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PubMed2000

Intrarenal angiotensin II augmentation in angiotensin II dependent hypertension.

In several models of angiotensin II (ANG II) dependent hypertension, intrarenal ANG II levels increase to a much greater extent than the circulating levels even though the renal renin levels are decreased. The 2-kidney-1-clip (2K1C) Goldblatt rat model is particularly intriguing because hypertension develops in the presence of an intact kidney which would be expected to maintain sodium balance and protect against hypertension. Although the non-clipped kidney becomes renin depleted, it exhibits enhanced microvascular reactivity and increased tubular fractional sodium reabsorption. The non-clipped kidney ANG II content is either elevated or unchanged and proximal tubular fluid ANG II concentrations are not suppressed compared to the nanomolar concentrations found in normal rats. These results suggest that intrarenal ANG II content can be regulated independently of renal renin content. A similar hypertensive process occurs in rats infused chronically with low doses of ANG II. Renal ANG II content increases over 14 days to a greater extent than the circulating concentrations. Functionally, ANG II infused rats demonstrate reduced sodium excretion and marked suppression of pressure natriuresis. These ANG II dependent influences on kidney function contribute to the maintenance of hypertension. Renal augmentation of ANG II, hypertension, and suppressed sodium excretion are blocked by AT1 receptor blockers. To study the mechanisms responsible for intrarenal ANG II augmentation, we infused a different form of ANG II (Val5 ANG II), that can be separated from endogenous ANG II by HPLC. These results indicated that the increased renal ANG II content was due to accumulation of circulating ANG II in addition to continued production of endogenous ANG II. The renal accumulation of Val5-ANG II was markedly reduced by concomitant treatment with the AT1 receptor blocker, losartan. In addition, we found an unchanged overall ANG II-AT1 receptor protein which probably contributes to the maintained ANG II dependent influences. Collectively, the data support the concept that there is internalization of ANG II through an AT1 receptor mediated process and that some of the internalized ANG II is protected from degradation. The augmented intrarenal ANG II coupled with sustained levels of AT1 receptors contribute to the continued ANG II dependent suppression of renal function and sodium excretion thereby maintaining the hypertension.

Angiotensin II↗
PubMed2005

Mechanism of induction of muscle protein degradation by angiotensin II.

Angiotensin I and II have been shown to directly induce protein degradation in skeletal muscle through an increased activity and expression of the ubiquitin-proteasome proteolytic pathway. This investigation determines the role of the nuclear transcription factor nuclear factor-kappaB (NF-kappaB) in this process. Using murine myotubes as a surrogate model system both angiotensin I and II were found to induce activation of protein kinase C (PKC), with a parabolic dose-response curve similar to the induction of total protein degradation. Activation of PKC was required for the induction of proteasome expression, since calphostin C, a highly specific inhibitor of PKC, attenuated both the increase in total protein degradation and in proteasome expression and functional activity increased by angiotensin II. PKC is known to activate I-kappaB kinase (IKK), which is responsible for the phosphorylation and subsequent degradation of I-kappaB. Both angiotensin I and II induced an early decrease in cytoplasmic I-kappaB levels followed by nuclear accumulation of NF-kappaB. Using an NF-kappaB luciferase construct this was shown to increase transcriptional activation of NF-kappaB regulated genes. Maximal luciferase expression was seen at the same concentrations of angiotensin I/II as those inducing protein degradation. Total protein degradation induced by both angiotensin I and II was attenuated by resveratrol, which prevented nuclear accumulation of NF-kappaB, confirming that activation of NF-kappaB was responsible for the increased protein degradation. These results suggest that induction of proteasome expression by angiotensin I/II involves a signalling pathway involving PKC and NF-kappaB.

Active Transport, Cell Nucleus↗
PubMed1996

Direct positive chronotropic effects of angiotensin II and angiotensin III in pithed rats and in rat isolated atria.

