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Adelino F Leite-Moreira

Publications and source records attributed to Adelino F Leite-Moreira.

At least 19 recordsLinked to original sources
PubMed2006

Endothelin ETA receptors and endothelium partially mediate the positive inotropic and lusitropic effects of angiotensin II.

We analyzed the influence of endothelin-1 and endocardial endothelium on the myocardial effects of angiotensin-II. Angiotensin-II (10(-9)-10(-5) M) was tested in rabbit right papillary muscles in absence (Protocol-A) or presence of PD-145065 (10(-7) M; Protocol-B), BQ-123 (10(-7) M; Protocol-C) or losartan (10(-6) M; Protocol-E), as well as, after removing the endocardial endothelium with Triton X-100 0.5% (Protocol-D). In Protocol-F increasing concentrations of endothelin-1 (10(-10)-10(-8) M) were added in presence of angiotensin-II (10(-7) M) after selective removal of the endocardial endothelium. In Protocol-A, angiotensin-II had dose-dependent positive inotropic and lusitropic effects, maximal at 10(-6) M increasing 122+/-13% active tension, 117+/-16% dT/dtmax and 86+/-9% dT/dtmin. In Protocols B, C and D the inotropic and lusitropic effects of angiotensin-II were significantly attenuated. The same concentration (10(-6) M) of angiotensin-II increased respectively 48+/-11%, 59+/-27% and 72+/-16% active tension; 54+/-14%, 54+/-20% and 32+/-9% dT/dtmax; and 39+/-8%, 48+/-19% and 59+/-11% dT/dtmin; and 40+/-10%. EC(50) for active tension significantly increased from -7.8+/-0.1 logM in Protocol A to -7.1+/-0.3, -6.7+/-0.4 and -6.8+/-0.3 logM in Protocols B, C and D respectively, while Emax decreased from 106+/-14% in Protocol A to 50+/-14 and 51+/-19% in Protocols B and C respectively, but did not significantly change in Protocol D (114+/-25%). Losartan completely blocked the inotropic and lusitropic effects of angiotensin-II, while the attenuation of these effects after the selective removal of the endocardial endothelium was blunted by concomitant administration of endothelin-1 (Protocol F). In conclusion, angiotensin-II has a dose-dependent positive inotropic effect that depends, to a great extent, on endothelin ETA receptor activation and intact endocardial endothelium.

Angiotensin II↗
PubMed2006

Myocardial dysfunction and neurohumoral activation without remodeling in left ventricle of monocrotaline-induced pulmonary hypertensive rats.

In monocrotaline (MCT)-induced pulmonary hypertension (PH), only the right ventricle (RV) endures overload, but both ventricles are exposed to enhanced neuroendocrine stimulation. To assess whether in long-standing PH the left ventricular (LV) myocardium molecular/contractile phenotype can be disturbed, we evaluated myocardial function, histology, and gene expression of autocrine/paracrine systems in rats with severe PH 6 wk after subcutaneous injection of 60 mg/kg MCT. The overloaded RV underwent myocardial hypertrophy (P < 0.001) and fibrosis (P = 0.014) as well as increased expression of angiotensin-converting enzyme (ACE) (8-fold; P < 0.001), endothelin-1 (ET-1) (6-fold; P < 0.001), and type B natriuretic peptide (BNP) (15-fold; P < 0.001). Despite the similar upregulation of ET-1 (8-fold; P < 0.001) and overexpression of ACE (4-fold; P < 0.001) without BNP elevation, the nonoverloaded LV myocardium was neither hypertrophic nor fibrotic. LV indexes of contractility (P < 0.001) and relaxation (P = 0.03) were abnormal, however, and LV muscle strips from MCT-treated compared with sham rats presented negative (P = 0.003) force-frequency relationships (FFR). Despite higher ET-1 production, BQ-123 (ET(A) antagonist) did not alter LV MCT-treated muscle strip contractility distinctly (P = 0.005) from the negative inotropic effect exerted on shams. Chronic daily therapy with 250 mg/kg bosentan (dual endothelin receptor antagonist) after MCT injection not only attenuated RV hypertrophy and local neuroendocrine activation but also completely reverted FFR of LV muscle strips to positive values. In conclusion, the LV myocardium is altered in advanced MCT-induced PH, undergoing neuroendocrine activation and contractile dysfunction in the absence of hypertrophy or fibrosis. Neuroendocrine mediators, particularly ET-1, may participate in this functional deterioration.

