Heterogeneity of Glycosylation of Circulating Active and Inactive Renin

ABSTRACT

Concanavalin A chromatography was used to examine rat plasma and the incubation medium of rat renal cortical slices, the objective being to assess the heterogeneity of glycosylation of active and inactive renin. Inactive renin was measured by activation with trypsin. Concanavalin A chromatography could separate both active and inactive renin in the plasma into three forms, including the unbound form, the loosely-bound form and the tightly-bound form, thereby suggesting the presence of differently glycosylated forms of active and inactive renin in the plasma. Rat renal cortical slices secreted all these three forms of active and inactive renin, hence these forms are mainly of renal origin. These results suggest that differently glycosylated forms of active and inactive renin are released from the kidney into the blood circulation.     

Adipose Tissue as an Endocrine Organ? A Review of Recent Data Related to Cardiovascular Complications of Endocrine Dysfunctions

Clinical and experimental data obtained in the last few years have modified the concept of adipose tissue as one solely directed at energy storage and release. The adipose tissue is a target organ for glucocorticoids and several studies have been carried out on the function of hypothalamic‐pituitary‐adrenal axis in obese subjects without conclusive results. A recent and innovative finding is that adipose tissue can produce cortisol from its inactive precursor, cortisone. The identification of leptin, a hormone synthesised by fat tissue, has ushered in the modern view of this tissue as a true endocrine organ. Leptin is produced primarily by subcutaneous and to a lesser extent by visceral adipose tissue, and has a central role in controlling body weight and, especially in regulating fat stores. Leptin is also involved in several complex functions, including physiological processes associated with puberty. Another hormone of fat tissue is angiotensinogen, which is produced in larger amounts by visceral than subcutaneous fat. Human and animals adipose tissue express a whole renin‐angiotensin system (RAS). Angiotensin II, the final effector of this system is probably produced locally by adipose tissue. The function of adipose RAS is not well known. RAS can participate together with other hormones and substances, in adipocyte differentiation and fat tissue growth, but could be also involved in the pathogenesis of complications of obesity including arterial hypertension.     

The Biochemistry of Aggression-Provoked Renin

The biochemistry of the renin-angiotensin system in aggressive mice may question a simple role of the system in blood pressure regulation. When male mice are fighting, their plasma concentration of active renin may rise several hundred fold without affecting blood pressure. The source of this renin is secretion to the blood from the submaxillary gland and the kidneys, but also small salivary glands may contribute. A further source may be salivary renin transferred by bites from one animal to another, as indicated by recent experiments. The renin concentration in saliva of an aggressor during a fight reaches values of 6000 GU/ml (15 mg/ml).

The huge increase in plasma renin is caused by fully enzymatic active 40 000 Mw renin. Preliminary data, collected in order to study whether this renin is active also in vivo, show the following: Inactive renin is present in a small invariable concentration. The renin substrate is consumed in vivo and the measured generation rate of angiotensin is that expected from the renin and substrate concentration.

The data seem to indicate that the high concentration of aggression-provoked renin is active in vivo. It is unknown how the mouse protects its blood pressure against this hyperactive pressor system.     

The renin angiotensin system and the metabolic syndrome

The renin angiotensin system (RAS; most well-known for its critical roles in the regulation of cardiovascular function and hydromineral balance) has regained the spotlight for its potential roles in various aspects of the metabolic syndrome. It may serve as a causal link among obesity and several co-morbidities. Drugs that reduce the synthesis or action of angiotensin-II (A-II; the primary effector peptide of the RAS) have been used to treat hypertension for decades and, more recently, clinical trials have determined the utility of these pharmacological agents to prevent insulin resistance. Moreover, there is evidence that the RAS contributes to body weight regulation by acting in various tissues. This review summarizes what is known of the actions of the RAS in the brain and throughout the body to influence various metabolic disorders. Special emphasis is given to the role of the RAS in body weight regulation.The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.     

