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PubMedDate not supplied

Embryonic stem cells and cardiomyocyte differentiation: phenotypic and molecular analyses.

Embryonic stem (ES) cell lines, derived from the inner cell mass (ICM) of blastocyst-stage embryos, are pluripotent and have a virtually unlimited capacity for self-renewal and differentiation into all cell types of an embryoproper. Both human and mouse ES cell lines are the subject of intensive investigation for potential applications in developmental biology and medicine. ES cells from both sources differentiate in vitro into cells of ecto-, endoand meso-dermal lineages, and robust cardiomyogenic differentiation is readily observed in spontaneously differentiating ES cells when cultured under appropriate conditions. Molecular, cellular and physiologic analyses demonstrate that ES cell-derived cardiomyocytes are functionally viable and that these cell derivatives exhibit characteristics typical of heart cells in early stages of cardiac development. Because terminal heart failure is characterized by a significant loss of cardiomyocytes, the use of human ES cell-derived progeny represents one possible source for cell transplantation therapies. With these issues in mind, this review will focus on the differentiation of pluripotent embryonic stem cells into cardiomyocytes as a developmental model, and the possible use of ES cell-derived cardiomyocytes as source of donor cells.

Animals↗
PubMed2003

Postnatal development of arterial pressure: influence of the intrauterine environment.

A substantial number of epidemiological studies have shown that small size at birth is associated with an increased risk of developing hypertension and metabolic dysfunction later in life; however these associations have not been found in all studies. In animals, several models have been used to investigate the effects of perturbations to the fetal environment on later arterial pressure, with differing effects on size at birth and arterial pressure. Ovine models include maternal dietary manipulations, antenatal glucocorticoid exposure, and restriction of placental size and function. In our laboratory, we have induced late gestational placental insufficiency and growth restriction in sheep by umbilico-placental embolisation; during the early postnatal period the growth restricted lambs remained small and were hypotensive relative to controls. More recent long-term studies indicate that these growth restricted animals were able to catch up in body weight within the first postnatal year; however, their arterial pressure remained lower than that of controls throughout the first 2 postnatal years (deltaMAP, -4.2 +/- 1.4 mmHg). This relative hypotension may be due to altered vascular or cardiac development resulting from increased vascular resistance or nutrient restriction during fetal life. As late gestational placental insufficiency led to a persistent reduction in arterial pressure from birth to adulthood, our findings do not support the hypothesis that restricted fetal growth per se leads to hypertension after birth. It is likely that the effects of a prenatal compromise on postnatal arterial pressure will vary depending on the nature of the associated developmental perturbations and their gestational timing.

Animals↗
PubMed1995

Effect of renal denervation on elevation of blood pressure in cold-exposed rats.

The objective of this experiment was to determine whether bilateral renal denervation (RD) prevents the elevation of blood pressure and cardiac hypertrophy characteristically induced by chronic exposure to cold. Four groups (nine male rats each) were used. The kidneys of two groups were bilaterally denervated, while the remaining two groups were sham operated. Systolic blood pressures of the four groups, measured indirectly from the tail, did not differ significantly during the control period and following RD. At this time, 1 RD and 1 sham-operated group was exposed to cold (5 degrees C, 41 degrees F). The remaining RD and sham-operated groups were kept at 25 degrees C. Blood pressure of the cold-exposed, sham-operated group increased significantly during the 1st week of cold exposure (125 +/- 2 mmHg; 1 mmHg = 133.3 Pa), and rose to 139 +/- 4 mmHg by the 5th week, whereas the blood pressure of the RD group exposed to cold remained at the control level (116 +/- 2 mmHg). Both RD and sham-operated cold-exposed groups developed cardiac hypertrophy with significantly increased resting heart rates compared with controls kept at 25 degrees C. Plasma renin activities and renal norepinephrine content of kidneys of both RD groups at 7 weeks after RD were significantly less than those of sham-operated controls, confirming that renal nerves had been severed. Thus, RD prevented the elevation of blood pressure induced by chronic exposure to cold but had no significant effect on cardiac hypertrophy.

Animals↗
PubMed2004

Natriuretic peptides, respiratory disease, and the right heart.

