Role of cardiac renin-angiotensin system in swimming induced physiological myocardial hypertrophy

To determine the contribution of cardiac renin-angiotensin system (RAS) to the physiological myocardial hypertrophy induced by swimming training and the relationship between locally produced and circulating RAS, both ventricular and plasma angiotensin (Ang) I and II contents, ventricular angiotensin converting enzyme (ACE) and plasma renin activity (PRA) were detected by means of radioimmunoassay and biochemical method. It was shown that after 5 weeks of swimming, the ventricular wet weight to body weight ratio (V/Bwt) and Ang II in both left and right ventricles and ACE activity increased markedly as compared with the controls (P < 0.05). Furthermore, significantly positive correlation was found between the ventricular Ang II and V/Bwt (r = 0.7721, P < 0.001), while the plasma Ang I and II and PRA remained at the control level. No correlation was found between plasma Ang II and V/Bwt. These above findings suggest that cardiac RAS may play an important role in physiological myocardial hypertrophy and to a large extent is in dependent on circulating RAS.     

Important role for angiotensin III and IV in the brain renin-angiotensin system

Children taught to sequence pairs of visual stimuli also performed additional sequences without direct training. In Experiment 1, the children were trained to produce a six-stimulus sequence (A > B > C > D > E > F) with one set of forms, and five overlapping two-stimulus sequences (A > B, B > C, C > D, D > E, and E > F) with another set of forms. Few of the children succeeded on tests for the untrained two- (e.g., B > D and B > E) and six-stimulus sequences derivable from the two-stimulus training. The children in Experiments 2 and 3 received only the overlapping sequence training before testing with refined protocols: Nearly all succeeded on tests of emergent sequences involving two, three, four, five, and six stimuli. The results suggest methods for examining transitive relations between pairs of the stimuli used in training and the development of a relation of order among all six of the stimuli involved.     

The brain renin-angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes

We have previously shown that mice transgenic for both the human renin and human angiotensinogen genes (RA+) exhibit appropriate tissue- and cell-specific expression of both transgenes, have 4-fold higher plasma angiotensin II (AII) levels, and are chronically hypertensive. However, the relative contribution of circulating and tissue-derived AII in causing hypertension in these animals is not known. We hypothesized that the brain renin-angiotensin system contributes to the elevated blood pressure in this model. To address this hypothesis, mean arterial pressure (MAP) and heart rate were measured in conscious, unrestrained mice after they were instrumented with intracerebroventricular cannulae and carotid arterial and jugular vein catheters. Intracerebroventricular administration of the selective AII type 1 (AT-1) receptor antagonist losartan (10 microgram, 1 microL) caused a significantly greater peak fall in MAP in RA+ mice than in nontransgenic RA- controls (-29+/-4 versus -4+/-2 mm Hg, P<0.01). To explore the mechanism of a central renin-angiotensin system-dependent hypertension in RA+ mice, we determined the relative depressor responses to intravenous administration of the ganglionic blocking agent hexamethonium (5 mg/kg) or an arginine vasopressin (AVP) V1 receptor antagonist (AVPX, 10 microgram/kg). Hexamethonium caused equal lowering of MAP in RA+ mice and controls (-46+/-3 versus -52+/-3, P>0.05), whereas AVPX caused a significantly greater fall in MAP in RA+ compared with RA- mice (-24+/-2 versus -6+/-1, P<0.01). Consistent with this was the observation that circulating AVP was 3-fold higher in RA+ mice than in control mice. These results suggest that increased activation of central AT-1 receptors, perhaps those located at sites involved in AVP release from the posterior pituitary gland, plays a role in the hypertension in RA+ mice. Furthermore, our finding that both human transgenes are expressed in brain regions of RA+ mice known to be involved in cardiovascular regulation raises the possibility that augmented local production of AII and increased activation of AT-1 receptors at these sites is involved.     

