Pulmonary Microcirculation in Experimental Model of Pulmonary Thromboembolism after Pretreatment with Chloroquine.

Changes of pulmonary microcirculation in response to pulmonary artery embolization after pretreatment with chloroquine were studied on the model of isolated perfused rabbit lungs. The increase in the pulmonary vascular resistance and pre- and postcapillary resistance was less pronounced than after pulmonary thromboembolism after pretreatment with mibefradil (T-type Ca2+ channels blocker) or nifedipine (L-type Ca2+ channels blocker). The shifts of capillary filtration coefficient correlated with changes in the precapillary resistance. When modeling pulmonary thromboembolism after pretreatment with chloroquine combined with glibenclamide (KATP channels blocker), the studied hemodynamics parameters increased to the same extent as after pretreatment with nifedipine. The results indicate that chloroquine exhibits the properties of an L- and T-type Ca2+ channels blocker and an activator of KATP channels.

Changes of Pulmonary Microhemodynamics in Experimental Pulmonary Thromboembolism after Pretreatment with K-Channel Activators.

Changes in pulmonary microhemodynamics in response to pulmonary embolism under conditions of activation of KATP channels with nicorandil, Kv channels with dapagliflozin, and BKCa channels with Evans blue were studied on isolated rabbit lungs. Under conditions of activation of KATP and BKCa channels, the constrictor reactions of the pulmonary arterial vessels during embolization of the pulmonary artery were less pronounced than in the control. Activation of BKCa channels reduced constrictor reactions of the pulmonary venous vessels, while activation of KATP and Kv channels eliminates them. The shifts of the capillary filtration coefficient are determined to a greater extent by the pre-/postcapillary resistance ratio, than by changes of the endothelial permeability. Pretreatment with dapagliflozin led to a decrease in the capillary filtration coefficient. It was established, that nimesulide exhibits properties of a BKCa-channel activator.

[Pulmonary artery denervation in pulmonary hypertension: physiological and clinical aspects]. / Denervatsiia legochnoi arterii pri legochnoi gipertenzii: fiziologicheskie i klinicheskie aspekty.

This article is a review of the findings of experimental and clinical studies of a new method of treatment of pulmonary hypertension - pulmonary artery denervation with the help of radiofrequency ablation, cryodenervation and ultrasonic impact. Pulmonary artery denervation results in decreased neurogenic tonic sympathetic and, probably, increased parasympathetic effects on pulmonary vessels. On models of experimental monocrotaline-induced pulmonary hypertension in various-species animals, it was determined that pulmonary artery denervation is followed by decreased activity of local pulmonary renin-angiotensin system, slowed processes of remodeling of pulmonary vessels, hypertrophy and fibrosis of the right ventricle, with inhibition of progression of pulmonary hypertension by means of suppression of extracellular signal-regulated kinase 1/2 (ERK 1/2) which regulates differentiation, proliferation and migration of smooth muscle cells. However, the problem of the pattern of pulmonary microcirculation changes (pre- and postcapillary resistance, capillary filtration coefficient) after pulmonary artery denervation warrants further study. The findings of clinical studies in patients with pulmonary hypertension suggest that pulmonary artery denervation inducing a decrease of pressure therein, as well as pulmonary vessel resistance did not lead to normalization of pulmonary haemodynamics.The mentioned impact partially removes the neurogenic component of multicircuit and multifactorial regulation of pulmonary circulation. Therefore, along with pulmonary artery denervation, further search for pharmacological agents selectively influencing pulmonary vessels remains a problem of current importance.

[Spontaneous fibrinolysis and possibilities of its acceleration in pulmonary embolism]. / Spontannyi fibrinoliz i vozmozhnosti ego uskoreniia pri tromboémbolii legochnoi arterii.

