased production of nitric oxide which seems to exert a protection against arrhythmias.
Animals↗
Myocardial, neural and vascular aspects of ischemic preconditioning.
Ischemic preconditioning can be obtained with brief coronary occlusions. It has been studied in different animal species including dogs, pigs, rabbits and rats. The suggested duration of the occlusions ranges from four periods of 5 min, separated from each other by 5 min of reperfusion, to one period of 2.5 min. In addition to the reduction of the size of a subsequent infarction, preconditioning is responsible for the attenuation of the ischemia-reperfusion injury. The protection has a short duration and does not exceed two hours. Myocardial, neural and endothelial factors are involved in preconditioning. The myocardial component includes an increased release of adenosine with activation of A1 adenosine receptors, the activation of a protein-kinase C and possibly of antioxidant enzymes. The neural component includes a reduction in the release of noradrenaline from the postganglionic sympathetic fibers and a reduced myocardial sensitivity to noradrenaline. The increased myocardial release of adenosine, together with the reduced adrenergic activity, is consistent with the reduction in myocardial metabolism which has been observed after preconditioning. The coronary vascular endothelium is concerned in an increased release of nitric oxide which seems to be responsible for a prevention of reperfusion arrhythmias. In addition to the protective effect exerted on the myocardium, ischemic preconditioning seems to be responsible for a change in the coronary responsiveness to short periods of occlusion followed by release. This change in responsiveness is mainly represented by a greater velocity of the increase in flow occurring in the coronary reactive hyperemia.
Animals↗
The role of nitric oxide in the initiation and in the duration of some vasodilator responses in the coronary circulation.
In the coronary bed vasodilation can be mediated by several mechanisms including endothelium-produced nitric oxide. To examine the contribution of nitric oxide, three different techniques to cause vasodilation in the coronary vessels were used in the anaesthetized dog: intracoronary injection of 1 microgram acetylcholine, sudden reduction of the aortic blood pressure inducing a myogenic response and transient occlusion followed by release of the left circumflex coronary artery causing reactive hyperaemia. Each manoeuvre was performed before and after intracoronary administration of 100 mg N-nitro-L-arginine, an inhibitor of the synthesis of nitric oxide. In contrast to previous investigations, the inhibition of nitric oxide synthesis was prevented from causing an increase in blood pressure by the use of a blood-pressure-compensating device. The results observed during each of the three techniques, suggest that the initial cause of the vasodilatation is not the result of the increase of the production of nitric oxide. However, subsequent to the initiation of vasodilation, an increase in the shear stress can result in an increase in the release of nitric oxide from the vascular endothelium, thus prolonging the vasodilatation obtained using each technique.
Acetylcholine↗
Properties of the myocardium affecting the coronary circulation.
The mean coronary blood flow increases in response to an increase in myocardial oxygen consumption. Conversely, an increase in coronary perfusion is itself reported to induce an increase in myocardial oxygen consumption. Such an effect can be explained by stretching of the myocardial fibers surrounding the vessels, which become more distended with an increase in perfusion. The flow in the left descending and circumflex coronary arteries is reduced in systole because of the compression exerted by the contracting myocardium on the intramyocardial vessels. Due to the thinner wall of the right ventricle, this reduction is not obvious in the right coronary artery. The intramyocardial pump model provides a satisfactory explanation of the mechanism by which contraction reduces the flow. It also explains the attenuation of the diastolic-systolic oscillations of flow which occurs in the presence of a stenosis of a large epicardial artery. The varying elastance model shows the dependence of the extent of the reduction of the flow in systole on myocardial contractile force rather than on the pressure developed in the ventricle by the contraction. However, although the ventricular systolic pressure does not affect the flow in hearts with a relatively thick wall, it contributes to the systolic reduction of flow in hearts with a relatively thin wall. Owing to a mechanism involving the coronary capacitance, contraction is also responsible for the level of coronary flow in diastole.
Animals↗
Control of coronary blood flow by endothelial release of nitric oxide.
