Tissue-specific regulation of gene expression for renin and angiotensinogen.
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Adrenal Glands↗
Biomedical subjects
K Lindpaintner
Publications and source records attributed to K Lindpaintner.
Intracardiac generation of angiotensin and its physiologic role.
The emerging recognition of the existence and potential biological significance of local tissue renin-angiotensin systems in a number of organs has fostered interest in a possible intrinsic cardiac renin-angiotensin system. Evidence for such a system was first provided by biochemical measurements of components of the renin-angiotensin system in cardiac tissue. It has recently been demonstrated that the genes coding for renin and angiotensinogen are expressed in all regions of the heart, an essential prerequisite for the postulated intracardiac biosynthesis of these proteins. Moreover, we have shown the presence of a functional and physiologically active pathway for the conversion of angiotensin I to angiotensin II in the beating mammalian heart. This conversion appears to be catalyzed by a specific cardiac converting enzyme that is susceptible to systemically administered converting-enzyme inhibitors. Evidence for the physiologic importance of the cardiac renin-angiotensin system comes from experimental data as well as indirect clinical evidence. The potent coronary vasoconstrictor properties of angiotensin II underscore its possible significance in myocardial ischemia and ischemic heart disease, in particular when viewed in the context of selective local activation. The long-known positive inotropic effects of angiotensin II are based on its direct myotropic properties and on its facilitatory effects on sympathetic neurotransmission and may be of added significance in metabolically compromised states. We have recently demonstrated that locally generated angiotensin may be a dominant etiologic factor in the pathogenesis of reperfusion arrhythmias. In addition, we have found experimental evidence for a deleterious effect of angiotensin II on myocardial metabolism in the setting of regional myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Acute ischemia as a contributing factor in torsade de pointes: treatment by coronary artery bypass grafting.
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Aged↗
Tissue renin-angiotensin systems: focus on the heart.
Recent findings support the existence of independently functioning, local renin-angiotensin systems in a number of tissues. The clinical importance that inhibitors of the renin-angiotensin system have gained in the treatment of hypertension and cardiac failure, as well as molecular biology data, suggest that a functional, tissue renin-angiotensin system is present in the heart. Using several experimental approaches we present evidence to support the existence and the possible physiopathological relevance of such a cardiac renin-angiotensin system. Tissue angiotensins were documented and quantified in different regions of the heart by high performance liquid chromatography combined with specific radio-immunoassay. Reduction of cardiac angiotensin after administration of converting enzyme inhibitors in nephrectomized animals indicates that these peptides are generated locally. Effects of converting enzyme inhibitors on angiotensin II-dependent facilitation of cardiac sympathetic tone further support this concept and emphasize the potential physiological role of a cardiac renin-angiotensin system. Further, direct evidence for local generation of angiotensin II in the myocardium is provided by assessment of the intracardiac conversion of angiotensin I to angiotensin II and by measurement of the activity of angiotensin converting enzyme in the heart.
Angiotensin II↗
Role of beta 1-adrenoceptors in hypertensive cardiac hypertrophy.
Experimental and clinical evidence indicates that cardiac hypertrophy in systemic hypertension may not simply result from the mechanical stress of increased afterload. Several lines of evidence suggest that sympathetic nervous influence stimulates cardiac growth. A previous study indicated that sympathetic tone may be important in the two-kidney, one-clip model of renovascular hypertension. Hence, we investigated the role of cardiac beta-receptors by testing the effects of the cardioselective beta-receptor blocker, atenolol, on regression and prevention of ventricular hypertrophy in this model. Renal hypertensive rats were assigned to a 'prevention' and a 'reversal' protocol, receiving the drug before or after the development of hypertension and cardiac hypertrophy. Untreated control animals developed severe hypertension (205 +/- 9 mmHg) and marked cardiac hypertrophy (heart weight/body weight ratio: 3.86 +/- 0.23 mg/g) when compared to sham-operated controls (129 +/- 1 mmHg and 2.38 +/- 0.06 mg/g, respectively). Atenolol (440 mg/kg per day) failed to prevent or reverse hypertension (213 +/- 5 and 194 +/- 11 mmHg) or cardiac hypertrophy (4.10 +/- 0.39 and 3.51 +/- 0.25 mg/g, respectively). Effective beta-blockade was verified by significantly lower heart rates in treated animals (382 +/- 10 and 368 +/- 9 beats/min, respectively) than untreated controls (486 +/- 28 beats/min; P less than 0.01). Similarly, plasma renin activity returned to baseline in atenolol-treated animals. Cardiac catecholamines were markedly decreased in hypertrophied hearts (significant only for norepinephrine) and remained unaffected by atenolol treatment. However, both the prevention and reversal protocol strikingly reduced mortality in hypertensive animals (0 and 14%, respectively, versus 57%; P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Segmental necrotising enterocolitis: pathological and clinical features of 22 cases in Bangladesh.