1. The direct positive chronotropic effects of angiotensin II (AII) and its degradation products angiotensin III (AIII) and angiotensin IV (AIV) were established in pithed rats and in rat spontaneously beating right atria. 2. In pithed rats, AII, AIII and AIV caused dose-dependent tachycardia with similar maximal responses (110 beats min-1). The beta-adrenoceptor antagonist propranolol (3.37 x 10(-6) mol kg-1) but not the alpha 1-adrenoceptor antagonist prazosin (2.38 x 10(-7) mol kg-1) significantly reduced these effects (P < 0.05; n = 7-8), but 20-25% of the responses could not be blocked by propranolol. 3. In isolated atria, AII, AIII and AIV caused concentration-dependent increases in beating rate with similar maximal responses to AII and AIII (34.3 +/- 0.4 and 34.7 +/- 0.4 beats min-1; n = 9-10), and a lower maximal response to AIV (26.8 +/- 0.6 beats min-1; P < 0.05; n = 8). AIII was about 9 times less potent than AII, whereas AIV proved approximately 3800 times less potent than AII. Neither propranolol (1 microM) nor prazosin (1 microM) could influence the effects of the angiotensin peptides. 4. In isolated atria, the selective AT1-receptor antagonist, losartan (10, 100 and 300 nM) caused parallel rightward shifts of the concentration-response curves for AII and AIII, whereas the selective AT2- receptor antagonist PD123177 (1 microM) did not influence the effects of AII and AIII. The aminopeptidase-A and -M inhibitor amastatin (10 microM), significantly steepened the slope of the AIII curves and increased the potency of AIII about 6 fold. Amastatin did not influence the responses to AII. 5. Our results indicate that both in vivo and in vitro, exogenous AII and AIII induced a direct dose-dependent chronotropic effect, which is independent of the adrenergic system. This chronotropic effect is mediated by AT1-subtype receptors.

Adrenergic alpha-Antagonists↗
PubMed1989

Mechanisms of the angiotensin II effects on the exploratory behavior of rats in open field. II. Interaction of angiotensin II with yohimbine.

The effects of the octapeptide angiotensin II (AT II) and its interaction with yohimbine, an alpha 2-adrenoceptor antagonist, on the exploratory behavior of male rats in open field were studied. AT II (0.1 and 0.5 microgram intracerebroventricularly, i.c.v) increased the open field behavior, mainly ambulation and rearing. Yohimbine (1 and 3 mg/kg) significantly reduced the stimulatory effects of AT II, mainly on ambulation. It is suggested that the augmented release of noradrenaline (NA) resulting from alpha 2-adrenoceptor blockade decreases the exploratory behavior effects of AT II. An interaction between AT II receptors and NA-ergic neurotransmission in the brain might be taken into consideration as an explanation of the influence of yohimbine on AT II effects in open field behavior.

Angiotensin II↗
PubMed1986

Participation of angiotensin II in learning and memory. II. Interactions of angiotensin II with dopaminergic drugs.

The effect of angiotensin II (ATII) and of its interactions with dopaminergic drugs injected post-trial on retention in active avoidance tasks in shuttle-box-trained rats were studied. ATII at doses of 0.10 and 0.50 micrograms administered intracerebroventricularly (i.c.v.) immediately after training improved retention. The dopaminergic receptor agonist apomorphine at a dose of 0.10 mg/kg injected intraperitoneally (i.p.) facilitated retention whereas elymoclavine (a dopaminergic agonist) at a dose of 2.5 mg/kg i.p. had no effect. ATII at a dose of 0.10 micrograms i.c.v. administered after apomorphine 0.10 mg/kg or elymoclavine 2.5 mg/kg exerted a stronger retention-facilitating effect. The dopaminergic receptor antagonist haloperidol at a dose of 1 mg/kg i.p. markedly impaired retention. ATII at a dose of 0.50 micrograms administered after haloperidol (1 mg/kg) did not exercise its retention-facilitating effect. It is concluded that the retention facilitating effects of ATII are realized through interactions with brain dopaminergic transmission.

Angiotensin II↗
PubMed2002

Effect of angiotensin II and angiotensin(1-7) on hematopoietic recovery after intravenous chemotherapy.

