Inotropic synthetic drug in tablets. Negative chronotropic (based on inotropic action)

Inotropic drugs are a group of drugs that increase the force of myocardial contraction.

CLASSIFICATION
Cardiac glycosides (see section "Cardiac glycosides").
Non-glycoside inotropic drugs.
✧ Stimulants β 1-adrenergic receptors (dobutamine, dopamine).
✧ Phosphodiesterase inhibitors (amrinone℘ and milrinone ℘; they are not registered in the Russian Federation; allowed only for short courses with circulatory decompensation).
✧ Calcium sensitizers (levosimendan).

MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS
Stimulantsβ 1 -adrenergic receptors
The drugs of this group, administered intravenously, affect the following receptors:
β1- adrenoceptors (positive inotropic and chronotropic action);
β2-adrenergic receptors (bronchodilation, expansion of peripheral vessels);
dopamine receptors (increased renal blood flow and filtration, dilatation of the mesenteric and coronary arteries).
A positive inotropic effect is always combined with other clinical manifestations, which can have both positive and negative effects on the clinical picture of AHF. Dobutamine - selectiveβ1- adrenomimetic, but it also has a weak effect onβ 2 - and α 1-adrenergic receptors. With the introduction of conventional doses, an inotropic effect develops, sinceβ1-stimulating effect on the myocardium prevails. A drug
does not stimulate dopamine receptors regardless of dose, therefore, renal blood flow increases only due to an increase in stroke volume.

Phosphodiesterase inhibitors. The drugs of this subgroup, increasing myocardial contractility, also lead to a decrease in peripheral vascular resistance, which allows you to influence both preload and afterload in AHF.

calcium sensitizers. The drug of this group (levosimendan) increases the affinity of Ca 2+ to troponin C, which increases myocardial contraction. It also has a vasodilating effect (reducing the tone of the veins and arteries). Levosimendan has an active metabolite with a similar mechanism of action and a half-life of 80 hours, which causes a hemodynamic effect for 3 days after a single dose of the drug.

Clinical Significance
Phosphodiesterase inhibitors may increase mortality.
In acute left ventricular failure secondary to acute myocardial infarction, the administration of levosimendan was accompanied by a decrease in mortality, achieved in the first 2 weeks after the start of treatment, which persisted in the future (for 6 months of observation).
Levosimendan is superior to dobutamine fornii effects on blood circulation in patients with severe decompensation of CHF and low cardiac output.

INDICATIONS
Acute heart failure. Their purpose does not depend on the presence of venous congestion or pulmonary edema. There are several algorithms for prescribing inotropic drugs.
Shock due to an overdose of vasodilators, blood loss, dehydration.
Inotropic drugs should be prescribed strictly individually, it is necessary to evaluate the indicators of central hemodynamics, and also change the dose of inotropic drugs in accordance with
with the clinical picture.

Dosing
Dobutamine. The initial infusion rate is 2–3 μg per 1 kg of body weight per minute. With the introduction of dobutamine in combination with vasodilators, control of the pulmonary artery wedge pressure is necessary. If the patient received beta-adrenergic blockers, then the action of dobutamine will develop only after the elimination of beta-adrenergic blocker.

Algorithm for the use of inotropic drugs (national recommendations).

Algorithm for the use of inotropic drugs (American Heart Association).

Dopamine. The clinical effects of dopamine are dose dependent.
At low doses (2 μg per 1 kg of body weight per minute or less in terms of lean body weight), the drug stimulates D 1 - and D 2-receptors, which is accompanied by vasodilatation of the mesentery and kidneys and allows you to increase GFR in case of refractoriness to the action of diuretics.
In medium doses (2-5 mcg per 1 kg of body weight per minute), the drug stimulatesβ1-adrenergic receptors of the myocardium with an increase in cardiac output.
At high doses (5–10 micrograms per kg of body weight per minute), dopamine activatesα 1-adrenergic receptors, which leads to an increase in peripheral vascular resistance, LV filling pressure, tachycardia. As a rule, high doses are prescribed in emergency cases to quickly increase SBP.

Clinical features:
tachycardia is always more pronounced with dopamine compared with dobutamine;
the calculation of the dose is carried out only on lean, and not on the total body weight;
persistent tachycardia and / or arrhythmia that occurred with the introduction of a "renal dose" indicate that the rate of administration of the drug is too high.

