Inotropic action

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

Sircar and co-workers reported that some pyrazol-3-ones possess potent and selective inhibitory phosphodiesterase activity which is primarily responsible for their inotropic action (87JOC1724). 

Apelins and the Apelin Receptor. Figure 3 Scheme illustrating the hypothesised mechanisms of control of human (a) vasculartone and (b) cardiac contractility by apelin peptides ( ). In the vasculature, apelins (released via the small vesicles of the constitutive pathway) may act directly to activate apelin receptors on the underlying smooth muscle to produce vasoconstriction. This response may be modified by apelin peptides feeding back onto apelin receptors on endothelial cells to stimulate the release of dilators, such as nitric oxide. In heart, apelin peptides, released from endocardial endothelial cells, activate apelin receptors on cardiomyocytes to elicit positive inotropic actions. 

Discuss the use of other drugs with positive inotropic action. 

Cardiotonic drugs increase the force of the contraction of the muscle (myocardium) of the heart. This is called a positive inotropic action. When the force of contraction of the myocardium is increased, the amount of blood leaving the left ventricle at the time of each contraction is increased. When the amount of blood leaving the left ventricle is increased, cardiac output (the amount of blood leaving the left ventricle with each contraction) is increased. 

When a cardiotonic drug is administered, die positive inotropic action increases the force of die contraction, resulting in an increased cardiac output. When cardiac output is increased, the blood supply to die kidneys and otiier vital organs is increased. Water, electrolytes, and waste products are removed in adequate amounts, and tiie symptoms of inadequate heart action or HF are relieved, hi most instances, the heart rate also decreases. This occurs because vital organs are now receiving an adequate blood supply because of the increased force of myocardial contraction. 

Hattori Y, Levi R Effect of PGDj on cardiac con- 43 tractihty a negative inotropism secondary to coronary vasoconstriction conceals a primary positive inotropic action. J Pharmacol Exp Ther 1986 237 ... 

Palytoxin (PTX) is one of the most potent marine toxins known and the lethal dose (LD q) of the toxin in mice is 0.5 Mg/kg when injected i.v. The molecular structure of the toxin has been determined fully (1,2). PTX causes contractions in smooth muscle (i) and has a positive inotropic action in cardiac muscle (4-6). PTX also induces membrane depolarization in intestinal smooth (i), skeletal (4), and heart muscles (5-7), myelinated fibers (8), spinal cord (9), and squid axons (10). PTX has been demonstrated to cause NE release from adrenergic neurons (11,12). Biochemical studies have indicated that PTX causes a release of K from erythrocytes, which is followed by hemolysis (13-15). The PTX-induced release of K from erythrocytes is depress by ouabain and that the binding of ouabain to the membrane fragments is inhibited by PTX (15). 

Bradycardia, decreased conduction (atrioventricular block at high doses), small negative inotropic action... 

Adverse effects are generally mild some nausea may occur. Its posihve inotropic action can result in myocardial ischaemia in patients with coronary artery disease. 

Dopamine is used in the treatment of shock owing to inadequate cardiac output (cardiogenic shock), which may be due to myocardial infarction or congestive heart failure. It is also used in the treatment of septic shock, since renal circulation is frequently compromised in this condition. An advantage of using dopamine in the treatment of shock is that its inotropic action increases cardiac output while dilating renal blood vessels and thereby increasing renal blood flow. 

Owing to the negative inotropic action of quinidine, it is contraindicated in congestive heart failure and hypotension. 

A unique property of bretylium as an antiarrhythmic agent is its positive inotropic action. This effect, related to its actions on the sympathetic nervous system, includes an initial release of neuronal stores of norepinephrine followed shortly by a prolonged period of inhibition of direct or reflex-associated neuronal norepinephrine release. The onset of bretylium-induced hypotension is delayed 1 to 2 hours because the initial catecholamine release maintains arterial pressure before this time. 

The hyperthyroid patients are relatively resistant to inotropic action but more prone to arrhythmic action of digoxin. 

CVS The levodopa produces its CVS effect by being converted into dopamine. It acts by stimulating alpha adrenergic receptors in blood and produce vasoconstriction and may raise the blood pressure. It also acts by stimulating betaadrenergic receptors in heart and produce tachycardia and increase force of myocardial contraction (positive inotropic action). 

These drugs inhibit Ca + mediated slow channel inward current, thus inhibiting Ca + mediated depolarization. Phase 4 depolarization in SA node and Purkinje fibres is reduced. They also prolong AV nodal effective refractory period thus AV conduction is slowed. There is also negative inotropic action. 

Digoxin remains the mainstay of treatment for patients with chronic myocardial failure. Other drugs with inotropic and/or vasodilator properties, including the catecholamines and phosphodiesterase III (PDE) inhibitors, are used in the treatment of acute cardiac failure. The inotropic actions of most of these drugs result from a direct or indirect elevation of [Ca2-i-]i (intracellular Ca2+ concentration). This acts as a trigger for a process which leads to increased contractile state and cardiac contraction (Figures 8.3 and 8.4). Myofilament calcium sensitisers increase the sensitivity of contractile proteins to calcium. Some newer drugs, such as vesnarinone, have multiple mechanisms of action. 

Isoproterenol (isoprenaline) is a very potent 3-receptor agonist and has little effect on receptors. The drug has positive chronotropic and inotropic actions because isoproterenol activates 3 receptors almost exclusively, it is a potent vasodilator. These actions lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure and a lesser decrease or a slight increase in systolic pressure (Table 9-4 Figure 9-6). 

Ang II also interacts with the autonomic nervous system. It stimulates autonomic ganglia, increases the release of epinephrine and norepinephrine from the adrenal medulla, and—what is most important—facilitates sympathetic transmission by an action at adrenergic nerve terminals. The latter effect involves both increased release and reduced reuptake of norepinephrine. Ang II also has a less important direct positive inotropic action on the heart. 

NPY produces a variety of central nervous system effects, including increased feeding (it is one of the most potent orexigenic molecules in the brain), hypotension, hypothermia, respiratory depression, and activation of the hypothalamic-pituitary-adrenal axis. Other effects include vasoconstriction of cerebral blood vessels, positive chronotropic and inotropic actions on the heart, and hypertension. The peptide is a potent renal vasoconstrictor and suppresses renin secretion, but can cause diuresis and natriuresis. Prejunctional neuronal actions include inhibition of transmitter release from sympathetic and parasympathetic nerves. Vascular actions include direct vasoconstriction, potentiation of the action of vasoconstrictors, and inhibition of the action of vasodilators. 

The positive benefits of extracts of two species of Digitalis purpurea (foxglove and lanata) were recognized long before the active constituents were isolated and structurally characterized. The cardiac glycosides, which include digoxin, digitoxin, and deslanoside, exert a powerful and selective positive inotropic action on the cardiac muscle (see Chapter 35). 

Ibopamine, which is active orally, is capable of eliciting peripheral and renal vasodilation, positive vasodilation, and a positive inotropic action. Ibopamine is converted to epinine, which is the active drug. 

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