Biomedical subjects

C Heymes

Publications and source records attributed to C Heymes.

30 records · Page 2Linked to original sources

PubMed1998

Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes.

Recent studies have pointed out the differential role of angiotensin II (Ang II) receptor subtypes, AT1 and AT2, in cardiac hypertrophy and fibrosis during pathological cardiac growth. Because senescence is characterized by an important cardiovascular remodeling, we examined the age-related expression of cardiac Ang II receptors in rats. AT1 and AT2 receptor subtype messenger RNA (mRNA) levels were quantitated by RT-PCR. In parallel, specific Ang II densities were determined in competition binding experiments using specific antagonists. AT1a and AT1b mRNA levels were markedly up-regulated (5.6-fold) in the left ventricle of 24-month-old rats compared with 3-month-old rats, but not in the right ventricle. In contrast, AT2 gene expression was increased in both ventricles of senescent rats (4.2- and 2.8-fold in the left and right ventricles, respectively). Similarly, AT1 and AT2 gene expression was increased 2.3- and 2-fold, respectively, in freshly isolated cardiomyocytes from aged rats. Furthermore, AT1 and AT2 specific binding was increased in the aged left ventricular myocardium. Even though the mechanistic pathway of this up-regulation of Ang II receptor subtype gene expression might be intrinsic to developmental gene reprogramming, the up-regulation of AT1 mRNA accumulation in the left ventricle during aging could also be secondary to age-related hemodynamic changes, whereas increased AT2 gene expression in both ventricles may depend upon hormonal and humoral factors.

Aging↗

PubMed1997

Heart rate and heart rate variability, a pharmacological target.

Heart rate varies with respiration, blood pressure, emotion, etc., and heart rate variability (HRV) is presently one of the best indices to predict fatal issues in cardiac failure and after myocardial infarction. HRV depends on various reflexes. In addition, parallel studies of HRV and the myocardial adrenergic and muscarinic transduction system in experimental models of cardiac hypertrophy (CH) have suggested that the myocardial phenotype at the sinus-node level may also play a role. A transgenic strain of mice with atrial overexpression of the beta 1-adrenergic receptors was generated with attenuated HRV, which demonstrates that the phenotype itself is a determinant of HRV. HRV is explored by noninvasive techniques, including simple determination of the standard error of the mean, time-domain analysis, and Fourier transformation. We recently developed a time and frequency domain method of analysis, the smoothed pseudo-Wigner-Ville transformation, which allows better exploration of nonstationarity. Nonlinear methods have also been applied due to the extreme complexity of the biological determinants, and have provided evidence of a chaotic attractor in certain conditions. It is proposed that in steady state a very simple process, which is not completely deterministic, could better explain intermit interval regulations than chaotic behavior. In contrast, under extreme circumstances the regulation proceeds using chaotic behavior. Arrhythmias and HRV can be quantitated in 16-month-old unanesthetized spontaneously hypertensive rats (SHR). Ventricular premature beats are more frequent in SHR than in age-matched controls; they disappear after converting enzyme inhibition (CEI) relative to the reduction of both cardiac hypertrophy and ventricular fibrosis. HRV is attenuated in SHR, as it is in compensatory CH in humans. When CH is prevented, HRV returns to normal. CEI is therefore antiarrhythmic. Another pharmacological application of this concept concerns the bradycardic agents that may improve HRV.

Animals↗

PubMed1996

Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure.

