Effects of angiotensin II on arterial pressure, renin and aldosterone during exercise

To evaluate the effect of isotonic exercise on the response to angiotensin II, angiotensin II in saline solution was infused intravenously (7.5 ng X kg-1 X min-1) in seven normal sodium replete male volunteers before, during and after a graded uninterrupted exercise test on the bicycle ergometer until exhaustion. The subjects performed a similar exercise test on another day under randomized conditions when saline solution only was infused. At rest in recumbency angiotensin II infusion increased plasma angiotensin II from 17 to 162 pg X ml-1 (P less than 0.001). When the tests with and without angiotensin II are compared, the difference in plasma angiotensin II throughout the experiment ranged from 86 to 145 pg X ml-1. The difference in mean intra-arterial pressure averaged 17 mmHg at recumbent rest, 12 mmHg in the sitting position, 9 mmHg at 10% of peak work rate and declined progressively throughout the exercise test to become non-significant at the higher levels of activity. Plasma renin activity rose with increasing levels of activity but angiotensin II significantly reduced the increase. Plasma aldosterone, only measured at rest and at peak exercise, was higher during angiotensin II infusion; the difference in plasma aldosterone was significant at rest, but not at peak exercise. In conclusion, the exercise-induced elevation of angiotensin II does not appear to be an important factor in the increase of blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

[DES-ASP1] angiotensin II in the sheep: Blood levels and its effect on plasma renin concentration

The present study describes an improved method for measuring angiotensin III in arterial blood. This was accomplished by SE-sephadex column to separate angiotensin II from angiotensin III prior to radioimmunoassay. The arterial concentration of angiotensin III measured before and after 24 to 48 hours sodium depletion by acute cannulation of parotid gland was 12.4 ± 1.7 fmol/ml (SEM, n=7) and 49.8 ± 10.3 fmol/ml (SEM, n=7) respectively. The arterial concentration of Val⁴-angiotensin III obtained from continuous infusion of Val⁴-angiotensin III at rates of 24 and 48 nmol/h in sodium deficient sheep were 245 ± 32.5 fmol/ml (n=6) and 330 ± 11.4 fmol/ ml (n=7) respectively. The clearance rate of exogenous Val⁴-angiotensin III in sodium deficient sheep after correction for endogenous level was calculated to be 140 ± 13.6 L/h (SEM, n=13). This was in the same order as Ile⁵-angiotensin II and Ile⁴-angiotensin III reported earlier in sodium replete sheep. Prolonged intravenous infusion of Val⁴-angiotensin III at a rate of 48 nmol/h in sodium- deficient sheep suppressed plasma renin concentration to the same extent as equimolar infusions of angiotensin II. This suggests that angiotensin III may inhibit renin secretion by a similar mechanism to angiotensin II.     

Influence of season on plasma antidiuretic hormone, angiotensin II, aldosterone and plasma renin activity in young volunteers

We investigated seasonal changes in hormonal and thermoregulatory responses. Eight volunteers were subjected to the experiment at four times of the year: around the vernal and autumnal equinoxes, and at the summer and winter solstices at latitude 35° N. Plasma antidiuretic hormone (ADH), angiotensin II (ANG II), aldosterone (ALD) and plasma renin activity (PRA) were analyzed before and after water immersion. Seasonal changes in thermoregulatory responses were assessed by measuring core temperature and sweat rate during immersion of the leg in hot water (at 42°C) for 30 min in a room maintained at 26°C. The concentration of plasma ADH and ALD before water immersion was significantly higher in summer than in other seasons. The concentrations of ANG II and PRA did not show seasonal variations. Changes in tympanic temperature during water immersion showed significant differences between seasons, and were higher in winter than in other seasons. The sweat rate was significantly higher in summer than in other seasons. In summary, ADH and ALD concentrations displayed a seasonal rhythm with marked elevation in summer; this may be a compensative mechanism to prevent dehydration from increased sweat loss during summer due to heat acclimatization.     