To describe the pathology and clinical features of segmental necrotising enterocolitis (SNE) in children and adults, 22 diarrhoeal patients (median age two years, range two months to 50 years) in Bangladesh with this lesion detected at autopsy were examined and compared with two groups of diarrhoeal control patients. Gross pathology consisted of purplish or black mucosal or transmural discoloration with erosions or ulcerations in segments of the jejunum or ileum of 18 cases and of the colon alone in four cases. Two patients had intestinal perforations. Microscopically all specimens showed coagulation necrosis or haemorrhagic necrosis indicative of mucosal ischaemia. In 20 cases there was submucosal oedema and nine showed pneumatosis of the bowel. From 11, one or more of the invasive diarrhoeal pathogens Shigella, Campylobacter and Entamoeba histolytica were detected. From the comparison with controls significant associations were found for a long duration of diarrhoea, blood and mucus in stool, abdominal distension or tenderness, shock not attributable to hypovolaemia, septicaemia, and low concentration of serum protein (p less than 0.05). These findings indicated that segmental necrotising enterocolitis develops sometimes as a fatal complication of prolonged diarrhoeal illnesses associated with shock and hypoproteinaemia and is caused by ischaemic injury to the intestinal mucosa.
Adolescent↗
Effects of chronic progressive myocardial hypertrophy on indexes of cardiac autonomic innervation.
The development of cardiac hypertrophy is associated with marked changes in cardiac autonomic innervation. Significant and sustained reductions of myocardial catecholamine stores and activities of tyrosine hydroxylase and dopamine beta-hydroxylase have been reported in models of acutely induced ventricular hypertrophy. Conversely, activity of choline acetyltransferase, a marker of parasympathetic nervous function, shows transient increases during the development of acute right ventricular hypertrophy. The potential physiological importance of these changes prompted us to examine a clinically more relevant model of slowly progressive ventricular hypertrophy. Application of a loose band around the pulmonary artery of weanling guinea pigs resulted in a growth-related progressive right ventricular pressure overload. Right ventricular weight-to-body-weight ratio was increased significantly and progressively at 9 and 18 weeks in banded animals (0.92 +/- 0.05 and 1.31 +/- 0.11 mg/g, respectively, p less than 0.01) compared with sham-operated controls (0.55 +/- 0.02 and 0.59 +/- 0.01 mg/g, respectively) but showed no further gain at 27 weeks (1.41 +/- 0.10 mg/g). Activities of tyrosine hydroxylase and dopamine beta-hydroxylase remained unchanged in all experiment groups, while right ventricular contents of norepinephrine in banded animals at 18 and 27 weeks exhibited sustained and progressive increases (2.45 +/- 0.11 and 3.40 +/- 0.19 micrograms/right ventricle, respectively) over controls (1.80 +/- 0.13 and 2.40 +/- 0.22 micrograms/right ventricle, respectively, p less than 0.01). The activity of choline acetyltransferase was markedly elevated in banded animals at 18 weeks (32.6 +/- 2.7 nmol/hr/right ventricle) but returned to baseline by 27 weeks (22.8 +/- 1.4 nmol/hr/right ventricle).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Role of myocardial hypertrophy in trophic stimulation of indices of sympathetic cardiac innervation.
Indices of cardiac sympathetic innervation have commonly been found depressed in the failing, hypertrophied heart. In contrast, we have recently demonstrated that hemodynamically compensated, very gradually developing right ventricular hypertrophy is associated with an increase in sympathetic nervous markers. The present experiments were performed to corroborate these findings in a model of acutely induced right ventricular hypertrophy, and to further characterize changes in markers of autonomic innervation associated with cardiac hypertrophy. Male guinea pigs underwent either pulmonary artery banding (P) with an acutely constricting ligature, or bilateral stellate ganglionectomy (S), or both (PS). Appropriate sham procedures were performed in animals subjected to only one intervention; controls (C) underwent sham-S and sham-P. Groups of animals were sacrificed at 10 and 20 days after surgery. Cardiac tissues were weighed and subsequently analyzed for activities of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), two enzymes catalyzing the biosynthesis of catecholamines (CAs), and of choline acetyltransferase (CAT), a marker of parasympathetic activity, as well as for norepinephrine (NE). S resulted in profound depletions of cardiac NE of 88-92% and in significant decreases in the activities of DBH and TH. Marked right ventricular hypertrophy developed rapidly following P, and was not modified by S. Similar to our previous results, acute right ventricular hypertrophy was associated with moderate increases (10-20%) of sympathetic markers; following S, these increases (of presumably residual sympathetic innervation) were greatly enhanced, amounting to 171% and 105% for NE at 10 and 20 days, respectively. In contrast, sympathetic markers in the left ventricle of stellatectomized animals were not affected by P. Activity of CAT remained unaltered by the experimental interventions. Our experiments indicate that increases in markers of sympathetic innervation may be a common feature of the early, compensated stage of cardiac hypertrophy, regardless of its time course. Sympathetic neural mechanisms do not appear to play a stimulatory or trophic role in the hypertrophic process. Conversely, they seem to be secondary in nature, suggesting a possible stimulatory influence of hypertrophying myocardium on sympathetic cardiac nerves.