This review contains the data concerning the mechanisms of spontaneous fibrinolysis in pulmonary vessels and possibilities of its acceleration in pulmonary embolism. The spontaneous fibrinolysis system is known to be sequential and multifactorial, with the interaction of accelerators (t-PA and u-PA) and inhibitors (alpha-2-antiplasmin, PAI-1, TAFI). The fibrinolytic processes take place in case of prevailing reactions of accelerating factors over inhibiting ones. The endothelium of pulmonary vessels possesses pronounced antithrombogenic and profibrinolytic properties, therefore, the processes of fibrinolysis in the pulmonary vascular bed normally occur more intensively than in the vessels of the systemic circulation. The membrane proteins of the endothelium annexins A2 activate plasminogen, whereas thrombomodulin inhibits the activity of PAI-1. The main approaches to increase the fibrinolysis intensity in conditions of pulmonary embolism may be aimed at elevating the activity of fibrinolytic enzymes (enhancing the synthesis of annexins A2, the use of NMDA-receptor antagonists) and suppressing its inhibitors (the use of monoclonal antibodies to alpha-2-antiplasmin, as well as plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI). Promising directions for future research can be the synthesis of a new generation of tissue-type plasminogen activators, and investigations of the possibility of clinical application of antithrombin and thrombomodulin, angiotensin converting enzyme inhibitors and cortisol antagonists. To meet these challenges, it is necessary to develop new models of venous thrombosis and acute pulmonary embolism in different animal species, with the assessment of the changes in the venous haemodynamics and pulmonary microcirculation on the background of administration of a new class of fibrinolytic agents.

Pulmonary Microcirculation during Experimental Pulmonary Thromboembolism under Conditions of Activation and Blockade of Muscarinic Acetylcholine Receptors.

Changes in pulmonary microcirculation were studied in isolated perfused rabbit lungs during modelling pulmonary thromboembolism under conditions of acetylcholine infusion against the background of treatment with M1 acetylcholine receptor blocker pirenzepine or blockade of muscarinic acetylcholine receptors with atropine. In the first case, the increase in pulmonary artery pressure was less pronounced than in case of atropine treatment. In response to pulmonary embolism after acetylcholine infusion against the background of pirenzepine pretreatment, the capillary hydrostatic pressure and postcapillary resistance did not change, while after atropine treatment, these parameters increased. In case of pulmonary embolism after acetylcholine infusion combined with selective blockade of M1 muscarinic acetylcholine receptors, the capillary filtration coefficient increased to a greater extent, than in the control and after blockade of muscarinic acetylcholine receptors.

Role of ß3-Adrenoceptor Activation in Changes of Pulmonary Microhemodynamics after Experimental Pulmonary Thromboembolism.

Changes in pulmonary microhemodynamics during modelling of pulmonary thromboembolism against the background of nebivolol and mirabegron pretreatment were studied in isolated perfused rabbit lungs. In both cases, the pulmonary artery pressure and precapillary and pulmonary vascular resistance increased to a greater extent than in control animals, but the increase in capillary hydrostatic pressure was less pronounced. The postcapillary resistance did not change in pulmonary embolism against the background of nebivolol administration and increased in case of mirabegron pretreatment; capillary filtration coefficient after nebivolol pretreatment increased less markedly than after mirabegron administration. The increase in capillary filtration coefficient after activation of ß3-adrenoceptors with the specified drugs depended on the ratio of constriction of pulmonary veins, capillary hydrostatic pressure, and endothelial permeability.

[Adrenergic mechanisms of regulation of pulmonary microvessels tonicity and endothelial permeability]. / Adrenergicheskie mekhanizmy reguliatsii tonusa mikrososudov legkikh i pronitsaemosti éndoteliia.

The review contains the data on adrenergic mechanisms of regulation of pulmonary microvessels tonicity and endothelial permeability. On smooth muscle cells of pulmonary vessels there are postsynaptic α1A-, α1B-, α1D- and α2A-, α2B-, α2C-adrenoreceptors whose activation by norepinephrine induces vasoconstriction. Excitation of ß1- and ß2-subtypes of adrenoreceptors leads to vasodilatation, Activation of α1-2- and ß1-3-adrenoreceptors of the endothelium contributes to enhancement of nitric oxide synthesis. The resulting reaction of pulmonary microvessels in response to administration of catecholamines appears be determined by interaction of adrenergic mechanisms of regulation of tonicity of smooth muscle cells and synthesis of nitric oxide by the endothelium. Constrictor and dilator reactions of pulmonary venous vessels in response to activation of α- and ß-adrenoreceptors, respectively, are more pronounced than in pulmonary arteries and make a significant contribution to the shifts of pulmonary vascular resistance. Excitation of α2- and ß2-adrenoreceptors of endothelial cells of microvessels of the lungs contributes to a decrease in their permeability. In order to find out the role of adrenergic mechanisms in shifts of the capillary filtration coefficient in simulating various pathology of pulmonary circulation, it is necessary to carry out integral studies that would make it possible to evaluate alterations in macro- and microhaemodynamics of the lungs.