Levosimendan. The introduction of the drug begins with a loading dose (12–24 μg per 1 kg of body weight for 10 minutes), and then they switch to a long-term infusion (0.05–0.1 μg per 1 kg of body weight). An increase in stroke volume, a decrease in pulmonary artery wedge pressure are dose-dependent. In some cases it is possibleincreasing the dose of the drug to 0.2 μg per 1 kg of body weight. The drug is effective only in the absence of hypovolemia. Levosimendan is compatible withβ -blockers and does not lead to an increase in the number of rhythm disturbances.

Features of prescribing inotropic drugs to patients with decompensated chronic heart failure
Due to a pronounced adverse effect on the prognosis, non-glycoside inotropic drugs can only be prescribed in the form of short courses (up to 10-14 days) with a clinical picture of persistent arterial hypotension in patients with severe CHF decompensation and a reflex kidney.

SIDE EFFECTS
Tachycardia.
Supraventricular and ventricular arrhythmias.
Subsequent increase in left ventricular dysfunction (due to increased energy consumption to ensure increasing myocardial work).
Nausea and vomiting (dopamine in high doses).

General provisions

The goal of inotropic support is to provide maximum tissue oxygenation (assessed by plasma lactate concentration and mixed venous blood oxygenation), and not to increase cardiac output.
In clinical practice, catecholamines and their derivatives are used as inotropes. They have a complex hemodynamic effect due to α- and β-adrenergic effects and differ in their predominant effect on certain receptors. Below is a description of the hemodynamic effects of the main catecholamines.

Isoprenaline

Pharmacology

Isoprenaline is a synthetic agonist of β-adrenergic receptors (β 1 and β 2) and does not affect α-adrenergic receptors. The drug dilates the bronchi, during blockade it acts as a pacemaker, affecting the sinus node, increases conductivity and reduces the refractory period of the atrioventricular node. It has a positive inotropic effect. It has an effect on skeletal muscles and blood vessels. The half-life is 5 minutes.

Drug Interactions

The effect increases when co-administered with tricyclic antidepressants.
β-blockers are isoprenaline antagonists.
Sympathomimetics may potentiate the action of isoprenaline.
Gaseous anesthetics, by increasing the sensitivity of the myocardium, can cause arrhythmias.
Digoxin increases the risk of tachyarrhythmias.

epinephrine

Pharmacology

Epinephrine is a selective β 2 -adrenergic agonist (the effect on β 2 -adrenergic receptors is 10 times greater than the effect on β 1 -adrenergic receptors), but also affects α-adrenergic receptors, without differentially affecting α 1 - and α 2 -adrenergic receptors.
Usually it has little effect on the level of mean blood pressure, with the exception of cases of prescribing the drug against the background of non-selective blockade of β-adrenergic receptors, in which the vasodilating effect of epinephrine mediated by the action on β 2 -adrenergic receptors is lost and its vasopressor effect sharply increases (α 1 -selective blockade does not cause such an effect ).

Application area

Anaphylactic shock, angioedema and allergic reactions.
The scope of epinephrine as an inotropic agent is limited only to septic shock, in which it has advantages over dobutamine. However, the drug causes a significant decrease in renal blood flow (up to 40%) and can only be administered together with dopamine in the renal dose.
Heart failure.
Open angle glaucoma.
As an adjunct to local anesthetics.

Doses

0.2-1 mg intramuscularly for acute allergic reactions and anaphylaxis.
1 mg in cardiac arrest.
In case of shock, 1-10 mcg / min is administered drip.

Pharmacokinetics

Due to rapid metabolism in the liver and nervous tissue and 50% plasma protein binding, the half-life of epinephrine is 3 minutes.

Side effects

Arrhythmias.
Intracerebral hemorrhage (with overdose).
Pulmonary edema (with overdose).
Ischemic necrosis at the injection site.
Restlessness, dyspnea, palpitations, tremors, weakness, cold extremities.

drug interaction

Tricyclic immunosuppressants.
Anesthetics.
β-blockers.
Quinidine and digoxin (arrhythmia often occurs).
α-Adrenergic agonists block the α-effects of epinephrine.