Animals↗
Acute myocardial necrosis during administration of amsacrine.
The authors report a case of focal myocardial necrosis, presenting clinically as an acute myocardial infarction during the administration of the antineoplastic drug, amsacrine, in a patient without coronary artery disease. In addition to the recognized arrhythmic complications, the authors emphasize myocardial necrosis as a possible further manifestation of amsacrine-related cardiotoxicity.
Aminoacridines↗
Role of sodium in hypertensive cardiac hypertrophy.
Cardiac hypertrophy in systemic hypertension may not result simply from increased afterload. Previous studies indicate that factors other than blood pressure may influence cardiac hypertrophy. We evaluated the effects of dietary sodium restriction in two-kidney one-clip renal hypertensive rats. After the renal artery had been clipped, the rats received a normal diet until hypertension was established; thereafter, a sodium-deficient diet was instituted in one group. Clipped rats on a regular diet had significantly higher systolic blood pressures than sham-operated controls (205 +/- 9 vs. 129 +/- 1 mm Hg, respectively). Sodium restriction did not reverse hypertension (190 +/- 8 mm Hg), but led to a significant reduction of relative heart weight compared to rats on the normal diet (2.94 +/- 0.24 vs. 3.86 +/- 0.23 mg/g, respectively; P less than 0.01). The hypertrophied hearts of animals on the regular diet showed depressed tissue catecholamines (significant only for norepinephrine); sodium restriction resulted in a restoration to normal levels. Thus, we demonstrated a dissociation of blood pressure and cardiac hypertrophy in the two-kidney one-clip model, similar to previous findings in other models. Our results support the concept that factors other than blood pressure contribute to cardiac hypertrophy. Dietary sodium intake appears to be one such factor. In addition, a possible role of the sympathetic nervous system is suggested.
Animals↗
Use of animal models to search for candidate genes associated with essential hypertension.
The use of inbred genetically hypertensive animal models enables the dissection of the underlying complex genetic traits into its individual components, and thus the elucidation and characterization of causative genes and gene variants. In addition, genetically hypertensive animal models will also be useful for the investigation of genetic characteristics that influence the effectiveness of antihypertensive therapy with specific pharmacologic agents. This report will discuss three different strategies that have recently been used for the identification of candidate gene loci or candidate genes for hypertension. The possibility to transfer of genetic data derived in animal models to human hypertension will also be considered.
Animals↗
Molecular biology, endocrinology, and pharmacology of the cardiac renin-angiotensin system.
Recent evidence for the existence of extrarenal tissue renin-angiotensin systems has raised the question whether such a system also exists in the heart. In this communication, we present evidence for a cardiac renin-angiotensin system based on molecular biological and biochemical data. In addition, we address the question whether the components of this system interact as a locally integrated, biologically functioning unit. Using radiolabeled cRNA probes prepared from specific cDNA fragments, we were able to document renin and angiotensinogen gene expression in atria and ventricles of the rat heart by Northern blot and liquid hybridization analysis. Relative signal strength for both mRNAs was highest in the atria, followed by the right and left ventricle. Using specific, HPLC-controlled RIAs for angiotensin peptides, we demonstrated the presence of both angiotensin I and angiotensin II in all anatomical regions of the monkey and rat heart. Similarly, the presence of converting enzyme activity was ascertained by direct in vitro determinations. Additional experiments evaluating the spontaneous release of angiotensinogen from isolated, perfused rat hearts revealed a bimodal pattern of high, but rapidly declining rates during the first hour (perhaps representing the washout of a pool sequestered from plasma), followed by a prolonged period of steady, low level release, consistent with the secretion of locally synthesized protein. In separate experiments aimed at examining the possible local integration of the components of the cardiac renin-angiotensin system, we measured angiotensin II concentrations in the coronary sinus effluent of isolated, perfused rat hearts. Infusion of angiotensin I resulted in the prompt appearance of angiotensin II, amounting to a single pass fractional conversion of 6.42 +/- 0.33%.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