Pulmonary Microcirculation in Experimental Model of Pulmonary Thromboembolism under Conditions of α-Adrenoceptor Blockade.

Changes in the pulmonary microcirculation in isolated perfused rabbit lungs during modeling of pulmonary thromboembolism were studied in control animals and against the background of α-adrenoceptors blockade with phentolamine. Intravenous injection of emboli to control animals was followed by an increase in pressure in the pulmonary artery, mean capillary hydrostatic pressure, capillary filtration coefficient, pulmonary vascular resistance, as well as precapillary and postcapillary resistances. Against the background of α-adrenoceptor blockade, the increase in most parameters was less pronounced than in control animals, while capillary filtration coefficient increased more drastically. Thus, adrenergic mechanisms are involved in the constrictor reactions of both arterial and venous pulmonary vessels under conditions of pulmonary thromboembolism.

Peculiarities of Blood Flow Changes in Venae Cavae during Experimental Pulmonary Embolism.

The model of acute pulmonary embolism in rabbits demonstrated reduced pulmonary blood flow, cardiac output, left atrial pressure, and blood flow in venae cavae against the background of elevated left pulmonary artery pressure and increased pulmonary vascular resistance. Simultaneously, the blood flow in the superior vena cava decreased to a lesser extent than that in the inferior vena cava, which was a characteristic feature of the model of pulmonary pathology. In contrast, when histamine was infused into the left jugular vein to equally elevate pressure in pulmonary artery as in the above model, the blood flow in the superior vena cava decreased to a greater extent than that in inferior vena cava. During stenosis of inferior vena cava that decreased the cardiac output to the level observed during modeled pulmonary embolism, the blood flows in both venae cavae dropped equally.

[Role of the endothelium in pathogenesis of chronic postembolic pulmonary hypertension].

The review contains the data concerning the role of the endothelium in the development of chronic postembolic pulmonary hypertension. It is noted that this pathology is associated with changes in the balance of vasoconstrictors and vasodilators, as well as haemostasis factors synthesized by the endothelium, thus leading to remodelling of not only pulmonary arterioles but venous pulmonary vessels. Along with it, the mechanisms of the endothelial function and biochemical markers of this process in patients with chronic postembolic pulmonary hypertension remain insufficiently studied. Such markers may be an increase in blood plasma concentrations of fibrinopeptide A, factor VIII, von Willebrand factor, endothelin I and vascular endothelial growth factor along with a decrease in the level of thrombomodulin.

[THE PULMONARY HEMODYNAMICS FOLLOWING EXPERIMENTAL PULMONARY THROMBOEMBOLISM AND AFTER BLOCKADE OF THE ALPHA-ADRENOCEPTORS].

In acute experiments on the anesthetized rabbits the pulmonary hemodynamics changes following pulmonary thromboembolism were studied in animals with intact circulation and isolated lungs perfusion in the control series and after the blockade of the alpha-adrenoceptors. Following pulmonary embolism in animals with intact circulation in the control group and after the blockade of alpha-adrenoceptors the pulmonary artery pressure and pulmonary vascular resistance increased, but the pulmonary artery flow decreased to the same extent. However, in control animals, the cardiac output decreased more, than the pulmonary flow; the superior vena cava flow was decreased less, than inferior vena cava flow. After the blockade of the alpha-adrenoceptors there were no any imbalance between the decreasing of the cardiac output and pulmonary flow as well as between the decreasing of superior and inferior venae cavae flows. In animals with perfused lungs after the blockade of the alpha-adrenoceptors the pulmonary artery pressure following pulmonary embolism increased to the same level as in animals with intact circulation, however, in the first case the pulmonary vascular resistance increased four times less than in the last one. Thus, we concluded, that following pulmonary thromboembolism the activation of the alpha adrenergic mechanisms could not only promote to increase the resistance of the pulmonary vessels, but these mechanisms are also involved in the changes of the capacitive function of the pulmonary vessels.

[Pulmonary hemodynamics following experimental myocardial ischemia after the blockade of adrenergic receptors].

