Mechanism Of Positive Inotropic Effect Research Articles

Mechanism of Positive Inotropic Effect of Vincanine on Cardiac Muscle Contraction Activity

In the present study, the dose-dependent effect of the alkaloid vincanine on the contractile activity of rat heart papillary muscle was investigated and it was found to increase the force of muscle contraction at all concentrations. The half-maximal inotropic effect concentration (ED50) of vincanine was 21.8 μM, respectively. Studies of the effect of this alkaloid on the cardiomyocyte Na+-channel in the presence of its blocker lidocaine showed that the positive inotropic effect of vincanine does not involve the Na+-channel. When studying the effect of vincanine on Сa2+L-channels in the presence of nifedipine (IC50=0.01 μM), the positive inotropic effect of vincanine (50 μM) alkaloid was partially reduced. In general, it was found that the positive inotropic effect of vincanine on the force of papillary muscle contraction is partially mediated by Сa2+L-channels and mainly Na+/Сa2+ exchange.

Novel in vivo and in vitro mechanisms of positive inotropic effect of atractylodin.

This study was to investigate the inotropic effect of atractylodin and its underlying mechanism. The cardiac pressure-volume loop (P-V loop), Langendroff-perfused isolated rat heart, patch-clamp, Ca2+ transient and western blot techniques were used. The results demonstrated that atractylodin (3mg/kg, ip) remarkably increased the left ventricular stroke work, cardiac output, stroke volume, heart rate, ejection fraction, end-systolic pressure, peak rates of rise and fall of left ventricular pressures (+dP/dtmax , -dP/dtmax ), the slopes of end-systolic pressure-volume relationship (also named as end-systolic elastance, Ees) and reducing end-systolic volume and end-diastolic volume in the in vivo rat study. Also, atractylodin (3mg/kg, ip) significantly decreased diastolic blood pressure and the arterial elastance (Ea) without significant systolic blood pressure change. In addition, atractylodin (0.1, 1, 10µmol/L) also increased the isolated rat heart left ventricular developed pressure which is the difference between the systolic and diastolic pressure in non-pacing and pacing modes. Furthermore, JMV-2959 (1μmol/L), a ghrelin receptor unbiased antagonist, blocked the increased left ventricular developed pressure of atractylodin in isolated rat hearts. Finally, atractylodin (5µmol/L) increased the amplitude of Ca2+ transient by enhancing SERCA2a activity, the sarcoplasmic reticulum Ca2+ content and the phosphorylation of phospholamban at 16-serine. These results demonstrated that atractylodin had a positive inotropic effect by enhancing SERCA2a activity which might be mediated by acting ghrelin receptor in myocardium. In conclusion, atractylodin which had the positive inotropic effect and decreased diastolic blood pressure might serve as an agent for the treatment of heart failure in clinical settings.

Investigation of the Mechanisms of Positive Inotropic Effect of (–)–Epigallocatechin 3–O–gallate

Investigation of the Mechanisms of Positive Inotropic Effect of (–)–Epigallocatechin 3–O–gallate

Obestatin as contractile mediator of excised frog heart

AbstractThe aim of this study is to investigate the mechanism of positive inotropic effect of obestatin on in vitro heart preparations of Rana ridibunda frog. The application of increasing amounts of obestatin in the concentration range from 1 μmol/l to 1 μmol/l significantly enhances the force of contraction of excised and cannulated frog hearts. This effect was partially reduced in the presence of prazosin (3 μmol/l). Propranolol (30 μmol/l), pertussis toxin (2 ng/ml) and the specific inhibitor of cAMP-dependent protein kinase (PKA) Rp-adenosine 3′,5′-cyclic monophosphothioate triethylamine (30 μmol/l) completely blocked the obestatin-induced increase of the force of frog heart contractions. It is concluded that, via its receptor molecule, obestatin activates neuronal pertussis toxin sensitive G-protein(s) that further enhance the secretion of epinephrine from sympathetic neurons. This epinephrine activates mainly the myocardial β-adrenoreceptors and PKA downstream targets, and is responsible for the observed positive inotropic effect of obestatin. An alternative explanation of our data is that obestatin directly enhances the effect of myocardial β-adrenergic signaling.

