Human Myocardial Trabeculae Research Articles

Pharmacology of mitochondrial permeability transition pore inhibitors.

It is now firmly established that an important event in the formation of reperfusion injury of the heart is the opening of mitochondrial permeability transition pores (mPTPs), which changes the permeability of the mitochondria. mPTP opening results in the death of cardiomyocytes through activation of apoptosis and necroptosis. Experimental studies have shown that pharmacological inhibition of mPTP opening promotes the reduction in the infarct size and the suppression of apoptosis. Indeed, studies have shown the efficacy of mPTP inhibitors in animal models of myocardial reperfusion and isolated human myocardial trabeculae. However, clinical trials of cyclosporin A and TRO40303 have not provided a clear answer to the question of the effectiveness of mPTP inhibitors in patients with acute myocardial infarction. This article presents an analysis of possible approaches for the pharmacological regulation of mPTP during reperfusion injury of the heart.

Direct Inotropic Effects of Exogenous and Endogenous Urotensin-II

Background— Urotensin-II (U-II) is an endogenous peptide upregulated in failing hearts. To date, insights into the myocardial actions of U-II have been obscured by its potent vasoconstrictor effects and interspecies differences in physiological responses to U-II. Methods and Results— We examined the direct effects of exogenous U-II on in vitro contractility in nonfailing and failing human myocardial trabeculae (n=47). Rapid cooling contractures (RCC) were used to examine sarcoplasmic reticulum Ca 2+ load. In nonfailing myocardium, exogenous U-II increased developed force (DF), rates of force generation and decline and RCC amplitude suggesting increased sarcoplasmic reticulum Ca 2+ load. In isolated myocyte suspensions from nonfailing hearts, U-II increased phospholamban phosphorylation. In failing myocardium, exogenous U-II reduced DF and rates of force generation and decline without a significant change in RCC amplitude in trabeculae or a change in phospholamban phosphorylation in myocytes. To examine the effects of endogenous U-II, we administered the peptidic U-II receptor antagonist (UT-A) GSK248451A to isolated trabeculae. UT-A induced a decrease in DF in nonfailing myocardium and an increase in DF in failing myocardium. UT-A increased RCC amplitude slightly in both nonfailing and failing myocardium. During ongoing UT-A, exogenous U-II had little effect on DF and RCC amplitude, confirming effective receptor blockade. Conclusions— U-II modulates contractility independent of vasoconstriction with opposite effects in failing and nonfailing hearts. Positive inotropic responses to UT-A alone suggests that increased endogenous U-II constrains contractility in failing hearts via an autocrine or paracrine mechanism. These findings support a potential therapeutic role for UT-A in heart failure.

Vasoactive intestinal peptide has a direct positive inotropic effect on isolated human myocardial trabeculae.

The aim of the present study was to assess the inotropic effects of vasoactive intestinal peptide (VIP) on isolated myocardial trabeculae from the right atrium and the left ventricle of human hearts. Furthermore, using reverse transcriptase-PCR, we wanted to determine the presence of mRNAs encoding the three cloned human VIP receptors, VPAC(1), VPAC(2) and PAC(1). The trabeculae were paced at 1.0 Hz in tissue baths, and changes in isometric contractile force upon exposure to agonist were studied. VIP had a potent positive inotropic effect in some of the atrial and ventricular trabeculae tested. This effect was almost completely blocked by the VIP-receptor antagonist VIP-(6-28). mRNAs encoding the human VPAC(1), VPAC(2) and PAC(1) receptors were detected in human myocardial trabeculae from both the right atrium and the left ventricle. In conclusion, VIP has a direct positive inotropic effect in both the atria and the ventricles of the human heart. The presence of mRNAs for the VPAC(1), VPAC(2) and PAC(1) receptors suggest that VIP may mediate its effect via these receptors.

Vasoactive intestinal peptide has a direct positive inotropic effect on isolated human myocardial trabeculae

The aim of the present study was to assess the inotropic effects of vasoactive intestinal peptide (VIP) on isolated myocardial trabeculae from the right atrium and the left ventricle of human hearts. Furthermore, using reverse transcriptase-PCR, we wanted to determine the presence of mRNAs encoding the three cloned human VIP receptors, VPAC1, VPAC2 and PAC1. The trabeculae were paced at 1.0Hz in tissue baths, and changes in isometric contractile force upon exposure to agonist were studied. VIP had a potent positive inotropic effect in some of the atrial and ventricular trabeculae tested. This effect was almost completely blocked by the VIP-receptor antagonist VIP-(6-28). mRNAs encoding the human VPAC1, VPAC2 and PAC1 receptors were detected in human myocardial trabeculae from both the right atrium and the left ventricle. In conclusion, VIP has a direct positive inotropic effect in both the atria and the ventricles of the human heart. The presence of mRNAs for the VPAC1, VPAC2 and PAC1 receptors suggest that VIP may mediate its effect via these receptors.

Positive inotropic responses mediated by endothelin ET(A) and ET(B) receptors in human myocardial trabeculae.

