Changes In Angiotensin Research Articles

Humoral regulation during cold-induced coronary arterial spasm

Previous attempts to define the etiology of coronary arterial spasm have been focused on mechanisms such as autonomic nervous dysfunction and/or enhanced platelet activation. In the present study, humoral regulation was investigated in patients with vasospastic angina and scintigraphically documented transient myocardial perfusion abnormalities after a peripheral cold pressor test. Serial changes in angiotensin II, epi- and norepinephrine as well as thromboxane B2 (the stable derivate of thromboxane A2), and malondialdehyde were determined at baseline (I), immediately after 5 minutes cold water hand immersion (II), and following 10 minutes recovery (III). Angiotensin II and epinephrine remained unchanged during observation (I vs II, II vs III: P = NS). Norepinephrine was elevated after cold (I vs II: P < 0.001) and normalized after 10 minutes (I vs III: P = ns). Thromboxane B2 and malondialdehyde increased continuously (I vs III: P < 0.05 and I vs III: P < 0.002, respectively). Further radiothin-layer chromatography results indicate an activation of platelet function during myocardial ischemia. Our results do not establish a cause-effect relationship but, together with other evidence, they may suggest that thromboxane A2 is unlikely to be the cause of spasm. It might, however, play an important role in the maintenance of vasoconstriction.

Sympathetic modulation of renal hemodynamics, renin release and sodium excretion.

In anesthetized animals it has been shown previously, that the influence of electrical stimulation of efferent renal nerves on renal function with increasing stimulation frequencies can be graded; renin release is affected at low, sodium excretion at intermediate and vascular resistance at high stimulation frequencies. Experiments in conscious dogs are reviewed, which present evidence for a similar functional dissociation under physiological conditions. Moderate activations of the renal sympathetic nerves, which do not change renal blood flow 1) decrease sodium excretion independent of changes in angiotensin II, 2) interact with the pressure-dependent mechanism of renin release by resetting its threshold pressure and 3) modulate autoregulation by increasing the lower limits of glomerular filtration rate and renal blood flow-autoregulation. These findings may contribute to our understanding of the role of the renal nerves in the pathophysiology of congestive heart failure and hypertension.

Increased angiotensin II receptor binding with age in isolated rat glomeruli

The current investigation was performed to determine whether there are changes in the renin-angiotensin system with increasing age in rats. Experiments were performed on male Sprague-Dawley rats (50 to 165 days old). There were no changes in plasma renin activity or angiotensin II concentrations, but the number of angiotensin II binding sites in isolated glomeruli increased with increasing age (r = 0.87, P less than 0.01). Since rat weight varies directly with age, we studied the possibility that the increase in receptor number was due to changes in glomerular morphometrics. In a separate group of experiments the diameter of isolated glomeruli was measured, and assuming spherical shape, glomerular volume and surface area were calculated. Glomerular diameter increased with age and weight of the rats (r = 0.99, P less than 0.001). There was a strong linear correlation between the changes in angiotensin II receptor number and glomerular surface area (r = 0.99, P less than 0.001). The number of receptors per unit surface area was independent of rat weight or age (1224 receptors/micron 2). To test the hypothesis that the apparent increase in glomerular angiotensin II receptor sites with increasing age was due to the shape of the glomerulus, additional binding studies were performed on membranes prepared from isolated glomeruli. There were no differences in the number of angiotensin II receptors in membranes from 63 and 112 day-old rats (888 +/- 115 vs. 925 +/- 128 fmol/mg). In additional experiments the effects of increasing age on angiotensin modulation of renal function were studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogen effects on angiotensin receptors are modulated by pituitary in female rats