Contraindications

Hyperthyroidism.
Hypertension.
Angle-closure glaucoma.

dopamine

Pharmacology

Dopamine affects several types of receptors. In small doses, it activates α 1 - and α 2 dopamine receptors. α 1 dopamine receptors are localized in vascular smooth muscle and are responsible for vasodilation in the renal, mesenteric, cerebral and coronary circulation. α 1 dopamine receptors are located in the postganglionic endings of the sympathetic nerves and ganglia of the autonomic nervous system. At an average dose, dopamine activates β 1 -adrenergic receptors, having positive chronotropic and inotropic effects, and at high doses, it additionally activates α 1 - and α 2 -adrenergic receptors, eliminating the vasodilating effect on the renal vessels.

Application area

Used to improve renal blood flow in patients with impaired renal perfusion, usually against the background of multiple organ failure. There is little evidence regarding the effect of dopamine on the clinical outcome of the disease.

Pharmacokinetics

Dopamine is taken up by sympathetic nerves and is rapidly distributed throughout the body. The half-life is 9 minutes, and the volume of distribution is 0.9 l / kg, but the state of equilibrium occurs within 10 minutes (ie, faster than expected). Metabolized in the liver.

Side effects

Arrhythmias are rarely seen.
Hypertension at very high doses.
Extravasation can cause skin necrosis. In this case, phentolamine is injected into the ischemic zone as an antidote.
Headache, nausea, vomiting, palpitations, mydriasis.
Increased catabolism.

Drug Interactions

MAO inhibitors.
α-Adrenergic blockers may enhance the vasodilatory effect.
β-blockers may enhance the hypertensive effect.
Ergotamine enhances peripheral vasodilation.

Contraindications

Pheochromocytoma.
Tachyarrhythmia (without treatment).

dobutamine

Pharmacology

Dobutamine is a derivative of isoprenaline. In practice, a racemic mixture of a dextrorotatory isomer selective for β 1 and β 2 adrenoreceptors and a levorotatory isomer having an α 1 selective effect is used. The effects on β2-adrenergic receptors (vasodilatation of mesenteric and musculoskeletal vessels) and α 1 -adrenergic receptors (vasoconstriction) suppress each other, so dobutamine has little effect on blood pressure unless administered at a high dose. It has less, compared with dopamine, arrhythmogenic effect.

Application area

Inotropic support for heart failure.
In septic shock and liver failure, it can cause vasodilation, therefore it is not the most preferred inotropic drug.
Used in functional diagnostics for cardiological stress tests.

Pharmacokinetics

Rapidly metabolized in the liver. It has an elimination half-life of 2.5 minutes and a volume of distribution of 0.21 l/kg.

Side effects

Arrhythmias.
With an increase in cardiac output, myocardial ischemia may occur.
The hypotensive effect can be minimized by the simultaneous administration of dopamine in a vasoconstrictive dose. This combination of drugs may be required to treat patients with sepsis or liver failure.
Allergic reactions are extremely rare.
Skin necrosis may occur at the injection site.

drug interaction

α-Adrenergic agonists increase vasodilation and cause hypotension.

Contraindications

Low filling pressure.
Arrhythmias.
Cardiac tamponade.
Heart valve defects (aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy).
Established hypersensitivity to the drug.

norepinephrine

Pharmacology

Norepinephrine, like epinephrine, has an α-adrenergic effect, but to a lesser extent affects most β 1 -adrenergic receptors and has a very low β 2 -adrenergic activity. The weakness of β 2 -adrenergic influence leads to the predominance of the vasoconstrictor effect, more pronounced than that of epinephrine. Norepinephrine is prescribed for acute hypotension, but due to its negligible effect on cardiac output and the ability to cause pronounced vasospasm, this drug can significantly increase tissue ischemia (especially in the kidneys, skin, liver and skeletal muscles). Norepinephrine infusion should not be interrupted suddenly, as this is dangerous with a sharp drop in blood pressure.

drug interaction

Tricyclic antidepressants (blocking the re-entry of catecholamines into nerve endings) increase the sensitivity of receptors to epinephrine and norepinephrine by 2-4 times. MAO inhibitors (for example, tranylcyprominr and pargyline) significantly potentiate the effect of dopamine, so it should be started with a dose equal to 1/10 of the usual initial dose, i.e. 0.2 µg/(kghmin).