It is well-recognized that atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are raised in conditions with ventricular volume and pressure overload. In addition to this established role in left ventricular congestive cardiac failure, there is good evidence that BNP has a diagnostic role in right ventricular (RV) dysfunction and pulmonary arterial hypertension (PAH). For example, BNP levels can be used to differentiate between dyspneic patients with pure respiratory defects and those with RV dysfunction. Studies in patients with PAH have demonstrated significant correlations between BNP levels and mean pulmonary arterial pressure as well as pulmonary vascular resistance. Additionally, BNP has a prognostic role in patients with RV pressure overload and pulmonary hypertension, and it offers a noninvasive test that can be used to guide therapy in patients with PAH. However, although measured plasma proBNP levels are raised in conditions with RV overload, its biological significance is still not well-understood. In this article, we review the general physiologic and potential therapeutic role of natriuretic peptides in respiratory disease, RV dysfunction, and PAH. Furthermore, we assess the various clues toward natriuretic peptide action coming from laboratory studies. ANP and BNP knockout mice develop cardiac fibrosis and hypertrophy. Potentiation of the natriuretic pathway has been shown to reduce cardiac hypertrophy and PAH. This is likely to take place as a result of increased intracellular cyclic guanosine monophosphate levels and subsequent pulmonary vasorelaxant activity. In view of this evidence, there may be a rationale for the therapeutic use of recombinant BNP or neutral endopeptidase inhibitors under conditions of RV dysfunction and PAH.

Animals↗
PubMed1998

Myocardial interatrial septum loses its epithelial organization by mesenchymal influence. Structural and ultrastructural study.

During atrial septation, the septum primum fuses with the atrioventricular endocardial cushions and myocardial-mesenchymal interactions occur. In order to evaluate the cellular events that take place during this particular interaction a structural, ultrastructural and histochemical study was performed. Our findings indicate that from the fourth day of development, the distal myocardium of the interatrial septum, which interacts with mesenchymal tissue, loses its appearance of an epithelial sheet and becomes a loosely organized tissue. The distal myocytes of the interatrial septum which get progressively separated show features of migratory cells, the final localization of which is the mesenchymal tissue of the adjacent endocardial cushions. These tissue changes involve basal membrane disruption, reduction in the number of desmosomes and intercalated discs with the subsequent appearance of large intercellular spaces between myocytes, myofibrillar disarrangement and acquisition by myocytes of a secretory phenotype characterized by numerous cytoplasmic vesicles. These events occur in a similar way in the atrioventricular canal, where a myocardial-mesenchymal interaction also occurs. In both regions the mesenchymal endocardial cushions and its associated extracellular matrix seem to direct the dissociation of the myocardial tissue and the subsequent migratory cellular behaviour of the interacting myocytes. This is an interesting, and little known, example of a cellular phenotypic transformation during cardiac development.

Animals↗
PubMed2001

Fetal cardiac performance in uncomplicated and well-controlled maternal type I diabetes.

OBJECTIVE: To study the impact of well-controlled, uncomplicated maternal diabetes on fetal cardiac development and performance. METHODS: The following variables were studied in 45 fetuses of type I diabetic women by means of mid- and late-trimester echocardiography: interventricular septal thickness; aortic and pulmonary valve diameters; peak and time-to-peak flow velocity of the great arteries; the ratio between peak velocities during early (E) and late (A) ventricular filling at the level of the atrioventricular values; ventricular fractional shortenings; and output. The findings were compared to age-matched control groups of normal fetuses. RESULTS: A significant augmentation of interventricular septal thickness was demonstrated for mid-trimester fetuses of diabetic women, which progressed further towards the end of pregnancy. However, the indices of diastolic and systolic function remained comparable between the gestational age-matched groups. CONCLUSION: Progressive myocardial thickening occurs commonly in mid- and late-trimester fetuses of uncomplicated and well-controlled diabetic pregnancies. The observed degree of hypertrophy is generally mild and does not affect age-related changes in fetal cardiac function.

Adult↗
PubMed1998

Prenatal exposures and congenital heart defects in Down syndrome infants.

