CAPTOPRIL MAGNIFIES THE INCREASE IN ANGIOTENSIN I-CONVERTING ENZYME ACTIVITY IN RATS WITH AMINONUCLEOSIDE NEPHROSIS

1. Serum, tissue and urine angiotensin I-converting enzyme (ACE) activity was estimated in the following groups of rats: saline-injected rats (controls); captopril-treated (CAP) control animals (CONTROL-CAP); puromycin aminonucleoside (PAN)-induced nephrotic syndrome (NS); and CAP-treated animals with NS (NS-CAP). 2. Serum ACE activity increased in the CONTROL-CAP, NS, and NS-CAP groups. The increase in the NS-CAP group was significantly higher compared with the NS or CONTROL-CAP groups. 3. In the CONTROL-CAP group, tissue ACE decreased in brain, heart and adrenal glands, and remained unchanged in the lung, testis, kidney, small intestine and liver. In the NS group, tissue ACE activity increased in the lung and testis, decreased in the brain and heart, and remained unchanged in the small intestine, adrenal glands, kidney and liver. Tissue ACE activity increased significantly in the NS-CAP group compared with the other groups. This increase in tissue ACE may contribute to an increase in the serum ACE activity in the NS-CAP group compared with the NS group. 4. Urine ACE activity increased in the NS and NS-CAP groups, although the rise in the NS-CAP group was significantly higher. The urine ACE correlated significantly with the circulating levels of this enzyme in the NS and NS-CAP groups. The loss of ACE in the urine in the presence of an increased serum ACE activity indicates that the biosynthesis of tissue ACE and its release into the bloodstream must be elevated.     

EFFECT OF LONG-TERM TREATMENT WITH AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR ON THE RENIN-ANGIOTENSIN SYSTEM IN SPONTANEOUSLY HYPERTENSIVE RATS

1. To obtain information on regulation of the brain renin-angiotensin system, the effect of long-term administration of angiotensin-converting enzyme (ACE) inhibitor on brain renin and angiotensinogen mRNA was studied. 2. Spirapril (3 mg/kg) was orally administered daily for 8 weeks to spontaneously hypertensive rats (SHR) from 12 weeks after birth. Renin and angiotensinogen mRNA in the brain and kidney were then quantitated by Northern blot analyses with [32P]-labelled rat renin and angiotensinogen cDNA as hybridization probes. Plasma renin activity (PRA), angiotensin II (AII) concentration, plasma ACE activity and brain tissue ACE activity were also measured. 3. Compared with the control group, the Spirapril-treated group had significantly lower blood pressure (P less than 0.01), significantly higher PRA (P less than 0.01), a not significantly different plasma AII concentration, and lower plasma and brain ACE activities (P less than 0.01). Interestingly, the brain renin and angiotensinogen mRNA levels of the two groups were similar, but the renal renin mRNA level was significantly higher in the Spirapril-treated group (P less than 0.01). 4. These results indicate that the mRNA levels of brain renin and angiotensinogen were not affected by chronic ACE inhibition in the circulation and suggest that AII in the brain might not be affected by systemic ACE inhibition.     

FUNCTIONS OF THE RENIN-ANGIOTENSIN SYSTEM DURING DEVELOPMENT

1. From studies in chronically catheterized fetal sheep and other species, it can be shown that the renin-angiotensin system (RAS) is active during intra-uterine life. Levels of angiotensin II (AII) in fetal sheep are similar to maternal. 2. The fetal RAS plays a role in maintenance of arterial pressure. The extent to which it does so depends on the level of activity of the system. 3. The distribution of renin within the fetal rat kidney is much more widespread than in the adult. The fetal kidney, like other vascular beds has high levels of the AT₂ angiotensin receptor subtype. With maturation the proportion of the AT₁ receptor subtype increases. 4. Blockade of the fetal RAS with angiotensin converting enzyme (ACE) inhibitors or with the non-peptide AII antagonist (losartan) caused a fall in fetal glomerular filtration rate (GFR) and a rise in renal blood flow (RBF). AII reverses the fall in GFR even though RBF decreases. 5. The fraction of the filtered sodium load reabsorbed by the proximal tubule was not affected when the fetal RAS was blocked by captopril or losartan. High doses of infused AII had no effect on renal reabsorption of sodium, in the short term, but in the long term depressed fractional proximal reabsorption. 6. Only in high doses does AII stimulate the secretion of aldosterone from the fetal adrenal. 7. Since the fetal RAS is responsible for maintenance of GFR and physiological levels of AII do not stimulate either proximal tubular sodium reabsorption nor aldosterone secretion, it is proposed that during intra-uterine life the fetal RAS maintains the renal excretion of sodium and water into the amniotic cavity, thus ensuring an adequate volume of amniotic fluid for normal growth and development.     