Dobutamine is not a substrate for MAO.

Milrinone

Milrinone belongs to the group of phosphodiesterase (type III) inhibitors. Its cardiac effects may be due to its effect on calcium and fast sodium channels. β-Adrenergic agonists enhance the positive inotropic effect of a million.

Side effects

Enoximonr

Enoximone is a phosphodiesterase (type IV) inhibitor. The drug is 20 times more active than aminophylline, its half-life is approximately 1.5 hours. It is broken down to active metabolites with 10% enoximonar activity with a half-life of 15 hours. It is used to treat congestive heart failure, it can be prescribed both in tablet form, as well as intravenously.

Side effects

Patients with hypovolemia may develop hypotension and/or cardiovascular collapse.

Bicarbonate of soda

Pharmacology

Sodium bicarbonate plays an important role as a buffer in the body. Its effect is short-lived. The administration of sodium bicarbonate results in sodium overload and carbon dioxide formation, which leads to intracellular acidosis and reduces the force of myocardial contraction. Therefore, the drug should be administered with great caution. Along with this, sodium bicarbonate shifts the oxyhemoglobin dissociation curve to the left and reduces the effective delivery of oxygen to tissues. Moderate acidosis causes vasodilation of the brain, so its correction may impair cerebral blood flow in patients with cerebral edema.

Application area

Severe metabolic acidosis (there are conflicting data regarding use in diabetic ketoacidosis).
Severe hyperkalemia.
The use of sodium bicarbonate in CPR is best avoided, as cardiac massage and artificial respiration are sufficient.

Dose

Released in the form of 8.4% solution (hypertonic, 1 ml contains 1 mmol bicarbonate ion) and 1.26% solution (isotonic). Usually administered as a bolus of 50-100 ml under the control of arterial blood pH and hemodynamic monitoring. According to the recommendations of the British Council for Resuscitation, an approximate dose of 8.4% sodium bicarbonate solution can be calculated as follows:
Dose in ml (mol) = [BExt (kg)]/3, where BE is the base deficiency.

Thus, a patient with a body weight of 60 kg, having a base deficiency of -20, needs 400 ml of 8.4% sodium bicarbonate solution to normalize the pH. This volume contains 400 mmol sodium. From our point of view, this is a lot, so it is desirable to adjust the pH to the level of 7.0-7.1 by prescribing 50-100 ml of sodium bicarbonate, followed by an assessment of arterial blood gases and repeated administration of the drug if necessary. This allows you to gain enough time to conduct more effective and safer diagnostic and treatment measures and treat the disease that led to the development of acidosis.

Side effects

Extravasation results in tissue necrosis. If possible, the drug is administered through a central catheter.
With simultaneous administration with calcium preparations, calcifications are formed in the catheter, which can lead to microembolism.

Adrenalin. This hormone is formed in the adrenal medulla and adrenergic nerve endings, is a direct-acting catecholamine, causes stimulation of several adrenoreceptors at once: a1-, beta1- and beta2- Stimulation of a1-adrenergic receptors is accompanied by a pronounced vasoconstrictor effect - a general systemic vasoconstriction, including precapillary vessels skin, mucous membranes, kidney vessels, as well as a pronounced narrowing of the veins. Stimulation of beta1-adrenergic receptors is accompanied by a distinct positive chronotropic and inotropic effect. Stimulation of beta2-adrenergic receptors causes bronchial dilatation.

Adrenaline is often indispensable in critical situations, since it can restore spontaneous cardiac activity during asystole, increase blood pressure during shock, improve the automatism of the heart and myocardial contractility, and increase heart rate. This drug stops bronchospasm and is often the drug of choice for anaphylactic shock. It is used mainly as a first aid and rarely for long-term therapy.

Solution preparation. Adrenaline hydrochloride is available as a 0.1% solution in 1 ml ampoules (diluted 1:1000 or 1 mg/ml). For intravenous infusion, 1 ml of a 0.1% solution of adrenaline hydrochloride is diluted in 250 ml of isotonic sodium chloride solution, which creates a concentration of 4 μg / ml.

