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Biomedical subjects

O Chung

Publications and source records attributed to O Chung.

At least 19 recordsLinked to original sources
PubMed2001

Significance of timing of angiotensin AT1 receptor blockade in rats with myocardial infarction-induced heart failure.

OBJECTIVE: Blockade of angiotensin AT(1) receptors has been shown to prevent cardiac remodeling and improve left ventricular function and survival after myocardial infarction (MI). However, the timing of initiation of treatment has not been fully elucidated. Therefore, the purpose of the present study was to compare the effects of very early (30 min after MI), early (3 and 24 h after MI) and delayed (7 days after MI) treatments with the angiotensin AT(1) receptor antagonist fonsartan (HR 720) on cardiac morphological and hemodynamic parameters in a rat model of MI-induced heart failure and to establish the therapeutic window for the start of treatment. METHODS: Male Wistar rats underwent coronary ligation and were randomized fonsartan (HR720) treatment starting 30 min, 3 h, 24 h and 7 days after MI or no treatment. Treatment was continued up to 6 weeks post MI. RESULTS: Fonsartan (HR720) treatment attenuated cardiac hypertrophy when treatment started 30 min or later after MI, limited infarct size when treatment initiated 3 and 24 h after MI, decreased left ventricular end-diastolic pressure when treatment started 3 h to 7 days after MI, and improved dP/dt(max) when treatment commenced 24 h and 7 days after MI compared to untreated infarct group. CONCLUSION: Our results show that angiotensin AT(1) receptor blockade with fonsartan (HR720) produced the best cardioprotective effects when treatment was started 3 to 24 h after MI although a start of treatment 7 days following MI still could improve functional parameters. These results suggest an optimal time window for the start of treatment with angiotensin AT(1) receptor antagonists seems to be between 3 and 24 h post MI.

Angiotensin Receptor Antagonists↗
PubMed2000

Cardioprotective effects of the Na(+)/H(+)-exchange inhibitor cariporide in infarct-induced heart failure.

OBJECTIVE: We investigated the effect of chronic treatment with the new Na(+)/H(+)-exchange inhibitor, cariporide, on cardiac function and remodelling 6 weeks after myocardial infarction (MI) in rats. METHODS: Treatment with cariporide was commenced either 1 week pre or 30 min, 3 h, 24 h or 7 days after ligation of the left ventricular artery and was continued until haemodynamic parameters were obtained 6 weeks after MI in conscious rats. RESULTS: Compared to sham animals, untreated MI-controls developed pronounced heart failure after 6 weeks. Basal left ventricular end-diastolic pressure (in mmHg) was reduced in the groups in which cariporide was started 1 week pre (16.0+/-1.7) or 30 min (12.5+/-1.1), 3 h (11.8+/-1.0) and 24 h (13.0+/-2.5) after MI compared to untreated MI-controls (22. 4+/-1.5; P<0.01). Basal myocardial contractility (in 1000 mmHg/s) was only increased when treatment was initiated after 30 min (9. 0+/-0.7), 3 h (8.5+/-0.3) and 24 h (8.0+/-0.7) compared to untreated MI-controls (5.8+/-0.7; P<0.05-0.01). Infarct size (in % of left ventricular circumference) was 40.0+/-2.1 in MI-controls and was decreased when treatment was begun after 30 min (32.6+/-2.7) or 3 h (32.4+/-2.3) (P<0.05). In animals, in which cariporide was started 3 h after induction of MI, heart weight/body weight ratio was significantly decreased, indicating reduced cardiac hypertrophy. When treatment started 7 days after MI, cariporide did not exert any beneficial actions on structural and functional cardiac parameters. CONCLUSION: Our results show for the first time that chronic treatment with the Na(+)/H(+)-exchange inhibitor cariporide engendered marked cardioprotective effects when commenced before and up to 24 h after MI. The optimal time for the start of treatment was between 30 min and 3 h post MI.