Angiotensinogen↗
PubMed2006

Cardiovascular endothelins: essential regulators of cardiovascular homeostasis.

The endothelin (ET) system consists of 3 ET isopeptides, several isoforms of activating peptidases, and 2 G-protein-coupled receptors, ETA and ETB, that are linked to multiple signaling pathways. In the cardiovascular system, the components of the ET family are expressed in several tissues, notably the vascular endothelium, smooth muscle cells, and cardiomyocytes. There is general agreement that ETs play important physiological roles in the regulation of normal cardiovascular function, and excessive generation of ET isopeptides has been linked to major cardiovascular pathologies, including hypertension and heart failure. However, several recent clinical trials with ET receptor antagonists were disappointing. In the present review, the authors take the stance that ETs are mainly and foremost essential regulators of cardiovascular function, hence that antagonizing normal ET actions, even in patients, will potentially do more harm than good. To support this notion, we describe the predominant roles of ETs in blood vessels, which are (indirect) vasodilatation and ET clearance from plasma and interstitial spaces, against the background of the subcellular mechanisms mediating these effects. Furthermore, important roles of ETs in regulating and adapting heart functions to different needs are addressed, including recent progress in understanding the effects of ETs on diastolic function, adaptations to changes in preload, and the interactions between endocardial-derived ET-1 and myocardial pump function. Finally, the potential dangers (and gains) resulting from the suppression of excessive generation or activity of ETs occurring in some cardiovascular pathological states, such as hypertension, myocardial ischemia, and heart failure, are discussed.

Animals↗
PubMed2006

Inotropic and lusitropic effects of ghrelin and their modulation by the endocardial endothelium, NO, prostaglandins, GHS-R1a and KCa channels.

Contractile effects of ghrelin (10(-9) to 10(-6) M) were tested in rat papillary muscles of normal (n = 50) and hypertrophic (n = 16) right ventricles (RV). RV hypertrophy was induced by pulmonary hypertension using monocrotaline. In normal muscles, ghrelin was added either alone (n = 9) or after pre-treatment with indomethacin (cycloxygenase inhibitor, 10(-5) M; n = 10), L-nitro-L-arginin (NO synthase inhibitor, 10(-4) M; n = 9), D-Lys(3)-GHRP-6 (GHS-R1a antagonist; 10(-4) M; n = 8) or apamin+charybdotoxin (KCa channels blockers; 10(-6) M, n =7 ), as well as after damaging the endocardial endothelium (n = 7). In hypertrophic muscles, ghrelin was added either alone (n = 9) or after pre-treatment with apamin+charybdotoxin (10(-6 M, n=7). Ghrelin concentration-dependently decreased active tension (AT) and maximal velocity of tension rise (negative inotropic effect), as well as, maximal velocity of tension decay (negative lusitropic effect) and time to AT (onset of relaxation). These effects were maximal at 10(-6) M, similar in normal and hypertrophic muscles and were significantly altered only by apamin+charybdotoxin, indomethacin and L-nitro-L-arginin. Apamin+charybdotoxin attenuated the negative inotropic effect, while indomethacin and L-nitro-L-arginin, respectively, blunted and exacerbated the premature onset of relaxation. In conclusion, ghrelin induces negative inotropic and lusitropic effects and an earlier onset of relaxation in normal and hypertrophic myocardium, which are independent of GHS-R1a, since they were not affected by D-Lys(3)-GHRP-6. The negative inotropic effect is partly mediated by KCa channels, while the earlier onset of relaxation is modulated by prostaglandins and NO.

Animals↗
PubMed2006

Remote myocardium gene expression after 30 and 120 min of ischaemia in the rat.