Doses for intravenous administration:

1) in any form of cardiac arrest (asystole, VF, electromechanical dissociation), the initial dose is 1 ml of a 0.1% solution of adrenaline hydrochloride diluted in 10 ml of isotonic sodium chloride solution;

2) with anaphylactic shock and anaphylactic reactions - 3-5 ml of a 0.1% solution of adrenaline hydrochloride diluted in 10 ml of isotonic sodium chloride solution. Subsequent infusion at a rate of 2 to 4 mcg / min;

3) with persistent arterial hypotension, the initial rate of administration is 2 μg / min, if there is no effect, the rate is increased until the required level of blood pressure is reached;

4) action depending on the rate of administration:

Less than 1 mcg / min - vasoconstrictor,

From 1 to 4 mcg / min - cardiostimulating,

From 5 to 20 mcg / min - a-adrenergic stimulant,

More than 20 mcg / min - the predominant a-adrenergic stimulant.

Side effect: adrenaline can cause subendocardial ischemia and even myocardial infarction, arrhythmias and metabolic acidosis; small doses of the drug can lead to acute renal failure. In this regard, the drug is not widely used for long-term intravenous therapy.

Norepinephrine. Natural catecholamine, which is the precursor of adrenaline. It is synthesized in the postsynaptic endings of the sympathetic nerves and performs a neurotransmitter function. Norepinephrine stimulates a-, beta1-adrenergic receptors, almost no effect on beta2-adrenergic receptors. It differs from adrenaline in a stronger vasoconstrictor and pressor action, less stimulating effect on automatism and contractile ability of the myocardium. The drug causes a significant increase in peripheral vascular resistance, reduces blood flow in the intestines, kidneys and liver, causing severe renal and mesenteric vasoconstriction. The addition of small doses of dopamine (1 µg/kg/min) helps to preserve renal blood flow when norepinephrine is administered.

Indications for use: persistent and significant hypotension with a drop in blood pressure below 70 mm Hg, as well as a significant decrease in OPSS.

Solution preparation. The contents of 2 ampoules (4 mg of norepinephrine hydrotartrate are diluted in 500 ml of isotonic sodium chloride solution or 5% glucose solution, which creates a concentration of 16 μg / ml).

Doses for intravenous administration. The initial rate of administration is 0.5-1 μg / min by titration until the effect is obtained. Doses of 1-2 mcg/min increase CO, more than 3 mcg/min - have a vasoconstrictor effect. With refractory shock, the dose can be increased to 8-30 mcg / min.

Side effect. With prolonged infusion, renal failure and other complications (gangrene of the extremities) associated with the vasoconstrictor effects of the drug may develop. With extravasal administration of the drug, necrosis may occur, which requires chipping the extravasate area with a solution of phentolamine.

Dopamine. It is the precursor of norepinephrine. It stimulates a- and beta-receptors, has a specific effect only on dopaminergic receptors. The effect of this drug is largely dependent on the dose.

Indications for use: acute heart failure, cardiogenic and septic shock; the initial (oliguric) stage of acute renal failure.

Solution preparation. Dopamine hydrochloride (dopamine) is available in 200 mg ampoules. 400 mg of the drug (2 ampoules) are diluted in 250 ml of isotonic sodium chloride solution or 5% glucose solution. In this solution, the concentration of dopamine is 1600 µg/ml.

Doses for intravenous administration: 1) the initial rate of administration is 1 μg / (kg-min), then it is increased until the desired effect is obtained;

2) small doses - 1-3 mcg / (kg-min) are administered intravenously; while dopamine acts mainly on the celiac and especially the renal region, causing vasodilation of these areas and contributing to an increase in renal and mesenteric blood flow; 3) with a gradual increase in speed to 10 µg/(kg-min), peripheral vasoconstriction and pulmonary occlusive pressure increase; 4) high doses - 5-15 mcg / (kg-min) stimulate myocardial beta1 receptors, have an indirect effect due to the release of noradrenaline in the myocardium, i.e. have a distinct inotropic effect; 5) in doses above 20 mcg / (kg-min), dopamine can cause vasospasm of the kidneys and mesentery.

To determine the optimal hemodynamic effect, it is necessary to monitor hemodynamic parameters. If tachycardia occurs, it is recommended to reduce the dose or discontinue further administration. Do not mix the drug with sodium bicarbonate, as it is inactivated. Long-term use of a- and beta-agonists reduces the effectiveness of beta-adrenergic regulation, the myocardium becomes less sensitive to the inotropic effects of catecholamines, up to the complete loss of the hemodynamic response.