The purpose of this study was to determine whether there are important differences in maternal and environmental prenatal risk factors between liveborn Down syndrome infants with congenital heart defects and Down syndrome infants without heart defects. Using a case control study design, we evaluated the risk associated with maternal illness, drug ingestion, substance usage, and chemical exposures in the home or workplace. The period of risk selected was 3 months before and 3 months after the last menstrual period, because cardiac development occurs early, before the mother may become aware of her pregnancy. Because fetal survival in Down syndrome may be more vulnerable to various exposures, controls were selected who also had trisomy 21. Of 171 infants studied, 89 were cases with congenital heart disease, and 82 were controls without heart disease. All interviews were performed by one nurse practitioner using a structured standardized questionnaire. Cases and controls had similar maternal ages, family incomes, parental education levels, and contraceptive practices before pregnancy. No differences were found between case and control mothers for maternal illness, medication use, or consumption of caffeinated beverages, cigarettes, or alcohol. Reporting of recreational drug usage was infrequent, may reflect underreporting, and did not differ between cases and controls. Maternal exposures were commonly reported for pesticides (50%), hair dyes (22%), craft paints (8%), varnishes (7%), and solvents (3.5%). However, in none of the categories was maternal exposure significantly more prevalent among case mothers than among control mothers. The failure of this study to identify risk factors for cardiac malformations may be attributable to the small differences in reported frequencies reducing statistical power or to the possibility that cardiac malformation in Down syndrome is a direct result of chromosomal duplication.

Case-Control Studies↗
PubMed2000

Characterization of homo- and heterodimerization of cardiac Csx/Nkx2.5 homeoprotein.

Csx/Nkx2.5 is an evolutionarily conserved homeodomain (HD)-containing transcription factor that is essential for early cardiac development. We found that the HD of Csx/Nkx2.5 binds as a monomer as well as a dimer to its DNA binding sites in the promoter of the atrial natriuretic factor (ANF) gene, an in vivo target gene of Csx/Nkx2.5. Csx/Nkx2.5 physically interacts with each other in vitro as well as in cells, and the HD is critical for homodimerization. Lys(193) and Arg(194), located at the COOH-terminal end of HD, are essential for dimerization. Lys(193) is also required for a specific interaction with the zinc finger transcription factor GATA4. Csx/Nkx2.5 can heterodimerize with other NK2 homeodomain proteins, Nkx2.3 and Nkx2.6/Tix, with different affinities. A single missense mutation, Ile(183) to Pro in the HD of Csx/Nkx2.5, preserved homodimerization function, but totally abolished DNA binding. Ile(183) --> Pro mutant acts in an inhibitory manner on wild type Csx/Nkx2.5 transcriptional activity through the ANF promoter in 10T1/2 cells. However, Ile(183) --> Pro mutant does not inhibit wild type Csx/Nkx2.5 function on the ANF promoter in cultured neonatal cardiac myocytes, possibly due to failure of dimerization in the presence of the target DNA. These results suggest that complex protein-protein interactions of Csx/Nkx2.5 play a role in its transcriptional regulatory function.

Animals↗
PubMed1998

Regulation of voltage-gated K+ channel expression in the developing mammalian myocardium.

As in neurons, depolarization-activated, Ca2+-independent outward K+ currents play prominent roles in shaping the waveforms of action potentials in myocardial cells. Several different types of voltage-gated K+ currents that contribute to the distinct phases of action potential repolarization have been characterized in myocardial cells isolated from different species, as well as in cells isolated from different regions of the heart in the same species. Important among these are the transient outward current, I(to), similar to the neuronal K+ current IA, and several components of delayed rectification, including I(Kr)[IK(rapid)], I(Ks)(IK(slow)], and I(Kur)[IK(ultrarapid)]. The properties of these currents in different species and cell types are remarkably similar, suggesting that the molecular correlates of functional voltage-gated K+ channel types are also the same. A number of voltage-gated K+ channel (Kv) pore-forming (alpha) and accessory (beta) subunits have now been cloned from heart cDNA libraries, and a variety of experimental approaches are being exploited to determine the molecular relationships between these subunits and functional voltage-gated myocardial K+ channels. Considerable progress has been made recently in defining these relationships, and the results obtained to date indeed suggest that distinct molecular entities underlie the different types of voltage-gated K+ channels characterized electrophysiologically in myocardial cells. Marked changes in the densities and/or the properties of voltage-gated K+ currents occur during normal cardiac development, as well as in conjunction with myocardial damage or disease, and there is considerable interest in understanding the molecular mechanisms underlying these changes. Although there is evidence for transcriptional, translational, and posttranslational regulation of functional voltage-gated K+ channel expression, we are only beginning to understand the underlying mechanisms; further studies focussed on delineating the molecular mechanisms controlling functional K+ channel expression are clearly warranted.

Animals↗
PubMed1990

[Cerebral malformation of the conceptus associated with maternal bacterial endocarditis and with aortic valve replacement during pregnancy].