PURPOSE: Previous studies have shown that angiotensin peptides stimulate the proliferation of hematopoietic progenitors in vitro, promote survival after exposure to lethal irradiation as well as accelerate the recovery of white blood cells (WBC), i.e., lymphocytes, monocytes and neutrophils, and platelets. These changes in the level of formed elements in the blood after irradiation was thought to be due to increases in the numbers of bone marrow progenitors including myeloid, erythroid and megakaryocyte progenitors by the action of angiotensin peptides. In view of these findings, the effect of angiotensin peptides on recovery after chemotherapy was assessed. MATERIALS AND METHODS: The effect of angiotensin II (AII) and angiotensin(1-7) (A1-7) on the recovery of WBC and platelets in the blood, as well as the number of myeloid, erythroid and megakaryocyte progenitors in the bone marrow and the number of myeloid progenitors in the blood after intravenous administration of chemotherapeutic drugs was assessed in a mouse model. RESULTS. In initial studies, subcutaneous administration of 10 or 100 microg/kg per day of AII starting either 2 days before or 2 days after intravenous administration of 5-fluorouracil (5FU) accelerated WBC recovery (return to baseline between 7 and 14 days). Further, consistent with previous observations, the number of myeloid progenitors in the bone marrow and blood was increased after systemic administration of angiotensin peptides. The comparability of A(1-7) and AII in their effect on hematopoietic recovery after chemotherapy was shown in subsequent studies. Daily administration of both AII and A(1-7) increased platelet numbers in the peripheral blood and myeloid, erythroid and megakaryocyte progenitors in the bone marrow. As 5FU is not a stem cell toxin, these studies were repeated with administration of A(1-7) initiated before or after intravenous cyclophosphamide. Following treatment with A(1-7) before cyclophosphamide the numbers of circulating WBC initially increased and then decreased starting on day 14. Following treatment with A(1-7) 2 days after cyclophosphamide the numbers of WBC and the numbers of myeloid progenitors increased in the peripheral blood and bone marrow. CONCLUSIONS: These findings suggest that angiotensin peptides accelerate hematopoietic recovery in multiple cellular lineages after chemotherapy, perhaps through an increase in the number of early hematopoietic progenitors.

Angiotensin I↗
PubMed1996

Tachyphylaxis to angiotensin II and [Phe4]-angiotensin II in the rat mesentery in vivo.

The existence of tachyphylaxis to angiotensin II (Ang II) in vivo is not unequivocally established, and the hydroxyl group of the Tyr4 residue of Ang II has been suggested as a determinant of tachyphylaxis. In view of these observations, we conducted a series of experiments to assess and compare the ability of Ang II and [Phe4]-Ang II to induce tachyphylaxis in vivo. All experiments were performed in the autoperfused rat mesenteric vascular bed. The tachyphylaxis to intramesenteric (IMA) infusions of Ang II was minimal, and after 120 min of continuous infusion (33 pmol/min), Ang II retained most of its vasoconstrictor activity (67.7 +/- 6.6% of the initial response). Also most of the agonist activity was retained even when Ang II was administered continuously in a dose-increasing manner (1-33 pmol/min). Continuous IMA infusions of single doses of [Phe4]-Ang II caused an initial full response that rapidly declined, and after 120 min retained only 18.2 +/- 9.2% of the initial response. Single continuous IMA infusion of [Phe4]-Ang II induced greater vasoconstrictor responses compared with vascular responses to the same doses delivered after the infusion of smaller doses. This difference was significant (P < .001, unpaired Student's t test) for all doses (10, 100, 330 and 1000 pmol/min) of [Phe4]-Ang II. In conclusion, although the development of tachyphylaxis to Ang II in vivo is minimal, tachyphylaxis to [Phe4]-Ang II does occur (at least in rat mesenteric vascular bed). Thus, omission of the hydroxyl group in position 4 dramatically increases the tachyphylactic potential, while preserving full agonist activity. These results suggest that the hydroxyl group of Tyr4 may protect the Ang II receptor from changes that induce tachyphylaxis.

Angiotensin II↗
PubMed1981

The conformation of angiotensin II. II. The rates of peptide NH exchange with solvent for [Asn1, Val5]angiotensin II, angiotensin III and saralasin.