Side effects: 1) increased DZLK, tachyarrhythmias may occur; 2) in high doses can cause severe vasoconstriction.

Dobutamine (dobutrex). It is a synthetic catecholamine that has a pronounced inotropic effect. The main mechanism of its action is the stimulation of beta receptors and an increase in myocardial contractility. Unlike dopamine, dobutamine does not have a splanchnic vasodilating effect, but tends to systemic vasodilation. It increases heart rate and DZLK to a lesser extent. In this regard, dobutamine is indicated in the treatment of heart failure with low CO, high peripheral resistance against the background of normal or elevated blood pressure. When using dobutamine, like dopamine, ventricular arrhythmias are possible. An increase in heart rate by more than 10% of the initial level can cause an increase in the zone of myocardial ischemia. In patients with concomitant vascular lesions, ischemic necrosis of the fingers is possible. In many patients treated with dobutamine, there was an increase in systolic blood pressure by 10-20 mm Hg, and in some cases, hypotension.

Indications for use. Dobutamine is prescribed for acute and chronic heart failure caused by cardiac (acute myocardial infarction, cardiogenic shock) and non-cardiac causes (acute circulatory failure after injury, during and after surgery), especially in cases where the mean blood pressure is above 70 mm Hg. Art., and the pressure in the system of a small circle is above normal values. Assign with increased ventricular filling pressure and the risk of overloading the right heart, leading to pulmonary edema; with a reduced MOS due to the PEEP regimen during mechanical ventilation. During treatment with dobutamine, as with other catecholamines, careful monitoring of heart rate, heart rate, ECG, blood pressure and infusion rate is necessary. Hypovolaemia must be corrected before starting treatment.

Solution preparation. A vial of dobutamine containing 250 mg of the drug is diluted in 250 ml of 5% glucose solution to a concentration of 1 mg / ml. Saline dilution solutions are not recommended as SG ions may interfere with dissolution. Do not mix dobutamine solution with alkaline solutions.

Side effect. Patients with hypovolemia may experience tachycardia. According to P. Marino, ventricular arrhythmias are sometimes observed.

Contraindicated in hypertrophic cardiomyopathy. Due to its short half-life, dobutamine is administered continuously intravenously. The effect of the drug occurs in the period from 1 to 2 minutes. It usually takes no more than 10 minutes to create its stable plasma concentration and ensure the maximum effect. The use of a loading dose is not recommended.

Doses. The rate of intravenous administration of the drug, necessary to increase the stroke and minute volume of the heart, ranges from 2.5 to 10 μg / (kg-min). It is often necessary to increase the dose to 20 mcg / (kg-min), in more rare cases - more than 20 mcg / (kg-min). Dobutamine doses above 40 µg/(kg-min) may be toxic.

Dobutamine can be used in combination with dopamine to increase systemic BP in hypotension, increase renal blood flow and urine output, and prevent the risk of pulmonary congestion seen with dopamine alone. The short half-life of beta-adrenergic receptor stimulants, equal to several minutes, allows you to very quickly adapt the administered dose to the needs of hemodynamics.

Digoxin. Unlike beta-adrenergic agonists, digitalis glycosides have a long half-life (35 hours) and are eliminated by the kidneys. Therefore, they are less manageable and their use, especially in intensive care units, is associated with the risk of possible complications. If sinus rhythm is maintained, their use is contraindicated. With hypokalemia, renal failure against the background of hypoxia, manifestations of digitalis intoxication occur especially often. The inotropic effect of glycosides is due to the inhibition of Na-K-ATPase, which is associated with the stimulation of Ca2+ metabolism. Digoxin is indicated for atrial fibrillation with VT and paroxysmal atrial fibrillation. For intravenous injections in adults, it is used at a dose of 0.25-0.5 mg (1-2 ml of a 0.025% solution). Introduce it slowly into 10 ml of 20% or 40% glucose solution. In emergency situations, 0.75-1.5 mg of digoxin is diluted in 250 ml of a 5% dextrose or glucose solution and administered intravenously over 2 hours. The required level of the drug in the blood serum is 1-2 ng / ml.

homeometric regulation

The force of contraction of the heart fiber can also change with changes in pressure (afterload). The rise in blood pressure increases the resistance to expulsion of blood and shortening of the heart muscle. As a result, one would expect a drop in VR. However, it has been repeatedly demonstrated that the SV remains constant over a wide range of resistances (Anrep phenomenon).