The aim of the present study was to determine possible inotropic effects mediated by endothelin ET(A) and ET(B) receptors in human myocardial trabeculae from the right atrium and the left ventricle. Isolated trabeculae from human hearts were paced at 1.0 Hz in tissue baths, and changes in isometric contractile force upon exposure to agonist were studied. Endothelin-1 (ET-1) and ET-3 had a strong positive inotropic effect in all trabeculae. ET-1 was significantly more potent than ET-3 in both atrial (P < 0.001) and ventricular (P < 0.05) trabeculae. Preincubation with the ET(A) receptor antagonist FR139317 (1 microM) decreased significantly (P < 0.005) the potency of ET- I in both atrial and ventricular trabeculae, without any significant changes in Emax (maximum effect obtained with an agonist). The ET(B) receptor agonist IRL 1620 had a positive inotropic effect only in some trabeculae, and the ET(B) receptor antagonist BQ 788 (1 microM) almost completely blocked this effect. These results suggest that both ET(A) and ET(B) receptors mediate positive inotropic responses at both the atrial and ventricular level in the human heart.

Positive inotropic responses mediated by endothelin ETA and ETB receptors in human myocardial trabeculae

The aim of the present study was to determine possible inotropic effects mediated by endothelin ETA and ETB receptors in human myocardial trabeculae from the right atrium and the left ventricle. Isolated trabeculae from human hearts were paced at 1.0 Hz in tissue baths, and changes in isometric contractile force upon exposure to agonist were studied. Endothelin-1 (ET-1) and ET-3 had a strong positive inotropic effect in all trabeculae. ET-1 was significantly more potent than ET-3 in both atrial (P &amp;lt; 0.001) and ventricular (P &amp;lt; 0.05) trabeculae. Preincubation with the ETA receptor antagonist FR139317 (1 μM) decreased significantly (P &amp;lt; 0.005) the potency of ET-1 in both atrial and ventricular trabeculae, without any significant changes in Emax (maximum effect obtained with an agonist). The ETB receptor agonist IRL 1620 had a positive inotropic effect only in some trabeculae, and the ETB receptor antagonist BQ 788 (1 μM) almost completely blocked this effect. These results suggest that both ETA and ETB receptors mediate positive inotropic responses at both the atrial and ventricular level in the human heart.

Positive inotropy mediated via CGRP receptors in isolated human myocardial trabeculae

Isometric contractile force were studied on isolated human myocardial trabeculae that were paced at 1.0 Hz in tissue baths. Alpha calcitonin gene-related peptide (α-CGRP) had a potent positive inotropic effect in most trabeculae from both the right atrium and left ventricle, and this effect was partially antagonized by the CGRP 1 receptor antagonist α-CGRP-(8-37) (10 −6 M). Amylin and the CGRP 2 receptor agonist [Cys(acetylmethoxy) 2,7]CGRP had a positive inotropic effect in some trabeculae, whereas adrenomedullin had no inotropic effect. Using reverse transcriptase–polymerase chain reaction (PCR) mRNAs encoding the human calcitonin receptor-like receptor and the receptor associated modifying proteins (RAMPs) RAMP1, RAMP2, and RAMP3 were detected in human myocardial trabeculae from both the right atrium and left ventricle. In conclusion, functional CGRP 1 and CGRP 2 receptors may mediate a positive inotropic effect at both the atrial and ventricular level of the human heart. mRNAs for calcitonin receptor-like receptor and specific RAMPs further support the presence of CGRP receptors.

Evidence for an influence of mechanical restitution on beat-to-beat variations in haemodynamics during chronic atrial fibrillation in patients.

We tested the hypothesis that beat-to-beat changes in haemodynamics during atrial fibrillation include an effect of each preceding R-R interval through the interval-strength relationship (mechanical restitution). The variation in stroke volume and pulse pressure characteristic of atrial fibrillation is usually ascribed to time dependent ventricular filling. We measured the maximum rate of rise of left ventricular pressure (LVdP/dtmax), and aortic blood velocity and its integral in patients with atrial fibrillation undergoing cardiac catheterisation. The contractile response of isometric human myocardial trabeculae to sequences of atrial fibrillation was also studied, using the recorded ECGs as stimuli. The trabeculae were obtained from the resected right ventricular outflow tracts of patients with Fallot's tetralogy undergoing operative correction. Beat-to-beat variations in contractile function during atrial fibrillation in the patients were recorded as LVdP/dtmax and left ventricular ejection (ascending aortic) velocity integral (proportional to stroke volume). Both these indices correlated well with the response to the same ECG (R wave) sequences in the isometric model measured as the maximum rate of rise of force, dF/dtmax, r = 0.72 to 0.81, p, 0.0001. When short pre-preceding intervals were excluded (minimizing the effect of post-extrasystolic potentiation), these variables showed a positive curvilinear relationship to preceding interval typical of mechanical restitution. Mechanical restitution, which causes beat-to-beat changes in inotropic state, accounts in part for the changes in stroke volume in atrial fibrillation.