Positive inotropic effect

Inhibition of the Na+/K+-ATPase leads to a loss of potassium and an increase of sodium within the cell. Secondary intracellular calcium is increased via the Na VCa -exchanger. This results in a positive inotropic effect in the myocardium, with an increase of peak force and a decrease in time to peak tension. Besides this, cardiac glycosides increase vagal activity by effects on the central vagal nuclei, the nodose ganglion and increase in sensitivity of the sinus node to acetylcholine. 

Dopamine produces dose-dependent hemodynamic effects because of its relative affinity for cq-, /Jr, /J2-, and Dr (vascular dopaminergic) receptors. Positive inotropic effects mediated primarily by / -receptors become more prominent with doses of 2 to 5 mcg/kg/min. At doses between 5 to 10 mcg/kg/min, chronotropic and -mediated vasoconstricting effects become more prominent. Especially at higher doses, dopamine alters several parameters that increase myocardial oxygen demand and potentially decrease myocardial blood flow, worsening ischemia in some patients with coronary artery disease. 

HT4 receptors are also present in the pig and human hearts, primarily located in the atrium [9]. Experiments showed that stimulation of these receptors can result in tachycardia and can trigger positive inotropic effects. Moreover, it has been demonstrated that the 5-HT4 receptor is present in the human detrusor muscle and facilitates a cholinergic mechanism which may lead to increased bladder contractions [10]. Finally, acute (but not repeated) stimulation of 5-HT4 receptors present on the human adrenal cortex has been reported to trigger the release of corticosterone and aldosterone [11]. 

In addition to modification of calcium influx/efflux, other mechanisms like inhibition of slow inward current [363] and nickel-calcium exchange [364] have been suggested to explain the positive inotropic effects of nickel. Moreover, these inotropic effects might be mediated by an action of nickel on the outside surface of the cardiac cell membrane, where nickel inhibits the ATP-dependent component of the calcium extrusion, thereby causing contraction-enhancement [364, 365],... 

Flosequinan has a positive inotropic effect and shows a tendency to increase the heart rate, atrioventricular conduction in patients with atrial fibrillation and neurohormonal activation. Although the precise mechanisms involved have remained unclear up to now [29], this drug has been used to treat congestive heart failure (CHF). The FDA approved flosequinan (Manoplax) in 1993. However, the drug was withdrawn a year later because the PROFILE (prospective randomized flosequinan longevity evaluation) study indicated that flosequinan had adverse effects on survival, and that beneficial effects on the symptoms of heart failure did not last beyond the first 3 months of therapy, after which patients on the dmg had a higher rate of hospitalization than patients taking a placebo [14]. 

The data indicated that cochlearenine (11) exhibited dose dependent bradycardiac effect along with mild positive inotropic effect followed by cardiac suppression at higher dose, which is an interesting observation, as the dmgs with bradycardiac effect without accompanying negative effect is considered relatively safe for its use in cardioactive disorders like hypertension, palpitations and ischemic heart disease. 

From this series, compound MCI-154 (CAS 98326-33-1) (30) has been investigated in detail [95,96]. In vivo studies (anaesthetized dogs) revealed that doses of 0.3-100 tg/kg (i.v. administration) of MCI-154 produce dose-dependent increases in dF/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance. The positive inotropic effect of (30) has been found to be superior to that exhibited by amrinone and milrinone [97,98]. It has been stated that MCI-154 exerts its activity probably by increasing the calcium-ion sensitivity of the contractile protein system of the cardiac skinned fibres [99,100]. A recent investigation suggests that inhibition of phosphodiesterase III is an important component of its cardiotonic activity [101]. 

In the rat, we observed a decrease of the spontaneous frequency of right atrial preparations and biphasic inotropic effects in left atrial preparations. Negative effects were not antagonized by atropine. The positive inotropic effect was modified very little by prior reserpinization or prior exposure to propranolol and phentolamine but was sensitive to Mn ions. On the other hand. 

Dopamine is found in every sympathetic neuron and ganglion in the CNS. As a drug, and in addition to stimulation of dopaminergic receptors, dopamine indirectly stimulates both a- and )3-adrenoreceptors. Dopamine also causes a release of endogenous norepinephrine. The mechanism of action is based on the excitatory effect on )3-adrenoreceptors (in low and moderate doses), as well as on a-adrenoreceptors (in large doses). It has a positive inotropic effect on the heart, increases blood supply, selectively widens renal and mesenteric blood vessels, does not elevate blood pressure, and slightly increases the frequency of heartbeats. 