Effects of static magnetic fields on plasma levels of angiotensin II and aldosterone associated with arterial blood pressure in genetically hypertensive rats

Effects of static magnetic fields (SMFs) on development of hypertension were investigated using young male, stroke resistant, spontaneously hypertensive rats (SHRs) beginning at 7 weeks of age. SHRs were randomly assigned to two different exposure groups or an unexposed group. The SHRs in the exposure groups were constantly exposed to two different types of external SMFs of 3.0-10.0 mT or 8.0-25.0 mT for 12 weeks. The SMFs were generated from permanent magnetic plates attached to the rat cage. The blood pressure (BP) of each rat was determined at weekly intervals using indirect tail-cuff method. The SMFs suppressed and retarded the development of hypertension in both exposed groups to a statistically significant extent for several weeks, as compared with an unexposed group. The antipressor effects were related to the extent of reduction in plasma levels of angiotensin II and aldosterone in the SHRs. These results suggest that the SMFs of mT intensities with spatial gradients could be attributable to suppression of early BP elevation via hormonal regulatory system.     

Sarcosine1,glycine8 angiotensin II is an AT1 angiotensin II receptor subtype selective antagonist

Studies predating the discovery of the two major subtypes of angiotensin II (Ang II) receptors, AT1 and AT2, revealed anomalous characteristics of sarcosine1,glycine8 Ang II (Sar1,Gly8 Ang II). It competed poorly for 125I-Ang II binding in bovine brain but potently antagonized dipsogenic responses to intracerebroventricularly administered Ang II. Subsequent recognition that bovine brain contains AT(2) receptors, while dipsogenic responses to Ang II are mediated by AT1 receptors, suggests that Sar1,Gly(8) Ang II is AT1 selective. Sar1,Gly8 Ang II competed for 125I-sarcosine1,isoleucine8 Ang II binding to AT1 receptors in pituitary, liver and adrenal (the latter with the AT2 selective antagonist PD 123,319) with Ki's of 0.66, 1.40 and 1.36 nM, respectively. In contrast, the Ki of Sar1,Gly8 Ang II for AT2 receptors in rat adrenal (with the selective AT1 antagonist losartan) was 52 nM. 125I-Sar1,Gly8 Ang II (0.5-3 nM) bound to AT1 receptors in pituitary, liver, heart, adrenal, and hypothalamic membranes with high affinity (Kd=0.43, 1.6, 2.3, 0.96 and 1.8 nM, respectively), but showed no saturable binding to the adrenal AT2 receptor. 125I-Sar1,Gly8 Ang II selectively labeled AT1 receptors in sections of adrenal using receptor autoradiography. Thus, binding studies reveal Sar1,Gly8 Ang II to be the first angiotensin peptide analog to show AT1 receptor selectivity. 125I-Sar1,Gly8 Ang II offers a new means to selectively radiolabel AT1 receptors and may help to characterize ligand docking sites and agonist switches for AT1 versus AT2 receptors.     

Effects of acute exercise and prolonged exercise training on blood pressure, vasopressin and plasma renin activity in spontaneously hypertensive rats

The purpose of this study was to investigate the effect of swimming training on systolic blood pressure (BPs), plasma and brain vasopressin (AVP), and plasma renin activity (PRA) in spontaneously hypertensive rats (SHR) during rest and after exercise. Resting and postexercise heart rate, as well as blood parameters such as packed cell volume (PCV), haemoglobin concentration (Hb), plasma sodium and potassium concentrations ([Na+], [K+]) osmolality and proteins were also studied. Hypophyseal AVP had reduced significantly after exercise in the SHR, whereas PRA had increased significantly in the Wistar-Kyoto (WKY) strain used as normotensive controls. Plasma AVP concentration increased in both strains. By the end of the experiment, training had reduced body mass and BPs by only 10% and 6%, respectively. Maximal oxygen uptake was increased 10% and plasma osmolality 2% by training. The postexercise elevation of heart rate was not significantly attenuated by training. A statistically significant reduction in postexercise plasma osmolality (10%) and [Na+] (4%) was observed. These results suggested that swimming training reduced BPs. Plasma and brain AVP played a small role in the hypertensive process of SHR in basal conditions because changes in AVP contents did not correlate with those of BPs. Moreover, there were no differences between SHR and WKY in plasma, hypophyseal and hypothalamic AVP content in these basal conditions. Finally, during moderate exercise a haemodilution probably occurred with an increase of plasma protein content. This was confirmed by the exercise-induced increase of plasma AVP and the reduction of hypophyseal AVP content, suggesting a release of this hormone, which probably contributed to the water retention and haemodilution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of captopril (SQ 14225) on blood pressure,plasma renin activity and angiotensin I converting enzyme activity.