Angiotensin II (Ang II) is both a vasoactive and a potent growth-promoting factor for vascular smooth muscle cells. Little is known about the in vivo contribution of AT1 and AT2 receptor activation to the biological action of Ang II. Therefore, we investigated the effect of AT1 or AT2 subtype receptor chronic blockade by losartan or PD123319 on the vascular hypertrophy in rats with Ang II-induced hypertension. Normotensive rats received for 3 wk subcutaneous infusions of Ang II (120 ng/kg per min), or Ang II + PD 123319 (30 mg/kg per d), or Ang II + losartan (10 mg/kg per d) or PD 123319 alone, and were compared with control animals. In normotensive animals, chronic blockade of AT2 receptors did not affect the plasma level of angiotensin II and the vascular reactivity to angiotensin II mediated by the AT1 receptor. Chronic blockade of AT1I in rats receiving Ang II resulted in normal arterial pressure, but it induced significant aortic hypertrophy and fibrosis. Chronic blockade of AT2 receptors in Ang II-induced hypertensive rats had no effect on arterial pressure, but antagonized the effect of Ang II on arterial hypertrophy and fibrosis, suggesting that in vivo vasotrophic effects of Ang II are at least partially mediated via AT2 subtype receptors.

Angiotensin II↗

PubMed1995

Molecular and cellular biology of the senescent hypertrophied and failing heart.

During aging, experimental studies have revealed various cellular changes, principal among which is myocyte hypertrophy, which compensates for the loss of myocytes and is associated with fibrosis. The expression of alpha-myosin heavy chain is replaced by that of the isogene beta-myosin, which leads to decreased myosin adenosine triphosphatase (ATPase) activity. In consequence, contraction is slower and more energetically economical. The Ca(2+)-ATPase of the sarcoplasmic reticulum and Na+/Ca2+ exchange activity are decreased, which probably explains the reduced velocity of relaxation. Membrane receptors are also modified, since the density of both the total beta-adrenergic and muscarinic receptors is decreased. The senescent heart is able to hypertrophy in response to overload and to adapt to the new requirements. Similar alterations are observed both in the senescent heart and in the overloaded heart, in clinical as well as in experimental studies; however, differences do exist, especially in terms of fibrosis and arrhythmias.

Adaptation, Physiological↗

PubMed1995

Trandolapril decreases prevalence of ventricular ectopic activity in middle-aged SHR.

BACKGROUND: Although severe arrhythmias are still a major problem in patients with left ventricular hypertrophy (LVH), the relationship between ventricular remodeling and its regression or prevention, and the prevalence of ventricular premature beats (VPB) or more sustained arrhythmias are still poorly explored in hypertensive heart disease. METHODS AND RESULTS: Holter monitoring was used to quantify supraventricular premature beats and VPB and heart rate (HR) in middle-aged spontaneously hypertensive rats (SHR) and Wistar rats treated for 3 months with trandolapril (ACE inhibitor, 0.3 mg/kg per day). Hypertrophy and fibrosis were morphometrically determined. Statistical analysis was performed with the use of simple regression and multivariate data analysis (cluster and correspondence analysis). SHR have higher cardiac mass and fibrosis, more VPB, and a decreased HR. Cluster analysis demonstrated that trandolapril was only effective in SHR. Trandolapril significantly reduced cardiac hypertrophy, fibrosis, and VPB incidence and increased the HR. Simple regression analysis showed that VPB incidence correlated to both hypertrophy and fibrosis. Correspondence analysis evidenced a strong correlation between hypertrophy, fibrosis, and VPB, but only for severe hypertrophy, and the correlation disappeared for moderate hypertrophy. CONCLUSIONS: After trandolapril treatment, the regression of VPB incidence not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved including the myocardial phenotype and new calcium metabolism. Our model of Holter monitoring in conscious middle-aged SHR and multivariate data analysis might be useful in correlating myocardial structural modifications and ectopic activity.

Aging↗

PubMed1994

Molecular basis of regression of cardiac hypertrophy.

Cardiac hypertrophy due to a chronic mechanical overload puts into play a biologic cascade, including a trigger (the mechanical stretch), a transmitter (very likely to be the phosphoinositol pathway), and the final target (which is the DNA). The permanent changes in genetic expression resulting from the activation of this cascade allows the heart to produce normal active tension at a lower cost in terms of energy expenditure. The process is reversible, providing the treatment reduces the real load on the heart--i.e., not only the peripheral resistances but also the aortic impedance--during a period of time that has to be several times the half-life of cardiac proteins, and also that the treatment has an effect on the detrimental consequences of cardiac hypertrophy, namely, the systolic and diastolic dysfunction and the incidence of arrhythmias. In this report semisenescent spontaneously hypertensive rats were treated for 3 months with the converting enzyme inhibitor trandolapril. The treatment had a rather modest effect on blood pressure but resulted in a pronounced reduction in cardiac hypertrophy and in cardiac fibrosis, an improved coronary reserve, and attenuated both the effects of anoxia on the left ventricular diastolic compliance and the incidence of ventricular arrhythmias.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Is the senescent heart overloaded and already failing?