The aim of the present study was to investigate how early the onset of ischaemia-induced changes in gene expression is in remote myocardium, and whether these changes would be different for left and right ventricles. Wistar rats (n=27) were randomly assigned to left coronary artery (LCA) ligation for 30 or 120 min and sham groups. Evans Blue infusion revealed antero-apical left ventricle (LV) and left intraventricular (IV) septal ischaemia (35.5+/-0.6% of LV mass). LCA ligation induced transient LV systolic dysfunction and sustained biventricular slowing of relaxation. Regarding mRNA levels, type B natriuretic peptide (BNP) was upregulated in the LV at 30 (+370+/-191%) and 120 min (+221+/-112%), whilst in the right ventricle (RV) this was only significant at 120 min (+128+/-39%). Hipoxia-inducible factor 1alpha and interleukin 6 overexpression positively correlated with BNP. Inducible NO synthase upregulation was present in both ventricles at 120 min (LV, +327+/-195%; RV, +311+/-122%), but only in the RV at 30 min (+256+/-88%). Insulin-like growth factor 1 increased in both ventricles at 30 (RV, +59+/-18%; LV, +567+/-192%) and 120 min (RV, +69+/-33%; LV, +120+/-24%). Prepro-endothelin-1 was upregulated in the RV at 120 min (+77+/-25%). Ca2+-handling proteins were selectively changed in the LV at 120 min (sarcoplasmic reticulum Ca2+ ATPase, 53+/-7%; phospholamban, +31+/-4%; Na+-Ca2+ exchanger, 31+/-6%), while Na+-H+ exchanger was altered only in the RV (-79+/-5%, 30 min; +155+/-70%, 120 min). Tumour necrosis factor-alpha and angiotensin converting enzyme were not significantly altered. A very rapid modulation of remote myocardium gene expression takes place during myocardial ischaemia, involving not only the LV but also the RV. These changes are different in the two ventricles and in the same direction as those observed in heart failure.

Animals↗
PubMed2006

Angiotensin II acutely decreases myocardial stiffness: a novel AT1, PKC and Na+/H+ exchanger-mediated effect.

Acute effects of angiotensin II (AngII) on diastolic properties of the myocardium were investigated. Increasing concentrations of AngII (10(-9) to 10(-5) M) were added to rabbit papillary muscles in the absence (n=11) or presence of: (i) AT1 receptor antagonists, losartan (10(-6) M; n=7) or ZD-7155 (10(-7) M; n=8); (ii) ZD-7155 (10(-7) M) plus AT2 receptor antagonist PD-123,319 (2 x 10(-6) M; n=6); (iii) PKC inhibitor, chelerythrine (10(-5) M; n=8); or (iv) Na(+)/H(+) exchanger (NHE) inhibitor, 5-(N-methyl-N-isobutyl)-amiloride (10(-6) M; n=10). Passive length-tension relations were constructed before and after a single concentration of AngII (10(-5) M, n=6). Effects of AngII infusion (10 microg kg(-1) min(-1)) were evaluated in in situ rabbit hearts. AngII concentration dependently increased inotropy and resting muscle length (RL). At 10(-5) M, active tension increased 43.3+/-6.25% and RL 1.96+/-0.4%. Correcting RL to its initial value resulted in a 46+/-4% decrease of resting tension, indicating decreased muscle stiffness, as confirmed by the right and downward shift of the passive length-tension relation promoted by AngII. In the intact heart, at matched systolic pressures of 112 mmHg, AngII decreased end-diastolic pressures from 10.3+/-0.3 to 5.9+/-0.5 mmHg, and minimal diastolic pressures from 8.4+/-0.5 to 4.6+/-0.6 mmHg. AT1 blockade inhibited AngII effects on myocardial inotropy and stiffness, while PKC or NHE inhibition only significantly attenuated its effects on resting length and tension. In conclusion, AngII decreases myocardial stiffness, an effect that requires AT1 receptor activation and is mediated by PKC and NHE. This represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that AngII is a powerful regulator of cardiac filling.

Alkaloids↗
PubMed2006

Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia.

Ghrelin is a strong physiologic growth hormone secretagogue that exhibits endocrine and non-endocrine actions. In this study, ghrelin expression in humans and rats was evaluated throughout development of normal and hypoplastic lungs associated with congenital diaphragmatic hernia (CDH). Additionally, the effect of antenatal treatment with ghrelin in the nitrofen-induced CDH rat model was tested. In normal lungs, ghrelin was expressed in the primitive epithelium at early stages of development and decreased in levels of expression with gestational age. In hypoplastic lungs ghrelin was overexpressed in both human and rat CDH fetuses when compared with controls. Exogenous administration of ghrelin to nitrofen-treated dams led to an attenuation of pulmonary hypoplasia of CDH pups. Furthermore, the growth hormone, secretagogue receptor (GHSR1a), could not be amplified from human or rat fetal lungs by RT-PCR. In conclusion, of all the lungs studied so far, the fetal lung is one of the first to express ghrelin during development and might be considered a new source of circulating fetal ghrelin. Overexpression of ghrelin in hypoplastic lungs and the effect of exogenous administration of ghrelin to nitrofen-treated dams strongly suggest a role for ghrelin in mechanisms involved in attenuation of fetal lung hypoplasia, most likely through a GHSR1a-independent pathway.