In acute experiments in anesthetized rabbits the changes of the pulmonary hemodynamics following 60 s myocardial ischemia in the region of the descendent left coronary artery were studied in control animals and after the blockade of α-adrenoreceptors by phentolamine or ß-adrenoreceptors by propranolol. Following myocardial ischemia in control animals the pulmonary artery pressure and flow decreased, the pulmonary vascular resistance did not change, the left atrial pressure elevated; the cardiac output decreased more than pulmonary artery flow. Following myocardial ischemia after the blockade of ß-adrenoreceptors the pulmonary artery pressure decreased more than in control animals, the pulmonary artery flow was decreased in the same level as in the last case. The pulmonary vascular resistance was diminished, the left atrial pressure increased; the pulmonary artery flow and cardiac output decreased in the same level. Following myocardial ischemia after the blockade of ß-adrenoreceptors the pulmonary artery pressure and pulmonary vascular resistance decreased more than after the blockade of α-adrenoreceptors, the left atrial pressure did not change. In both cases the pulmonary artery flow decreased in the same level and its changes were correlated with venous return shifts. The differences of the pulmonary artery changes following myocardial ischemia after the blockade of α- and ß-adrenoreceptors are caused not only the different pulmonary vascular resistance changes, but also the left atrial pressure.

[Hemodynamic mechanisms of the superior and inferior vena cava flow changes following experimental myocardial ischemia].

In acute experiments in anesthetized cats myocardial left ventricular ischemia caused the decreasing of the arterial pressure, cardiac output, superior and inferior vena cava flow and venous return. The diminishing of the superior vena cava flow was caused by the decreasing of the cardiac output, increasing of the vascular resistance and decreasing of the blood flow in the region of the brachiocephalica artery. The inferior vena cava flow decreased following the diminishing of the cardiac output and abdominal aorta blood flow, while vascular resistance in this region did not change. In acute experiments in anesthetized rabbits following myocardial ischemia after the blockade of N-cholinoreceptors the superior and inferior vena cava flow decreased in the same level as in control animals. Following myocardial ischemia after the blockade of α-adrenoreceptors the superior and inferior vena cava flow decreased more significant, than in control animals.

Changes in pulmonary hemodynamics induced by experimental myocardial ischemia in nitroglycerin- or acetylcholine-treated rabbits.

The responses of cardiovascular parameters to left-ventricular myocardial ischemia induced under control conditions and after administration of nitroglycerin or acetylcholine were examined in rabbits. In nitroglycerine-treated rabbits, experimental myocardial ischemia produced less pronounced depressor BP shifts in the pulmonary artery than those produced by ischemia in controls (prior to pharmacological treatment) or by experimental ischemia provoked after acetylcholine infusion. Control and experimental ischemia (provoked after nitroglycerin or acetylcholine administration) induced the same drop in pulmonary blood fl ow accompanied with insignificant changes in vascular pulmonary resistance. Experimental ischemia produced smaller pressure increase in left atrium of nitroglycerine-treated rabbits (evidencing a smaller drop in left ventricular contractility) than the control ischemia performed prior to pharmacological treatment, or the experimental ischemia in acetylcholine-treated rabbits, which attested to protective effect of nitroglycerin against ischemia.

[The role of the adreno-cholinergic interaction in the pulmonary hemodynamics changes following myocardial ischemia].

In acute experiments in anesthetized rabbits the pulmonary hemodynamics changes were studied following 60 s myocardial ischemia in the region of the descendent left coronary artery in control state and after the blockade of M- or N-cholinoreceptors and acetylcholine infusion. Following myocardial ischemia in control animals the pulmonary artery pressure and flow decreased, the pulmonary vascular resistance was not changed. Following myocardial ischemia after the blockade of M-cholinoreceptors by atropine the changes of pulmonary hemodynamics were the same as in control animals, the cardiac output decreased twice as more as in control animals. Following myocardial ischemia after the blockade of N-cholinoreceptors by hexamethonium the pulmonary hemodynamics changes were the same as in the control rabbits. Following myocardial ischemia after the acetylcholine infusion the pulmonary artery flow decreased more than the cardiac output, the pulmonary vascular resistance was diminished. The disbalance of the cardiac output and pulmonary artery flow changes has revealed the significance of the adreno-cholinergic interaction in the changes of the pulmonary vessels capacitance and resistive functions following myocardial ischemia.

[The pulmonary hemodynamics changes following experimental myocardial ischemia in rabbits with decreased arterial pressure].

