[Endothelial control of coronary circulation].
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Coronary Circulation↗
Biomedical subjects
D Gattullo
Publications and source records attributed to D Gattullo.
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 heart rate after inhibition of nitric oxide release in the anaesthetized dog.
1. The effect of nitric oxide (NO) inhibition on heart rate was studied in anaesthetized vagotomized dogs. 2. The effect of changes of baroreceptor stimulation was prevented using an arterial pressure reservoir. 3. After NO-inhibitor (Nitro-L-arginine), heart rate decreased by 8% in spite of an unchanged pressure. 4. When upstream pressure was increased by constriction of the descending aorta, heart rate decreased by 4% before and after inhibition. Owing to the vagotomy this decrease was attributed to a sympathetic tone reduction following baroreceptor stimulation. 5. The results show that NO-inhibition reduces heart rate independently of an increased baroreceptor stimulation and does not reduce the basal sympathetic control on the sinus-atrial node.
Anesthesia, General↗
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↗
The effect of the inhibition of the endothelial release of nitric oxide on coronary reactive hyperaemia in the anaesthetized dog.
The effect of the inhibition of the endothelial release of nitric oxide (NO) on the hyperaemia which follows a 10 s coronary occlusion was studied in anaesthetized dogs. Aortic blood pressure was kept constant during the experiments using an arterial reservoir connected with the femoral arteries. The blood flow in the left circumflex coronary artery was recorded with an electromagnetic flow probe. A 10 s coronary occlusion was performed before and after intracoronary infusion of Nitro-L-arginine (LNNA), at the dose of 100 mg in 20 min. The effect of LNNA in preventing the release of NO by the endothelium was demonstrated by the reduced coronary hyperaemia which follows the intracoronary infusion of acetylcholine. After LNNA the baseline coronary flow was not altered. Following the release of the coronary occlusion the peak amplitude of the reactive hyperaemia was not significantly changed, while the duration was reduced to almost a half of the control. The results suggest that in the intact dog NO is not important in the regulation of the baseline coronary vasomotor tone. It may also be argued that the peak amplitude of the hyperaemia is not significantly affected by LNNA either because the inhibition of the release of nitric oxide is counteracted by a greater production of adenosine, or because a mechanism not affected by nitric oxide (e.g. a myogenic mechanism) is involved in the reactive hyperaemia. In contrast the reduction of the duration of the hyperaemia after the inhibitor may depend on a reduced effect of the shear stress of the blood on the endothelium during the reactive hyperaemia.
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↗
The effect of pure right ventricular ischemia on right and left ventricular performance in the anesthetized dog.
This study was planned to investigate the effect of ischemic dysfunction of the free wall of the right ventricle on right and left ventricular performance in the presence of a normally contracting interventricular septum. The experiments were performed in 6 anesthetized dogs in which echocardiogram, electrocardiogram, aortic blood pressure and left and right ventricular pressure were recorded. In the dog, the contractility of the septum is not affected by the occlusion of the right coronary artery which does not perfuse this part of the myocardium. Complete occlusion of the major individual ventricular branches and partial occlusion of the main right coronary artery did not impair right ventricular performance. Only complete occlusion of the main artery affected right and left ventricular function as revealed by echocardiogram. Reduced output by the ischemic right ventricle caused a reduction in left ventricular diastolic and systolic dimensions and in left ventricular developed pressure without any effect on left ventricular end-diastolic pressure.
Animals↗
"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↗
[The myogenic mechanism in the autoregulation of the coronary vascular bed].
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Animals↗
The mechanical and electrical effects of rhinoceros viper (Bitis nasicornis) venom on the isolated perfused guinea pig heart and atrial preparations.
The mechanical and electrical effects of the venom of Bitis nasicornis were studied on the guinea-pig Langendorff and left atrial myocardium preparations. While Langendorff preparations were treated with individual doses of 0.1, 0.6 and 1.4 mg, isolated left atria were treated using concentrations of 2.0, 20 and 200 micrograms/ml of venom in the perfusion solution. In the Langendorff preparation, transient increases in left ventricular systolic pressure (LVSP) and heart rate (HR) were seen after 0.1 mg of venom. When 0.6 mg of venom was given, the increases were followed by decreases, while 1.4 mg doses simply induced decreases in LVSP and HR. After both 0.6 and 1.4 mg doses the decreases were accompanied by increases in left ventricular diastolic pressure. In addition to these mechanical effects, transient increases in HR with atrio-ventricular blocks, ventricular extrasystoles and tachycardia were observed after each dose. In the left atrium the 2 micrograms/ml venom concentration produced an increase, followed by a decrease, in the maximum tension developed, which was only seen to decrease with higher concentrations of 20 and 200 micrograms/ml of venom. A dose dependent significant reduction in the action potential duration was observed for the doses of 0.6 and 1.4 mg in the ventricle and for all three concentrations in the atrium.
Action Potentials↗
Acidotic effect of gaboon viper (Bitis gabonica) venom in the urethane-anaesthetized rat.
1. Intravenous venom (4 mg/kg) caused a non-compensated metabolic acidosis. 2. Bicarbonate concentration, base excess, standard base excess and pH all fell dramatically. 3. A respiratory impairment occurred characterized by pulmonary oedema and a fall in arterial pO2. 4. Acidosis occurred soon after venom when pO2 was still normal, indicating that changes in tissue metabolism contributed to the acidosis independently of reduced oxygen availability.
Acid-Base Equilibrium↗
The haemodynamic effect of Bitis nasicornis (rhinoceros horned viper) venom.
1. Intravenous venom (0.0625 mg/kg) in the dog caused an immediate increase in coronary blood flow due to a fall in coronary vascular resistance (CVR). 2. Subsequently, total peripheral resistance (TPR) fell causing a significant reduction in aortic blood pressure (ABP). 3. CVR and TPR returned to normal after 20 min but ABP did not recover completely. 4. The failure of ABP to recover was due to decreased stroke volume and cardiac output (CO). 5. Animals died after four doubling doses of venom following irreversible reductions in CO, ABP and coronary flow.
Animals↗