Heart failure mainly occurs during the last decades of life, and it is important to know if the senescent heart is not an already failing heart. During aging, both contraction and relaxation of papillary muscle are impaired. Such an impairment is compensated in vivo and the cardiac output remains normal. In spite of a loss in myocytes, the heart weight/body weight ratio is unchanged, but the myocytes are bigger. Arrhythmias are permanent and are accompanied by a loss of the normal heart rate variability. Changes in specific mRNAs include: a shift in myosin heavy chain (MHC) isogene expression leading to an increased beta MHC content; decreased densities of Ca2+ ATPase of the sarcoplasmic reticulum, beta 1-adrenergic receptor, and muscarinic receptors; and attenuation of the Na+/Ca2+ exchange activity. Most of these changes, but not all, resemble those observed during cardiac overload and are accompanied by an increased duration of both the action potential and the intracellular calcium transient. However, the senescent heart is still able to further modify its phenotype in response to mechanical overload. The senescent heart is a diseased heart, and the origin of the "disease" is multifactorial and includes the general process of senescence, hormonal changes, and the myocardial consequences of senescence of the vessels.

Aging↗

PubMed1994

Activation of angiotensinogen and angiotensin-converting enzyme gene expression in the left ventricle of senescent rats.

BACKGROUND: During senescence, the plasma angiotensin II concentration is decreased, but the regulation of intracardiac angiotensin II synthesis has never been investigated. The purpose of this work was to determine the cardiac content of both angiotensinogen (ANG) and angiotensin-converting enzyme (ACE) mRNAs in 24-month-old Wistar rats. METHODS AND RESULTS: Total cardiac RNAs and known amounts of ANG and ACE mRNA transcripts, used as standards, were hybridized on slot blots with specific cDNA probes. The quantities of ANG and ACE mRNA were evaluated from the regression lines obtained with fragments of ANG and ACE mRNA in vitro transcripts. With aging, while the overall plasma renin-angiotensin system (RAS) activity decreased, in the left ventricle (LV) the amounts of ANG and ACE mRNAs were increased by fivefold (P < .01) and 2.5-fold (P < .01), respectively, compared with young adult controls. By contrast, in the right ventricle (RV) the same mRNA levels remained unchanged. In parallel, we also found an enhanced expression of the atrial natriuretic factor (ANF) in the LV but not in the RV. CONCLUSIONS: During senescence, the depressed circulating RAS activity is in contrast to the increase of both ANG and ACE mRNA levels in the LV. Such an upregulation in both gene activities is more likely to be related to the age-associated changes in arterial compliance rather than to hormonal changes, since (1) this regulation is found only in the LV and (2) the same pattern of regulation is also observed for the ANF mRNA level.

Aging↗

PubMedDate not supplied

Myocardial determinants in regulation of the heart rate.