The present studies were designed to test the hypothesis that changes in angiotensin II (ANG II) receptors might modulate the altered target tissue responsiveness accompanying estradiol administration. Estradiol was infused continuously in oophorectomized female rats by employing minipumps to achieve plasma estradiol levels and simulating pregnancy levels in the rat. Aldosterone was also infused in control and experimental animals to avoid estrogen-induced changes in renin and ANG II. ANG II binding constants were determined in radioreceptor assays. Estradiol increased binding site concentration in adrenal glomerulosa by 76% and decreased binding sites of uterine myometrium and glomeruli by 45 and 24%, respectively. There was an accompanying increase in the affinity of ANG II binding to adrenal glomerulosa and uterine myometrium. Because estrogen is a potent stimulus of prolactin release from the pituitary of rodents, studies were also designed to test the hypothesis that prolactin may mediate some or all of the estrogen-induced effects observed. Hypophysectomy abolished estradiol stimulation of prolactin release and most ANG II receptor changes. The only effect that persisted was a 41% decrease in the density of uterine receptors. Prolactin administration to pituitary intact rats was associated with a 50% increase in receptor density of adrenal glomerulosa simulating estradiol administration. However, the changes in glomeruli and uterine myometrium were opposite in that both tissues also increased receptor density, suggesting that prolactin was not the sole mediator of the estrogen-induced receptor changes. In conclusion, regulation of ANG II receptors in a number of diverse target tissues by estradiol is complex with contributions from estrogens and pituitary factors, which include but do not exclusively involve prolactin.

Regulation of primate angiotensin II receptors during altered sodium intake.

In the rat, angiotensin II receptors of the adrenal glomerulosa and smooth muscle undergo reciprocal regulatory changes that parallel the changes in target cell sensitivity to angiotensin II during altered sodium intake. In primates, the relative importance of angiotensin II receptor regulation during sodium-induced changes in angiotensin II sensitivity is not clear. To evaluate the role of angiotensin II receptor regulation in the primate, we analyzed the changes in angiotensin II receptors of adrenal and bladder membrane-rich particles after 4 to 6 days of high or low sodium intake in the monkey (Macaca fascicularis). Consistent with the decreased pressor response to angiotensin II, smooth muscle angiotensin II receptors were fewer in sodium-restricted monkeys (93 +/- 17 fmol/mg) than in sodium-loaded monkeys (171 +/- 6 fmol/mg). However, in contrast to the rat, changes in zona glomerulosa angiotensin II receptors in monkey adrenal were similar to those in smooth muscle, decreasing with sodium restriction and increasing with sodium loading (344 +/- 64 and 660 +/- 68 fmol/mg, respectively). There was no change in angiotensin II receptor affinity in either smooth muscle or adrenal particles during altered sodium intake. Concomitant with the decrease in adrenal angiotensin II receptors, 18-hydroxylase activity was increased twofold in adrenal mitochondria from sodium-restricted monkeys (74 +/- 8 fmol/mg/min) compared with sodium-loaded animals (28 +/- 11 fmol/mg/min). The increased sensitivity of the primate adrenal to angiotensin II despite a fall in angiotensin II receptors indicates that full activation of steroidogenesis by angiotensin II can be maintained with partial receptor occupancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic hormone, the renin-aldosterone axis, and blood pressure-electrolyte homeostasis.

The renin-angiotensin-aldosterone axis exerts major control over sodium and potassium balance and arterial blood pressure. These three functions are continuously regulated by changes in angiotensin II and aldosterone levels in response to wide variations in dietary intake of sodium and potassium. In addition, changes in intrarenal physical factors cause changes in the supply of distal tubular sodium that, in turn, work to determine sodium and potassium excretion and to modulate the release of renal renin. However, certain aspects of sodium homeostasis cannot be fully explained either by the activity of the renin system or by intrarenal physical factors, and this has led investigators to search for other natriuretic hormonal mechanisms. Recently, it has become clear that atrial tissue contains a group of peptides, at least one of which is probably secreted as a regulatory hormone. In animals, these atrial peptides produce immediate, marked natriuresis associated with a rise in glomerular filtration rate (but no alteration of total renal flow) and a simultaneous decrease in arterial blood pressure. Atrial peptides also inhibit renal renin secretion and adrenal cortical secretion of aldosterone, and they oppose the vasoconstrictive action of angiotensin II. One of these atrial peptides may therefore be the long-sought natriuretic hormone, though in a different form and shape than was envisioned. The fact that atrial peptide works to oppose the renin system at four points suggests that this new hormone could have a major complementary role in long-term regulation of blood pressure and electrolyte homeostasis. In this construction the renin system primarily defends sodium balance and blood pressure, with the atrial hormone having an increasing counter-influence in situations involving high blood pressure or sodium surfeit. We can soon expect to learn more about this atrial hormone, including which peptide is the active circulating hormone, what induces or inhibits its release, and what part it plays in cardiovascular diseases.