Animals↗
PubMed2006

M-mode and Doppler echocardiographic reference values for male New Zealand white rabbits.

OBJECTIVE: To determine M-mode and Doppler echocardiographic reference values in healthy New Zealand white rabbits. ANIMALS: 52 healthy male rabbits. PROCEDURES: The rabbits were anesthetized and M-mode measurements of the left ventricle, left atrium, and aorta and Doppler measurements of pulmonary and aortic outflow and mitral inflow were recorded. RESULTS: Mean +/- SD heart rate during echocardiographic examination was 155 +/- 29 beats/min. Mean +/- SD measurements in diastole and systole for the interventricular septum thickness, left ventricular internal diameter, and left ventricular free wall thickness were 2.03 +/- 0.37 mm and 3.05 +/- 0.45 mm; 14.37 +/- 1.49 mm and 10.25 +/- 1.22 mm; and 2.16 +/- 0.25 and 3.48 +/- 0.55 mm, respectively. Mean +/- SD left atrial-to-aortic diameter ratio was 1.17 +/- 0.14, and mean +/- SD mitral valve E-point-to-septal separation interval was 1.71 +/- 0.29 mm. Mean +/- SD for fractional shortening and ejection fraction were 30.13 +/- 2.98% and 61.29 +/- 4.66%, respectively. Mean +/- SD maximal aortic and pulmonary artery outflow velocities were 0.85 +/- 0.11 m/s and 0.59 +/- 0.10 m/s, respectively, and the peak E-to-peak A wave velocity ratio of the mitral valve was 2.19 +/- 0.46. CONCLUSIONS AND CLINICAL RELEVANCE: Results provide echocardiographic reference values for young adult male New Zealand white rabbits anesthetized with ketamine and medetomidine. Values obtained from unanesthetized rabbits, rabbits sedated with other agents, or rabbits of different size may differ from those reported here.

Animals↗
PubMed2006

Ghrelin reverses molecular, structural and hemodynamic alterations of the right ventricle in pulmonary hypertension.

Ghrelin is an endogenous peptide that has a dual effect by activating specific receptors and by stimulating release of growth hormone. There is increasing evidence that ghrelin has a potent vasodilator effect. Recently, we demonstrated that exogenous administration of ghrelin modulates its endogenous levels and attenuates the majority of alterations induced by monocrotaline (MCT). In the present study, we evaluate the effects of chronic administration of ghrelin on hemodynamic and morphometric parameters of the right ventricle, as well as on myocardial levels of SERCA2a and endothelin-1. Adult Wistar rats were injected with MCT (60 mg/kg, sc) or just the vehicle (day 0). One week later, the animals treated with MCT were randomly divided into two groups and treated with ghrelin (100 microg/kg, bid, sc) or with a similar volume of vehicle. Between days 21-25 the animals were instrumented to record right ventricular (RV) pressures and samples were collected for morphological and molecular analysis. Ghrelin treatment attenuated the effects of MCT, namely: RV myocyte fiber diameter, pulmonary vascular remodeling (evaluated by % medial wall thickness of peripheral arteries), RV peak systolic pressure, RV end-diastolic pressure, time constant tau, and SERCA2a and endothelin-1 mRNA levels. Chronic ghrelin administration attenuates MCT-induced pulmonary hypertension, vascular remodeling and RV hypertrophy. These results suggest a potential therapeutic role for the ghrelin-growth hormone axis in pulmonary hypertension.

Animals↗
PubMed2006

Obligatory role of the endocardial endothelium in the increase of myocardial distensibility induced by endothelin-1.