The amide hydrogen exchange rates in H2O of two angiotensin agonists (angiotensinamide and angiotensin III) and one angiotensin antagonist (saralasin) have been measured at room temperature by the transfer of solvent saturation method. The NH of His6 is observed to exchange more slowly than predicted for all three peptides, suggesting that it is a participant in an intramolecular hydrogen bond. The NH-C alpha H 1H-NMR coupling constants are measured and found to be constant over the pH range of 5.0 to 6.5. The results are compared with those previously obtained for human angiotensin II and interpreted in terms of a dominant three-dimensional structure common to all four molecules. Two models for this structure are evaluated using the observed NH-C alpha H coupling constants and the reported activity of conformationally restrained derivatives.

Angiotensin Amide↗
PubMed1986

Effect of angiotensin II infusion on glomerular angiotensin II receptor in rats.

Previous studies by other investigators have shown that sodium depletion causes down-regulation of angiotensin II receptors in renal glomeruli, which is ascribed to elevation of circulating angiotensin II levels. The present study was designed to determine whether elevation of circulating angiotensin II levels alone can down-regulate its own receptors without changes in the sodium balance. Rats were infused with angiotensin II at 50 ng/min intraperitoneally for 24 h or 7 d, then glomeruli were isolated by a mechanical sieving technique and used in a radioreceptor assay for angiotensin II. Angiotensin II infusion for 24 h and for 7 d both significantly suppressed plasma renin activity, and elevated plasma angiotensin II level (3-fold) but did not affect the plasma sodium and potassium or differences between dietary intake and urinary excretion of these electrolytes. By Scatchard analyses significant down-regulation of angiotensin II receptor number was demonstrated in renal glomeruli derived from rats infused with angiotensin II for either 24 h (32% decrease from the control value) or 7 d (37% decrease). No significant changes in receptor affinity were observed after 24 h of angiotensin II infusion, although the infusion for 7 d slightly but significantly decreased Kd (to 2.57 +/- 0.08 nM from 3.17 +/- 0.19, P less than 0.01). From these results, we conclude that circulating angiotensin II level itself can regulate the number of its own receptors in renal glomeruli even in the absence of changes in the sodium balance.

Angiotensin II↗
PubMed2006

Down-regulation of cardiac apelin system in hypertrophied and failing hearts: Possible role of angiotensin II-angiotensin type 1 receptor system.

Cardiac apelin has recently been suggested to contribute to the pathophysiology of heart failure (HF) in humans. In animal experiments, its infusion acutely improved systolic as well as diastolic LV function. Although its deficit could critically determine the cardiac dysfunction, its regulatory mechanism is unknown. Accordingly, we investigated the role and regulation of the cardiac apelin system in the diseased heart using Dahl salt-sensitive rats, which show a distinctive transition from compensatory LV hypertrophy (LVH) to HF. In the compensatory LVH stage, apelin and its receptor APJ mRNA showed no change compared with control animals, while these were markedly down-regulated in the HF stage (72% and 57% decrease, respectively). The rats were chronically treated with telmisartan (angiotensin type 1 receptor blocker [ARB], 5 mg/kg/day, n=9), ONO-4817 (matrix metalloproteinase [MMP] inhibitor, 200 mg/kg/day, n=9), bisoprolol (beta blocker, 3 mg/kg/day, n=6) or vehicle (0.5%CMC, n=9) from the LVH stage. Although the functional improvements were similar among the three treated groups 6 weeks after treatment, restoration of cardiac apelin and APJ expression was observed only in the ARB group. Furthermore, in angiotensin II-infused rats, cardiac apelin mRNA was decreased after 24 h of treatment and its restoration was achieved by treatment with ARB. These results indicate that the cardiac apelin system is markedly down-regulated in experimental HF and may be regulated by the angiotensin II-angiotensin type 1 receptor system directly. Inhibition of the renin-angiotensin system may have beneficial effects, at least in part, through restoration of the cardiac apelin system in the treatment of HF.

Angiotensin II↗
PubMed1979

Drinking behaviour in rats treated with isoprenaline, angiotensin II or angiotensin antagonists.