Treatment of Status Asthmaticus—Hormone Changes before and after Aminophylline i.v. Drip Therapy

The treatment of status asthmaticus is one of the most important factors in controlling the patient with asthma attacks. We have studied hormone changes in status asthmaticus and considered what is the best treatment in the asthma attack condition in children. Antidiuretic hormone (ADH), renin activity, and aldosterone activity are elevated in severe asthma attack conditions, and these high levels are correlated with high levels in Wood's clinical score. It is theoretical that patients with dehydration and respiratory failure show such elevation in hormones, and it is well known that under such conditions β₂-stimulant enhances renin production. From our study, it is concluded that β₂2 -stimulant subcutaneous injection must be considered in status asthmaticus. In children, amminophylline i.v. drip therapy may be one of the best treatments in status asthmaticus.     

Influence of upright activity on plasma renin activity and aldosterone concentration in children

Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in 156 healthy infants and children under basal conditions of normal diet and recumbency. PRA and PAC were also evaluated during and after stimulation of the renin-angiotension-aldosterone system by postural change. Basal values of PRA significantly declined with increasing age. Postural change by standing up resulted in an increase of PRA and PAC in all age groups. The increment of PRA but not of PAC was greater in older than in younger children. Neither the basal nor the stimulated levels of PRA and PAC were influenced by sex, body weight, body surface area, serum sodium, serum potassium, creatinine, and 24-h urine secretion of sodium and potassium. Both PRA and PAC returned to the basal levels within 60 min after resuming recumbent posture.     

Tagesprofile von Plasmaaldosteron,-Cortisol, -Renin, -Angiotensinogen und -Angiotensinasen bei Normalpersonen

Zusammenfassung An 6 normalen männlichen Freiwilligen im Alter von 20–26 Jahren wurden Plasmacortisol und -renin stündlich, Plasmaaldosteron, -angiotensinogen und -angiotensinasen alle 3 Std über jeweils 24 Std unter Kontrollbedingungen und anschließend unter Suppression der ACTH-Freisetzung durch Dexamethason gemessen.Die höchsten Cortisolspiegel fanden sich gegen 7 Uhr, die niedrigsten zwischen 21 und 1 Uhr. Die Gabe von Dexamethason führte zu konstant niedrigen Cortisolkonzentrationen.Aldosteron war unter Kontrollbedingungen und unter Dexamethason gegen 4 Uhr am höchsten und zeigte niedrigste Werte zwischen 16 und 22 Uhr. Zwischen den mittleren Aldosteronkonzentrationen entsprechender Zeitpunkte der Kontroll- und der Dexamethasonperiode bestanden keine signifikanten Unterschiede.Ähnlich dem Aldosteron zeigte das Plasmarenin Maximalwerte gegen 4 Uhr. Alle Mittelwerte entsprechender Zeitpunkte zwischen 7 und 23 Uhr und die jeweiligen 24 Std-Mittelwerte jedes einzelnen Probanden waren unter dem Einfluß von Dexamethason signifikant erhöht.Für die Existenz circadianer Rhythmen des Angiotensinogens und der Angiotensinasen konnte kein Anhalt gewonnen werden. Dexamethason bewirkte keine signifikanten Veränderungen dieser Parameter.Die Ergebnisse deuten darauf hin, daß die circadianen Rhythmen von Aldosteron und Renin miteinander vergleichbar, jedoch nicht exakt mit dem des Cortisols synchronisiert sind. Unter der Hemmung der ACTH-Freisetzung durch Dexamethason steigt die Reninaktivität an, der Aldosteronspiegel bleibt unverändert. Angiotensinogen und die Angiotensinasen, Parameter, die die aktive Konzentration des Angiotensin II beeinflussen können, scheinen an der Regulation des Aldosterons nicht beteiligt zu sein.Die Ergebnisse wurden auf dem 21. Symposiom der Deutschen Gesellschaft für Endokrinologie und auf dem Symposiom Aktuelle Probleme der Hochdruck- und Nierenkrankheiten anläßlich des 75. Geburtstages von Herrn Prof. Dr. E. Wollheim vorgetragen.     