VASOCONSTRICTOR RESPONSES TO COMPONENTS OF THE RENIN-ANGIOTENSIN SYSTEM IN CYCLOSPORIN-INDUCED HYPERTENSION IN THE RAT

1. Since plasma renin activity is increased in cyclosporin A (CsA)-induced hypertension in the rat, the role of the vascular renin-angiotensin system (RAS) in CsA-induced hypertension was investigated in rat mesenteric resistance vessels. 2. Female Wistar rats received CsA (10 mg/kg per day, s.c.) or vehicle for 30 days. CsA treatment increased tail-cuff systolic blood pressure (CsA treated 135 ± 3 mmHg vs control 125 ± 1 mmHg, P<0.0001). 3. Mesenteric resistance arteries (200–300 μm) were isolated and mounted in a microvessel myograph. Concentration-response curves to tetradecapeptide renin substrate (10-¹¹-10^?6 mol/L), angiotensin I (10-^l1-10^?6 mol/L) and angiotensin II (10-¹²-10^?6 mol/L) showed no differences between CsA-treated and control groups. 4. Mesenteric vascular angiotensin-converting enzyme (ACE) characteristics were determined by radioligand binding. There were no differences in the content or affinity of ACE between CsA-treated and control rats. 5. These results suggest that the mesenteric vascular RAS does not play a major role in CsA-induced hypertension in the rat.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: TRANSGENIC RATS: TOOLS TO STUDY THE FUNCTION OF THE RENIN-ANGIOTENSIN SYSTEM

• 1 The development of the transgenic technology for the rat allowed the evaluation of gene functions in the cardiovascular system in vivo. New insights have been gained particularly in the functions of the renin-angiotensin system (RAS), as most transgenic rat models established so far carry genes of this system.
• 2 TGR(mREN2)27 is a rat harbouring the mouse Ren-2 gene and exhibiting fulminant hypertension. The plasma RAS in this animal is down-regulated; however, the tissue-specific production of angiotensin II is activated (e.g. in the adrenal gland, the brain and the vessel wall). The physiological consequences of this activation, which finally leads to hypertension, can be studied in TGR(mREN2)27, rendering it a valuable tool in the functional analysis of tissue RAS.
• 3 TGR(hREN) and TGR(hAOGEN) carry the human genes for renin and angiotensinogen, respectively. In these animals the species-specific interaction of the two proteins and the expression pattern of the genes can be studied. Furthermore, these animals can be used to test renin-inhibitory drugs for use in antihypertensive therapy.
• 4 Further refinement of transgenic methodology (e.g. by the development of gene targeting in rats), should enhance our understanding of the functions of the RAS in cardiovascular regulation.

     

ANTEROVENTRAL WALL OF THE THIRD VENTRICLE AND DORSAL LAMINA TERMINALIS: HEADQUARTERS FOR CONTROL OF BODY FLUID HOMEOSTASIS?

1. The subfornical organ, median preoptic nucleus and the organum vasculosum of the lamina terminalis (OVLT) are a series of structures situated in the anterior wall of the third ventricle and form the lamina terminalis. The OVLT and ventral part of the median preoptic nucleus are part of a region known as the anteroventral third ventricle region.
2. Data from many laboratories, using techniques ranging from lesions, electrophysiology, neuropharmacology, Fos expression, immunohistochemistry and receptor localization, indicate that the tissue in the lamina terminalis plays a major role in many aspects of body fluid and electrolyte balance.
3. The subfornical organ and OVLT lack the blood-brain barrier and detect alterations in plasma tonicity and the concentrations of circulating hormones such as angiotensin II and possibly atrial natriuretic peptide and relaxin.
4. This information is then integrated within the lamina terminalis (probably in the median preoptic nucleus) with neural signals from other brain regions. The neural output from the lamina terminalis is distributed to a number of effector sites including the paraventricular (both parvo- and magno-cellular parts) and supraoptic nuclei and influences vasopressin secretion, water drinking, salt intake, renin secretion, renal sodium excretion and cardiovascular regulation.