A twenty-three years old woman, without previous heart disease developed endocarditis with negative bloods cultures on the fourth month of her third pregnancy. Fever was controlled through antibiotics, however she developed cardiac insufficiency and was submitted to surgery for replacement of aortic valve with a bioprosthesis. The post operative period showed no problems and the patient was discharged on the forty second day after admission. On the thirty ninth week of pregnancy she gave cesarean birth, without complications. The newly born, apgar 5 (1 min.) and 7 (5 min) presented signs of neurological problems, characterized on the second month as a cerebral atrophy. Among various possible factors, the most likely would be cardiopulmonary bypass circulation as the cause of the neurological malformation.

Adult↗
PubMed1991

Clinical and angiographic observations on resuscitated victims of exercise-related sudden ischemic death.

The clinical and angiographic findings of 17 resuscitated victims of exercise-related sudden ischemic death are reported in an attempt to elucidate the mechanism(s) of these deaths. Ten survivors developed cardiac arrest during or after sporting activities (group A) and 7 others during or after an exercise stress test (group B). There were 15 men and 2 women. The mean age of group A was 46 years and of group B 55 years. Coronary risk factors, as well as previous angina and myocardial infarction, were more frequent in group B. Only 3 of the 17 survivors had anginal symptoms before sudden death. Sudden death in group A was associated with acute myocardial infarction in 8 and unstable angina in 2 and was associated in group B with acute myocardial infarction in 2, unstable angina in 3 and silent ischemia in 2. Coronary angiography was acutely performed in 15 patients. In most patients the ischemia-related coronary artery was totally or subtotally occluded. Clinical and angiographic findings indicate that exercise-related sudden ischemic death was due to an acute coronary event--in most cases unexpected and unpredictable. It is suggested that exercise-induced intracoronary changes were probably responsible for the development of acute coronary (sub)occlusion and sudden death.

Angina, Unstable↗
PubMed1993

[Effects of quinapril on the development of hypertension, cardiac hypertrophy and stroke in salt-sensitive Dahl rats and stroke-prone spontaneously hypertensive rats].

The effects of repeated administration of quinapril (10 mg/kg/day) on the development of hypertension, cardiac hypertrophy and survival rate were examined, and compared with those of enalapril (10 mg/kg) in salt-sensitive Dahl (Dahl S) rats and 1% saline-loaded stroke-prone spontaneously hypertensive rats (SHRSP). The Dahl S rats were treated with the drugs at 10 to 20 weeks of age and the SHRSP, at 8-19 weeks of age. (1) In the Dahl S rats, salt loading rapidly raised systolic blood pressure, which was around 220 mmHg at 10 weeks of age. Both quinapril and enalapril significantly prevented the development of hypertension (below 160 mmHg) and cardiac hypertrophy. Age-associated histopathological alterations in the kidney and mesenteric artery in Dahl S rats were suppressed by the drug treatment. (2) Salt-loaded SHRSP rapidly developed severe hypertension (270 mmHg at 12 weeks of age) accompanied with stroke signs, and 19 animals out of 20 died by the end of the experiment. Both quinapril and enalapril significantly inhibited the age-associated development of hypertension and markedly improved the survival rate (only two animals out of 16 died in both groups). These results suggest that quinapril has protective actions against age-associated development of hypertension and cardiac hypertrophy, and as a result, it prolongs the life span.

Animals↗
PubMed2003

Expression and distribution of the calcitonin receptor-like receptor in the developing rat heart.

During ontogenesis the 52 amino acid peptide adrenomedullin is first expressed in the heart and it is essential for normal cardiovascular development. Recent work suggests that most adrenomedullin effects are conveyed via the calcitonin receptor-like receptor (CRLR) in combination with appropriate receptor activity-modifying proteins (RAMPs). Here, we investigated the expression of these components during the development of the rat heart, focusing on the period of coronary vascular development. Using RT-PCR, transcripts for CRLR, RAMP1 and RAMP2 were detected at all stages from E 14 to adulthood. The distribution of CRLR was investigated by immunohistochemistry, and endothelial cells and their precursors identified with monoclonal antibodies against RECA-1 and flk-1. On E 14, intense CRLR immunoreactivity was observed in endothelial cells of the large vessels and the endocardial cushions at the AV-junction. Small CRLR immunoreactive cell clusters were located in the wall of the outflow tract and subepicardially in the ventricular wall. On E 16, tubes of CRLR immunoreactive cells formed a subepicardial plexus, from which they penetrated radially towards the trabecular network and entered at E 18. Smooth muscle cells of coronary arteries gained a moderate CRLR immunoreactivity at E 20 which persisted at this intensity up to P 8 and then decreased. At the same time, CRLR immunoreactivity of endothelial cells in coronary arteries vanished while those of coronary veins still exhibited intense CRLR immunoreactivity. These data suggest multiple functions of the adrenomedullin/CRLR signaling pathway in cardiac development, among which the most prominent appears to be the early outgrowth and proliferation of the immature endothelial cells of the coronary vasculature.