This study investigated how the endocardial endothelium (EE) and particularly endothelial type B (ET(B)) receptors influence the effects of endothelin-1 (ET-1) on diastolic distensibility. ET-1 (0.1, 1, and 10 nM) was tested in rabbit papillary muscles (Krebs-Ringer; 1.8 mM CaCl2, 35 degrees C) (i) with intact EE (n = 10), (ii) with damaged EE (0.5% Triton X-100, n = 11), and (iii) in the presence of RES-701-1 (selective endothelial ET(B1) receptor antagonist, 1 microM, n = 6). Additionally, increasing doses (0.1 nM to 1 microM) of Sarafotoxin S6c (SRTXc, a selective ET(B) receptor agonist) and IRL-1620 (a selective endothelial ET(B1) agonist) were studied (i) in muscles with intact EE (n = 7 and n = 6, respectively) and (ii) after damaging the EE (n = 8 and n = 7, respectively). In papillary muscles with intact EE, ET-1 induced dose-dependent positive inotropic and lusitropic effects. At 10 nM, active tension (AT) increased 78% +/- 17%, maximum velocity of tension rise (dT/dt(max)) increased 82% +/- 10%, and maximum velocity of tension decline (dT/dt(min)) increased 77% +/- 17%. These effects were maintained when ET-1 was given after damaging the EE (AT increased 70% +/- 12%, dT/dt(max) increased 93% +/- 14%, and dT/dt(min) increased 56% +/- 14%), but were significantly reduced in the presence of RES-701-1 (AT increased 30% +/- 6%, dT/dt(max) increased 37% +/- 7%, and dT/ dt(min) increased 29% +/- 9%). ET-1 reduced resting tension (RT) and increased diastolic distensibility by 3% +/- 1%, 5% +/- 1%, and 9% +/- 2% (at 0.1, 1, and 10 nM, respectively) in muscles with intact EE. This effect was abolished after damaging the EE or in the presence of RES-701-1. In muscles with intact EE, SRTXc had no significant effects, whereas, when given after damaging the EE, SRTXc (1 microM) increased inotropy and lusitropy (AT increased 116% +/- 24%, dT/dt(max) 110% +/- 28%, and dT/dt(min) 88% +/- 19%) without affecting RT. IRL-1620 dose-dependently decreased AT, dT/dt(max), and dT/dt(min) in muscles with intact EE-effects that were abolished after EE damage. No significant effects were elicited by IRL-1620 in RT. ET-1-induced increase in myocardial distensibility, previously shown to be mediated by ET(A) receptor stimulation, requires an intact EE and active endothelial ET(B1) receptors.

Animals↗
PubMed2006

Impaired response to ET(B) receptor stimulation in heart failure: functional evidence of endocardial endothelial dysfunction?

Inotropic effects of selective ET(B) receptor stimulation depend on the functional integrity of the endocardial endothelium (EE), which is negative when it is intact and positive when it is damaged. These results have been attributed to the existence of two subtypes of ET(B) receptors in the heart: (i) ET(B1), located on the EE, decreases inotropy; (ii) ET(B2), located on myocardial cells, increases inotropy. In the present study we investigated the functional integrity of the EE in a heart failure (HF) model (doxorubicin-induced cardiomyopathy) by evaluating the contractile response to ET(B1) receptor stimulation. New Zealand White rabbits were treated with doxorubicin (DOX-HF, 1 mg/kg, iv, twice weekly for 8 weeks) or with saline. Contractile effects of increasing doses of a selective agonist of endothelial ET(B) receptors, IRL-1620 (10(-9) to 10(-6) M), were studied in papillary muscles (Krebs-Ringer: 1.8 mM CaCl2, 35 degrees C) from control (n = 10) and DOX-HF rabbits (n = 7). Isotonic and isometric twitches were recorded and analyzed. Reported parameters included active tension (AT) and maximum velocities of tension rise (dT/dt(max)) and decline (dT/dt(min)). On echocardiography, DOX-HF rabbits had increased left ventricular (LV) end-diastolic and end-systolic diameters and reduced ejection fraction (52% +/- 2% vs. 61% +/- 1%). Contrary to control papillary muscles, DOX-HF muscles showed a steady decrease in contractility between 1 and 4 Hz. In the control group, IRL-1620 induced dose-dependent negative inotropic and lusitropic effects that decreased at 10(-6) M: 26% +/- 3%, AT; 17% +/- 3%, dT/dt(max); and 16% +/- 5%, dT/dt(min). In the DOX-HF group, these effects were significantly reduced. At the same concentration, IRL-1620 decreased AT (8% +/- 3%) and dT/dt(max) (8% +/- 3%), without significantly affecting dT/dt(min). This study showed an impaired response to endothelial ET(B) receptor stimulation, providing for the first time strong evidence of the occurrence of EE dysfunction in the failing heart and further highlighting the potential use of ET(B) receptor stimulation as a marker of EE function.

Animals↗
PubMed2005

Acute changes of biventricular gene expression in volume and right ventricular pressure overload.