Cold exposure regulates the renin-angiotensin system

The effect of cold exposure on the systemic renin-angiotensin system and on regulation of the angiotensin II (Ang II) receptor was examined in target organs for Ang II with cardiovascular relevance (left ventricle, kidney, lung) and metabolic relevance [interscapular brown adipose tissue (ISBAT), liver] to the functional consequences of cold exposure. In time course studies, the effects were examined of 4 hr or 1, 3 and 7 days of exposure to cold (4 degrees C) on plasma Ang II concentration and Ang II receptor binding characteristics in rat liver. Plasma Ang II concentration increased 10-fold after 4 hr of cold exposure, returned to control levels at days 1 and 3 of cold exposure, and was again increased (2-fold) at 7 days of cold exposure. The affinity of [125I]Sar1, Ile8-Ang II binding in membranes prepared from rat liver was not altered in cold-exposed rats. The density (Bmax) of binding sites in liver from cold-exposed rats was increased by day 1 and remained elevated over time-matched controls. Alterations in Ang II receptor density did not parallel plasma Ang II concentration in their time course, suggesting that cold-induced regulation of the Ang II receptor was not substrate mediated. In rats from the 7-day time point of cold exposure, Ang II receptor binding characteristics were examined in ISBAT and lung. Increases in Ang II receptor density were evident in ISBAT but not lung. To determine whether cold-induced increases in food intake contributed to elevations in plasma Ang II concentration and/or Ang II receptor density, a group of cold-exposed rats (7 days) were pair-fed to food intake levels of control rats. Pair-feeding of cold-exposed rats eliminated increases in plasma Ang II and norepinephrine concentration but did not prevent increases in Ang II receptor density in liver, ISBAT, kidney and left ventricle. Moreover, increases in Ang II receptor density were augmented in kidney and left ventricle from cold-exposed rats that were pair-fed. Results from these studies demonstrate that cold exposure resulted in an increase in plasma Ang II concentration through mechanisms related to increased food intake. Elevations in food intake in cold-exposed rats contributed to tissue-specific increases in Ang II receptor density. Moreover, cold-induced increases in Ang II receptor density were not related to plasma Ang II concentration.     

Investigations on the renin-angiotensin system in acute severe asthma

The renin-angiotensin system is activated in acute severe asthma. The precise mechanism of activation is at present unknown, but may involve, beta2-agonists, catecholamines or proteases released in airway inflammation. This study aims to identify potential factors involved in the activation of the renin-angiotensin system in acute asthma. Forty asthmatics with severe exacerbations of asthma, assessed by measurement of peak expiratory flow rate (mean (SD) 35 (18)% predicted), oxygen saturation (94 (4)%) and pulse rate (108 (16) beats x min(-1)) were recruited. Nineteen (48%) asthmatics had elevated plasma angiotensin II levels (median (interquartile range) 10.9 (4.3-23.5) pg x mL(-1) (normal range 3-12 pg x mL(-1))) and 10 (25%) had elevated plasma renin concentration (22.0 (10.0-50.0) microU x mL(-1) (normal range 9-50 microU x mL(-1))). Plasma renin and angiotensin II correlated strongly, implying renin-dependent angiotensin II formation. No correlation was found between plasma salbutamol, adrenaline, nor-adrenaline, endothelin-1, histamine, eosinophilic cationic protein, serum angio-tensin-converting enzyme (ACE) activity, total immunoglobulin E (IgE), urea and electrolytes, indicators of the severity of the attack, atopic status, blood pressure and renin or angiotensin II levels. We conclude that although a subpopulation of asthmatics appear to have raised renin and angiotensin II during attacks of acute, severe asthma, the mechanism of activation of the renin-angiotensin system remains unclear.     

The renin-angiotensin system in left ventricular remodeling

Left ventricular remodeling is a dynamic process that occurs in reaction to an insult to the myocardium. The response to either loss of cells, as may occur following myocardial infarction, or to hemodynamic overload, as may occur in aortic stenosis, is an attempt to maintain cardiac output and normalize wall tension. This is accomplished through the activation of the renin-angiotensin system and hypertrophy of noninfarcted segments of the myocardium. in the case of moderate or large infarctions these mechanisms fail to normalize wall stress. The stimulus to further remodeling remains, viable myocytes hypertrophy (with greater increases in cell length than width), the mass-to-volume ratio increases, and an exponential increase in wall stress results. This increase in myocyte tension has been associated with premature myocyte cell death. Thus, a vicious cycle is established wherein overstretch of the myocardium while sustaining cardiac output leads to progressive myocyte loss and left ventricular dilation. The renin-angiotensin system plays an integral role in this process. Its inhibition by angiotensin-converting enzyme (ACE) inhibitors both chronically and immediately after myocardial infarction has been shown to decrease left ventricular volumes and reduce mortality. Controversy exists regarding the mechanism through which ACE inhibitors exert their effects. ACE inhibitors reduce afterload/preload, circulating angiotensin II levels, and raise circulating levels of bradykinin. It is not yet clear which mechanism is responsible for the greatest impact on left ventricular dilation and mortality. inhibition of the renin-angiotensin system is clearly beneficial to cardiac performance as well as morbidity and mortality when myocardium is lost and heart failure ensues. Specific modes of action require further definition, including local and systemic effects. Possible benefits of angiotensin receptor blockade versus augmentation of bradykinin requires definition, setting the stage for further study, while the beneficial therapeutic use of these agents continues.     

