Positive inotropic concentration

FIGURE 2.18 Inotropic and lusitropic responses of guinea pig left atria to (3-adrenoceptor stimulation. Panels A to C isometric tension waveforms of cardiac contraction (ordinates are mg tension abscissae are msec), (a) Effect of 0.3 nM isoproterenol on the waveform. The wave is shortened due to an increase in the rate of diastolic relaxation, whereas no inotropic response (change in peak tension) is observed at this concentration, (b) A further shortening of waveform duration (lusitropic response) is observed with 3 nM isoproterenol. This is concomitant with positive inotropic response (increase maximal tension), (c) This trend continues with 100 nM isoproterenol, (d) Dose-response curves for ino tropy (filled circles) and lusitropy (open circles) in guinea pig atria for isoproterenol, (e) Dose-response curves for inotropy (filled circles) and lusitropy (open circles) in guinea pig atria for the P-adrenoceptor partial agonist prenalterol. Data redrawn from [6]. 

Just as Class III agents can exhibit positive inotropy, some positive inotropic agents demonstrate Class III electrophysiologic activity. The increase in intracellular calcium-ion concentration produced by the inotropic... 

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. 

Early evidence that prejunctional histamine H3-receptors may modulate the sympathetic nerve activity on the heart was provided by Luo et al., (1991). These authors clearly stated that the selective H3-agonist (R)a-methylhistamine attenuates the inotropic response induced by transmural stimulation of the adrenergic nerve terminals in the isolated right atrium, without affecting basal contractile force of the preparation or the positive inotropic effect elicited by exogenous noradrenaline. The effect of (R)a-methylhistamine, which is not modified by Hi and H2-receptor blockade, was reversed by the specific H3-receptor antagonist thioperamide, at concentrations which do not influence the inhibitory activity mediated by other presynaptic receptors, like a2-adrenoceptors. 

Cardiac glycosides cause a positive inotropic effect which means an increase of the cardiac beat volume by enhanced contraction ability. The reason for this is supposed to be aligned with the direct inhibition of the transport enzyme sodium/ potassium-ATPase. The decrease of sodium ions enhances the calcium ion concentration, which activates the myofibrillic enzyme and inactivates proteins like tropo-myocine and tropomine. Till present, a final proof for this hypothesis is lacking, the toxicity, however, is definitely aligned with these effects [97]. 

Positive inotropic agents enhance cardiac muscle contractility, and thus increase cardiac output. Although these drugs act by different mechanisms, in each case the inotropic action is the result of an increased cytoplasmic calcium concentration that enhances the contractility of cardiac muscle. 

In electrically driven guinea-pig atria, callipeltin A induces a positive inotropic effect at concentrations ranging between 0.7 and 2.5 jlM [108,109]. Callipeltin A appears to display an Na-ionophore action, since resting aorta responded to callipeltin A in a dose-dependent manner, with EC50 at 0.44 p,M, which was not inhibited by common calcium channel blockers. Callipeltin A also increased Na efflux of Na-loaded erythrocytes, with EC50 at 0.51 p,M [110]. 

At low concentrations, the catecholamines, epinephrine, and norepinephrine exert positive inotropic effects on the myocardium. High concentrations, however, can cause cardiac lesions (Balazs and Ferrans, 1978 Inoue et al., 1998). Even physiologic concentrations, when extended over time, lead to cardiac damage as shown by Szakacs and Melhnan (1960). The LD50 of norepinephrine in rats is 680 mg/kg, but at doses as low as 0.02 mg/kg, focal necrotic lesions are produced. 

The disappointing results with positive inotropic drugs in treating acute and chronic heart failure may be due to the fact that they increase both systolic and diastolic calcium concentrations in the myocardium (2). 

Digoxin, the most commonly used cardiac glycoside, is indicated for the treatment of CHF and for the treatment of supraventricular tachyarrhythmias. It possesses positive inotropic and electro-physiological effects resulting from the inhibition of Na, K -ATPase, which increases intracellular sodium ion concentrations. This increase in intracellular sodium ions slows down calcium extrusion from the cell, resulting in an increase in intracyto-plasmic calcium and, thereby, an increase in the contractile force. 

Pimobendan is a new positive inotropic agent that is said to be a calcium-sensitizing agent, which increases the force of contraction at a given prevailing calcium ion concentration. It has been evaluated in dogs but not yet in horses. 

Some PHOSPHODIESTERASE INHIBITORS (e.g. cnoximone and milrinone) are valuable, and some exert most of their effect on the myocardium (those acting at a heart-specific subtype of this enzyme (type III phosphodiesterase) to raise the intracellular concentration of cAMP) and may be used as positive INOTROPIC AGENTS in the short-term treatment of severe congestive heart failure. 

Since cAMP is a ubiquitous intracellular chemical mediator, particularly important as a second messenger on receptor activation by many mediators, it follows that enhancement of concentrations or prolongation of action of cAMP will have marked actions. Since f-adrenoceptors signal through this route to directly elevate cAMP, whereas agents that inhibit phosphodiesterase indirectly elevate it, commonly the effects of these two drug classes are very similar (e.g. relaxation of smooth muscle, and positive inotropic actions on the heart). 

The aqueous extract of stem bark of M. pterygosperma has been investigated for its effect on various pharmacological parameters. In cardiovascular profile, at lower concentrations the extract produces a dose dependent positive inotropic effect and at higher concentrations (0.1-1 pg) a dose dependent negative inotropic effect on the isolated frog heart is observed. It... 

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