Central losartan blocks natriuretic, vasopressin, and pressor responses to central hypertonic NaCl in sheep

1998 ◽  
Vol 275 (2) ◽  
pp. R548-R554 ◽  
Author(s):  
Michael L. Mathai ◽  
Mark D. Evered ◽  
Michael J. McKinley
Keyword(s):  
Arterial Pressure ◽  
Hypertonic Saline ◽  
Pressor Response ◽  
Electrolyte Balance ◽  
Neural Pathways ◽  
Intracerebroventricular Administration ◽  
Ang Ii ◽  
Intracerebroventricular Infusion ◽  
The Central Nervous System ◽  
Vasopressin Secretion

This study investigated the effect of intracerebroventricular administration of the angiotensin AT1 receptor antagonist losartan on the natriuresis, pressor effect, and arginine vasopressin (AVP) secretion caused by intracerebroventricular infusion of either ANG II, hypertonic saline, or carbachol. Losartan (1 mg/h) or artificial cerebrospinal fluid (CSF) was infused into the lateral ventricle before, during, and after infusions of either ANG II at 10 μg/h for 1 h, 0.75 mol/l NaCl at 50 μl/min for 20 min, or carbachol at 1.66 μg/min for 15 min. Intracerebroventricular infusions of ANG II, 0.75 mol/l NaCl, or carbachol caused increases in renal Na+ and K+ excretion, arterial pressure, and plasma AVP levels. Increases in arterial pressure, Na+ excretion, and plasma AVP concentration ([AVP]) in response to intracerebroventricular ANG II or intracerebroventricular 0.75 mol/l NaCl were either abolished or attenuated by intracerebroventricular infusion of losartan but not by intracerebroventricular infusion of artificial CSF or intravenous losartan. Intracerebroventricular losartan did not reduce the increase in plasma [AVP] or arterial pressure in response to intracerebroventricular carbachol, but it did attenuate the natriuretic response to intracerebroventricular carbachol. We conclude that an intracerebroventricular dose of losartan (1 mg/h) that inhibits responses to intracerebroventricular ANG II also inhibits vasopressin secretion, natriuresis, and the pressor response to intracerebroventricular hypertonic saline. These results suggest that common neural pathways are involved in the responses induced by intracerebroventricular administration of ANG II and intracerebroventricular hypertonic NaCl. We propose that intracerebroventricular infusion of hypertonic saline activates angiotensinergic pathways in the central nervous system subserving the regulation of fluid and electrolyte balance and arterial pressure in sheep.

Central angiotensin II and PGE2 act independently to increase blood pressure in conscious sheep

1987 ◽  
Vol 252 (1) ◽  
pp. R73-R77
Author(s):  
B. A. Breuhaus ◽  
J. E. Chimoskey
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Pressor Response ◽  
Renin Angiotensin System ◽  
Cyclooxygenase Inhibitors ◽  
Ang Ii ◽  
Intracerebroventricular Infusion ◽  
Flunixin Meglumine ◽  
The Brain

Conscious adult female sheep chronically prepared with nonocclusive indwelling vascular and cerebroventricular catheters were used to determine whether centrally administered prostaglandin E2 (PGE2) increases blood pressure by activation of the brain renin angiotensin system or whether centrally administered angiotensin II (ANG II) increases blood pressure by stimulating prostaglandin synthesis in the brain. Intracerebroventricular (ivt) ANG II, 50 ng X kg-1 X min-1, increased arterial pressure 23 mmHg (P less than 0.01) 30 min after the start of infusion. Infusion of the ANG II antagonist [Sar1-Thr8]ANG II (sarthran), 1,000 ng X kg-1 X min-1 ivt, had no effect on arterial pressure when given by itself but reduced the ivt ANG II-induced pressor response to 5 mmHg (P less than 0.05) when the two peptides were infused at the same time. Intracerebroventricular infusion of sarthran did not alter the pressor responses to intracarotid (ic) PGE2 or to ivt PGE2. Blood pressure increased 21 mmHg (P less than 0.01) 30 min after the start of PGE2 infusion when PGE2 was given ic by itself, compared with 17 mmHg (P less than 0.01) when PGE2 was given ic at the same time as sarthran was given ivt. Blood pressure increased 14 mmHg (P less than 0.01) 30 min after the start of PGE2 infusion when PGE2 was given ivt by itself, compared with 16 mmHg (P less than 0.01) when PGE2 was given ivt at the same time as sarthran was given ivt. Pretreatment with the cyclooxygenase inhibitors indomethacin, 4 mg/kg sc, or flunixin meglumine, 3 mg/kg iv, did not alter the ivt ANG II-induced pressor response.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain angiotensinergic pathways mediate renal nerve inhibition by central hypertonic NaCl in conscious sheep