Seven patients with essential hypertension and seven patients with hypertension associated with renal artery stenosis received captopril (SQ 14225), an inhibitor of angiotensin I converting enzyme. There was a significant reduction in mean blood pressure, from 176/113 +/- 4/3 mm Hg during the control period to 140/90 +/- 5/3 mm Hg during captopril administration. Five patients received captopril alone and nine patients needed hydrochlorothiazide in addition to control their blood pressure. Captopril produced a significant increase in peripheral plasma renin activity. When measured 12 hours after the administration of captopril the angiotensin I converting enzyme activity was found to be similar to that during the control period even though the blood pressure was at or near normal. These findings indicate that although captopril is an effective antihypertensive agent, its action does not depend only on inhibition of plasma angiotensin I converting enzyme activity.     

The effect of naloxone on blood pressure, heart rate, plasma catecholamines, renin activity and aldosterone following exercise in healthy males

There is evidence that endogenous opioids are involved in blood pressure regulation. In the present study the effect of naloxone on the cardiovascular, sympathoadrenomedullary and renin-aldosterone response to physical exercise was investigated in 8 healthy males. Each subject performed a submaximal work test twice, i.e. with and without naloxone. The test consisted of ergometer bicycling for 10 minutes on 50% of the maximal working capacity (MWC), immediately followed by 10 min on 80% of MWC. Ten minutes before exercise the subjects received in a single blind randomized order a bolus dose of naloxone (100 micrograms/kg) or a corresponding volume of the preservatives of the naloxone preparation (control) followed by a slow infusion of naloxone (50 micrograms/kg/h) or preservatives, respectively. Naloxone was without effect on the exercise-induced changes in systolic blood pressure, heart rate, plasma noradrenaline, renin activity and aldosterone, but the adrenaline response increased markedly. The present results indicate that opioid receptors are involved in the plasma adrenaline response to submaximal exercise, but not in the regulation of systolic blood pressure, heart rate, plasma noradrenaline, renin activity and plasma aldosterone.     

Effects of water intake on variations of plasma renin activity (PRA) and blood aldosterone during physical exercise in man]

In man, increase of renin and aldosterone levels in sera resulting from a brief and heavy muscular exercise on bicyle ergometer is notably reduced but not abolished by massive hydration.     

Reduction of blood clearance rate of [Val5] angiotensin II by [Sar1, ILE8] angiotensin II in sheep

The present study examines the effect of [Sar¹, Ile⁸] angiotensin II ([Sar¹, Ile⁸] ANG II) on the blood clearance rate of [Val⁵] angiotensin II ([Val⁵] ANG II) in conscious, sodium-replete sheep. Animals were infused simultaneously with [Val⁵] ANG II and [Sar¹, Ile⁸] ANG II at a rate of 42 nmol/h and 6 μmol/h respectively. Blood [Val⁵] ANG II was quantitatively determined with care taken in separating [Val⁵] ANG II from [Sar¹, Ile⁸] ANG II prior to radioimmunoassay. The blood clearance rate of [Val⁵] ANG II calculated from infusion rate/blood concentration was significantly different before and during [Sar¹, Ile⁸] ANG II infusion, being 141 ± 13 L/h (n = 12) and 95 ± 10 L/h (n = 12) respectively. Plasma renin concentration remained suppressed after the commencement of [Sar¹, Ile⁸] ANG II infusion. $\text{In-vitro}$ studies showed no significant decrease in the rate of degradation of [Val⁵] ANG II in blood in the presence of [Sar¹, Ile⁸] ANG II. Possible interpretation of this reduction of blood clearance rate of [Val⁵] ANG II by 45 ± 15 L/h (n = 6) was discussed.     

