Myocardial hypertrophy, angiotensin, and ACE inhibitors.

The renin-angiotensin system has long been known as a potent determinant of cardiovascular homeostasis and a powerful regulator of vascular hemodynamics. Over the last twenty years, it has become clear that components of the renin-angiotensin system are present in and, in many instances, synthesized in local tissues. The role of some of these local renin systems is now becoming clear, but the role, if any, of local production of angiotensin II in the heart and vasculature remains unknown.

Expression of viral T-antigen in pathological tissues from transgenic mice carrying JC-SV40 chimeric DNAs.

Immunostaining methods were used to detect viral T-antigen and the cellular protein p53 in pathological tissues obtained from transgenic mice carrying JC-SV40 hybrid viral DNAs. A transgenic mouse carrying the SV40 regulatory region and JC virus (JCV) T-antigen-coding sequences exhibited an SV40-characteristic choroid plexus papilloma that expressed JCV T-antigen and p53. JCV-associated pathology was observed in two other mice in which the JCV regulatory signals directed SV40 T-antigen-induced adrenal neuroblastomas and brain neoplastic cells.

Endothelin modulates angiotensin II-induced mitogenesis of human mesangial cells.

Angiotensin II (ANG II) elicits either a hypertrophic or hyperplastic response depending on culture conditions. Human mesangial cell (HMC)-generated endothelin (ET) plays a role in mediating the hyperplastic effects of arginine vasopressin. The interaction between ANG II and ET is not described in HMC.

Prior arterial injury enhances luciferase expression following in vivo gene transfer.

We determined the time course of gene expression following DNA/Lipofectin transfection of normal or previously injured arterial segments using direct intraluminal infusion following surgical exposure. Constructs possessing the firefly luciferase cDNA regulated by Simian virus 40, Rous sarcoma virus, or alpha-actin promoter were incubated together with Lipofectin for 30 minutes. Arterial segments were assayed for luciferase activity following harvest at 2-21 days.

The interaction of insulin and angiotensin II on the regulation of human neuroblastoma cell growth.

This laboratory has previously reported that angiotensin II is a growth factor for human SH-SY5Y neuroblastoma cells, and that a variety of converting enzyme inhibitors and angiotensin II antagonists reduce thymidine incorporation into the DNA of these cells. In the present study, insulin, at 5 micrograms/mL, was found to stimulate thymidine incorporation in SH-SY5Y cells. The insulin effect was only partially inhibited by the converting enzyme inhibitors enalapril, quinapril, and quinaprilat, whereas it was markedly or totally blunted by the angiotensin II antagonists DuP753 and PD123177.

Development of innovative therapies in the large multispecialty clinic setting.

Innovation is intrinsic to medicine and to medical progress. As American medicine enters the twenty-first century, it is confronted with enormous opportunities to innovate both in the science and practice of medicine. Indeed, medicine is challenged to do so by society.

Microsphere and dilution techniques for the determination of blood flows and volumes in conscious mice.

Although the mouse is the most commonly used transgenic species, little is known regarding cardiovascular and fluid homeostasis in this animal. Therefore, the reference microsphere and dilution techniques were adapted for the measurement of cardiac output (CO), regional blood flows, and intravascular fluid volumes in the conscious mouse. Previously acclimatized C3H mice were studied 4-5 h after surgery and recovery from anesthesia.

The use of antisense oligonucleotides to establish autocrine angiotensin growth effects in human neuroblastoma and mesangial cells.

Local renin-angiotensin systems (RAS) exist in many cell types, and angiotensin II (AII) has growth regulatory effects in some tissues. We demonstrated the presence of angiotensinogen (ANG) mRNA in cultured human mesangial cells (MC) and SHSY-5Y human neuroblastoma cells using reverse transcription and the polymerase chain reaction (RT/PCR) followed by hybridization to a human ANG-specific oligonucleotide probe. We speculated, therefore, that AII might act in an autocrine or paracrine fashion to regulate the growth of mesangial cells and neuroblastoma cells.

Growth factors and cardiovascular structure. Implications for calcium antagonist therapy.

Abnormalities of cellular growth regulation are integral to the development of cardiovascular disorders such as atherogenesis, ventricular hypertrophy, and diabetic glomerulopathy. Moreover, cellular growth is in large measure controlled by peptide and nonpeptide growth factors that mediate their actions, in part, through the transcriptional regulation of normal cellular genes called protooncogenes. Because angiotensin II is one such growth regulatory factor and because changes in intracellular calcium are intimately involved in the action of angiotensin and other growth factors, it is likely that inhibitors of angiotensin action and calcium-channel-blocking agents will be found to have useful growth regulatory properties.

Angiotensin-converting enzyme inhibition reduces neuroblastoma cell growth rate.

Because of the known capacity of angiotensin II to serve as a growth factor in multiple tissues, we elected to study the effects of renin-angiotensin system inhibition on the growth of human SH-SY5Y neuroblastoma cells. Cells were treated with captopril (0.05-5 mg/ml), enalapril, or enalaprilat (0.

Angiotensin and the regulation of cellular growth. Pathophysiologic implications for cardiovascular and noncardiovascular tissues.