1. Nitric oxide (NO) is released from vascular endothelium following conversion of L-arginine to L-citrulline by calcium-calmodulin-dependent 'constitutive' NO-synthase. 2. Nitric oxide release occurs under basal conditions, in response to chemical stimuli (acetylcholine, bradykinin, thrombin, prostacyclin, serotonin, etc.) and in response to changes in shear stress (effects of blood velocity on vascular endothelium). 3. Analogues of L-arginine inhibit NO and are widely used to study the effects of NO on the cardiovascular system: in intact animals, these inhibitors cause vasoconstriction, leading to an increase in arterial blood pressure (ABP) and bradycardia. 4. Bradycardia induced by NO inhibitors is due, in part, to baroreceptor activity following the increase in ABP and in part to a direct effect on the sino-atrial node. 5. In the intact animals and isolated perfused heart, NO inhibitors cause coronary vasoconstriction and hence a reduction in basal coronary flow. This effect, however, is not seen in isolated coronary vessels. 6. From experiments in which ABP did not change, NO does not appear to have an important role in regulating coronary vasomotor tone under basal conditions. 7. Nitric oxide appears to be involved in the duration of reactive hyperaemia following coronary vascular occlusion but is not involved to any significant extent in the peak amplitude of hyperaemia. 8. Responses to vasodilator stimuli which do not involve NO in the initiation of the vasodilation may be prolonged by the effect of increased blood flow (shear stress) which releases NO and potentiates hyperaemia.
Animals↗
Increases in coronary intravascular pressure during maximal coronary vasodilatation in the anaesthetized dog.
The present study was planned to investigate whether or not, after complete suppression of vasomotor tone, increases in intravascular blood pressure distend the coronary vasculature causing passive decreases in the resistance to the coronary arterial inflow during the diastole. In anaesthetized dogs, aortic and left ventricular pressures and flow in the left circumflex coronary artery were recorded. Coronary flow was derived using an electromagnetic flowmeter. Transient (10 s) increases in intravascular blood pressure in a range above 70 mm Hg were produced by mechanical constriction of the descending thoracic aorta. In the presence of a normal vasomotor tone the increase in blood pressure caused an autoregulatory increase in the mean diastolic coronary inflow resistance. After maximal vasodilatation by dipyridamole, no change in inflow resistance was induced by the increase in intravascular blood pressure. It may be argued that while a non-maximal vasodilatation is reported to increase coronary distensibility, at a blood pressure of 70 mm Hg the complete suppression of the vasomotor tone brings the vascular radius to a size which cannot be further distended by an increase in blood pressure.
Animals↗
[100 years after his death: Jacopo Moleschott and his time (commemoration held at the Academy of Medicine in Turin on October 14, 1994)].
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Germany↗
Tachycardia and coronary blood flow: non-invasive estimation during Valsalva manoeuvre and exercise.
Simultaneous changes in cycle length and coronary blood flow were studied during Valsalva manoeuvre and supine cycloergometer exercise test in 10 male patients (mean age 48 +/- 12 years) who had successfully undergone myocardial revascularization by surgical anastomosis of the left internal mammary artery on the left anterior descending coronary artery. Blood velocity curves in the left internal mammary artery were obtained by a non-invasive continuous-wave Doppler probe at rest, in the last phase of the expiratory effort of the Valsalva manoeuvre and at the maximum load attained during the exercise test. Mean arterial pressure by sphygmomanometer, and cardiac cycle length on the basis of Doppler recording were measured. Mean blood velocity, the length of the blood column entering the coronary bed at each cycle (cardiac cycle times mean velocity), an index of blood cell acceleration (the ratio of mean velocity to cardiac cycle), and an index of coronary resistance (the ratio of mean pressure to mean velocity), were calculated. For approximately the same change in cycle length, coronary resistance decreased in exercise, with an increased mean velocity, but increased in Valsalva, with no changes in mean velocity. The length of the blood column entering the coronary bed at each cycle was unchanged in exercise, with a marked increase in the acceleration index, while it decreased in Valsalva. Therefore, we hypothesize that tachycardia has a limiting effect on sympathetic coronary constriction in Valsalva when cardiac external work is decreased, and an additional vasodilatory effect on coronary bed in exercise when external work is increased.
Adult↗
"Resistance" to left ventricular outflow studied in anesthetized dogs.
A simple method is proposed to determine resistance to left ventricular output from the evaluation of a parameter Z, given by the ratio of peak systolic pressure and the corresponding instantaneous blood flow. The method, derived from the basic equation of the Windkessel model, is applied to analyze pressure and flow data measured in the ascending aorta of anesthetized dogs. The Z values obtained in this way are found to be closely related to resistance calculated from the ratio of mean aortic pressure and mean flow over the cardiac cycle. Effects of abrupt changes of resistance obtained by removing an aortic constriction are also analyzed according to the same basic Windkessel equation and the results show the same close relationship to resistance.
Animals↗
[The effect of maximal vasodilation on the distensibility of the coronary vascular bed].