1997 ◽  
Vol 272 (2) ◽  
pp. R593-R600 ◽  
Author(s):  
C. N. May ◽  
R. M. McAllen
Keyword(s):  
Arterial Pressure ◽  
Hypertonic Saline ◽  
Diastolic Pressure ◽  
Venous Pressure ◽  
Chloride Concentration ◽  
Plasma Renin ◽  
Renal Nerve ◽  
Intracerebroventricular Infusion ◽  
Conscious Sheep ◽  
Renal Sympathetic

The renal sympathetic responses to infusion of hypertonic solutions into the lateral cerebral ventricles were investigated in conscious sheep. Intracerebroventricular infusion of artificial cerebrospinal fluid (CSF) containing 0.6 M NaCl, at 1 ml/h for 20 min, reduced renal sympathetic nerve activity (RSNA) by 81 +/- 5% (n = 6, P < 0.001). Plasma renin concentration also fell (P < 0.05), whereas arterial pressure increased by 6.4 +/- 0.7 mmHg (P < 0.01). Intracerebroventricular hypertonic sorbitol (0.9 M in CSF at 1 ml/h) had no effect. The AT1 receptor antagonist losartan (1 mg/h) abolished the plasma renin and arterial pressure responses to intracerebroventricular hypertonic saline and significantly reduced the fall in RSNA to 17 +/- 10% (P < 0.001). During intracerebroventricular hypertonic saline, the baroreflex relation of RSNA to diastolic pressure was shifted to the left and that to central venous pressure was abolished compared with control relations obtained by manipulating pressure with intravenous phenylephrine. These findings indicate that 1) RSNA is inhibited by a central mechanism that senses high sodium (or perhaps chloride) concentration rather than hypertonicity; 2) this inhibition occurs independently of reflexes from high- and low-pressure baroreceptors, although these may enhance the inhibition; and 3) inhibition of RSNA by hypertonic saline involves a central angiotensinergic pathway.

Mechanisms of centrally administered ET-1-induced increases in systemic arterial pressure and AVP secretion

1997 ◽  
Vol 272 (1) ◽  
pp. E126-E132 ◽  
Author(s):  
N. F. Rossi ◽  
D. S. O'Leary ◽  
H. Chen
Keyword(s):  
Arterial Pressure ◽  
Peak Plasma ◽  
Pressor Response ◽  
Cardiovascular Responses ◽  
Fold Increase ◽  
Systemic Arterial Pressure ◽  
Sympathetic Outflow ◽  
Central Administration ◽  
Eta Receptor ◽  
The Central Nervous System

Endothelins (ET) within the central nervous system (CNS) alter systemic cardiovascular responses and arginine vasopressin (AVP) secretion. These experiments were designed to ascertain whether the rise in systemic arterial pressure after central administration of ET-1 is mediated by enhancing sympathetic outflow and/or circulating AVP. In Long-Evans (LE/LE) rats, intracerebroventricular injection of 1-10 pmol ET-1 dose dependently increased mean arterial pressure (MAP). Peak response occurred 7-12 min after ET-1 and was inhibited by ETA receptor antagonism. Systemic vasopressin (V1) receptor blockade did not inhibit the pressor response, and rats with central diabetes insipidus (DI/DI) displayed an identical rise in MAP. Ganglionic blockade prevented ET-1-induced hemodynamic effects. Peak plasma AVP levels occurred 60 min after ET-1, as the pressor response began to wane. In sinoaortic-denervated LE/LE rats, ET-1 elicited a 10-fold increase in AVP secretion that coincided with the hemodynamic changes and was blocked by BQ-123. Thus ET-1 via ETA receptors within the CNS induced a concentration-dependent increase in systemic arterial pressure mediated by enhanced sympathetic outflow but not by circulating AVP. Reflex baroreceptor activation attenuated AVP release.

scholarly journals Overexpression of Central ACE2 (Angiotensin-Converting Enzyme 2) Attenuates the Pressor Response to Chronic Central Infusion of Ang II (Angiotensin II)

Hypertension ◽  
2020 ◽  
Vol 76 (5) ◽  
pp. 1514-1525
Author(s):  
Anyun Ma ◽  
Lie Gao ◽  
Ahmed M. Wafi ◽  
Li Yu ◽  
Tara Rudebush ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Angiotensin Converting Enzyme ◽  
Pressor Response ◽  
Rostral Ventrolateral Medulla ◽  
Ventrolateral Medulla ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Intracerebroventricular Infusion