Animals↗
PubMed1997

Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation--a report from the Société Française de Greffe de Moelle.

PURPOSE: To evaluate growth, thyroid function, puberty, cardiac function, and the incidence of cataracts in children who received allogeneic bone marrow transplantation (BMT) for acute myeloblastic leukemia (AML) in first complete remission (CR) after a preparation with or without total-body irradiation (TBI). PATIENTS AND METHODS: Among 45 children studied, 26 received busulfan-cyclophosphamide (Bu-Cy) in preparation for transplantation and 19 received TBI. TBI was fractionated in nine cases and delivered as a single dose in 10. Four children in the Bu-Cy group and none in the TBI group had received prior cranial radiation. The mean follow-up duration after BMT was 5.9 years for the whole group. RESULTS: The mean cumulative changes in height SD score (SDS) were -0.86 at 3 years and -1.56 at 5 years in the TBI group, whereas these changes were only -0.05 and -0.17 in the Bu-Cy group (P < .01 at 3 and 5 years). The 6-year probability of hypothyroidism was 9% +/- 8% in the Bu-Cy group and 43% +/- 15% after TBI (P < .02). Pubertal development after Bu-Cy was assessable in two girls and five boys: both girls had primary ovarian failure, whereas Leydig cell function appeared to be preserved in the five boys. One child who had received anthracycline when he was less than 1 year old developed cardiac dysfunction 4 years after Bu-Cy. The 6-year probability of cataracts was 70% +/- 13% in the TBI group and 0% after Bu-Cy. CONCLUSION: The use of Bu-Cy represents an alternative transplant cytoreductive regimen for children with AML in first CR, which can reduce the risk of posttransplant growth impairment, thyroid dysfunction, Leydig cell damage, and the incidence of cataracts.

Adolescent↗
PubMed1993

[Value of thallium-dipyridamole myocardial scintigraphy in coronary patients in non cardiac surgery].

Cardiac assessment is of particular importance in patients with documented or suspected coronary artery disease (CAD) as well as in all those patients undergoing vascular surgery. Use of dipyridamole thallium scintigraphy (DTS) in this population could help to detect significant coronary artery narrowing, together with the location and quantification of the areas of myocardium in jeopardy. Such information might lead to changing the surgical procedure, or to starting other treatment, such as coronary angioplasty or bypass graft surgery, thereby diminishing the morbidity and mortality associated with surgery in these high-risk patients. The ability of DTS to predict acute postoperative ischaemic events has been suggested by several studies. Various shortcomings of DTS used as a preoperative screening test have been pointed out in some recent papers. Therefore it is concluded that: 1) DTS should not be used as a routine preoperative test in vascular surgical patients. DTS is not accurate enough when used in patients without any clinical findings suggestive of CAD, 2) DTS may prove more useful in stratifying patients with an intermediate probability of developing cardiac complications. In such patients, the test will not provide a linear "all or nothing" result, but, when taken together with the clinical findings and the nature of the surgical procedure, a complex stratification, 3) Because of progress in the perioperative management of high-risk patients, positive findings on preoperative DTS may not correlate perfectly with perioperative cardiac events, 4) As several factors influence thallium uptake after dipyridamole, DTS does not have a perfect specificity, thus leading to order an excessive number of coronary angiographies. Some patients will be seen as having a false-positive DTS, 5) Preoperative screening DTS leads to cardiac catheterization and hence to revascularisation, independently of symtomatology. Further studies must be undertaken to determine whether this approach will improve short and long term patient survival.

Coronary Disease↗
PubMed2005

Impact of hypoxia on early chick embryo growth and cardiovascular function.