Various effects of angiotensin II on amygdaloid neuronal activity in normotensive control and hypertensive transgenic [TGR(mREN-2)27] rats.

The effects of iontophoretically ejected angiotensin II (Ang II) on the firing rate of neurons in the basolateral complex and the central and cortical amygdala were investigated in two strains of urethane anesthetized rats. In normotensive Sprague-Dawley rats, Ang II induced a significant increase in the discharge rate of responsive amygdaloid neurons. In contrast, in the hypertensive transgenic [TGR(mREN-2)27] rats with higher brain Ang II level, Ang II more often caused inhibitory effects on the amygdaloid firing rate in comparison with controls. The distribution of nonresponsive, excited, and inhibited neurons differed significantly in the two rat strains. Moreover, the responsiveness of amygdaloid neurons was significantly higher in transgenic rats in comparison with controls. Both the increase and the decrease in the firing rate caused by Ang II could be blocked either by angiotensin AT(1) or by AT(2) receptor-specific antagonists. In many cases, the Ang II-induced decrease in the firing rate was antagonized by bicuculline, a gamma-aminobutyric acid (GABA(A)) antagonist. The higher responsiveness of amygdaloid neurons in transgenic rats as well as the predominance of inhibitory effects, presumedly mediated by GABAergic interneurons, could change the output of the amygdala and its influence on thirst, kidney, and cardiovascular function or on processes of learning and anxiety.     

Effects of angiotensin II on the spontaneous activity of rostral ventrolateral medullary cardiovascular neurons and blood pressure in spontaneously hypertensive rats

The interactive role of rostral ventrolateral medulla (RVL) cardiovascular neurons and brain angiotensin II (Ang II) in regulating the arterial blood pressure was examined by recording simultaneously the spontaneous activity of these spinal projecting neurons and the arterial blood pressure in the pentobarbital-anesthetized spontaneously hypertensive rat (SHR) and its normotensive control, the Wistar Kyoto rat (WKY). It was found that Ang II elicited dose-dependent excitatory responses in a subpopulation of RVL cardiovascular neurons, followed by a subsequent increase in blood pressure. These effects of Ang II were significantly greater in SHR than in WKY. The effects were attenuated or abolished by co-administration of Ang II antagonist, [Sar¹, Ile⁸]-Ang II. Pre-administration of [Sar¹, Ile⁸]-Ang II to RVL using bilateral microinjection attenuated the blood pressure effects of intracerebroventricularly administered Ang II by as much as 70%. These results indicated that spinal projecting RVL cardiovascular neurons are important in mediating the pressor action of Ang II. The enhanced sensitivity and responsiveness of RVL cardiovascular neurons to Ang II may be pertinent to the genesis of hypertension in adult SHR.     

Biological activity of the novel cyclic angiotensin II analogue [Sar1,Lys3,Glu5]ANG II

Summary This study was undertaken to investigate the biological activity of the cyclic amide-linked analogue of angiotensin II (ANG II), [Sar¹,Lys³,Glu⁵]ANG II, in both ex vivo and in vivo experiments. This constrained analogue was designed on the basis of a recently suggested conformational model for ANG II-induced receptor activation, which is characterized by a Tyr-Ile-His backbone bend and the clustering of the three aromatic rings (Tyr, His, Phe). After [Sar¹,Lys³,Glu⁵]ANG II was found to have contractile activity (15% of ANG II in the rat uterus assay), it was administered in anesthetized rabbits where it produced an immediate and dose-dependent increase in blood pressure, which peaked within minutes, was sustained as long as the drug was given, and was gradually returned to baseline after discontinuation of the drip. The blood pressure response to the cyclic analogue was of less magnitude compared to that elicited by an isovolemic and equimolar solution of ANG II. These data confirm the importance of a properly oriented ring cluster, allowing the charge-relay conformation proposed for ANG II.     