We investigated the mechanism by which ACE2 (angiotensin-converting enzyme 2) overexpression alters neurohumoral outflow and central oxidative stress. Nrf2 (nuclear factor [erythroid-derived 2]-like 2) is a master antioxidant transcription factor that regulates cytoprotective and antioxidant genes. We hypothesized that upregulation of central ACE2 inhibits the pressor response to Ang II (angiotensin II) by reducing reactive oxygen species through a Nrf2/antioxidant enzyme–mediated mechanism in the rostral ventrolateral medulla. Synapsin human Angiotensin Converting Enzyme 2 positive (SynhACE2 +/+ ) mice and their littermate controls synhACE2 −/− were used to evaluate the consequence of intracerebroventricular infusion of Ang II. In control mice, Ang II infusion evoked a significant increase in blood pressure and norepinephrine excretion, along with polydipsia and polyuria. The pressor effect of central Ang II was completely blocked in synhACE2 +/+ mice. Polydipsia, norepinephrine excretion, and markers of oxidative stress in response to central Ang II were also reduced in synhACE2 +/+ mice. The MasR (Mas receptor) agonist Ang 1–7 and blocker A779 had no effects on blood pressure. synhACE2 +/+ mice showed enhanced expression of Nrf2 in the rostral ventrolateral medulla which was blunted following Ang II infusion. Ang II evoked nuclear translocation of Nrf2 in cultured Neuro 2A (N2A) cells. In synhACE2 −/− mice, the central Ang II pressor response was attenuated by simultaneous intracerebroventricular infusion of the Nrf2 activator sulforaphane; blood pressure was enhanced by knockdown of Nrf2 in the rostral ventrolateral medulla in Nrf2 floxed (Nrf2 f/f ) mice. These data suggest that the hypertensive effects of intracerebroventricular Ang II are attenuated by selective overexpression of brain synhACE2 and may be mediated by Nrf2-upregulated antioxidant enzymes in the rostral ventrolateral medulla.

Renal nerve inhibition by central NaCl and ANG II is abolished by lesions of the lamina terminalis

2000 ◽  
Vol 279 (5) ◽  
pp. R1827-R1833 ◽  
Author(s):  
C. N. May ◽  
R. M. McAllen ◽  
M. J. McKinley
Keyword(s):  
Hypertonic Saline ◽  
Third Ventricle ◽  
Plasma Renin ◽  
Anterior Wall ◽  
Lamina Terminalis ◽  
Ang Ii ◽  
Renal Nerve ◽  
Intracerebroventricular Infusion ◽  
Conscious Sheep ◽  
Nerve Inhibition

The lamina terminalis is situated in the anterior wall of the third ventricle and plays a major role in fluid and electrolyte homeostasis and cardiovascular regulation. The present study examined whether the effects of intracerebroventricular infusion of hypertonic saline and ANG II on renal sympathetic nerve activity (RSNA) were mediated by the lamina terminalis. In control, conscious sheep ( n = 5), intracerebroventricular infusions of 0.6 M NaCl (1 ml/h for 20 min) and ANG II (10 nmol/h for 30 min) increased mean arterial pressure (MAP) by 6 ± 1 ( P < 0.001) and 14 ± 3 mmHg ( P < 0.001) and inhibited RSNA by 80 ± 6 ( P < 0.001) and 89 ± 7% ( P < 0.001), respectively. Both treatments reduced plasma renin concentration (PRC). Intracerebroventricular infusion of artificial cerebrospinal fluid (1 ml/h for 30 min) had no effect. In conscious sheep with lesions of the lamina terminalis ( n = 6), all of the responses to intracerebroventricular hypertonic saline and ANG II were abolished. In conclusion, the effects of intracerebroventricular hypertonic saline and ANG II on RSNA, PRC, and MAP depend on the integrity of the lamina terminalis, indicating that this site plays an essential role in coordinating the homeostatic responses to changes in brain Na+ concentration.