The Changes in Angiotensin Converting Enzyme Activities to Hypertension in SHRSP and WKY

The Changes in Angiotensin Converting Enzyme Activities to Hypertension in SHRSP and WKY

Effects of Prolonged and Brief Infusions of Noradrenaline on Arterial Pressure and on the Plasma Concentrations of Active Renin, Angiotensin II, Aldosterone and Potassium

Conscious male beagle dogs were given constant intravenous infusions of noradrenaline for 14 days, four receiving 125 ng/kg/min and four 250 ng/kg/min. Before, during and after these infusions dose-response studies were done in which additional noradrenaline was infused at 500, 1000 and 2000 ng/kg/min, each rate for 1 h. Blood samples were taken before and during infusions for measurement of haematocrit and plasma concentrations of noradrenaline, active renin, angiotensin II, aldosterone, sodium and potassium. Fourteen-day infusion of noradrenaline at 125 ng/kg/min did not raise blood pressure significantly though infusion at 250 ng/kg/min did, but for the first week of infusion only. Heart rate decreased significantly at both rates. Arterial pressure fell markedly and significantly on stopping infusion. Mean plasma concentrations of renin, angiotensin II and aldosterone tended to be lower during prolonged infusion of noradrenaline, but only the fall of renin during the second week was significant in one group of dogs. Noradrenaline at higher rates significantly raised blood pressure and increased plasma concentrations of renin and angiotensin II. Plasma aldosterone concentration did not rise significantly, perhaps because plasma potassium concentration decreased; in support of this theory changes of plasma aldosterone correlated with changes of plasma potassium but not with changes of angiotensin II. The rise in arterial pressure during dose-response studies was related to the increase of plasma noradrenaline. Prolonged infusion of noradrenaline did not alter the dose-response relation between plasma noradrenaline concentration and arterial pressure.

Relationship of renal hemodynamic and functional changes following intravascular contrast to the renin-angiotensin system and renal prostacyclin in the dog.

Deterioration in renal function has been observed after the use of intravascular contrast media. In an attempt to identify factors responsible for this phenomenon, meglumine iothalamate (Conray 60), in a dosage range of 2.5-3.3 ml/kg, was injected as a bolus into the aorta of dogs. Serial measurements were made of parameters of renal function as well as of changes in aortic and renal venous levels of angiotensin II, renin activity, and 6-keto-PGF1 alpha, the stable metabolite of prostacyclin. The major findings were (1) an initial, brief increase followed by approximately a 20% sustained decrease in renal blood flow and creatinine clearance, (2) no significant changes in angiotensin II and renin levels, and (3) a significant decline in the renal secretory rate of 6-keto-PGF1 alpha. These observations suggest that the suppression of prostacyclin, rather than the activation of the renin-angiotensin system, may contribute to the renal function changes attending the use of intravascular contrast media.

Mechanism of adrenal angiotensin II receptor changes after nephrectomy in rats.

At 48 h after bilateral nephrectomy in rats there is a two- to threefold increase in the number of adrenal angiotensin II receptors and a decrease in Kd of smooth muscle angiotensin II receptors. These changes have been attributed to the absence of circulating angiotensin II. Serum K+, which increases after nephrectomy may be an important and overlooked modulator. Therefore, the present experiments were designed to assess the role of K+ as a regulator of angiotensin II receptors after nephrectomy. Serum K+ was controlled with Na polystyrene sulfonate (Kayexalate), a resin designed to exchange Na+ for K+ in the gastrointestinal tract. Acutely nephrectomized rats were divided into two groups: experimental animals received Kayexalate resin every 12 h for four doses, and controls received Kayexalate exchanged with KCl in vitro before gavage. There was a significant positive correlation serum K+ and aldosterone (r = 0.78, P less than 0.001). Kayexalate maintained a normal serum K+ of 5.9 +/- 0.2 meq/liter (n = 27), aldosterone 25 +/- 3 ng/dl (n = 27) and adrenal receptor concentration of 934 +/- 156 fmol/mg protein (n = 4). Control animals had significantly higher serum K+ of 10.5 +/- 0.4 meq/liter (n = 23), aldosterone 435 +/- 32 (n = 23), and adrenal receptors of 2726 +/- 235 fmol/mg protein (n = 4). There was a linear relationship between serum K+ and number of adrenal receptors (r = 0.87). No such relationship was present in uterine smooth muscle. Therefore, these studies demonstrate that K+ modulates the number of adrenal but not smooth muscle angiotensin II receptors after nephrectomy. This is the first evidence that potassium modulates angiotensin II receptors independently of changes in angiotensin II blood levels.