Effects of continuous angiotensin I-converting enzyme blockade on blood pressure, sympathetic activity and renin-angiotensin system in stroke-prone spontaneously hypertensive rats

The purpose of this study was to examine the effects of continuous angiotensin converting enzyme (ACE) blockade in stroke-prone spontaneously hypertensive rats (sp-SHR) on the renin-angiotensin system and on sympathetic activity. The pressor response to angiotensin II (AII) and norepinephrine (NE) were also examined after chronic blockade of ACE and compared to that of saline-treated controls. Captopril treatment had no effect on body weight. Serum ACE was significantly reduced on day 1; an effect that persisted through day 6 and day 10. Plasma renin activity (PRA) was elevated significantly on day 1 and remained at this high level throughout the 10 day observation period. Plasma NE was not altered by the chronic ACE blockade except on day 1, where there was a slight elevation of plasma NE in both groups. Pressor responses to AII and NE were not changed after chronic captopril treatment. It is observed that chronic inhibition of the renin-angiotensin system with captopril in sp-SHR resulted in a reduction of blood pressure, reduced serum ACE activity and elevated PRA. The constant plasma NE levels suggest that chronic inhibition of the renin-angiotensin system does not affect sympathetic activity. This study also indicates that long term inhibition of ACE does not alter pressor responses to either AII or NE.     

A comparative study of plasma renin activity, aldosterone and atrial natriuretic hormone between normotensive and hypertensive people living at below sea level altitude (Jordan Valley) and those residing at moderate altitude above

A cross-sectional study was designed to investigate the association of the levels of plasma renin activity (PRA) and aldosterone (ALDO) and atrial natriuretic hormone (ANH) with the rates of hypertension prevalence in people living at 340 meters below sea level, the Jordan Valley (JV) and those residing at 620 meters above sea level, Irbid City. 1072 natives from the JV and 1402 natives from Irbid City were covered by a questionnaire to estimate hypertension prevalence in the JV and Irbid city (population age: 35-65 years). Male subjects were selected from the JV (24 hypertensives, 46+/-15 years old, and 93 normotensives, 33+/-13 years old) and from Irbid City (31 hypertensives, 47+/-12 years old, and 89 normotensives, 40+/-13 years old) to evaluate the levels of PRA, ALDO and ANH. Hypertension was less common in the JV than in Irbid City (9.9% vs. 13.6%). The levels of PRA in the hypertensive subjects compared to the normotensive subjects were lower in the JV (1.7+/-1.0 vs. 2.6+/-1.4 ng/ml/hr) but were similar in Irbid City (2.9+/-2.7 vs. 3.2+/-2.7). The levels of ALDO in the hypertensive subjects compared to the normotensive subjects were similar in the JV (119+/-58 vs. 139+/-66 pg/ml) but were higher in Irbid City (199+/-112 vs. 146+/-84). The levels of ANH in the hypertensive subjects compared to the normotensive subjects were lower in the JV (13.9+/-9.3 vs. 28.0+/-12.7 ng/ml) and were also lower in Irbid City (21.0+/-12.2 vs. 26.7+/-11.6).     

Importance of the N-terminal domain of the type I angiotension II antagonist [Sar1,Ile8]ANG II for receptor blockade

Analogues of the Type I angiotensin (ANG) antagonist, [Sar1,Ile8]ANG II, in which the N-terminal dipeptide was modified were synthesized by the solid phase method and purified by reversed-phase HPLC. Antagonist potencies (pA2) of the peptides were determined on the rat isolated uterus using ANG II as the agonist. Substitution of the Arg residue occupying position 2 of [Sar1,Ile8]ANG II (pA2 8.1) by Gly, Ala, Nle, Phe, Pro or Sar reduced the antagonist potency to pA2 = 7.0, 6.8, 6.7, 6.8, 5.8 and 5.3, respectively. Deletion of the N-terminal Sar residue in these same peptides gave pA2 = 6.8, 5.7, 5.5, 5.9, 6.1 and 7.5, respectively. The characteristically long duration of action of [Sar1,Ile8] was absent for all of these analogues including (des1, Sar2, Ile8]ANG II. These findings demonstrate that the antagonist potencies of Type I angiotensin antagonists for smooth muscle receptors, and also the long duration of action, are dependent on the location of positive charges within the peptide and on the conformation of the molecule in determining favorable electrostatic interactions with the receptor. A model is proposed in which the two positively charged loci on the angiotensin molecule (N-terminus and Arg) interact with two corresponding anionic binding sites on the smooth muscle receptor. The possibility that the prolonged duration of action of [Sar1, Ile8]ANG II results from binding to a different site on the angiotensin receptor from that occupied by ANG II is discussed in relation to the present findings.     