The ovarian renin-angiotensin system in reproductive physiology

The identification of the presence of prorenin, renin, angiotensinogen, angiotensin-converting enzyme, angiotensin II (Ang II), and Ang II receptors in the ovary suggests that there is a functional ovarian renin-angiotensin system (RAS). It could play a significant role in such areas of ovarian physiology as follicular development, steroidogenesis, oocyte maturation, ovulation, and follicle atresia. Expression of the ovarian RAS is regulated by gonadotropins. Ang II, a bioactive octapeptide of RAS, has important effects as a paracrine/autocrine regulator at different stages of the reproductive cycle. Ang II modulates ovarian steroidogenesis and formation of the corpus luteum and also stimulates oocyte maturation and ovulation via Ang II receptors on granulosa cells. In addition, increasing evidence demonstrates that Ang II is a major factor in regulating the function of atretic follicles. In any physiologic system, aberrations result in the development of pathologic states. Disturbances in the ovarian RAS can be the cause or the result of such reproductive disorders as polycystic ovary syndrome, ovarian hyperstimulation syndrome, ovarian tumors, and ectopic pregnancy. Data support the concept of an active and regulated RAS in ovarian follicles. Species differences observed in the expression of ovarian RAS suggest varying functional roles among species with respect to ovarian physiology.     

Structure of the renin-angiotensin system and its significance in the body

Renin-angiotensin system (RAS) is a methabolic pathway producing octapeptid angiotensin II (AII) with vasoconstrictive effects, which is also involved in the regulation of water homeostasis and electrolyte balance in the organism. Genes encoding individual components of the RAS can be considered as "candidate genes" for some cardiovascular diseases e.g. hypertension or myocardial infarction. Besides the circulating RAS, also local tissue systems exist. Local RASs are involved in various physiological functions e.g. regulation of growth and proliferation, apoptosis or signal transmission where AII serves as the neurotransmitter.     

Renal trauma and hypertension: the role of renin

Three patients developed hypertension following renal trauma. Trauma produced perinephric hematoma in two and renal artery thrombosis in one. Renal vein plasma renin activity (PRA) from the traumatized kidney was three to eight times greater than renal vein PRA from the untraumatized (contralateral) kidney. Peripheral PRA was elevated in all. A surgical operation lowered peripheral PRA to normal in all, but corrected hypertension in only two of three. Preoperative medical treatment with renin-suppressing pharmacologic agents correctly predicted this response to surgery. Postoperative renal vein PRA in the remaining hypertensive patient demonstrated that surgery successfully alleviated the abnormality in renin secretion. These studies suggest that excessive renin secretion initiate but other unidentified factors may contribute to the hypertension observed after renal trauma.     

Salt sensitive blood pressure and the renin-angiotensin system in hypertension

The relationship between (excessive) use of sodium chloride and the blood pressure is still equivocal. Blood pressure responses to alterations in dietary salt consumption vary greatly between individuals, which has led to the concept of salt sensitivity. Although the mechanisms which determine the degree of salt sensitivity are not fully understood, the renin-angiotensin system seems to play a key role. A relative inability of this system to respond promptly to alterations in salt intake may underlie the development of salt sensitivity. By administering drugs which block the renin-angiotensin system to patients with essential hypertension, blood pressure is rendered more sensitive to the effects of salt restriction and (or) diuretic treatment.     

Possible role of c-Jun in transcription of the mouse renin gene

In cell culture, cidofovir (CDV) was used to select a human cytomegalovirus (HCMV) strain with decreased drug susceptibility. The genotypic characterization of this virus revealed a single base substitution resulting in a K513N amino acid alteration in the viral DNA polymerase (UL54). Performed in parallel, the selection of HCMV for replication in the presence of ganciclovir (GCV) selected an M460V substitution in the phosphotransferase (UL97), as well as a K513N/V812L double substitution in DNA polymerase. Neither of the two DNA polymerase mutations has been previously identified in HCMV drug-resistant strains. To precisely elucidate their role in drug resistance, corresponding recombinant mutant viruses were generated by recombination of nine overlapping viral DNA fragments. The K513N recombinant virus showed 13- and 6.5-fold decreased susceptibility to CDV and GCV in vitro, respectively, compared with the wild-type recombinant virus. Mutation V812L was associated with a moderate (2-3-fold) decrease in susceptibility to CDV, GCV, foscarnet, and adefovir. A multiplicative interaction of the K513N and V812L mutations with regard to the profile and level of drug resistance was demonstrated in recombinant virus expressing both mutations. In vitro replication kinetic experiments revealed that the K513N mutation significantly decreased HCMV replication capacity. Consistent with this finding, the K513N mutant DNA polymerase exhibited reduced specific activity in comparison with the wild-type enzyme and was severely impaired in its 3'-5' exonuclease function. Unexpectedly, the K513N mutant enzyme showed no decrease in susceptibility to CDV-diphosphate or GCV-triphosphate. However, the K513N mutation decreased the susceptibility to CDV and GCV of the oriLyt plasmid replication in the transient transfection/infection assay, suggesting that the DNA replication of the K513N mutant virus is less sensitive to the corresponding inhibitors.     

