Urotensin II-Induced Increase in Myocardial Distensibility Is Modulated by Angiotensin II and Endothelin-1

Endogenous regulators, such as angiotensin-II (AngII), endothelin-1 (ET-1) and urotensin-II (U-II) are released from various cell types and their plasma levels are elevated in several cardiovascular diseases. The present study evaluated a potential crosstalk between these systems by investigating if the myocardial effects of U-II are modulated by AngII or ET-1. Effects of U-II (10(-8), 10(-7), 10(-6) M) were tested in rabbit papillary muscles in the absence and in the presence of losartan (selective AT, receptor antagonist), PD-145065 (nonselective ET-1 receptors antagonist), losartan plus PD-145065, AngII or ET-1. U-II promoted concentration-dependent negative inotropic and lusitropic effects that were abolished in all experimental conditions. Also, U-II increased resting muscle length up to 1.008 +/- 0.002 L/L(max). Correcting it to its initial value resulted in a 19.5 +/- 3.5 % decrease of resting tension, indicating increased muscle distensibility. This effect on muscle length was completely abolished in the presence of losartan and significantly attenuated by PD-145065 or losartan plus PD-145065. This effect was increased in the presence of AngII, resulting in a 27.5 +/- 3.9 % decrease of resting tension, but was unaffected by the presence of ET-1. This study demonstrated an interaction of the U-II system with the AngII and ET-1 systems in terms of regulation of systolic and diastolic function

Modulation of Myocardial Stiffness by beta-Adrenergic Stimulation Its Role in Normal and Failing Heart

The acute effects of ß-adrenergic stimulation on myocardial stiffness were evaluated. New-Zealand white rabbits were treated with saline (control group) or doxorubicin to induce heart failure (HF) (DOXO-HF group). Effects of isoprenaline (10 -10-1 -5 M), a non-selective ß-adrenergic agonist, were tested in papillary muscles from both groups. In the control group, the effects of isoprenaline were also evaluated in the presence of a damaged endocardial endothelium, atenolol (ßi-adrenoceptor antagonist), ICI-118551 (ßz-adrenoceptor antagonist), KT-5720 (PKA inhibitor), L-NNA (NO-synthase inhibitor), or indomethacin (cyclooxygenase inhibitor). Passive length-tension relations were constructed before and after adding isoprenaline (10 -5 M). In the control group, isoprenaline increased resting muscle length up to 1.017±0.006 L/L max. Correction of resting muscle length to its initial value resulted in a 28.5±3.1% decrease of resting tension, indicating decreased muscle stiffness, as confirmed by the isoprenaline-induced right-downward shift of the passive lengthtension relation. These effects were modulated by ßr and ß 2adrenoceptors and PKA. In DOXO-HF group, the effect on myocardial stiffness was significantly decreased. We conclude that ß-adrenergic stimulation is a relevant mechanism of acute neurohumoral modulation of the diastolic function. Furthermore, this study clarifies the mechanisms by which myocardial stiffness is decreased. (c) 2011 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic

Echocardiographic evaluation including tissue Doppler imaging in New Zealand white rabbits sedated with ketamine and midazolam

Limited data are available on the use of more recent echocardiographic parameters in the rabbit. Echocardiographic examination, including conventional echocardiography and tissue Doppler imaging (TDI), was performed on 26 male New Zealand white rabbits under ketamine-midazolam sedation. Particular emphasis was placed on the more recent systolic and diastolic parameters, such as myocardial performance index (Tei index) and mitral annular motion (from septal and lateral sides of the left ventricle) obtained using pulsed TDI. Parameters that assessed systolic and diastolic function (fractional shortening, Tei index, and maximal mitral E- and A-wave velocities) were comparable to those reported in the literature for rabbits in the awake state. The less cardiodepressive anaesthetic protocol could offer a good alternative in performing echocardiographic evaluation whenever such caution is necessary. TDI is feasible in healthy rabbits and potentially suitable for the investigation of left ventricle systolic and diastolic function

Exposure of humans to the zoonotic nematode Dirofilaria immitis in Northern Portugal