Oxygen tension is a critical factor for appropriate embryonic and fetal development. Chronic hypoxia exposure alters cardiovascular (CV) function and structure in the late fetus and newborn, yet the immature myocardium is considered to be less sensitive to hypoxia than the mature heart. We tested the hypothesis that hypoxia during the period of primary CV morphogenesis impairs immature embryonic CV function and embryo growth. We incubated fertile white Leghorn chick embryos in 15% oxygen (hypoxia) or 21% oxygen (control) until Hamburger-Hamilton stage 21 (3.5 d). We assessed in ovo viability and dysmorphic features and then measured ventricular pressure and dimensions and dorsal aortic arterial impedance at stage 21. Chronic hypoxia decreased viability and embryonic wet weight. Chronic hypoxia did not alter heart rate or the ventricular diastolic indices of end-diastolic pressure, maximum ventricular -dP/dt, or tau. Chronic hypoxia decreased maximum ventricular +dP/dt and peak pressure, increased ventricular end-systolic volume, and decreased ventricular ejection fraction, consistent with depressed systolic function. Arterial afterload (peripheral resistance) increased and both dorsal aortic SV and steady-state hydraulic power decreased in response to hypoxia. Thus, reduced oxygen tension during early cardiac development depresses ventricular function, increases ventricular impedance (afterload), delays growth, and decreases embryo survival, suggesting that a critical threshold of oxygen tension is required to support morphogenesis and cardiovascular function in the early embryo.

Animals↗
PubMed1994

Epicardial strains in embryonic chick ventricle at stages 16 through 24.

Embryonic cardiac development depends, in part, on the local biomechanical environment. Tracking the motions of microspheres attached to the embryonic chick ventricle, we computed two-dimensional epicardial strains at Hamburger-Hamilton stages 16, 18, 21, and 24 (2.5, 3.5, 4.0, and 4.5 days, respectively, of a 21-day incubation period). First, in a cross-sectional study, strains were measured in separate embryos at each stage (n > or = 19 per stage). Then, in a longitudinal study, strains were measured serially on the same heart, with the eggs resealed and reincubated between successive stages (n > or = 4 per stage). Although the heart undergoes major changes in mass, morphology, and loading during the studied stages, both studies showed that peak circumferential and longitudinal strains relative to end diastole were similar in magnitude (0.13 to 0.16) and did not change significantly across the stage range. The peak principal strains also showed no significant changes, with magnitudes of approximately 0.11 and 0.18. The shear strains were small, and their signs varied from one heart to another. These results suggest that wall strain is maintained within a relatively narrow range during primary cardiac morphogenesis.

Animals↗
PubMed1998

Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects.

Angiotensin (Ang) II has two major receptor isoforms, AT1 and AT2. Currently, AT1 antagonists are undergoing clinical trials in patients with cardiovascular diseases. Treatment with AT1 antagonists causes elevation of plasma Ang II which selectively binds to AT2 and exerts as yet undefined effects. Cardiac AT2 level is low in adult hearts, whereas its distribution ratio is increased during cardiac remodeling and its action is enhanced by application of AT1 antagonists. Although in AT2 knock-out mice sensitivity to the pressor action of Ang II was increased, underlying mechanisms remain undefined. Here, we report the unexpected finding that cardiac-specific overexpression of the AT2 gene using alpha-myosin heavy chain promoter resulted in decreased sensitivity to AT1-mediated pressor and chronotropic actions. AT2 protein undetectable in the hearts of wild-type mice was overexpressed in atria and ventricles of the AT2 transgenic (TG) mice and the proportions of AT2 relative to AT1 were 41% in atria and 45% in ventricles. No obvious morphological change was observed in the myocardium and there was no significant difference in cardiac development or heart to body weight ratio between wild-type and TG mice. Infusion of Ang II to AT2 TG mice caused a significantly attenuated increase in blood pressure response and the change was completely blocked by pretreatment with AT2 antagonist. This decreased sensitivity to Ang II-induced pressor action was mainly due to the AT2-mediated strong negative chronotropic effect and exerted by circulating Ang II in a physiological range that did not stimulate catecholamine release. Isolated hearts of AT2 transgenic mice perfused using a Langendorff apparatus also showed decreased chronotropic responses to Ang II with no effects on left ventricular dp/dt max values, and Ang II-induced activity of mitogen-activated protein kinase was inhibited in left ventricles in the transgenic mice. Although transient outward K+ current recorded in cardiomyocytes from AT2 TG mice was not influenced by AT2 activation, this study suggested that overexpression of AT2 decreases the sensitivity of pacemaker cells to Ang II. Our results demonstrate that stimulation of cardia AT2 exerts a novel antipressor action by inhibiting AT1-mediated chronotropic effects, and that application of AT1 antagonists to patients with cardiovascular diseases has beneficial pharmacotherapeutic effects of stimulating cardiac AT2.

Angiotensin II↗