Increase in Myofibrillar Ca2+ Sensitivity Induced by UD-CG 212 Cl, an Active Metabolite of Pimobendan, in Canine Ventricular Myocardium

We performed experiments in canine ventricular trabeculae loaded with aequorin to elucidate the mechanism of positive inotropic effect of UD-CG 212 Cl (4,5-dihydro-6-[2-(4-hydroxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3(2H)-pyridazinone), an active metabolite of pimobendan. The maximum response to UD-CG 212 Cl achieved at 10(-5) M was 18% of ISOmax and it was associated with an increase in Ca2+ transients of 7% of ISOmax. For a given increase in force, the increase in Ca2+ transients induced by UD-CG 212 Cl was less than that induced by elevation of [Ca2+]o. The positive inotropic effect of UD-CG 212 Cl was not associated with an impairment of relaxation and it was abolished by carbachol. In conclusion, UD-CG 212 Cl has a positive inotropic effect partly due to an increase in myofibrillar Ca2+ sensitivity that is exerted via cross talk with a signal transduction pathway that involves cAMP.

Subcellular mechanisms of the positive inotropic effect of angiotensin II in cat myocardium

1. Cat ventricular myocytes loaded with [Ca2+]i- and pHi-sensitive probes were used to examine the subcellular mechanism(s) of the Ang II-induced positive inotropic effect. Ang II (1 microM) produced parallel increases in contraction and Ca2+ transient amplitudes and a slowly developing intracellular alkalisation. Maximal increases in contraction amplitude and Ca2+ transient amplitude were 163 +/- 22 and 43 +/- 8 %, respectively, and occurred between 5 and 7 min after Ang II administration, whereas pHi increase (0.06 +/- 0.03 pH units) became significant only 15 min after the addition of Ang II. Furthermore, the inotropic effect of Ang II was preserved in the presence of Na+-H+ exchanger blockade. These results indicate that the positive inotropic effect of Ang II is independent of changes in pHi. 2. Similar increases in contractility produced by either elevating extracellular [Ca2+] or by Ang II application produced similar increases in peak systolic Ca2+ indicating that an increase in myofilament responsiveness to Ca2+ does not participate in the Ang II-induced positive inotropic effect. 3. Ang II significantly increased the L-type Ca2+ current, as assessed by using the perforated patch-clamp technique (peak current recorded at 0 mV: -1.88 +/- 0.16 pA pF-1 in control vs. -3.03 +/- 0.20 pA pF-1 after 6-8 min of administration of Ang II to the bath solution). 4. The positive inotropic effect of Ang II was not modified in the presence of either KB-R7943, a specific blocker of the Na+-Ca2+ exchanger, or ryanodine plus thapsigargin, used to block the sarcoplasmic reticulum function. 5. The above results allow us to conclude that in the cat ventricle the Ang II-induced positive inotropic effect is due to an increase in the intracellular Ca2+ transient, an enhancement of the L-type Ca2+ current being the dominant mechanism underlying this increase.

Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium.

We performed experiments in rabbit ventricular papillary muscles loaded with aequorin to elucidate the mechanism of positive inotropic effect (PIE) of OR-1896, an active metabolite of levosimendan. The concentration-response curve (CRC) for OR-1896 was biphasic: PIE of OR-1896 reached a plateau at 10(-5) M (first phase), and the CRC became steeper at 10(-3) M and higher (second phase). Maximal response of the first phase was 11% of the maximal response to isoproterenol (ISOmax) and associated with an increase in Ca2+ transients of 5% of ISOmax. For a given degree of PIE, the increase in Ca2+ transients by OR-1896 was lower than that induced by elevation of [Ca2+]o. The PIE of OR-1896 was not associated with impairment of relaxation, and it was abolished by carbachol. In conclusion, OR-1896 has a PIE partly due to an increase in myofibrillar Ca2+ sensitivity that is exerted through crosstalk with signal transduction mediated by cyclic adenosine monophosphate (cAMP).