1. Isoprenaline hydrochloride injected subcutaneously in rats given a choice test of 1.8% NaCl and water, first induced saline intake which started immediately and was almost concluded in 15 min, followed by a copious water intake. When either saline or water were given in a separate test, saline intake surpassed the water intake in the first 15 min.2. The delay of 15, 30 or 60 min after injection of isoprenaline, 100 mug/kg, before drinking was allowed, significantly reduced saline intake but did not modify the amount of water subsequently drunk.3. Isoprenaline caused a sudden drop in arterial blood pressure, the extent and duration depending on the dose. The time of maximum drop 3-4 min after injection coincided with the time the rat drank salt.4. Isoprenaline-induced saline drinking was significantly reduced after bilateral nephrectomy but water intake was unaffected.5. The beta-adrenoceptor blocking agent, propranolol, inhibited isoprenaline-induced NaCl and water intake, while the alpha-adrenoceptor antagonist phenoxybenzamine abolished isoprenaline-induced NaCl intake and enhanced water intake.6. Saralasin acetate (P-113), a competitive inhibitor of angiotensin II, given into the third brain ventricle, prevented the isoprenaline-induced NaCl and water intake as well as angiotensin II-induced drinking. The angiotensin converting enzyme inhibitor SQ-20881 reduced the isoprenaline-induced NaCl and water intake.7. In conclusion, hypotension might be a component of salt drinking evoked by isoprenaline although the dipsogenic action of beta-stimulation is mainly due to endogenous renin-angiotensin activation.

Angiotensin II↗
PubMed1975

Effect of angiotensin II and an angiotensin II inhibitor on renin secretion in the dog.

This study examined the effect of angiotensin II (AII) and (Sar-1Gly-8) AII, a competitive inhibitor of AII, on renin release in anesthetized dogs. An intravenous infusion of AII (25 ng/kg per min) raised BP 24 mmHg and lowered plasma renin activity (PRA) from 18.8 plus or minus 2.8 to 6.2 plus or minus 1. 3 ng/ml per h (P smaller than .001). When the intravenous infusion of AII inhibitor (1.0 mug/kg per min) was superimposed on the AII infusion, PRA rose from 6.5 plus or minus 22 to 12.3 plus or minus 3.6 ng/ml per h (P smaller than .02). Renal hemodynamics, BP, and urinary sodium excretion (UNaV) reverted toward pre-AII control values. A small dose of AII inhibitor (0.1 mu/kg per min) was then infused into one renal artery in animals receiving the constant intravenous infusion of AII. Renin secretion rate (RSR) increased significantly, not only in the infused kidney, but also in the contralateral kidney. In the latter there were no changes in renal hemodynamics or UNaV, and RSR was unimpaired by denervation of that kidney. The results suggest that the AII inhibitor blocks both the vascular and the renin-suppressing actions of AII and that the latter effect is more susceptible to inhibition.

Aminohippuric Acids↗
PubMed1992

Effects of aging and hypertension on plasma angiotensin II and platelet angiotensin II receptor density.

Plasma renin activity (PRA) declines with age in normal individuals, but the effect of age on plasma angiotensin II (ANG II) is less clear. A decline in plasma ANG II with age could result in altered platelet ANG II receptor density since plasma hormone levels influence their target organ receptors. To investigate this possibility, PRA, plasma ANG II, and platelet ANG II receptor density were examined in 17 young, 12 middle-aged, and 14 elderly healthy normotensive volunteers. To assess whether hypertension altered receptor density, these variables were also examined in 23 hypertensive patients. In normotensives, there was a negative correlation between age and PRA (r = -0.43, P < .05), no significant change in basal plasma ANG II with age, and a weak positive correlation between age and ANG II receptor density (r = 0.34, P < .05). Multiple regression analysis revealed that the relationship between age and ANG II receptor density was independent of the associated rise in mean arterial pressure with age (P < .05). Platelet ANG II receptor density was not significantly related to PRA or plasma ANG II. ANG II receptor affinity did not change with age. Neither PRA nor ANG II receptor density or affinity differed between hypertensives and normotensives of similar mean age, but plasma ANG II was significantly lower in hypertensives compared with normotensives. We concluded that aging is associated with a decline in supine PRA. The small decrease in plasma ANG II was not significant. Platelet ANG II receptor density increased with age primarily due to a small group of elderly subjects with elevated receptor density. There was no change in ANG II receptor density or affinity in hypertensives despite apparently lower plasma ANG II in these patients.