Analysis of Variance↗
PubMed1999

Effects of a novel angiotensin AT(1) receptor antagonist, HR720, on rats with myocardial infarction.

Cardiac remodeling after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of the present study was to assess the effects of chronic treatment with a novel angiotensin AT(1) receptor antagonist 2-butyl-4-(methylthio-)-1-[[2'[[[(propylamino)carbonyl]amino]sulfonyl ](1,1'-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate (HR720), on cardiac remodeling and left ventricular dysfunction in a rat model of large myocardial infarction. Rats were subjected to permanent ligation of the left coronary artery and were treated for six weeks with placebo or HR720 (3 mg/kg/day) initiated 24 h after surgery. Sham-operated rats served as normal controls. Mean arterial blood pressure, the maximum rate of rise of the left ventricular systolic pressure (dP/dt(max)), left ventricular end-diastolic pressure, left ventricular inner diameter and circumference, septal thickness, left ventricular collagen content and heart weight were measured at the end of the treatment. HR720 treatment versus placebo attenuated the cardiac hypertrophy (heart weight/body weight: 2.88+/-0.08 mg/g vs. 3.16+/-0.09 mg/g, P<0.05), reduced interstitial collagen content (3. 47+/-0.28% vs. 5.25+/-0.45%, P<0.01), limited infarct size (33.0+/-3. 0% vs. 41.5+/-2.3%, P<0.05), decreased left ventricular end-diastolic pressure (13.7+/-2.2 vs. 21.4+/-1.6 mm Hg, P<0.01) and improved dP/dt(max) (9000+/-430 vs. 6000+/-840 mm Hg/s, P<0.05). The present results demonstrate that chronic treatment with the angiotensin AT(1) receptor antagonist HR720 can limit infarct size, partially prevent cardiac hypertrophic remodeling and improve left ventricular function in rats with myocardial infarction.

Angiotensin Receptor Antagonists↗
PubMed1999

Angiotensin II receptor blockade and end-organ protection.

The renin-angiotensin system (RAS) is a widely studied hormonal system that comprises substrate-enzyme interactions, the end result of which is production of the active peptide angiotensin II (Ang II). Because Ang II affects blood pressure control, sodium and water homeostasis, and cardiovascular function and structure, a great deal of research effort has been directed toward blocking the RAS. Angiotensin II may also be involved in end-organ damage in hypertension, heart failure, and vascular disease. At least two subtypes of angiotensin II receptors have been identified: AT1 and AT2. The AT1 mediates all of the known actions of Ang II on blood pressure control. Additionally, research has indicated that the AT1 receptor modulates cardiac contractility and glomerular filtration, and increases renal tubular sodium reabsorption, and cardiac and vascular hypertrophy. Less is known regarding the function of the AT2 receptor. Evidence suggests that the AT2 receptor inhibits cell proliferation and reverses AT1-induced hypertrophy. Indeed, these receptors are thought to exert opposing effects. Angiotensin II AT1 receptor antagonists (AT1RA) inhibit the RAS at the receptor level by specifically blocking the AT1 receptor subtype. These drugs induce a dose-dependent blockade of Ang II effects, resulting in reduced blood pressure, urinary protein, and glomerular sclerosis. It is postulated that AT1RA may provide end-organ protection by blocking Ang II effects via the AT1 receptor, yet leaving the AT2 receptor unopposed. Consequently, these agents may reduce the morbidity and mortality that result from myocardial infarction (MI) and other conditions resulting from structural alterations in the heart, kidney, and vasculature.

Angiotensin II↗
PubMed1999

Angiotensin II receptor pharmacology and AT1-receptor blockers.