The renin-angiotensin system in diabetic nephropathy: the endothelial connection

Aspergillus species exhibit a distinct and clear fluorescence in Papanicolaou-stained cytological samples. The Papanicolaou (PAP) stain enhances the autofluorescence of cultured aspergilli and allows better cytological recognition of the fungus by fluorescence microscopy when it is not easily discerned from its surroundings by light microscopy. Morphological properties can be better distinguished and facilitate the differentiation of aspergillus organisms from other filamentous fungi. Neither light nor fluorescence microscopy, the cytological quality nor the presence of phagocytosed hyphae in alveolar macrophages allow distinction between infection and contamination with Aspergillus species. Only the presence of eosinophilic inflammation permits a tentative diagnosis of an Aspergillus infection. In conclusion, PAP fluorescence reduces the need for special stains, is superior to and quicker than other investigative techniques and enhances the sensitivity and specificity of cytological investigation when a rapid and reliable identification of Aspergillus is needed.     

The role of cyclic nucleotides in guinea-pig bladder contractility

1. The effects of phosphodiesterase (PDE) inhibition and forskolin pretreatment on the contractile responses of guinea-pig urinary bladder strips to electrical field stimulation, carbachol, ATP and KCl were studied. 2. Inhibition of cyclic AMP-specific PDE4 isozymes by rolipram significantly reduced the contractile response of bladder strips to field stimulation. Rolipram also suppressed the contractile response to low concentrations of carbachol, but potentiated the response to high concentrations. The contractile response to ATP was significantly reduced by rolipram treatment, but that to KCl was unaltered. 3. Inhibition of cyclic GMP-specific PDE5 isozymes by zaprinast had no effects on the contractile response of bladder strips to field stimulation, ATP or KCl. Zaprinast suppressed the contractile responses to 1 microM carbachol and potentiated the response to high concentrations. 4. Contractile responses to field stimulation and to carbachol after pretreatment with the adenylyl cyclase activator, forskolin, were qualitatively similar to those caused by rolipram treatment. beta-Adrenoceptor blockade with propranolol partially reversed the inhibitory effects of rolipram on the response to field stimulation. 5. Rolipram significantly reduced the contractile response of bladder strips from sensitized guinea-pigs to ovalbumin challenge, but zaprinast was ineffective. PDE inhibition had similar effects on the responsiveness of control and of sensitized guinea-pig bladder strips to field stimulation, carbachol, ATP and KCl. 6. The data suggest that the contractile response of guinea-pig bladder strips can be modified by increases in cyclic AMP levels.     

Physiologic actions and molecular expression of the renin-angiotensin system in the diabetic rat

Vascular permeability to intravenously injected horseradish peroxidase (HRP) was qualitatively examined in the hippocampus of ischemic Mongolian gerbil brains by light and electron microscopy. After 30 min of right common carotid artery occlusion followed by 90 min of reperfusion, the animal was perfused with a fixative and killed. Before the perfusion of the fixative, HRP was injected into the femoral vein. HRP was visualized with tetramethyl benzidine (TMB) and diamino-benzidine (DAB) for light and electron microscopy, respectively. Staining reaction with TMB for HRP appeared in medial or dorsal portions of the operated side of the hippocampus, especially around some vessels along the hippocampal fissure. Ultrastructural examination in the vessels along hippocampal fissure revealed that the endothelial cytoplasm contained HRP-filled vesicles or vacuoles in close proximity to the basal lamina, and seemed to be slightly electron-dense. Swollen pericytes, swollen astrocytic foot processes and perivascular cells with HRP-filled cytoplasm were also observed in that area. In this study, it was clearly demonstrated that intravascular macromolecules leaked transendothelially, through vessel walls in the hippocampal fissure, from the blood stream in the medial portions of the hippocampus during reperfusion following ischemia. These findings suggest that the blood-brain barrier in some vessels along the hippocampal fissure in the medial parts of the hippocampus is more vulnerable to ischemic insults than those in other brain areas.