Dirofilariosis caused by Dirofilaria immitis (heartworm) is a zoonosis, considered an endemic disease of dogs and cats in several countries of Western Europe, including Portugal. This study assesses the levels of D. immitis exposure in humans from Northern Portugal, to which end, 668 inhabitants of several districts belonging to two different climate areas (Csa: Bragança, Vila Real and Csb: Aveiro, Braga, Porto, Viseu) were tested for anti-D. immitis and anti-Wolbachia surface proteins (WSP) antibodies. The overall prevalence of seropositivity to both anti-D. immitis and WSP antibodies was 6.1%, which demonstrated the risk of infection with D. immitis in humans living in Northern Portugal. This study, carried out in a Western European country, contributes to the characterisation of the risk of infection with D. immitis among human population in this region of the continent. From a One Health point of view, the results of the current work also support the close relationship between dogs and people as a risk factor for human infectio

Neuregulin1/ErbB system: importance in the control of cardiovascular function

The family of Neuregulins (NRG), growth factors like epidermal growth factor, is known to induce growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells. This family comprises four members, being NRG1 the most largely studied, particularly at the cardiovascular level. The biological effects of NRG1 in the adult heart are mediated by the tyrosine kinase receptors ErbB. In the adult heart, NRG1 is expressed by cells of the endocardial endothelium and the cardiac microvascular endothelium, and the receptors ErbB2/ErbB4 are expressed by ventricular cardiomyocytes and are located in T-tubule system and intercalated disks in close proximity to the system components of excitation-contraction coupling. The importance of the NRG/ErbB signaling axis at the cardiovascular level became evident after discovering that patients treated with trastuzumab (inhibitory antibody against ErbB2, used in the treatment of breast cancer) can develop ventricular dysfunction and have higher risk of cardiomyopathy when co-administered with anthracyclines. Subsequent studies in vitro and in vivo have clarified the effects and the respective signaling pathways associated with the NRG/ErbB system in the adult heart. Some cardiovascular functions of the NRG1/ErbB system have been described at the vascular (stimulation of angiogenesis and ateroprotector effect) and myocardium level (negative inotropic effect) as well as effect on the survival, cell growth and organization of the cardiomyocytes (myofibrillar organization and cell-to-cell contact between cardiomyocytes). Furthermore, the interaction of this system with other neurohumoral mediators has been studied. Thus, there seems to be a physiological role in modulating the sympathovagal balance and an interaction with endothelin-1 signaling. All these effects result from the activation of different intracellular signaling cascades, as a consequence of the binding of NRG1 to ErbB receptors. Some cardiac signaling pathways identified until now include molecules such as MEK / Erk 1/2, phosphatidylinositol 3-kinase/ Akt, focal adhesion kinase, Gab (Grb-2-associated binder) family, vascular endothelial growth factor and NO production by endothelial nitric oxide synthase. Thus, the aim of this paper was to make an up-to-date review of existing information on NRG1/ErbB signaling axis, with particular focus on its cardiovascular effects

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Nitric oxide and prostaglandins - important players in endothelin-1 induced myocardial distensibility.

This study investigated whether endothelin (ET)-1-induced increase in myocardial distensibility is preserved in heart failure (HF) and whether it is modulated by nitric oxide (NO) and prostaglandins. New Zealand white rabbits were treated with doxorubicin (1 mg/kg, intravenously twice a week for 8 weeks, DOX-HF group) or saline (control group). Effects of ET-1 (0.1, 1, 10 nM) were tested in papillary muscles from the DOX-HF group and a control group in the presence of: i) intact endocardial endothelium (EE); ii) damaged EE; iii) N-G-nitro-L-arginine (L-NNA; NO synthase inhibitor), and iv) indomethacin (INDO; cyclooxygenase inhibitor). In the presence of an intact EE, ET-1 promoted concentration-dependent positive inotropic and lusitropic effects that were maintained after damaging the EE, in the presence of L-NNA or INDO and in the DOX-HF Group. ET-1 reduced resting tension at the end of the isometric twitch (increased diastolic distensibility) by 3.2 +/- 1.3 %, 6.0 +/- 1.6 % and 8.8 +/- 2.7 % (at 0.1, 1 and 10 nM, respectively), in muscles with intact EE, effect that was completely abolished after damaging EE, in the presence of L-NNA or INDO or in the DOX-HF Group. This study demonstrated that the increase in myocardial distensibility induced by ET-1 is absent in HF and is dependent of NO and prostaglandin release