Plasma angiotensin II concentrations and experimentally induced thirst.

The systemic administration of angiotensin II or its precursors will result in increased water intake. Several manipulations that result in hypovolemia and/or hypotension (extracellular thirst challenges) are known to activate the peripheral renin-angiotensin system and also produce drinking. Although there are without question multiple mediators of thirst associated with extracellular thirst challenges, one of the major factors responsible for water intake has been hypothesized to be the action of angiotensin II. In the experimental analysis of thirst, several types of hypovolemic-hypotensive manipulations have been employed. However, there is a paucity of data available that characterize the systematic changes of angiotensin II levels following such challenges. The present studies determined plasma angiotensin II levels and drinking responses after isoproterenol administration, caval ligation, and subcutaneous polyethylene glycol treatment. The experimental protocols for treatment of the animals closely approximated conditions commonly employed in the experimental analysis of thirst. The results indicated that endogenous levels of angiotensin II increase after these treatments to levels that in all likelihood are sufficient to make a substantial contribution to the drinking response.

Hormonal and hemodynamic changes induced by pentolinium and propranolol during surgical correction of scoliosis.

Deliberate hypotension has had variable success in decreasing blood losses and facilitating extensive surgical procedures. In this study, hemodynamic variables, catecholamines, plasma renin activity, and angiotensin II levels were studied in 11 patients undergoing operative correction of idiopathic scoliosis. Deliberate hypotension with mean arterial blood pressures ranging from 55 to 42 torr was provided with the ganglionic blocking agent, pentolinium tartrate, supplemented by beta blockade with propranolol during morphine–nitrous oxide anesthesia. Stroke volume index, systemic vascular resistance, and left ventricular stroke work index decreased 16, 19, and 40 per cent, respectively, with blood pressure reduction. Following the return to normal blood pressure, stroke volume index increased to a value 28 per cent greater than control, while systemic vascular resistance remained decreased. At this time left ventricular stroke work index increased slightly, but the increase was not statistically significant compared with control. The epinephrine level had risen from 59 to 270 pg/ml an hour after hypotension, probably secondary to infiltration of the skin prior to the surgical procedure. It had decreased to control levels by the end of the procedure. Norepinephrine and dopamine concentrations and plasma renin activity were unchanged. The angiotensin II level was significantly decreased, from 60 to 40 pg/ml, during deliberate hypotension. Blood loss correlated with left ventricular stroke work index, while changes in systemic vascular resistance and heart rate correlated well with changes in angiotensin II and plasma renin activity, respectively. The ability of ganglionic blockade and propranolol to inhibit the increases in catecholamines and angiotensin II during morphine–nitrous oxide anesthesia, hypotension, and surgical intervention may be of considerable importance.

Elevation of uterine angiotensin II receptors during early pregnancy in the rat.

The concentration of uterine receptors for angiotensin II was investigated during pregnancy in the rat by measuring binding of [l25I]angiotensin II to uterine particles at each day of pregnancy. Uterine angiotensin II receptors changed markedly throughout pregnancy, following a biphasic pattern. During the first half of pregnancy, the concentration of receptors rose by 3-fold from day 2 to day 9 and returned by day 12 to values similar to those of nonpregnant control rats. During the second half of pregnancy, uterine angiotensin II receptors remained below control values until 1 day after delivery. This low binding capacity was not due to occupancy of the angiotensin receptors or to enhanced degradation of the labeled ligand. The major changes in angiotensin II receptor concentration took place in the implantation area, with little or no alterations in the adjacent myometrium. When unilateral salpingectomy was performed on day 2 of pregnancy, the concentration of angiotensin II receptors was still increas...

