Negative 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. 

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 Unfortunately, the compound has been withdrawn because of multiple interactions with various other drugs. 

Immunostimulant activity. Fresh plant juice, in the ration of female mice, was active in ovalbumin-sensitized mice . Water extract of the dried root, taken orally by human adults, was active. A pharmaceutical solution containing fruit bodies of Tremella fuciformis, Daucus carom root, Astragalus mongholicus root and Zizyphus jujuba fruits, honey, vitamin A palmitate, zinc sulfate, and vitamin C is claimed useful as an immunostimulant for controlling AIDS, cancer, and infections L Inotropic effect (negative). Ethanol (80%) extract of the aerial parts, at a concentration of 0.3 mg/mL, was active on the guinea pig atrium . 

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]. 

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],... 

It is of interest that similar structural requirements appear to hold for vasodilation, negative inotropic activity and smooth muscle relaxation. This suggests a qualitative similarity... 

A quantitative structure-activity relationship for the negative inotropic activity of a small series of 1,4-dihydro-pyridines has been developed (47.). For 2,6-dimethyl-3,5-dicarbo-methoxy-4-(substituted phenyl)-1,4-dihydropyridines the effect of the phenyl substituent is determined primarily by steric effects. Thus, for ortho-substituted derivatives,... 

Structure-activity data are quite restricted for other classes of Ca2+ channel antagonists. For a limited series of verapamil derivatives carrying ring substituents (II), negative inotropic activity depends upon both electronic and steric properties of the substituent (52f53),... 

Experiments utilizing isolated superfused and blood perfused cardiac tissue preparations and isolated rat, rabbit, and cat whole hearts all demonstrate the potent, concentration-dependent, negative inotropic activity of the calcium inhibitory compounds (45 50, 90-95, 112, 113, 114, 118, 140, 141). Studies comparing the relative negative inotropic effects of several of the calcium inhibitory compounds indicate that those compounds exhibiting the most potent calcium inhibitory effects in vitro are the most effective in reducing cardiac contractility in vivo (6). Of those compounds most frequently compared, nifedipine and niludipine exhibit the most profound negative inotropic activity followed by verapamil (levo isomer), diltiazem and perhexiline (88, 89-142). 

Smooth Muscle. All known calcium inhibitory compounds decrease smooth muscle tone in both the coronary and peripheral circulations (11 , 114, 115, 140, 145-147). Comparative studies using dogs suggest that this effect varies in intensity but surpasses negative inotropic activity (114, 145). Nifedipine, verapamil and perhexiline exhibit their most pronounced vasodilator effects upon femoral arterial blood flow followed by coronary, renal, and mesenteric beds (44, 47,... 

Amlodipine has little effect on myocardial tissues. It does not significantly reduce conduction, nor does it have significant negative inotropic activity. 

Calcium-channel blockers in current clinical usage affect the slow L-type channel. They are usually classified by their chemical structure, which determines their selectivity for vascular smooth muscle over myocardium, and hence their potential to slow the heart rate (negative inotropic activity) see Table 23. T, (below). Interactions due to additive inotropic effects will therefore apply only to the benzothiazepine (diltiazem) and phenyla-Ikylamine-type (verapamil) calcium-channel blockers, and usually not to the dihydropyridine-type (e.g. nifedipine) calcium-channel blockers. All three types of calcium-channel blocker will have additive hypotensive effects with other drugs with blood-pressure lowering activity. 

Isopropyl alcohol extracts of the sponge Tethya aurantia were fractionated for a component with negative chronotropic and inotropic activity on isolated guinea pig atria 181). The bioactive substance was found to be adenosine. The extracts also contained allantoin (293), which is an intermediate in the purinolytic sequence. Dichloromethane and methanol extracts of a new species of the genus Echinodictyum showed strong activities on the isolated guinea-pig trachea 182). The active constituent was identified as 4-amino-5-bromopyrrolo[2,3-d]pyr-imidine (294). 

Hi-receptors in the adrenal medulla stimulates the release of the two catecholamines noradrenaline and adrenaline as well as enkephalins. In the heart, histamine produces negative inotropic effects via Hr receptor stimulation, but these are normally masked by the positive effects of H2-receptor stimulation on heart rate and force of contraction. Histamine Hi-receptors are widely distributed in human brain and highest densities are found in neocortex, hippocampus, nucleus accumbens, thalamus and posterior hypothalamus where they predominantly excite neuronal activity. Histamine Hrreceptor stimulation can also activate peripheral sensory nerve endings leading to itching and a surrounding vasodilatation ( flare ) due to an axonal reflex and the consequent release of peptide neurotransmitters from collateral nerve endings. 

Ryanodine leads to contracture of mammalian skeletal muscle, whereas it causes negative inotropism in cardiac muscle. This apparent opposite effects are due to difference in the Ca2+ extruding activity the released Ca2+ remains within cytoplasm in skeletal muscle because of low Ca2+ extruding activity, whereas the increased cytoplasmic Ca2+ is rapidly excluded out of the cytoplasm in cardiac muscle via Na+ -Ca2+ -exchange. 

Current data suggest little benefit on clinical outcomes beyond symptom relief for calcium channel blockers in the setting of ACS.43 Moreover, the use of first-generation shortacting dihydropyridines, such as nifedipine, should be avoided because they appear to worsen outcomes through their negative inotropic effects, induction of reflex sympathetic activation, tachycardia, and increased myocardial ischemia.43 Therefore, calcium channel blockers should be avoided in the acute management of MI unless there is a clear symptomatic need or a contraindication to p-blockers. 

In the heart, the effects on the parasympathetic limb predominate. Thus, cholinesterase inhibitors such as edrophonium, physostigmine, or neostigmine mimic the effects of vagal nerve activation on the heart. Negative chronotropic, dromotropic, and inotropic effects are produced, and cardiac output falls. The fall in cardiac output is attributable to bradycardia, decreased atrial contractility, and some reduction in ventricular contractility. The latter effect occurs as a result of prejunctional inhibition of norepinephrine release as well as inhibition of postjunctional cellular sympathetic effects. 

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