OBJECTIVE: We investigated the effects of acute volume and RV pressure overload on biventricular function and gene expression of BNP, pro-inflammatory cytokines (IL-6 and TNF-alpha), iNOS, growth factors (IGF-1, ppET-1), ACE and Ca2+-handling proteins (SERCA2a, phospholamban and calsequestrin). METHODS: Male Wistar rats (n=45) instrumented with pressure tip micromanometers in right (RV) and left ventricular (LV) cavities were assigned to one of three protocols: i) Acute RV pressure overload induced by pulmonary trunk banding in order to double RV peak systolic pressure, during 120 or 360 min; ii) acute volume overload induced by dextran40 infusion (5 ml/h), during 120 or 360 min; iii) Sham. RV and LV samples were collected for mRNA quantification. RESULTS: BNP upregulation was restricted to the overloaded ventricles. TNF-alpha, IL-6, ppET-1, SERCA2a and phospholamban gene activation was higher in volume than in pressure overload. IGF-1 overexpression was similar in both types of overload, but was limited to the RV. TNF-alpha and CSQ mRNA levels were increased in the non-overloaded LV after pulmonary trunk banding. No significant changes were detected in ACE or iNOS expression. RV end-diastolic pressures positively correlated with local expression of BNP, TNF-alpha, IL-6, IGF-1, ppET-1 and SERCA2a, while RV peak systolic pressures correlated only with local expression of IL-6, IGF-1 and ppET-1. CONCLUSIONS: Acute cardiac overload alters myocardial gene expression profile, distinctly in volume and pressure overload. These changes correlate more closely with diastolic than with systolic load. Nonetheless, gene activation is also present in the non-overloaded LV of selectively RV overloaded hearts.

Acute Disease↗
PubMed2005

Antenatal vitamin A administration attenuates lung hypoplasia by interfering with early instead of late determinants of lung underdevelopment in congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Early and late lung underdevelopment in congenital diaphragmatic hernia (CDH) is likely caused by nonmechanical (directly mediated by nitrofen) and mechanical (mediated by thoracic herniation) factors, respectively. The authors investigated if vitamin A enhances lung growth because of effects on both early and late determinants of lung hypoplasia. METHODS: Twenty-seven pregnant Wistar rats were exposed on embryonic day (E)9.5 to 100 mg of nitrofen or just olive oil. From nitrofen-exposed pregnant rats, 12 were treated at day 9.5 or 18.5 with 15,000 IU of vitamin A. Lungs were harvested at E18, E20, and E22, weighed, and analyzed for DNA and protein contents. Left and/or right lung hypoplasia was estimated by assessment of the ratios of lung to body weight and left to right lung weight. Fetuses were assigned to 5 experimental groups: baseline (exposed neither to nitrofen nor vitamin A), nitrofen (exposed to nitrofen without CDH), CDH (exposed to nitrofen with CDH), nitr+vitA (exposed to nitrofen without CDH and treated with vitamin A), and CDH+vitA (exposed to nitrofen with CDH and treated with vitamin A). RESULTS: Incidence of hernia was significantly reduced in fetuses treated with vitamin A. When vitamin A was administered at E9.5, the authors observed similar effect on lung hypoplasia measured through ratio of lung to body weight at E18 in the nitrofen and CDH groups (nitrofen 1.92% +/- 0.05%, CDH 1.92% +/- 0.04%), whereas lung hypoplasia was attenuated relative to baseline (2.45% +/- 0.05%) in 5% and 4% in nitrofen (nitr+vitA 2.05% +/- 0.03%) and CDH (CDH+vitA 2.08% +/- 0.04%) groups, respectively. At E20, lung hypoplasia was increased in CDH compared with nitrofen groups (nitrofen 2.52% +/- 0.1%, CDH 2.39% +/- 0.05%), whereas vitamin A attenuated lung hypoplasia, in relation to baseline (3.20% +/- 0.07%), 14% in both nitrofen-exposed groups (nitr+vitA 2.96% +/- 0.03%, CDH+vitA 2.83% +/- 0.03%). At E22, lung hypoplasia was significantly higher in CDH group than nitrofen group (nitrofen 2.13% +/- 0.06%, CDH 1.48% +/- 0.03%), whereas lung hypoplasia was attenuated in 9% of both nitrofen-exposed groups (nitr+vitA 2.35% +/- 0.06%, CDH+vitA 1.69% +/- 0.05%) in relation to baseline group (2.38% +/- 0.04%). Administration of vitamin A at E18.5 produced no significant effects on lung growth. CONCLUSIONS: The authors conclude from these results that antenatal administration of vitamin A attenuates lung hypoplasia in CDH by interfering with early determinants of lung underdevelopment. This finding may have clinical implications because prenatal diagnosis of human CDH commonly occurs after 16 weeks' gestation when late determinants of lung hypoplasia likely predominate.