Inotropic effects of OR-1896, an active metabolite of levosimendan, on canine ventricular myocardium

We performed experiments in dog ventricular trabeculae loaded with aequorin to elucidate the mechanism of positive inotropic effect of ( R)- N-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-acetamide (OR-1896), an active metabolite of ( R)-([4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono)-propanedinitrile (levosimendan). Concentration–response curve for OR-1896 was biphasic: positive inotropic effect of OR-1896 reached a plateau at 10 −5 M (1st phase) and the concentration–response curve became steeper at 10 −3 M and higher (2nd phase). Maximum response of the 1st phase was 29% of maximal response to isoproterenol and associated with an increase in Ca 2+ transients of 13% of the maximal response to isoproterenol. For a given increase in force, the increase in Ca 2+ transients by OR-1896 was lower than that induced by elevation of [Ca 2+] o. The positive inotropic effect of OR-1896 was not associated with impairment of relaxation and it was abolished by carbachol. In conclusion, OR-1896 has a positive inotropic effect partly due to an increase in myofibrillar Ca 2+ sensitivity that is exerted via cross-talk with signal transduction mediated by cAMP.

Mechanism of the Positive Inotropic Effect of Ketamine in Isolated Ferret Ventricular Papillary Muscle

Ketamine is a cardiovascular stimulant through its sympathomimetic effects; however, its direct inotropic effect has been reported as positive in rat and negative in rabbit ventricular myocardium. This study reexamines the effect of ketamine on the contractile properties of mammalian ventricular myocardium. In isolated, electrically stimulated ferret right ventricular papillary muscles, the authors assessed the inotropic effect of ketamine (10(-6) M to 3 x 10(-4) M in 0.5 log M increments) alone and in various pharmacologic conditions designed to delineate ketamine's site(s) of action. Ketamine exerted a positive inotropic effect that was maximal at 10(-4) M. Bupranolol (10(-7) M) abolished this positive inotropic effect, whereas phentolamine (10(-6) M) did not. Depletion of norepinephrine stores by reserpine also eliminated ketamine's positive inotropic effect, indicating that ketamine caused indirect activation of the beta-adrenoceptor. Ketamine did not exert a positive inotropic effect in the presence of simultaneous inhibition of neuronal norepinephrine uptake with desmethylimipramine (DMI) (5 x 10(-6) M) and extraneuronal uptake with corticosterone (5 x 10(-5) M). It is likely that ketamine's action is to inhibit norepinephrine uptake at the neuroeffector junction rather than to augment norepinephrine release. In the presence of corticosterone, ketamine exerted a smaller positive inotropic effect than that seen with ketamine alone. Ketamine produced a small increase in force development in the presence of DMI, but this did not reach statistical significance. Inhibition of neuronal catecholamine uptake appears to be the predominant mechanism of ketamine's positive inotropic effect.

Introduction: Mechanisms of positive inotropic effects

This review deals with the principal mechanisms which are known to play a role in positive inotropism: 1) The myoplasmic Ca2+ concentration may be increased by increases in cyclic AMP. Beside receptor-mediated stimulation (isoprenaline) or direct stimulation (forskolin) of the adenylate cyclase, the cyclic AMP may be increased by phosphodiesterase inhibition; 2) Cyclic AMP-independent activation of Ca2+ channels can be brought about by alpha-adrenergic agents (phenylephrine) or so-called calcium agonists; 3) Only a small increase in myoplasmic Na+ concentration can greatly enhance the force of contraction by an increase in the intracellular Ca2+ concentration. This is possible by inhibition of the Na+/K+-ATPase (glycosides) or by prolongation of the open state of Na+ channels (DPI 201-106); 4) A direct inhibition of the Na+/Ca2+ exchange has been discussed for amiloride; 5) A prolongation of the action potential induced by K+ channel-inhibiting agents such as 4-amino-pyridine may increase the myoplasmic Ca2+ concentration by a prolongation of the slow Ca2+ inward current; 6) An increased Ca2+ sensitivity of the contractile proteins has been demonstrated for a number of compounds in vitro; the contribution of such an effect to the overall positive inotropism is unknown because a calcium sensitizer without any effects on calcium or sodium movements is not yet available.