Stimulation of cardiac sympathetic nerve activity by central angiotensinergic mechanisms in conscious sheep

2004 ◽  
Vol 286 (6) ◽  
pp. R1051-R1056 ◽  
Author(s):  
Anna M. D. Watson ◽  
Rasim Mogulkoc ◽  
Robin M. McAllen ◽  
Clive N. May
Keyword(s):  
Heart Rate ◽  
Arterial Pressure ◽  
Hypertonic Saline ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Ang Ii ◽  
Cardiac Sympathetic Nerve ◽  
Nerve Activity ◽  
Cardiac Sympathetic Nerve Activity ◽  
Conscious Sheep

Central actions of angiotensin play an important role in cardiovascular control and have been implicated in the pathogenesis of hypertension and heart failure. One feature of centrally or peripherally administered angiotensin is that the bradycardia in response to an acute pressor effect is blunted. It is unknown whether after central angiotensin this is due partly to increased cardiac sympathetic nerve activity (CSNA). We recorded CSNA and arterial pressure in conscious sheep, at least 3 days after electrode implantation. The effects of intracerebroventricular infusions of ANG II (3 nmol/h for 30 min) and artificial cerebrospinal fluid (CSF) (1 ml/h) were determined. The response to intracerebroventricular hypertonic saline (0.6 M NaCl in CSF at 1 ml/h) was examined as there is evidence that hypertonic saline acts via angiotensinergic pathways. Intracerebroventricular angiotensin increased CSNA by 23 ± 7% ( P < 0.001) and mean arterial pressure (MAP) by 7.6 ± 1.2 mmHg ( P < 0.001) but did not significantly change heart rate ( n = 5). During intracerebroventricular ANG II the reflex relation between CSNA and diastolic blood pressure was significantly shifted to the right ( P < 0.01). Intracerebroventricular hypertonic saline increased CSNA (+9.4 ± 6.6%, P < 0.05) and MAP but did not alter heart rate. The responses to angiotensin and hypertonic saline were prevented by intracerebroventricular losartan (1 mg/h). In conclusion, in conscious sheep angiotensin acts within the brain to increase CSNA, despite increased MAP. The increase in CSNA may account partly for the lack of bradycardia in response to the increased arterial pressure. The responses to angiotensin and hypertonic saline were losartan sensitive, indicating they were mediated by angiotensin AT-1 receptors.

scholarly journals In Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated Mechanism

Hypertension ◽  
2021 ◽  
Author(s):  
Giannie Barsha ◽  
Katrina M. Mirabito Colafella ◽  
Sarah L. Walton ◽  
Tracey A. Gaspari ◽  
Iresha Spizzo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Arterial Pressure ◽  
Pressor Response ◽  
Ang Ii ◽  
Estrogen Replacement ◽  
Female Mice ◽  
Adult Females ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

Loss of ovarian hormones following menopause contributes to the rise in cardiovascular risk with age. Estrogen plays a protective role against hypertension and end-organ damage by modulating the depressor actions of the AT 2 R (angiotensin type 2 receptor). Our aim was to determine whether estrogen replacement in aged female mice can lower arterial pressure, improve endothelial function, and reduce organ fibrosis via an AT 2 R-mediated mechanism. Mean arterial pressure was measured via radiotelemetry in ovary-intact adult (3–4-month-old), aged (16–18-month-old; reproductively senescent) and aged–17β-estradiol (E 2 )–treated (3 µg/day SC) female mice, which were administered vehicle, Ang II (angiotensin II; 600 ng/[kg·min] SC) or Ang II+PD123319 (AT 2 R antagonist; 3 mg/[kg·day SC). On day 21 of treatment, aortic endothelium-dependent relaxation and cardiac and renal tissue (fibrosis and gene expression) were analyzed. Basal mean arterial pressure was lower in E 2 -treated aged mice (89±1 mm Hg, n=20) relative to aged controls (94±1 mm Hg; n=18, P =0.002). The Ang II pressor response was enhanced by ≈20 mm Hg in aged compared with adult females ( P =0.01). E 2 -treatment reduced the Ang II pressor response in aged females ( P =0.002), an effect that was reversed by PD123319 in the aged E 2 –Ang II group ( P =0.0009). E 2 -treatment increased renal AT 2 R (≈6-fold; P <0.0001) and MasR (Mas oncoreceptor; 2–3-fold, P <0.05) gene expression in aged females. However, neither Ang II–induced endothelial dysfunction nor the age-related increase in renal and cardiac fibrosis was restored by E 2 -treatment in aged female mice. In conclusion, estrogen replacement in aged females may reduce arterial pressure to levels observed in adult females, via an AT 2 R-mediated renal mechanism.