Components of the renin-angiotensin system can be found in the vasculature, although in most cases it is unclear how much, if any, of this renin in the vasculature is locally synthesized. Over recent years, a variety of novel actions of angiotensin II have been delineated which suggest that in appropriate physiologic or pathologic circumstances vascular angiotensin II can play an important role in determining vascular structure. Moreover, angiotensin II may play a role in neoplastic growth of vascular and nonvascular tissues.

Effects of ionic strength on endogenous nuclease activity in chelated and nonchelated chromatin.

Calf thymus chromatin, isolated using a standard (low ionic strength, but nonchelating) isolation protocol, dialyzed against either Tris-PMSF or Tris-EDTA, was reconstituted in a high salt compacting buffer (COM) or a low salt dispersing buffer (DIS) prior to digestion with endogenous nucleases. A greater level of enzyme activity occurred when chromatin was in a condensed state (COM buffer) and not chelated prior to digestion. In contrast, chromatin chelated by dialysis against Tris-EDTA prior to digestion showed higher levels of enzyme activity in the dispersed state (DIS buffer).

How to use continuous quality improvement theory and statistical quality control tools in a multispecialty clinic.

The management philosophy of continuous quality improvement (CQI) and the tools of statistical quality control (SQC) have the potential for advancing quality management in medicine as they have in industry. The authors report their favorable experience with the approach and explain how to adapt CQI principles and SQC charts and graphs, citing examples from their participation in a quality improvement effort in a multispecialty clinic serving a large hospital. The coupling of statistical techniques with modern approaches to outcome analysis may provide powerful tools not only for quality assurance and assessment but also for technology evaluation and resource allocation.

The cellular biology of angiotensin: paracrine, autocrine and intracrine actions in cardiovascular tissues.

A growing body of evidence suggests that angiotensin II, the effector protein of the renin-angiotensin system, is intimately involved with cell growth in target tissues. Most recently, evidence has been provided to indicate that angiotensin II is capable of inducing a hypertrophic response in cultured arterial smooth muscle cells. At the same time, considerable evidence has been developed to indicate that local analogs of the systemic renin-angiotensin system exist in multiple tissues and, in particular, in the vascular wall and the heart.

Emerging issues in the cellular biology of the cardiovascular system.

Current theory suggests that life began in a prebiologic era, progressed to a ribonucleic-deoxyribonucleic cellular era, and finally entered an era characterized by multicellular organisms. If this progression is correct, it is not surprising that, as medicine studies living organisms with increasing sophistication, factors that are initially discovered to have systemic effects are, in many instances, later determined to have paracrine, autocrine or even intracellular ("intracrine") effects. This schema is potentially of value in analyzing the pathogenesis of cardiovascular disease and, in particular, the development of the sequelae of hypertension.

New approaches to the study of the cellular biology of the cardiovascular system.

Recent findings suggest that the local renin-angiotensin systems, locally generated catecholamines, and possibly other locally generated peptides interact in a complex fashion to regulate the cellular biology of the myocardium, the vascular wall, and other tissues. New evidence indicates that the components of the renin-angiotensin system are synthesized in cardiovascular tissues, that the synthesis of these components can be modulated by pharmacologic agents, and that angiotensin II, the effector protein of the renin system, appears to be capable of producing hypertrophy or hyperplasia in specific tissues. In addition, recent studies suggest the participation of enhanced proto-oncogene transcriptional activity in the development of hyperplasia and hypertrophy in cardiovascular tissue.

Does the renin-angiotensin-aldosterone system modify cardiac structure and function in essential hypertension?

To determine the impact of the renin-angiotensin-aldosterone system on left ventricular function and structure, 36 untreated patients with essential hypertension (WHO class I and II) were examined. Posterior wall thickness, relative wall thickness, and left ventricular mass were determined by M-mode echocardiography. Plasma renin activity, aldosterone, angiotensin I, and angiotensin II levels were measured by radioimmunoassay.

[Periventricular leukomalacia in the newborn infant. Clinical and echographic diagnosis and follow-up].

Periventricular leukomalacia (PVL) is defined as an ischemic lesion of the brain of the preterm infant, characterized by infarction of the deep white matter surrounding the external angle of the lateral ventricles, a watershed area lacking collateral circulation, representing a typical "border zone" of vascular supply. This lesion is considered the neuroanatomic basis of motor and sensory impairments, as spastic diplegia or quadriplegia, mental retardation, visual and auditory deficits. An early diagnosis and the study of the developmental sequence of PVL, are recently become possible by realtime ultrasound scanning.

Cellular mechanisms of growth in cardiovascular tissue.

Left ventricular hypertrophy is a complex cellular response to a variety of pathologic states. In recent years it has become clear that a variety of hormones are present in the heart and may participate in the genesis of left ventricular hypertrophy. Our group has demonstrated the synthesis of renin by cultured canine arterial smooth muscle cells and has recently demonstrated the presence of renin and angiotensin II in myocardial cell preparations.

The renin-angiotensin systems.

The renin-angiotensin systems are important regulators of cardiovascular homeostasis and participate in a variety of pathological conditions. Recent advances have not only clarified the functioning of the systemic renin cascade but have also indicated the importance of the generation of angiotensin in tissues.

The myocardial intracellular renin-angiotensin system.

In recent years several tissues have been found to contain the components of the renin-angiotensin system. Locally synthesized renin could conceivably function in an endocrine, paracrine or autocrine manner. Isolated left ventricular cardiac myocytes of the rat were examined in the present study and renin and angiotensin II were detected in these cells.