Beneficial effects of add-on hydrochlorothiazide in rats with myocardial infarction optimally treated with quinapril

BACKGROUND: The antihypertensive and renoprotective effects of ACE inhibitor (ACEi) therapy are enhanced by inducing a negative sodium balance. Whether this strategy also improves outcome of chronic ACEi treatment after myocardial infarction (MI) is unknown. Therefore, we investigated whether hydrochlorothiazide (HCTZ) or dietary sodium restriction further improves survival in ACEi-treated rats with MI. METHODS: MI was induced by coronary ligation. After 2 weeks rats were randomised to quinapril (QUI), HCTZ added to quinapril (QUI+HCTZ), or low sodium diet added to quinapril (QUI+LS). Survival was monitored for 62 weeks, after which left ventricular (LV) pressures were measured and blood for neurohumoral characterisation was collected. A separate group of rats, subjected to the same procedure, was evaluated after 35 weeks. RESULTS: After 62 weeks, mortality was comparable in all groups. However, survival was improved by HCTZ until 35 weeks. This effect on survival was paralleled by decreased proteinuria and LV end-diastolic pressures in QUI+HCTZ rats at 35, but not 62 weeks. Plasma renin activity was significantly decreased in QUI+HCTZ rats at 35 weeks. Contrary to HCTZ, LS added to QUI caused no benefit. CONCLUSIONS: Adding HCTZ, but not LS, to quinapril improved survival, neurohumoral status, and proteinuria during the early chronic phase of experimental post-MI LV dysfunction. Since no adverse effects were observed, HCTZ may safely be used to improve ACEi therapy.     

Role of the sympathetic and renin angiotensin systems in the glucose-induced increase of blood pressure in rats

The pressor effect induced by acute hyperglycemia is not well understood, therefore, it was of interest to study the effect of intravenous glucose infusion on the mean arterial pressure of anesthetized Wistar rats. Animals received glucose (100 mg/kg/min, i.v.), mannitol or saline during 30 min, but only glucose increased the mean arterial pressure (about 40 mm Hg), plasma glucose, insulin and nitric oxide (NO). Pretreatment with reserpine or indorenate (a central antihypertensive) inhibited completely the pressor effect of glucose. Reserpine also decreased the plasma NO levels. Pretreatment with ramipril or with streptozotocin decreased the late phase of the glucose-induced pressor response and the NO levels, the latter treatment also abolishes insulin plasma concentrations. The present results suggest that the pressor effect induced by glucose has an early phase due to an increase of efferent sympathetic discharges and a delayed phase produced by the activation of the renin angiotensin system.     

AT1 antagonism by eprosartan lowers heart rate variability and baroreflex gain

INTRODUCTION: Blockade of the renin-angiotensin system (RAS) by ACE inhibitors has been demonstrated to reduce total mortality in cardiovascular diseases. This advantage was attributed in part to changes of autonomic cardiovascular control, exemplified by an increase of heart rate variability (HRV) and baroreflex gain (BRG). We sought to assess the effects of the angiotensin type 1 (AT1) receptor blocker eprosartan on HRV and BRG. MATERIALS AND METHODS: In a double-blind randomized cross-over design 25 young males took eprosartan (600 mg/day) and placebo each for a period of 7 days with a wash-out period of at least 4 weeks in between. At the end of the intake phases simultaneous recordings of arterial blood pressure (AP; Finapres) and electrocardiogram (ECG) were taken. Power spectra of HRV and arterial blood pressure variability (APV) were calculated by fast Fourier transform (FFT) and served to calculate BRG. Ang-II levels were measured by radioimmunoassay. RESULTS: Eprosartan tended to lower mean AP, it slightly increased heart rate (HR) (p<0.05), and markedly increased circulating Ang-II levels (p<0.01). Eprosartan diminished the total power of HRV (p<0.05) and the BRG (p<0.01). The low/high frequency (LF/HF) ratio of HRV and the APV were not altered. CONCLUSIONS: AT1 antagonism by eprosartan lowers heart rate variability and baroreflex gain. We speculate that these findings are due to the marked increase in circulating angiotensin II (Ang II). Further studies are needed to clarify whether angiotensin type 1 (AT1) blockers with potential actions inside the blood-brain barrier (BBB) may have different effects on HRV and BRG.