Angiotensin II (Ang II) has diverse physiological actions leading, for example, to increases in extracellular volume, peripheral vascular resistance and blood pressure, and has also been implicated in the regulation of cell growth and differentiation. Molecular cloning and pharmacological studies have defined two major classes of Ang II receptors, designated as AT1 and AT2. Most effects of Ang II are mediated by AT1 receptors. Much less is known about the physiological role of AT2 receptors. Recent evidence suggests involvement of AT2 receptors in development, cell differentiation, apoptosis and regeneration in various tissues. AT1 and AT2 receptors have been shown to exert counteracting effects on cellular growth and differentiation, vascular tone and the release of arginine vasopressin (AVP). In each condition the AT2 receptor appears to down-modulate actions mediated by the AT1 receptor, resulting in decreased cellular proliferation, decreased levels of serum AVP levels or decreased vasoconstrictor responses. In addition, in neuronal cell lines, the AT2 receptor reportedly exerts antiproliferative effects and promotes neurite outgrowth, an effect accompanied by significant changes in the gene expression pattern of growth- and differentiation-related genes.

Acrylates↗
PubMed1998

Effect of moxonidine on blood pressure and sympathetic tone in conscious spontaneously hypertensive rats.

The effects of moxonidine on blood pressure, heart rate and sympathetic tone were studied in conscious spontaneously hypertensive rats. Intravenous moxonidine (80 nmol) transiently increased blood pressure without affecting heart rate or splanchnic nerve activity. Moxonidine (20-80 nmol) given into the fourth cerebral ventricle dose-dependently lowered mean arterial pressure, heart rate and sympathetic outflow (maximally by 60 +/- 3 mm Hg, 148 +/- 10 beats min(-1) and 15 +/- 3 microV). Moxonidine was more effective by this route than after the injection into the lateral ventricle. Clonidine (20-80 nmol) produced an initial pressor response after both intracerebroventricular routes of administration. A decrease in blood pressure was observed only when clonidine was given into the fourth ventricle. Clonidine decreased heart rate and splanchnic nerve activity similarly like moxonidine when the substances were given into the fourth ventricle. The data imply that the hypotensive effect of moxonidine is related to central sympathoinhibition. The main site of this action appears to be in the brainstem region.

Animals↗
PubMed1998

Effects of the calcium channel antagonist mibefradil on haemodynamic and morphological parameters in myocardial infarction-induced cardiac failure in rats.

OBJECTIVE: Calcium channel antagonists (CCA) have been proposed for the prevention of cardiac events after myocardial infarction (MI). Mibefradil is a CCA featuring a selective blockade of T-type Ca2(+)-channels. The aim of the study was to characterize the effects of mibefradil on haemodynamic and morphological parameters in a model of postMI chronic heart failure and to establish the "therapeutic window" for the start of therapy. METHODS: MI was induced by permanent ligation of the left coronary artery in male normotensive Wistar rats. Animals were assigned to placebo- or mibefradil-treated (10 mg/kg/day p.o.) groups as follows: (1) sham operation; (2) MI placebo treatment; (3) 7 days preMI start of treatment; (4) 3 h postMI start of treatment; (5) 24 h postMI start of treatment; (6) 3 days postMI start of treatment; (7) 7 days postMI start of treatment. Treatment was continued for 6 weeks postMI. At this time point, mean arterial blood pressure (MAP), heart rate, left ventricular enddiastolic pressure (LVEDP) and contraction force (dP/dtmax) were measured in conscious rats at baseline and after methoxamine (MEX; 0.5-1.0 mg/h i.v.) stimulation to increase afterload. The hearts were subjected to histological determination of infarct size (IS), infarct length (IL), noninfarcted length (NL), left ventricular circumference (LVC), inner LV-diameter (LVD) and septal thickness (ST). RESULTS: Six weeks after MI, MAP was lowered, LVEDP increased and dP/dtmax reduced. Mibefradil treatment increased basal MAP in groups 3-5 compared to the placebo-treated MI group. Under mibefradil, LVEDP was reduced at baseline in groups 3-6 and, after MEX, in all groups. dP/dtmax was increased in groups 3-4 at baseline and after MEX. In the placebo-treated MI group, the infarcted area was 39% of the LV and heart weight, LVD and LVC were increased. Heart weights of mibefradil-treated rats (groups 3-6) did not differ from those of the placebo-treated group. Early onset of treatment with mibefradil reduced IS and IL and increased NL in groups 3-4. LVD and LVC were decreased in group 3 only. ST was increased in groups 3-5. CONCLUSION: Chronic treatment with mibefradil exerts beneficial actions on cardiac structure and performance in postMI cardiac failure in rats, especially when the onset of treatment is either prior to or within hours after the acute ischemic event.