This study aimed at investigating the changes in coronary vascular resistance induced by sudden increases in transmural pressure in the presence of a maximally vasodilated coronary bed. In anaesthetized open-chest dogs under artificial ventilation, aortic blood pressure, left ventricular pressure and the flow in the left circumflex coronary artery were recorded. The flow was derived by means of an electromagnetic flowmeter. Maximal vasodilatation was achieved by intracoronary infusion of dipyridamole (10-40 mg/h), increases in transmural pressure, starting from 70 mmHg, were obtained by constricting for 10 s the descending thoracic aorta with a plastic snare. While in the absence of vasodilatation the increase in pressure was accompanied with an increase in resistance because of an auto-regulatory response, when the coronary bed was maximally dilated the increase in pressure did not alter the coronary vascular resistance. These results seem to be in conflict with the observation that in the coronary circulation the distension of the vascular wall produced by increases in pressure is favoured by the reduction of the vasomotor tone. However, it may be argued that, while a reduction of the vasomotor tone can increase the vascular distensibility, a maximal vasodilatation, as it was seen in the resistance vessels of the skeletal muscles, brings the vascular diameter to such a size that no further distension can be induced when the transmural pressure is increased starting from a value of about 70 mmHg.
Animals↗
Coronary flow and left ventricular pressure during diastole in the anaesthetized dog.
There is controversy about the effect of left ventricular pressure on resistance of the intramyocardial coronary vessels. In anaesthetized dogs the effect of left ventricular pressure on coronary flow during diastole was studied using an extracorporeal circulation and allowing the heart to contract and relax isovolumically. At constant coronary perfusion pressure of about 45 mmHg with maximal coronary vasodilatation, produced by dipyridamole, increases in diastolic left ventricular pressure to 22 mmHg, producing a volume of 50 ml, did not affect diastolic coronary flow. It is suggested that in the intact animal over the physiological range of left ventricular diastolic pressure the resistance in the coronary vessels is not affected.
Anesthesia↗
Mechanical properties of the coronary vasculature: indirect evaluation.
Information on the mechanical properties of the coronary vascular bed can be obtained indirectly by modelling the vascular system. This indirect approach, unlike 'in vitro' measurements, allows to take into account the vasomotor conditions of the circulatory district as well as the effect of the surrounding embedding tissue on the vascular performance. An experimental manoeuvre of sudden occlusion and subsequent release of the thoracic descendent aorta on 5 anaesthetized dogs with open pericardium induces a step-like variation in the coronary perfusion pressure and the occurrence of oscillations in the mean coronary flow. Such a behaviour can be described using a second-order model ('windkessel'+inductance, which takes into account blood inertia in the large vessels). The value of the coefficients entering the equations have been obtained with a 'best-fit' procedure (minimum of the chi-squared variable) on the haemodynamical data. Coefficient variations are in agreement with the direct estimation of the myocardial compliance and volume, measured by Ultrasound Echocardiographic imaging (4-chamber projection mode).
Animals↗
[The myogenic mechanism in the autoregulation of the coronary vascular bed].
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Animals↗
Relationship between hyperaemic response and viscoelastic properties in the coronary circulation of the dog.
A sudden reduction in perfusion pressure evokes a transient hyperaemic response in the coronary arteries of anaesthetized dogs; its characteristics depend on the vasomotor tone. A heuristic model, which mimics the vascular bed with a lumped second-order system on the lines of the well-known Windkessel model, but accounting for the blood inertia, is proposed to describe that response and to quantify the viscoelastic properties of the system.
Animals↗
The mechanical effects of rhinoceros horned viper (Bitis nasicornis) venom on the isolated perfused guinea-pig heart.
In the guinea-pig Langendorff heart preparation, addition of 0.1 mg Bitis nasicornis venom to the perfusion solution caused transient increases in heart rate (HR) and left ventricular systolic pressure (LVSP) with peak increases at 2 min. With higher doses (0.6 and 1.4 mg), these increases were followed by the return of HR to normal, significant decreases in LVSP below control values and marked increases in left ventricular diastolic pressure. Histaminergic blockade with ranitidine reduced the positive responses. The results suggest that a venom component, possibly acting on intracellular calcium movement, could be responsible for both positive and negative effects.
Animals↗
The myogenic contribution to coronary autoregulation.
It seems now, mainly from the results of the experiments carried out in the Department of Human Anatomy and Physiology of the University of Turin, Italy, that there is an active myogenic response in the coronary vessels. In response to changes in the transmural pressure, both increases and decreases, in the coronary vessels transient contractions and relaxations (respectively) of the smooth muscle wall can be demonstrated. Although this suggested mechanism can not be fully integrated into a hypothesis explaining autoregulation of blood flow in the coronary vessels it does seem a strong possibility that it takes part; but further investigation will be necessary to clarify all aspects of this kind of regulation.
Animals↗