Heart rate is a function of at least three factors located in the sinus node, including the pacemaker and the activity of the sympathetic and vagal pathways. Heart rate varies during breathing and exercising. The is far from being a purely academic question because, after myocardial infarction or in cardiac insufficiency, reduced heart rate variability (HRV) represents the most valuable prognostic factor. HRV is usually considered index of the sympathovagal balance and is explored using time domain analysis, such as spectral analysis. Nevertheless, methods such as the Fast Fourier Transformation are not applicable to small rodents which have an unstable heart rate with asymmetric oscillations. Nonlinear methods show chaotic behavior under some conditions. A time and frequency domain method of analysis, the Wigner-Villé Transform, has been proposed for the study of HRV in both humans and small rodents, as a compromise between linear and nonlinear methods. We developed a method to quantify both arrhythmias and HRV in unanesthetized rodents. Such a method allows study of the relationship between the physiological parameters and the myocardial phenotype. Ventricular premature beats are more frequent in 16-month-old spontaneously hypertensive rats than in age-matched controls. In addition, HRV is attenuated in spontaneously hypertensive rats, as in compensatory cardiac hypertrophy in humans, and such attenuation is considered a prognostic index. Converting enzyme inhibition reduces in parallel arterial hypertension, cardiac hypertrophy, and ventricular fibrosis; it prevents ventricular premature beats and normalizes heart rate variability. It can be demonstrated that the incidence of ventricular premature beats is linked to the myocardial phenotype in terms of both cardiac hypertrophy and fibrosis. The two factors act as independent variables. HRV is correlated with the incidence of arrhythmias, suggesting that the beneficial effects of converting enzyme inhibition are related to prevention of arrhythmias.

Animals↗

PubMedDate not supplied

Neuronal nitric oxide synthase is expressed in rat vascular smooth muscle cells: activation by angiotensin II in hypertension.

The nitric oxide synthase (NOS) inhibitor nitro-L-arginine augmented the contractions to angiotensin (Ang) II in carotid artery rings without endothelium from spontaneously hypertensive rats (SHR) but not normotensive Wistar-Kyoto rats, suggesting the possibility of nonendothelial NOS activity in SHR arteries. In SHR artery without endothelium, the potentiation of Ang II contraction by nitro-L-arginine was prevented by L-arginine, but not by D-arginine, and was observed also in the presence of oxyhemoglobin, monomethyl-L-arginine, and 7-nitroindazole, but not in the presence of aminoguanidine. In further support of NOS activation by Ang II in nonendothelial cells, Ang II but not acetylcholine stimulated cGMP levels by 2-fold in SHR arteries without endothelium; nitro-L-arginine decreased both basal and Ang II-stimulated cGMP levels. When NOS activity in SHR arteries was measured, no calcium-independent L-citrulline formation was detectable, while up to 47% of the total calcium-dependent NOS activity was present in nonendothelial cells. Expression of neuronal NOS was revealed in the media of SHR arteries by immunohistochemistry, Western blot, and reverse transcriptase-polymerase chain reaction. Expression of this NOS isoform was greater in SHR than in Wistar-Kyoto rat preparations. Finally, endothelial NOS was observed in the endothelium, but no detectable levels of inducible NOS were found in these tissues. These results demonstrate the expression of neuronal NOS in rat vascular smooth muscle cells and its activation on stimulation by Ang II in spontaneously hypertensive, but not normotensive, animals.

Angiotensin II↗

PubMedDate not supplied

[Functions of AT2 receptors of angiotensin II].

The structure, the coding gene and expression of the AT2 subtype receptor of angiotensin II have been described recently; however, the possible role of this receptor remains unclear despite its presence in most mammalian tissues. The AT2 receptor is probably involved in fetal growth and adult tissue repair and remodelling, especially in the cardiovascular system. There are still conflicting results, in vitro and in vivo, as to whether AT2 receptors limit and/or accelerate the growing processes in the cardiovascular tissues.

Angiotensin II↗

PubMedDate not supplied

[The cardiovascular steroid system].

In this review, the authors describe: (1) the different types of glucocorticoid hormone receptors, on the cell membrane and two types inside the cell, the MR and GR (mineralo- and glucoreceptors); (2) the synthesis of the hormones with the decisive role of the final enzymes, 11 beta-hydroxylase and aldosterone-synthetase; (3) the increasing evidence for a cardiovascular steroid system in the vessels as well as in the myocardium. The authors have reported new data suggesting the existence of an endocrine cardiac steroidogenic system in the heart with a potential physiological and pathological relevance (for transmembrane ion transport and trophic alterations).

Adrenal Cortex Hormones↗