Intrarenal renin and angiotensins in glycerol-induced acute renal failure

Intrarenal renin and angiotensins in glycerol-induced acute renal failure. Intrarenal renin and angiotensins were measured in rats with glycerol-induced acute renal failure. Dehydrated, non-dehydrated and chronically saline-loaded animals were studied before and 1, 6, 17, 24, and 48 hours after glycerol injection. Dehydrated and nondehydrated animals had a significant increase in intrarenal renin 17 hours following glycerol injection, a time when renal failure was already established. Renal renin concentration after 3 weeks of saline-loading was significantly depressed. There was no change in intrarenal renin after the administration of glycerol in salt-loaded animals. Renal angiotensin I was unchanged early in acute renal failure in those animals which developed the syndrome (dehydrated and nondehydrated). There was, however, a marked increase 6 to 48 hours after glycerol administration. No changes were observed in the salt-loaded animals given glycerol. There was no increase in renal angiotensin II levels in all groups studied except for a small but significant increase 17 to 48 hours after glycerol administration in dehydrated animals; the magnitude of this elevation was small compared to the change in angiotensin I. Since changes in renal function preceded any change in the concentration of intrarenal renin and angiotensins, it is unlikely that angiotensins participate in the generation of this type of experimental acute renal failure. It cannot be ruled out, however, that at a later stage of acute renal failure these peptides play some role in the maintenance of the syndrome.

Role of ACTH, angiotensin and potassium in stress-induced aldosterone secretion

The relative roles of ACTH, angiotensin II and potassium concentration in aldosterone secretion have been studied, after acute jugular venous cannulation, in four conscious sheep with cervical adrenal transplants. Samples of adrenal venous blood for assay of cortisol and aldosterone secretion were drawn at 15 min intervals for 6 h, and related to samples drawn simultaneously for measurement of potassium and angiotensin. Cortisol secretion was used as an index of plasma ACTH. To assess the importance of ACTH, identical studies were repeated in each sheep, except for the addition of dexamethasone to suppress endogenous ACTH secretion. Immediately after cannulation, major fluctuations in cortisol and aldosterone secretion usually occurred together, whereas only small changes were observed in plasma potassium and angiotensin. Dexamethasone promptly reduced cortisol to undetectable levels, and appreciable but slower reductions in aldosterone were also seen, without consistent change in angiotensin or potassium concentration. The results suggest that angiotensin and potassium play a minor role in the stress related fluctuations of aldosterone secretion, which is largely determined by ACTH.

Aldosterone Production by Isolated Adrenal Glomenilosa Cells: Stimulation by Physiological Concentrations of Angiotensin II

The production of aldosterone by isolated canine zona glomerulosa cells was measured after the incubation of cell suspensions with angiotensin II and ACTH, and during changes in extracellular potassium concentration. Adrenal cell suspensions were prepared by collagenase digestion and physical dispersion of the capsular layer of the dog adrenal cortex, and aldosterone production was determined by direct radioimmunoassay of cell incubation media. The isolated dog adrenal cells were highly responsive to angiotensin II, with aldosterone production significantly stimulated by concentrations of the octapeptide as low as 10(-11)M. Thus, the steroidogenic response of zona glomerulosa cells was consistently observed at peptide concentrations within the physiological range of angiotensin II in dog plasma, i.e., 2.0-5.0 X 5.0 X 10(-11)M. The maximum aldosterone response of 3-8 times the basal level of steroid production was induced by 3 X 10(-10)M angiotensin II, and a decrease in aldosterone production occurred at peptide concentrations above 10(-9)M. The aldosterone response of isolated adrenal cells to ACTH was consistently less sensitive than their response to angiotensin II, by a factor of 10-20 fold. Aldosterone production was significantly increased by 10(-10)M ACTH, and reached a maximum at 10(-8)M ACTH. By contrast with angiotensin II, ACTH usually evoked a higher maximal level of aldosterone production, and did not produce a decline in steroidogenesis at peptide concentrations above the level which caused maximum stimulation of aldosterone formation. Changes in the potassium concentration of cell incubation media were also accompanied by marked effects upon aldosterone synthesis which was abolished in the absence of potassium and became detectable in the presence of 0.5 mM K+. After remaining constant between 2.5 and 4.0 mM K+, aldosterone production rose sharply above 4.5 mM K+ and reached a maximum at 8 mM K+. These observations provide direct evidence that aldosterone production by zona glomerulosa cells is influenced by changes in angiotensin II levels within the normal plasma range.