Effects of oral and intravenous fat load on blood pressure, endothelial function, sympathetic activity, and oxidative stress in obese healthy subjects

We compared the effects of high and low oral and intravenous (iv) fat load on blood pressure (BP), endothelial function, autonomic nervous system, and oxidative stress in obese healthy subjects. Thirteen obese subjects randomly received five 8-h infusions of iv saline, 20 (32 g, low iv fat) or 40 ml/h intralipid (64 g, high iv fat), and oral fat load at 32 (low oral) or 64 g (high oral). Systolic BP increased by 14 ± 10 (P = 0.007) and 12 ± 9 mmHg (P = 0.007) after low and high iv lipid infusions and by 13 ± 17 (P = 0.045) and 11 ± 11 mmHg (P = 0.040) after low and high oral fat loads, respectively. The baseline flow-mediated dilation was 9.4%, and it decreased by 3.8 ± 2.1 (P = 0.002) and 4.1 ± 3.1% (P < 0.001) after low and high iv lipid infusion and by 3.8 ± 1.8 (P = 0.002) and 5.0 ± 2.5% (P < 0.001) after low and high oral fat load, respectively. Oral and iv fat load stimulated oxidative stress, increased heart rate, and decreased R-R interval variability. Acute iv fat load decreased blood glucose by 6-10 mg/dl (P < 0.05) without changes in insulin concentration, whereas oral fat increased plasma insulin by 3.7-4.0 μU/ml (P < 0.01) without glycemic variations. Intravenous saline and both oral and iv fat load reduced leptin concentration from baseline (P < 0.01). In conclusion, acute fat load administered orally or intravenously significantly increased blood pressure, altered endothelial function, and activated sympathetic nervous system by mechanisms not likely depending on changes in leptin, glucose, and insulin levels in obese healthy subjects. Thus, fat load, independent of its source, has deleterious hemodynamic effects in obese subjects.     

The beta-arrestin pathway-selective type 1A angiotensin receptor (AT1A) agonist [Sar1,Ile4,Ile8]angiotensin II regulates a robust G protein-independent signaling network

The angiotensin II peptide analog [Sar(1),Ile(4),Ile(8)]AngII (SII) is a biased AT(1A) receptor agonist that stimulates receptor phosphorylation, β-arrestin recruitment, receptor internalization, and β-arrestin-dependent ERK1/2 activation without activating heterotrimeric G-proteins. To determine the scope of G-protein-independent AT(1A) receptor signaling, we performed a gel-based phosphoproteomic analysis of AngII and SII-induced signaling in HEK cells stably expressing AT(1A) receptors. A total of 34 differentially phosphorylated proteins were detected, of which 16 were unique to SII and eight to AngII stimulation. MALDI-TOF/TOF mass fingerprinting was employed to identify 24 SII-sensitive phosphoprotein spots, of which three (two peptide inhibitors of protein phosphatase 2A (I1PP2A and I2PP2A) and prostaglandin E synthase 3 (PGES3)) were selected for validation and further study. We found that phosphorylation of I2PP2A was associated with rapid and transient inhibition of a β-arrestin 2-associated pool of protein phosphatase 2A, leading to activation of Akt and increased phosphorylation of glycogen synthase kinase 3β in an arrestin signalsome complex. SII-stimulated PGES3 phosphorylation coincided with an increase in β-arrestin 1-associated PGES3 and an arrestin-dependent increase in cyclooxygenase 1-dependent prostaglandin E(2) synthesis. These findings suggest that AT(1A) receptors regulate a robust G protein-independent signaling network that affects protein phosphorylation and autocrine/paracrine prostaglandin production and that these pathways can be selectively modulated by biased ligands that antagonize G protein activation.