Analysis of Variance↗
PubMed1998

Receptors and their classification: focus on angiotensin II and the AT2 receptor.

Angiotensin II mediates its effects through angiotensin receptors. The use of specific angiotensin receptor ligands and the cloning of these receptors allows their classification. So far, the AT1, AT2 and atypical angiotensin II receptors are recognised. The AT1 receptor is responsible for the classical effects of the renin-angiotensin system such as vasoconstriction, renal salt and water retention, central osmo-control and stimulation of cell growth. The function of the AT2 receptor is far from clear but this receptor appears to be important in fetal development, cell growth inhibition and differentiation processes. This review describes the angiotensin receptors and focuses on the possible functions of the AT2 receptor.

Angiotensin II↗
PubMed1998

Physiological and pharmacological implications of AT1 versus AT2 receptors.

Angiotensin II (Ang II) has diverse physiological actions that lead, for instance, to increases in extracellular volume and peripheral vascular resistance and blood pressure, and it has also been implicated in the regulation of cell growth and differentiation. Molecular cloning and pharmacological studies have defined two major classes of Ang II receptors, designated AT1 and AT2. Most effects of Ang II are mediated by AT1 receptors. Much less is known about the physiological role of AT2 receptors. Recent evidence suggests involvement of AT2 receptors in development, cell differentiation, apoptosis, and regeneration in various tissues. AT1 and AT2 receptors have been shown to exert counteracting effects on cellular growth and differentiation, vascular tone, and the release of arginine vasopressin. In each condition, the AT2 receptor appears to down-modulate actions mediated by the AT1 receptor, resulting in decreased cellular proliferation, decreased levels of serum arginine vasopressin levels, or decreased vasoconstrictor responses. In addition, in neuronal cell lines, the AT2 receptor exerts antiproliferative actions and promotes neurite outgrowth, an effect accompanied by significant changes in the expression pattern of growth/differentiation-related genes.

Angiotensin I↗
PubMed1996

Physiologic and pharmacologic implications of AT1 versus AT2 receptors.

The renin-angiotensin system (RAS) is an important factor in the pathogenesis of cardiovascular diseases, including hypertension and congestive heart failure. The RAS also contributes to media hypertrophy and neointima formation. The recent development of specific, highly selective, nonpeptide angiotensin II (A II)-receptor ligands/antagonists was the basis for the identification of the A II-receptor subtypes, AT1 and AT2, which display a heterogeneous distribution. Virtually all known physiologic actions of A II have been attributed to AT1 receptors; much less is known about AT2 receptors. Cell growth, proliferation, or both are mediated by AT1 receptors, whereas stimulation of AT2 receptors leads to an inhibition of cell proliferation and possibly induces cell differentiation. Under physiologic conditions. AT1 receptors may facilitate angiogenesis while AT2 receptors inhibit it. Under pathophysiologic conditions. AT2 receptors could be up-regulated to control excessive growth mediated in part by AT1 receptors. Characterization of the angiotensin-receptor subtypes has advanced our knowledge of the various functions of A II in the pathogenesis of hypertension and related diseases. It is hoped that eventually we will be able to develop even more specific blocking agents of the pathogenic effects of A II.

Angiotensin II↗
PubMed1996

Angiotensin receptors.

