Inotropic activity

The cardiac effects of the calcium antagonists, ie, slowed rate (negative chronotropy) and decreased contractile force (negative inotropy), are prominent in isolated cardiac preparations. However, in the intact circulation, these effects may be masked by reflex compensatory adjustments to the hypotension that these agents produce. The negative inotropic activity of the calcium antagonists may be a problem in patients having heart failure, where contractility is already depressed, or in patients on concomitant -adrenoceptor blockers where reflex compensatory mechanisms are reduced. 

Increases cardiac output through positive inotropic activity... 

Sodium nitroprusside is a mixed arterial-venous vasodilator that acts directly on vascular smooth muscle to increase cardiac index and decrease venous pressure. Despite its lack of direct inotropic activity, nitroprusside exerts hemodynamic effects that are qualitatively similar to those of dobutamine and milrinone. However, nitroprusside generally decreases PAOP, SVR, and blood pressure more than those agents do. 

Substituted imidazo[2,l-3]thiazoles with a lactam ring derived from 2-iminothiazolidine-4-one 482 and from pyr-imidine-2,4,6-trione 483 and 6-substituted-2,3-dihydro-imidazo[2,l-3]thiazole with a bicyclic 2-indolinone system 125 were discovered as new cardotonic agents and showed a positive inotropic activity <1996EJM383, 1997EJM919>. 

Pyridazinylphenyl)acetamides (15) possess more in vitro and in vivo inotropic activity than milrinone (l,6-dihydro-2-methyl-6-oxo(3,4 -bipyridine)-... 

A variety of tricylic compounds [indenopyridazinones (19)] have been prepared as rigid structural modifications of compounds like CI-930 (16) [28,29]. Most of them have been found to retain the positive inotropic and direct vasodilator activity of the freely rotating pyridazinones [28]. Also, hydrazinopyridazines of type (20) have been investigated as structural analogues of CI-914 and Cl-930, respectively. Whereas considerable inotropic activity has been observed in this series as well, ring closure to triazolo[4,3-h]pyridazines resulted in significantly less potent compounds [30]. 

The inotropic effects of these agents are not mediated via direct stimulation of -adrenergic receptors or indirectly by release of catecholamines, but by selective inhibition of cardiac cAMP phosphodiesterase (PDE) type III [25,35-40]. Recently, it has been demonstrated that the imidazole core is primarily responsible for PDE isozyme specificity, whereas the dihydropyri-dazinone moiety is responsible for inhibitory potency the phenylene moiety obviously acts mainly as a spacer [26]. A five-point model for positive inotropic activity of PDE III inhibitors has been elaborated [41]. 

Moreover, there are patents on pyridazinone-derived cardiotonic compounds in which the phenyl substituent is separated from the pyridazinone system by an alkylene or alkylidene bridge [164,165] and on various azolyl-substituted pyridylpyridazinones of type (49) [166]. Cardiovascular 6-phen-ylpyridazines of type (50) have been patented [167], In Taiwan, cyclohexyl-ammonium 3,6-pyridazinediolate (51) has been reported to show positive inotropic activity [168]. 

Nifedipine -blockers suppress reflex tachycardia (favourable), but enhance the negative inotropic activity. 

Dihydropyridine-CA have been developed with a certain degree of vascular selectivity, which implies that at therapeutic doses such compounds would have less negative influence on cardiac contractile force or none at all. Indeed, a few of such compounds are devoid of cardiodepressant (negative inotropic) activity. Examples of such compounds are amlodipine, felodipine, isradip-ine, lacidipine, lercanidipine and manidipine. 

Mibefradil is a verapamil-like agent with a potentially attractive haemodynamic profile. It is a vasodilator, which also causes a reduction in heart rate, whereas it is devoid of negative inotropic activity. Some of its properties are attributed to its influence of calcium channels of the T- and N-types. Unfortunately, the compound has been withdrawn because of multiple interactions with various other drugs. 

Cardiac glycosides display positive inotropic activity by a direct effect on the myocardial cells, trig-... 

Digoxin, prototype of the cardiac glycosides, is frequently used postoperatively for the management of atrial fibrillation. This effect is based on the impairment of AV conduction and unrelated to digoxin s positive inotropic activity. In the treatment of post-operative atrial fibrillation digoxin may be... 