Cardiovascular Use with caution in patients with known or suspected heart disease. Because of the positive inotropic effects and side effects of anagrelide, a pretreatment cardiovascular examination is recommended along with careful monitoring during treatment. 

Pharmacology Bretylium tosylate inhibits norepinephrine release by depressing adrenergic nerve terminal excitability, inducing a chemical sympathectomy-like state. Bretylium blocks the release of norepinephrine in response to neuron stimulation. Peripheral adrenergic blockade causes orthostatic hypotension but has less effect on supine blood pressure. It has a positive inotropic effect on the myocardium. Pharmacokinetics Peak plasma concentration and peak hypotensive effects are seen within 1 hour of IM administration. However, suppression of premature ventricular beats is not maximal until 6 to 9 hours after dosing, when mean plasma concentration declines to less than 50% of peak level. Antifibrillatory effects occur within minutes of an IV injection. Suppression of ventricular tachycardia and other ventricular arrhythmias develops more slowly, usually 20 minutes to 2 hours after parenteral administration. 

The heart is innervated by both sympathetic and parasympathetic neurons however, their distribution in the heart is quite different. Postganglionic noradrenergic fibers from the stellate and inferior cervical ganglia innervate the sinoatrial (S-A) node and myocardial tissues of the atria and ventricles. Activation of the sympathetic outflow to the heart results in an increase in rate (positive chronotropic effect), in force of contraction (positive inotropic effect), conduction tissue (positive dro-motropic effect). 

An increase in sympathetic neuronal activity causes an increase in heart rate (positive chronotropic effect, or tachycardia) and an increase in cardiac contractile force (positive inotropic effect) such that the stroke output is increased. Cardiac output, which is a function of rate and stroke output, is thus increased. A physiological increase in sympathetic tone is almost always accompanied by a diminution of parasympathetic vagal tone this allows full expression of the effects of increased sympathetic tone on the activity of the heart. 

The current hypothesis regarding the cellular basis for the positive inotropic effect of digitalis helps to explain some of the wide individual variability in the dosage required to develop digitalis toxicity. Differences in pH, ischemia, Na+, K+, and Ca++ can each alter the likelihood of developing toxicity within the same patient and between individuals. 

Myocardial cell membrane ATPase, the enzyme present in heart muscle, is the site of action of the cardiac steroid glycosides, which have a specific action on the heart muscle. These drugs increase the force of contraction of the muscle (positive inotropic effect) as well as its conductivity and automaticity. They are also valuable in treating congestive heart failure, in which the circulatory needs of organs are no longer satisfied, and heart arrhythmias, in which the rhythm of the cardiac contractions is upset. The effect of the drug is that the force of contraction increases and the heart rate is slowed (chronotropic effect). Consequently, the cardiac output is elevated while the size of the heart decreases. 

The exterior of the myocardial enzyme, situated in the plasmalemma, is considered to be the specific binding site of cardiac steroid glycosides. It is believed that the positive inotropic effect is due to the inhibition of enzyme dephosphorylation and... 

Direct effects on the heart are determined largely by Bi receptors, although B2 and to a lesser extent a receptors are also involved, especially in heart failure. Beta-receptor activation results in increased calcium influx in cardiac cells. This has both electrical and mechanical consequences. Pacemaker activity—both normal (sinoatrial node) and abnormal (eg, Purkinje fibers)—is increased (positive chronotropic effect). Conduction velocity in the atrioventricular node is increased (positive dromotropic effect), and the refractory period is decreased. Intrinsic contractility is increased (positive inotropic effect), and relaxation is accelerated. As a result, the twitch response of isolated cardiac muscle is increased in tension but abbreviated in duration. In the intact heart, intraventricular pressure rises and falls more rapidly, and ejection time is decreased. These direct effects are easily demonstrated in the absence of reflexes evoked by changes in blood pressure, eg, in isolated myocardial preparations and in patients with ganglionic blockade. In the presence of normal reflex activity, the direct effects on heart rate may be dominated by a reflex response to blood pressure changes. Physiologic stimulation of the heart by catecholamines tends to increase coronary blood flow. 

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