INTRODUCTION: The octapeptide angiotensin II, the potent effector molecule of the renin-angiotensin system, has been implicated in the pathology of hypertension, in cardiovascular diseases like cardiac left ventricular hypertrophy and in structural alterations of the heart such as post-infarct remodelling. ANGIOTENSIN RECEPTORS: The development of highly selective angiotensin II receptor ligands allowed the identification of angiotensin II receptor subtypes, designated AT1, AT2, AT3 and AT4. Most of the known effects of angiotensin II can be attributed to the AT1 receptor (e.g. vasoconstriction, aldosterone and vasopressin release and proliferative effects on vascular smooth muscle and other cells). The AT1 receptor is coupled to G-proteins and engages classical intracellular second messenger systems, for example activation of phospholipase C or inhibition of adenylate cyclase. In contrast, the function and the signal transduction pathways of the AT2 receptor, which exhibits only a 32-34% homology to the AT1 receptor, are so far not fully understood. Coupling of the AT2 receptor to phosphatases and inhibitory actions on AT1 receptor- and growth factor-mediated proliferation in endothelial and other cells as well as induction of neuronal outgrowth in PC12w cells have been demonstrated. Due to its wide distribution in fetal tissues including the central nervous system and its transient reappearance in the adult organism under pathological conditions (for instance after myocardial infarction) the AT2 receptor has been associated with cell differentiation and regeneration. RECEPTOR ANTAGONISTS: The application of orally active AT1 receptor antagonists as antihypertensive drugs has, compared to angiotensin converting enzyme inhibitors, the potential advantage of a more specific renin-angiotensin system inhibition. It is conceivable that the AT2 receptor, left unopposed by AT1 receptor antagonists, contributes to some of the actions of these drugs.

Animals↗
PubMed1992

Spectrum analysis of sympathetic nerve activity and blood pressure in conscious rats.

This study tests whether the power spectrum of blood pressure (BP) provides information toward the sympathovagal balance of BP control by comparing the BP (femoral arterial catheter) spectrum with the spectrum of the efferent sympathetic nerve activity (SNA, bipolar electrode around splanchnic nerve). A remarkable resemblance between both spectra was found. A high-frequency component (HF) linked to respiration and a slower fluctuation type between 0.15 and 0.6 Hz (LF) were identified. There was a large and significant coherence only in the HF range of the BP and SNA power spectrum (P < 0.01). The phase lag of SNA and BP was roughly 200 ms. The recordings were repeated during pharmacological blockade in nine Wistar-Kyoto rats (WKY) and nine spontaneously hypertensive rats (SHR). alpha 1-Adrenoceptor blockade (prazosin) reduced the proportional LF power of BP in both rat strains (WKY P < 0.01, SHR P < 0.05) in favor of HF (WKY P < 0.01, SHR P < 0.01). Parasympathetic blockade (methylscopolamine) had no effect on proportions of power. Similarly, there were no significant differences in the proportional HF and LF power spectra of WKY and SHR. These data provide direct evidence for a relationship between the BP and SNA power spectra; however, only the acute changes in the sympathetic tone changed the LF-HF relationship.

Animals↗
PubMed1990

Mechanisms regulating somatostatin release and somatostatin-induced acetylcholine release from the myenteric plexus.

The present studies were performed to characterize the molecular form(s) of somatostatin present in the myenteric plexus and to examine some aspects of the regulatory mechanisms underlying somatostatin release and somatostatin-induced release of acetylcholine from this tissue. We observed the following: (1) Somatostatin-like immunoreactivity (SLI) is present in the myenteric plexus of the guinea pig ileum with somatostatin-14 being the predominant molecular form. (2) Somatostatin-like immunoreactivity is released from isolated myenteric ganglia after stimulation with veratridine or the ganglionic agonist dimethylphenylpiperazinium (DMPP). (3) Calcium entry via the N-type channel appears to play a dominant role in DMPP-induced release of SLI. (4) Somatostatin regulates its own release via a pertussis toxin-sensitive mechanism. (5) Under basal conditions somatostatin-14 stimulates release of acetylcholine in a concentration-dependent manner. (6) Calcium entry via L-type channels is associated with the release of acetylcholine evoked by somatostatin-14.

Acetylcholine↗