Differential regulation of central vasopressin in transgenic rats harboring the mouse Ren-2 gene

1994 ◽  
Vol 267 (3) ◽  
pp. R786-R791 ◽  
Author(s):  
A. Moriguchi ◽  
C. M. Ferrario ◽  
K. B. Brosnihan ◽  
D. Ganten ◽  
M. Morris
Keyword(s):  
Blood Pressure ◽  
Ang Ii ◽  
Intracerebroventricular Infusion ◽  
Renin Gene ◽  
The Central Nervous System ◽  
Angiotensin Peptide ◽  
Lower Brain Stem ◽  
The Brain ◽  
Rat Genome ◽  
Supraoptic Nuclei

The transgenic (TG) rat carrying the mouse renin gene (mRen-2d) has provided a unique opportunity to explore central interactions between the brain renin-angiotensin (RAS) and vasopressin (AVP) systems. To evaluate the hypothalamic vasopressin axis in the TG rat, we measured the central nervous system concentrations of AVP and determined the effect of angiotensin II (ANG II) and its NH2-terminal heptapeptide [angiotensin-(1-7)] on blood pressure, heart rate, and AVP release using brain microdialysis. Intracerebroventricular infusion of ANG II or ANG-(1-7) in control rats increased local AVP release from the paraventricular and supraoptic nuclei. The ANG II infusion was associated with a significant increase in blood pressure not observed with ANG-(1-7). In contrast, the angiotensin peptide-induced central AVP responses and the ANG II-induced blood pressure increase were absent in the TG animal. The plasma AVP responses to ANG II and ANG-(1-7) were comparable in the control and TG rats. The TG rats exhibited a 22-fold higher level of AVP in the dorsal lower brain stem but had lower AVP levels in the posterior pituitary and the median eminence compared with control rats. These results suggest that insertion of the mouse renin gene into the rat genome leads to alterations in the AVP axis in terms of AVP peptide content and angiotensin-induced cardiovascular and AVP responses.

Mechanism of pressor effects by angiotensin in the nucleus tractus solitarius of rats

1984 ◽  
Vol 247 (3) ◽  
pp. R575-R581 ◽  
Author(s):  
R. Casto ◽  
M. I. Phillips
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Nucleus Tractus Solitarius ◽  
Pressor Response ◽  
Dose Range ◽  
Ang Ii ◽  
Sympathetic Activation ◽  
Vasopressin Antagonist ◽  
Hypophysectomized Rats ◽  
Intact Rats

We recently reported that microinjection of angiotensin II (ANG II) into the nucleus tractus solitarius (NTS) results in an increase in mean arterial pressure (MAP) in urethan-anesthetized rats in a dose range of 50-500 ng. To investigate the mechanism of this response, hexamethonium (20 mg/kg iv) was used to inhibit sympathetic activation. There was a highly significant (P less than 0.001) reduction in the magnitude of the pressor response (4.7 +/- 1.1 mmHg) compared with preblockade ANG II (500 ng) responses (15.5 +/- 1.6 mmHg). A vasopressin antagonist and hypophysectomized rats were used to study the contribution of pituitary vasopressin. Injection of 500 ng ANG II in hypophysectomized rats produced a pressor response (14.8 +/- 3.2 mmHg) indistinguishable from that in intact controls (15.5 +/- 1.6 mmHg). Pretreatment with the vasopressin antagonist d(CH2)5Tyr(Me)AVP (1 microgram iv) in intact rats also had no effect on the magnitude of the pressor response (15.7 +/- 1.7 mmHg). Microinjection of ANG I and II produces an increase in arterial pressure. It is concluded that the angiotensin pressor response in the NTS is mediated by activation of descending sympathetic fibers and is not dependent on release of blood-borne pressor agents from the pituitary.

scholarly journals The (pro)renin receptor and body fluid homeostasis

2013 ◽  
Vol 305 (2) ◽  
pp. R104-R106 ◽  
Author(s):  
Theresa Cao ◽  
Yumei Feng
Keyword(s):  
Sympathetic Nerve ◽  
Body Fluid ◽  
Sympathetic Nerve Activity ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Nerve Activity ◽  
Fluid Homeostasis ◽  
Body Fluid Homeostasis ◽  
The Central Nervous System ◽  
Vasopressin Secretion

The renin-angiotensin system (RAS) has long been established as one of the major mechanisms of hypertension through the increased levels of angiotensin (ANG) II and its resulting effect on the sympathetic nerve activity, arterial vasoconstriction, water reabsorption, and retention, etc. In the central nervous system, RAS activation affects body fluid homeostasis through increases in sympathetic nerve activity, water intake, food intake, and arginine vasopressin secretion. Previous studies, however, have shown that ANG II can be made in the brain, and it could possibly be through a new component called the (pro)renin receptor. This review intends to summarize the central and peripheral effects of the PRR on body fluid homeostasis.

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