On the mechanism of positive inotropic effects of alpha-adrenoceptor agonists

The positive inotropic effect of the alpha 1-adrenoceptor agonist phenylephrine is accompanied by an increase in the presumed second messengers inositol 1,4,5-trisphosphate (1,4,5-IP3) and inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4). Both 1,4,5-IP3 and 1,3,4,5-IP4 sensitize myocardial contractile proteins in chemically skinned fibers. In addition to the Ca++ releasing effect of 1,4,5-IP3 from the sarcoplasmic reticulum the Ca++-sensitizing effect of the inositol phosphates may play a role in alpha 1-adrenergic positive inotropism. In isolated heart muscle preparations from patients with endstage heart failure (due to dilated cardiomyopathy) beta-adrenergic as well as alpha 1-adrenergic effects are reduced compared to preparations from healthy hearts. The reduced beta-adrenergic effects can in part be explained by an increased content of signal transducing G1-proteins. It is tempting to investigate whether other G proteins are also altered in severe congestive heart failure.

Mechanisms of positive inotropic effects and delayed relaxation produced by DPI 201-106 in mammalian working myocardium: effects on intracellular calcium handling.

1. We used the bioluminescent protein aequorin, which emits light when it combines with Ca2+, to test the hypothesis that the inotropic and lusitropic actions of DPI 201-106 are due to changes in intracellular Ca2+ handling in papillary muscles from ferrets and guinea-pigs. 2. DPI 201-106 increased peak isometric tension (T) in a dose-dependent manner, with an 83% increase in T as the concentration of DPI 201-106 was increased to 1 x 10(-5) M; however, peak [Ca2+]i did not increase significantly until the concentration of DPI 201-106 reached 3 x 10(-6) M, suggesting a sensitization of the contractile apparatus to Ca2+. 3. Tetrodotoxin (1 x 10(-6) M), which did not reduce the tension response significantly before DPI 201-106, decreased both [Ca2+]i and T in the presence of 1 x 10(-5) M DPI 201-106, suggesting involvement of a sodium channel activation mechanism; however, tetrodotoxin did not completely reverse the calcium sensitization. 4. The shift of the [Ca2+]i versus T relationship was not observed in the presence of another sodium channel agonist, veratridine (3 x 10(-7)-1 x 10(-6) M). 5. In the guinea-pig, DPI 201-106 markedly prolonged relaxation of tension (increase of 60% in the time from peak to 50% tension regression), which was accompanied by the appearance of a second component in the aequorin light signal; effects on relaxation were less prominent in the ferret. 6. Tension prolongation and the second component of the [Ca2+]i transient in the guinea-pig were exacerbated by increased [Ca2+]o and decreased by tetrodotoxin. Ryanodine (3 x 10(-7) M) markedly diminished the calcium transient in controls and the initial component of the calcium transient in the presence of DPI 201-106, but had only a modest effect on the second component. 7. We conclude that although sodium agonism plays a role, sensitization of the contractile apparatus to Ca2+ is an important mechanism in the positive inotropic action of DPI 201-106. 8. The negative lusitropic action of DPI 201-106 varies between ferret and guinea-pig, possibly reflecting differences between these two species in subcellular Ca2+ handling.

A study on the mechanism of positive inotropic effect of berberine on the myocardium: Wei-Min Huang, Zhi-Hao Zhang (Cardiovascular Research Lab, Shanghai Xu Hui District Hospital, Shanghai, PRC) and You-Qiu Xu (Department of Physiology, Shanghai Second Medical University, Shanghai, PRC)

A study on the mechanism of positive inotropic effect of berberine on the myocardium: Wei-Min Huang, Zhi-Hao Zhang (Cardiovascular Research Lab, Shanghai Xu Hui District Hospital, Shanghai, PRC) and You-Qiu Xu (Department of Physiology, Shanghai Second Medical University, Shanghai, PRC)

132) - Mechanisms of positive inotropic effect of grayanotoxin I on guinea pig papillary muscle

132) - Mechanisms of positive inotropic effect of grayanotoxin I on guinea pig papillary muscle