In acute experiments in rabbits the changes of the pulmonary hemodynamics following myocardial ischemia in the region of the descendent left coronary artery were studied in normotensive animals and after the infusion of histamine or isoproterenol. Following histamine intravenous in fusion the pulmonary artery pressure and pulmonary vascular resistance were increased, however the pulmonary artery flow decreased. In these conditions myocardial ischemia caused the returning of the elevated pulmonary artery pressure to normal level following the diminishing of the pulmonary artery flow to the same level as in normotensive rabbits. Meanwhile the pulmonary vascular resistance remained elevated. Following isoproterenol intravenous injection the isoproterenol artery pressured and flow, pulmonary vascular resistance were decreased. In these conditions myocardial ischemia caused the decrease of the isoproterenol artert pressure, more, than in normotensive rabbits, which was the result of diminishing left atrial pressure, however, the pulmonary artery flow and pulmonary vascular resistance decreased in both cases to the same level. Thus we concluded, that following myocardial ischemia in rabbits with decreased arterial pressure, the changes of pulmonary artery pressure depend on pulmonary artery flow and left atrial pressure changes. The shifts of the pulmonary artery flow depend on venous return ones and does not correlated with pulmonary vascular resistance changes.

[Hemodynamic mechanisms of the left atrial pressure changes after pressor and depressor vasoactive drug injection].

In acute experiments in anesthetized cats the changes of the left atrial pressure, left ventricular myocardial contractility, its relaxation, venous return and cardiac output were studied after catecholamines or acetylcholine and histamine intravenous injection. When arterial pressure was elevated and venous return with cardiac output increased to the same level, the left atrial pressure decreased if the left ventricular myocardial contractility and its relaxation rate were increased equally. However, the left atrial pressure elevated, if left ventricular myocardial relaxation increased less than myocardial contractility. When arterial pressure was depressed, the left atrial pressure decreased if left ventricular myocardial contractility decreased less than myocardial relaxation diminished. If left ventricular myocardial contractility decreased significantly, the left atrial pressure increased. In the last case the value of cardiac output was more, than venous return one. The data suggest that after injection of the pressor and depressor vasoactive drugs, if the shifts of the venous return and cardiac output are equal, the changes of the nature and value of the left atrial pressure are dependent on the relation of the left ventricular myocardial contractility and its relaxation rate.

[The adrenergic mechanisms are involved in the pulmonary hemodynamics changes following experimental myocardial ischemia in rabbits].

In acute experiments in anesthetized rabbits the changes of the pulmonary hemodynamics following myocardial ischemia in the region of the descendent left coronary artery were studied in control animals and after the blockade of alpha-adrenoreceptors by phentolamine or N-cholinoreceptors of autonomic ganglia by hexamethonium. Following myocardial ischemia in control animals the pulmonary artery pressure and flow decreased, the pulmonary vascular resistance was elevated not significantly, the cardiac output decreased more than pulmonary artery flow. Following myocardial ischemia after the blockade of alpha-adrenoreceptors the pulmonary artery flow and cardiac output decreased in the same level and the pulmonary vascular resistance was decreased. In these conditions the pulmonary artery pressure decreased more than in control animals, meanwhile the pulmonary artery flow was decreased in the same level as in the last case. Following myocardial ischemia after the blockade of N-cholinoreceptors the pulmonary hemodynamics changes were the same as they were following myocardial ischemia in the control rabbits, the cardiac output decreased more than pulmonary artery flow. The disbalance of the cardiac output and pulmonary artery flow changes in the case of myocardial ischemia was caused by the pulmonary vessel reactions following activations of the humoral adrenergic mechanisms.

Role of variations in pulmonary and cardiac hemodynamics in the reduction of the venous return during experimental ischemia of the left ventricular myocardium.

During left-ventricular myocardial ischemia, the decrease in the venous return is determined by reduction of cardiac output, which results from heart rate deceleration and decrease in left-ventricular stroke volume. The latter is related to a decrease in myocardial contractility and blood storage in the pulmonary circuit. Blood accumulation in the lungs is not observed during stimulation of the vagus nerve or treatment with propranolol (against the background of the same values of the negative chronotropic and inotropic effects as during myocardial ischemia). The left-ventricular stroke volume increases, while the cardiac output and venous return decrease to a lesser extent under these conditions.