The piperidines, e.g. thioridazine, pipothiazine and pericyazine, have the lowest potential to cause extrapyramidal effects. Thioridazine is one of the most sedative phenothiazines. It may decrease the inotropic activity of digitalis by its quinidine-like action, which can cause myocardial depression, decreased efficiency of repolarization, and increased risk of tachyarrhythmias. With thioridazine drug induced sexual dysfunction and especially cardiotox-icity with prolongation of the QT-interval are more frequently seen than with other phenothiazines. For the above reasons thioridazine is withdrawn from the market in many countries. 

Apart from AP-A, the best characterized of these polypeptides with respect to its biological activity is Anemonia sulcata toxin II (ATX II) [19]. This molecule is also cardioactive [28], as would be expected from its similarity to AP-A. Renaud et al. [29] have compared the activities of a number of sea anemone and scorpion toxins on isolated rat atria and found that anthopleurin-B (AP-B, also known as Ax II) had the highest potency and the greatest margin between the concentrations necessary for maximal inotropic activity and for provoking arrhythmias (0.3 versus 10 n . It was also found that sodium channels of rat cardiac cells in culture, which have a low affinity for tetrodotoxin (TTX), have a particularly high affinity for Type 1 anemone toxins [29], whereas Type 2 toxins [30] and scorpion toxins [31] had similar affinities for TTX-sensitive and TTX-insensitive channels in rat neuroblastoma cells and skeletal myotubes, respectively. 

The Anemonia sulcata polypeptides BDS I and II [40], which were claimed to have antihypertensive and antiviral activity, also bind to site 3 on neuronal sodium channels and have weak negative inotropic activity [41]. The points of similarity and difference between the solution structures of BDS I [40] and the long anemone polypeptides have been discussed previously [40,41] and will not be reiterated here suffice to say that the overall folds are similar but the Argl4 loop in the long polypeptides is truncated in BDS I and the molecule lacks several residues that have been shown to be important for activity. 

From A. membranaceous, Wang [145] obtained a saponin-enriched extract and studied its effect on the isolated heart of rats. At doses of more than 50 ftg/ml, the extract showed a positive inotropic effect, which turned negative at 30 p.g/ml. The mechanism was similar to that of cardiotonic glycosides. By bioactivity-guided fractionation, the active constituent with positive inotropic activity was isolated and characterized as astragaloside IV [146]. 

The use of Coleus Forskohlii seems to have possible cardiovascular benefits by acting as a vasodilator (lowers blood pressure), inhibition of platelet aggregation (reduced blood clotting), and positive inotropic activity in the heart (increased contractile force). 

Among the reported activities of hawthorn are positive inotropic activity, coronary vasodilatation, slowing of heart rate, and slight lowering of blood pressure. 

Similar studies on N-alkyl-substituted benzylamines show a sudden increase in line width broadening at a chain length of about Q (Figure 3.40). The sudden increase in strength of interaction corresponding to a n-value of about 3 is paralleled by a strong increase in negative inotropic activity [135],... 

A piperazine derivative (30) of 17 exhibits inotropic activity. The dication in the crystalline dihydrochloride has a center of symmetry and a chair-form ring. The C3H5CH2 units occupy trans equatorial positions, and take themselves ac conformations, thus giving an extended shape to the cationic species. The M—Cl—C4—N dihedral angle is (as calculated from coordinates) 125.2, and some other parameters are Cl—C2 (mean) 1.498, C2—C3 1.490 (3), Cl—C4 1.489 (3) A, C2—Cl—C4 (mean) 118.4 ... 

Although ET-1 has positive inotropic activity in vitro, administration of ET-1 in vivo decreases left ventricular contractility and cardiac output, a result of myocardial ischaemia secondary to coronary constriction [29]. ET-1 also has pro-arrhythmic activity which may be independent of effects on the coronary circulation [30]. 

Raschack, M. Relationship of antiarrhythmic to inotropic activity and antiarrhythmic qualities of the optical isomers of verapamil. Arch. Pharmacol. 1976, 294 (3), 285-291. 

In vivo, racemic dobutamine increases the inotropic activity of the heart to a much greater extent than it increa.ses chronotropic activity. This pharmacological profile has led to its use in treating congestive heart failure. Since /3 receptors are involved positively in both inotropic and chronotropic effects of the heart, the selective inotropic effect. seen with dobutamine cannot simply be due to its activity at P% receptors. Rather, this effect is the result of a combination of the inotropic effect of (-t- )-dohutamine on Px receptors and that of (-)-dobutamine mediated through 0 receptors. Thus, this is a case where a racemic mixture provides a more desirable pharmacological and therapeutic cITect than would cither enantiomer alone. 

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