Animals↗
PubMed2005

Modulation of the myocardial effects of selective ETB receptor stimulation and its implications for heart failure.

INTRODUCTION: Endothelin-1 (ET-1) acts on two types of receptors, ET(A) and ET(B). Recent functional studies suggest the existence of two ET(B) receptor subtypes in the heart: ET(B1), located on endocardial endothelial cells and responsible for negative inotropism, and ET(B2), located on myocardial cells and responsible for positive inotropism. The aim of the present study was to investigate the mechanisms underlying the myocardial effects of selective ET(B) receptor stimulation. METHODS: The study was performed on right papillary muscles from New Zealand white rabbits (n = 39; Krebs-Ringer; 1.8 mM CaCl2; 35 degrees C). The effects of sarafotoxin S6c (SRTXc, ET(B) agonist; 0.2 microM) were evaluated in muscles with: (i) intact endocardial endothelium (EE) (n = 6); (ii) damaged EE (Triton X100; 0.5%; n = 6); (iii) intact EE, in the presence of N(G)-nitro-L-arginine (L-NNA, nitric oxide synthase inhibitor; n = 6); (iv) intact EE, in the presence of indomethacin (INDO, cyclooxygenase inhibitor; n = 6); (v) intact EE, in the presence of BQ-123 (ET(A) antagonist; n = 7); and (vi) damaged EE, in the presence of BQ-123 (n = 8). Only significant results (mean +/- SEM, p < 0.05) are given, expressed as % change from baseline. RESULTS: In muscles with intact EE, SRTXc alone induced negative inotropic and lusitropic effects, decreasing active tension (AT) by 11.0 +/- 5.6%, maximum velocity of tension rise (dT/dt(max)) by 11.2 +/- 5.9% and maximum velocity of tension decline (dT/dt(min)) by 11.5 +/- 6.2%. However, after removal of EE, or in the presence of L-NNA or INDO, SRTXc increased AT by 35.2 +/- 11.7%, 22.8 +/- 2.9% and 15.2 +/- 3.4%, dT/dt(max) by 29.5 +/- 7.9%, 20.1 +/- 2.1% and 13.3 +/- 5.0%, and dT/dt(min) by 28.2 +/- 8.1%, 21.2 +/- 3.8% and 12.3 +/- 2.2%, respectively. In muscles with intact EE and in the presence of BQ-123, the negative inotropic and lusitropic effects of SRTXc were enhanced: AT decreased by 27.0 +/- 7.4%, dT/dt(max) by 13.3 +/- 4.9% and dT/dt(min) by 31.1 +/- 7.9%. On the other hand, the positive inotropic and lusitropic effects of SRTXc in the absence of intact EE were reversed in the presence of ET(A) blockade: AT decreased by 9.0 +/- 1.8%, dT/dt(max) by 4.1 +/- 3.5% and dT/dt(min) by 8.1 +/- 3.6%. CONCLUSIONS: The present study shows that the inotropic and lusitropic effects mediated by ET(B) receptors are modulated by endocardial endothelium and by ET(A) receptor activity. These results may have pathophysiological and therapeutic implications in heart failure, a condition in which ET-1 levels are increased and endothelial dysfunction may be present.

Animals↗
PubMed2005

Contractile effects of Ghrelin and expression of its receptor GHS-R1a in normal and hypertrophic myocardium.