In the increase in the force of contraction of the heart muscle with an increase in afterload, it was previously seen as a reflection of the "homeometric" self-regulation inherent in the heart, in contrast to the "heterometric" mechanism previously established by Starling. It was assumed that an increase in myocardial inotropy is involved in maintaining the value of SV. However, later it was found that the increase in resistance is accompanied by an increase in the end diastolic volume of the left ventricle, which is associated with a temporary increase in end-diastolic pressure, as well as myocardial extensibility associated with the influence of increased contraction force [Kapelko V.L. 1992]

In the context of sports activities, an increase in afterload is most often found during training aimed at developing strength and performing physical loads of a static nature. An increase in mean blood pressure during such exercises leads to an increase in the tension of the heart muscle, which, in turn, entails a pronounced increase in oxygen consumption, ATP resynthesis and activation of the synthesis of nucleic acids and proteins.

Inotropic effect of changes in heart rate

An important mechanism for the regulation of cardiac output is chronoinotropic dependence. There are two factors that affect the contractility of the heart in different directions: 1 - is aimed at reducing the strength of the subsequent contraction, is characterized by the rate of restoration of the ability to full contraction and is denoted by the term "mechanical restitution". Or mechanical restitution is the ability to restore the optimal force of contraction after the previous contraction, which can be determined through the relationship between the duration of the R--R interval and the contraction following it. 2 - increases the strength of the subsequent contraction with an increase in the previous contraction, denoted by the term "post-extrasystolic potentiation" and is determined through the relationship between the duration of the previous interval (R--R) and the strength of the subsequent contraction.

If the strength of contractions increases with an increase in the frequency of the rhythm, this is referred to as the Bowditch phenomenon (the positive effect of activation prevails over the negative one). If the strength of the contractions increases with the slowing of the rhythm frequency, then such a phenomenon is referred to as the "Woodworth's ladder". These phenomena are realized in a certain frequency range. When the frequency of contractions goes beyond the range, the force of contractions does not increase, but begins to fall.

The width of the range of these phenomena is determined by the state of the myocardium and the concentration of Ca 2+ in various cellular reserves.

In experimental studies by FZ Meyerson (1975) it was shown that in trained animals the inotropic effect of increasing heart rate is significantly higher than in control animals. This gives grounds to assert that under the influence of regular physical loads, the power of the mechanisms responsible for ion transport increases significantly. We are talking about an increase in the power of the mechanisms responsible for the removal of Ca 2+ from the sarcoplasm, i.e. calcium pump SPR and Na-Ca-exchange mechanism of the sarcolemma.

Opportunities for non-invasive study of the parameters of mechanical restitution and post-extrasystolic potentiation appeared among researchers due to the use of the method of transesophageal electrical stimulation in a stochastic mode. They performed electrical stimulation with a random sequence of impulses, registering synchronously the rheographic curve. On the basis of changes in the amplitude of the rewave and the duration of the period of exile, changes in myocardial contractility were judged. Later V.Fantyufiev et al. (1991) showed that such approaches can be successfully used not only in the clinic, but also in the functional diagnostic studies of athletes. Thanks to the study of the curves of mechanical restitution and post-extrasystolic potentiation in athletes, the authors were able to prove that these curves can significantly change with adaptation disorders to physical stress and overvoltage, and the introduction of magnesium ions or blockade of calcium current can significantly improve the contractility of the heart in some athletes. With an increase in heart rate, there is also an increase in the rate of the process of relaxation of the heart. This phenomenon was named by IT. Udelnov (1975) "rhythm-diastolic dependence". Later, F.Z. Meyerson and V.I. Kapelko (1978) proved that the rate of relaxation increases not only with an increase in frequency, but also with an increase in the amplitude or strength of contractions in the physiological range. They found that the relationship between contraction and relaxation is an important regularity in the activity of the heart and is the basis for a stable adaptation of the heart to stress.

In conclusion, it should be emphasized that regular sports training contributes to the improvement of cardiac regulation mechanisms, which ensures the economization of the work of the heart at rest and its maximum performance during extreme physical exertion.