Adult↗
PubMed1976

Stimulating effects of angiotensin I, angiotensin II and des-Asp1-angiotensin II on steroid production in vitro and its inhibition by Sar1-Ala8-angiotensin II.

Two of the agents known to block the renin-angiotensin-aldosterone system, namely Sar1-Ala8-angiotensin II and the nonapeptide SQ 20881, have been used to clarify the role of angiotensin II (AII) and its cogeners upon the steroidogenesis in isolated fasciculata cells from bovine adrenal tissue. It could be concluded that: (1) des-Asp1-angiotensin II is as active as AII on steroidogenesis from bovine fasciculata cells; (2) angiotensin I, although less potent, stimulates steroid production without being converted to AII or des-Asp1-AII, and (3) Sar1-Ala8-AII inhibits all three peptides in a competitive manner. The presence of a common receptor for all these three peptides is suggested.

Adrenal Cortex Hormones↗
PubMed1996

Angiotensin II and angiotensin-(1-7) effects on free cytosolic sodium, intracellular pH, and the Na(+)-H+ antiporter in vascular smooth muscle.

The aim of the present study was to define the effects of angiotensin II (Ang II) and Ang-(1-7) on free cytosolic Na+ (Na+i), intracellular pH (pHi), and the Na(+)-H+ antiporter in cultured vascular smooth muscle cells from rat aorta. Cells were loaded with either BCECF-AM or SBFI-AM for measurement of pHi and Na+i, respectively. Ang II (10(-6) mol/L) caused a rapid rise in Na+i followed by a progressive increase that peaked at about 10 minutes (from 11 +/- 1.5 to 16 +/- 1.5 mmol/L, P < .001), whereas Ang-(1-7) (10(-6) mol/L) did not affect Na+i significantly (from 11.5 +/- 1.1 to 11.8 +/- 0.07 mmol/L). The effect of Ang II on Na+i was concentration dependent (delta Na+i, 5.1 +/- 0.9, 3.8 +/- 0.6, 1.6 +/- 0.6, and 0.14 +/- 0.18 mmol/L with decreasing concentrations of 10(-6), 10(-7), 10(-8), and 10(-9) mol/L, respectively). Ang II caused a brief acidification followed by an increase in pHi (from 7.34 +/- 0.03 to 7.43 +/- 0.03 after 10 minutes, P < .005), and Ang-(1-7) had no significant effect on pHi (from 7.23 +/- 0.03 to 7.23 +/- 0.03). To investigate whether pHi and Na+i changes induced by Ang II were due to cell Na+ entry via stimulation of the Na(+)-H+ antiporter, we pretreated cells with EIPA (25 mumol/L) or ouabain (2.0 mmol/L). Ang II in the presence of ouabain caused a greater increase than that seen with ouabain alone (delta Na+i, 13 +/- 1.5 versus 6.3 +/- 1.2 mmol/L, P < .0025). EIPA by itself decreased Na+i and pHi. After EIPA, Ang II failed to increase both Na+i and pHi, demonstrating that the Na(+)-H+ antiporter is responsible for the rises in Na+i and pHi during stimulation with Ang II. To further characterize the mechanism of Ang II action, we exposed cells to an Ang II type I receptor antagonist (L-158,809, 10(-6) mol/L) or two different type 2 receptor antagonists (PD 123177 and CGP 421112A, 10(-6) mol/L). L-158,809 completely blocked the rise in pHi caused by Ang II, whereas PD 123177 and CGP 421112A did not. We conclude that Ang II increases both Na+i and pHi, and both effects are mediated by stimulation of the Na(+)-H+ antiporter. Ang-(1-7), by contrast, has no significant effect on Na+i, pHi, or the Na(+)-H+ antiporter. Stimulation of this antiporter by Ang II is exerted through the type 1 receptor.

Amiloride↗