INTRODUCTION: Ghrelin, isolated in 1999, is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a). Recent studies suggest that it may influence the function of normal and failing hearts. Nonetheless, it has been difficult to differentiate its effects on the intrinsic properties of the myocardium from the secondary effects resulting from growth hormone release and vasomotor action. This study investigated the contractile effects of ghrelin and expression of its receptor GHS-R1a in normal and hypertrophic myocardium. METHODS: Adult Wistar rats randomly received monocrotaline (MCT; n=9; 60 mg/kg, s.c.) or vehicle (n=7; 1 ml/kg). Three weeks later, after right ventricular (RV) hemodynamic evaluation, the effects of 10(-6) M of a pentapeptide active fragment of ghrelin (fG) were tested on contractile parameters of RV papillary muscles (Normal, n=7; MCT, n=9). GHS-R1a mRNA expression was estimated in RV transmural free-wall samples (Normal, n=7; MCT, n=9), using real-time RT-PCR. RESULTS: In the Normal group, fG reduced active tension (AT), maximum velocity of tension rise (dT/dt(max)) and maximum velocity of tension decline (dT/dt(min)), by 27.9 +/- 4.0%, 28.5 +/- 6.7% and 21.4 +/- 4.2% respectively. In the MCT group, fG reduced AT, dT/dt(max) and dT/dt(min) by 24.1 +/- 6.3%, 24.3 +/- 6.5% and 24.5 +/- 6.1% respectively. GHS-R1a mRNA expression was similar in the two groups (Normal: 2.3*10(5) +/- 5.4*10(4); MCT: 3.0*10(5) +/- 1.1*10(5): p > 0.05). CONCLUSION: This study shows that ghrelin has negative inotropic and lusitropic effects. These effects and expression of its receptor are preserved in RV hypertrophy, suggesting that ghrelin may be a new target in progression to heart failure.

Animals↗
PubMed2005

Apelin: a novel neurohumoral modulator of the cardiovascular system. Pathophysiologic importance and potential use as a therapeutic target.

Apelin is a recently discovered vasoactive peptide that has been demonstrated to be the endogenous ligand of the APJ receptor. It was named 'apelin' after APJ endogenous ligand. This G protein-coupled receptor (GPCR), originally identified by O'Dowd et al. in 1993, has a close identity with the angiotensin II type 1 (AT1) receptor, but does not bind angiotensin-II. Although apelin and APJ have been found to be ubiquitously expressed in peripheral tissues, particularly the heart and lungs, as well as various regions of the central nervous system, the physiologic actions of apelin remain largely unknown. Nevertheless, some cardiovascular functions of the apelin/APJ system have been described, such as endothelium-dependent vasodilatation, vasoconstriction by direct action on the smooth muscle and positive inotropism. Other reported physiologic actions of apelin include: (1) its role as endocrine adipokine; (2) contribution to fluid homeostasis and thirst regulation; (3) participation as coreceptor in the process of human immunodeficiency virus type 1 infection; and (4) regulation of immune response. The involvement of apelin/APJ in the pathophysiology of heart failure (HF) and its potential as a therapeutic target in this syndrome have also been proposed. In the course of HF progression, plasma levels of apelin are significantly increased in the early stages, decreasing progressively towards normal in the advanced stages of the disease. Given the increasing number of studies focusing on the apelin/APJ system, the goal of this paper was to make an up-to-date review of existing information on apelin and APJ, with particular focus on their cardiovascular actions and potential use as a therapeutic target in HF.

Animals↗
PubMed2005

Activation profile of pro-inflammatory cytokines in acute cardiac overload.

INTRODUCTION: Pro-inflammatory cytokines have been implicated in ventricular remodeling during heart failure progression. In the present study, we investigated the effects of acute volume and RV pressure overload on biventricular hemodynamics and myocardial gene expression of IL-6 and TNF-alpha. METHODS: Male Wistar rats (n = 45) instrumented with RV and LV tip micromanometers were randomly assigned to one of three protocols: i) acute RV pressure overload (PrOv) induced by pulmonary trunk banding in order to double RV peak systolic pressure, for 120 or 360 min; ii) acute volume overload (VolOv) induced by dextran40 infusion (5 ml/h), for 120 or 360 min; iii) Sham. Free wall samples from the RV and LV were collected for mRNA quantification. RESULTS: In the RV, acute overload induced IL-6 and TNF-alpha gene expression, higher in VolOv (IL-6: + 669.7 +/- 263.4%; TNF-alpha: + 5149.9 +/- 1099.0%; 360 min) than in PrOv (IL-6: + 64.9 +/- 44.2%; TNF-alpha: + 628.1 +/- 229.3%; 360 min). In PrOv, TNF-alpha mRNA levels in the LV were increased, in the absence of ventricular overload. IL-6 and TNF-alpha mRNA levels did not correlate in the LV, while in the RV a positive correlation was found (r = 0.574; p < 0.001). CONCLUSIONS: Acute cardiac overload induces overexpression of pro-inflammatory cytokines. This gene activation is not uniform, being higher in volume overload and involving both load-dependent and load-independent mechanisms.

Animals↗