INOTROPIC ACTION (literally, imposing force"), a change in the amplitude of heart contractions under the influence of various physiological and pharmacological agents. Positive I. action, i.e., an increase in the amplitude of heart contractions, is caused by irritation of the accelerators; negative I. d. - obtained by irritation of the vagus nerves. Corresponding effects are given by vago- and sympathetic-comimetic poisons and salt ions. However, the I. d. of this or that agent depends on a number of conditions: pH, composition of the flushing fluid "or blood, intracardiac pressure, heart rate, and therefore a prerequisite for the observation of I. d. is work under constant conditions (artificially excited heart rhythm and etc.), the inotropy of various parts of the heart can change independently of the inotropy of the remaining parts. I. P. Pavlov managed to find a branch in the plexus cardiacus of a dog that gives a positive inotropic effect on the left ventricle alone. The pathways were studied in more detail by I. D. Hoffman (Hofmann): he found that the specific "inotropic nerves" of the frog heart are the nerves of the interventricular septum, the stimulation of which gives a purely inotropic effect without chronotropic changes; after cutting these nerves, irritation of the common vago-sympathetic trunk no longer gives any inotropic effect. salts Potassium salts have a negative I. D., this effect is not observed after atropinization.Sodium in high concentrations has the same effect; however, this action may depend on the fact that hypertonic. solutions generally have a negative I. d. A decrease in the content of NaCl in the washing liquid gives + I. e. Lithium and ammonium salts have +I. d.; rubidium acts like potassium. Calcium acts + inotropically and even leads to systolic. stop. The absence of calcium in the washing fluid gives a negative inotropic effect. Barium and strontium generally act like Ca. Magnesium acts antagonistically towards both Ca and K. Heavy metal salts give negative. inotropic action. However, the effect of the aforementioned salts may be absent or ■ distorted when the pH of the lavage fluid changes and after preliminary treatment of the heart with other (often antagonistic) agents. From anions, one can note a negative I. d. iodine compounds, lactic acid and cyanide salts, small doses of which, however, act + inotropically. Drugs and alcohol are negatively inotropic; in very small doses + I. Carbohydrates (glucose) when added to the washing liquid (as an energy source) are given on an isolated heart + I.d. Digitalis affects inotropy not only indirectly (acting on the vessels and the autonomic nervous system), but also directly affecting the heart muscle (small doses are positive, large doses are negative), especially on the left ventricle. Adrenaline, by reducing the latency period of the contraction and shortening the systole, usually gives +I. d.; this effect is less pronounced in frogs than in warm-blooded ones. However, here, as with many vegetative poisons, everything depends on the dose and on the state of the heart. The effect of camphor also depends on the dose: small ones give +I. d., large -I. d.; it is especially clearly expressed on pathologically changed hearts. Cocaine in very small doses has a positive inotropic effect, in large doses it has a negative effect. Atropine, according to the latest observations of Kisch, excites n in the first phase of its action. vagus and therefore gives a negative ID. Poisons of the muscarine group act like irritation of the vagus nerve. Veratrin and strychnine given in small doses give +I. e. Caffeine affects inotropy Ch. arr. indirectly, by changing the heart rate; but with a tired heart, applied in small doses, it acts directly on the muscle of the heart + inotrope. (On the relationship between inotropic, dromotropic and chronotropic actions, see the corresponding words.) Lit.: As her L., Intrafcardiales Nervensystem (Hndb. d. norm, u.path. Physiologie, hrsg. v. A. Bethe, G. Bergmann u.a., B. VII, T. 1, V., 1926); Hofmann P., tlber die Funktion der Scheidenwandner-ven des Froschberzens, Arch. f. d. ges. Physiologie, B. LX, 1895; Kisch B., Pharmakologie des Herzens (Hndb. d. norm. u. path. Physiologie, h sg. v. A. Bethe, G. Bergmann u. a., B. VII, t. 1, V., 1926); Pav-1 o f f I., Ober den Einfluss des Vagus auf die Arbeit der linken Herzkammer, Arch. 1. Anat. u. Phvsiology. 1887, p. 452; S tr a ub W., Die Digitalisgruppe (Hndb. d. experimentellen Pharmakologie, hrsg. v. A. Heffter, B. II, Halfte 2, B., 1924). A. Zubkov.