Effects of Low Salt Plus Upright Posture, Angiotensin II, ACTH, and Potassium upon Plasma Renin Activity, Aldosterone, and Cortisol

In order to study the control system of plasma aldosterone in human, we examined the effects of low salt plus upright posture, angiotensin II, ACTH and potassium upon plasma renin activity, aldosterone and cortisol in five subjects who were supposed to be normal. All of the procedures, low salt diet with below 3 g of salt and 2 hr-upright posture, 0.25 mg of Cortrosyn, angiotensin infusion to increase 20 mmHg of diastolic pressure for an hour, and 30 mEq of potassium infusion stimulated plasma aldosterone significantly. Furthermore, in each subject the degrees of response to each of these stimulations were almost same.In an old woman aged 68, responses to all of stimulations were significantly lower than those in other subjects.Plasma cortisol was significantly stimulated by ACTH, but slightly reduced by potassium infusion. From these results, it is certain that plasma aldosteron levels are easily affected by a small amount of changes in angiotensin, ACTH, potassium and sodium. However, responses of aldosterone to these changes seem to be decreased in old subjects.

RAISED PLASMA ANGIOTENSIN II AND ALDOSTERONE DURING DIETARY SODIUM RESTRICTION IN MAN

Dietary sodium restriction in five normal subjects led to highly significant increases of plasma-angiotensin-II after 2 days. These changes became even more pronounced after 4 and 5 days. There were parallel increases in plasma-aldosterone. Both angiotensin II and aldosterone returned to control values after sodium repletion. There was a significant positive correlation between concurrent measurements of plasma-aldosterone and plasma-angiotensin-II, and a significant inverse correlation between concurrent plasma-aldosterone and serum-sodium. These findings differ from two other studies of similar design, where dietary sodium restriction produced no detectable change in angiotensin II, despite in one instance a pronounced increase in aldosterone similar to that observed in this study.

Evaluation of angiotension II metabolism in sheep by radioimmunoassay.

The immunoreactive material detected in sheep arterial blood by the radioimmunoassay procedure was shown to be predominantly the octapeptide angiotensin II and to be the valine-5 form. Levels in venous blood were 60% of arterial. A reasonably proportionate relationship was demonstrated between angiotensin II and sodium loss and renin during the onset of sodium deficiency. Following a single injection of angiotensin II into sheep, the biological half-life of the peptide was found to be less than 1 min. The change in blood pressure after injection of the angiotensin II closely followed the change in angiotensin II concentration determined by the immunoassay. Continuous infusion of angiotensin II until plateaued levels were reached allowed calculation of the blood clearance rate, which was approximately 100 1/hr. Knowledge of the blood clearance rate allowed calculation of angiotensin II production rates during sodium deficiency and following renin infusion. A linear relationship existed between the differen...

The dynamics of the renin-angiotensin system

We have used the blood-bathed organ technique (Vane 1964) to study the liberation of renin into the bloodstream and the subsequent formation of angiotensin I and angiotensin II. The rat isolated colon was superfused (Gaddum 1953) continuously with heparinized blood from dogs, to detect changes in angiotensin II concentration in the blood (Regoli &amp; Vane 1964, 1966). The release of renin from the kidney can be induced either by a large fall in perfusion pressure (Skinner, McCubbin &amp; Page 1963; Regoli &amp; Vane 1966) or by haemorrhage (Scornik &amp; Paladini 1964) The fact that a slow haemorrhage can induce secretion of renin without a fall in arterial blood pressure (Hodge, Lowe &amp; Vane 1966 a ) led to experiments which showed that secretion of renin is under reflex control; one afferent limb of the reflex probably originates in stretch receptors in the venous or low pressure side of the circulation and is mediated by afferent nerves in the vagus. The efferent pathway is the renal sympathetic supply (Hodge, Lowe &amp; Vane 1966 a , b ).