Angiotensin II Type 1 Receptors and Systemic Hemodynamic and Renal Responses to Stress and Altered Blood Volume in Conscious Rabbits (original) (raw)
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Kidney International, 2003
Effects of angiotensin II receptor antagonism on the renal hemodynamic response to cardiovascular stress.BackgroundTo elucidate the effect of the angiotensin type 1 (AT1) receptor antagonist (AT1RA) eprosartan (E) on renal hemodynamics in normotensive and borderline hypertensive subjects, we investigated the hormonal and renal hemodynamic responses during cardiopulmonary stress testing.MethodsIn a prospective, double-blind, randomized, placebo-controlled crossover study, the effects of E
Hypertension, 2001
The angiotensin II type 2 (AT 2 ) receptor is present in rat kidney; however, its function is not well understood. The purpose of this study was to evaluate the role of the AT 2 receptor in blood pressure (BP) regulation. The effects of selective inhibition of the renal AT 2 receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) were examined in conscious uninephrectomized rats. Oligodeoxynucleotides (AS-ODN or scrambled [S-ODN]) were infused directly into the renal interstitial space by using an osmotic pump at 1 L/h for 7 days. Texas red-labeled AS-ODN was distributed in renal tubules in the infused but not the contralateral kidney of normal rats. Continuous renal interstitial infusion of the AS-ODN, but not S-ODN, caused a significant (PϽ0.01) increase in BP 1 to 5 days after the initiation of the infusion. AS-ODN-treated rats experienced an increase in systolic BP from 109Ϯ4 to 130Ϯ4 mm Hg (nϭ8, PϽ0.01), whereas S-ODN-treated (nϭ8) and vehicle-treated (nϭ8) rats did not show any significant change in BP. On day 5 of the oligodeoxynucleotide infusion, AS-ODN-treated rats exhibited a greater pressor response to systemic angiotensin II infusion (30 ng/kg per hour) than did S-ODN-treated rats (PϽ0.01). Renal interstitial fluid cGMP decreased from 11.9Ϯ0.8 to 3.6Ϯ0.5 pmol/mL (PϽ0.001), and bradykinin decreased from 0.05Ϯ0.05 to 0.18Ϯ0.03 ng/mL (PϽ0.001) in response to AS-ODN, but they were not significantly changed in response to S-ODN. To evaluate the effects of AS-ODN and S-ODN on AT 2 receptor expression, Western Blot analysis was performed on treated kidneys. Kidneys treated with AS-ODN had Ϸ40% less expression of AT 2 receptor than did kidneys treated with S-ODN or vehicle (PϽ0.05). These results suggest that AS-ODN directed selectively against the renal AT 2 receptor decreased receptor expression and caused an increase in BP. We conclude that the renal AT 2 receptor plays an important role in the regulation of BP via a bradykinin/cGMP vasodilator signaling cascade. (Hypertension. 2001;37:1285-1291.)
Acta Physiologica, 2009
Aim: This study investigated the influence of angiotensin II (Ang II) receptor and adrenergic blockade on the renal vasoconstrictions caused by Ang II and adrenergic agonists in spontaneously hypertensive rats (SHR).Methods: Forty-eight SHR were subjected to 7 days of losartan (10 mg kg−1 day−1 p.o.), carvedilol (5 mg kg−1 day−1 p.o.) or losartan + carvedilol (10 mg kg−1 day−1 + 5 mg kg−1 day−1 p.o.). On day 8, the rats were anaesthetized and renal vasoconstrictor experiments performed. One group of rats underwent acute unilateral renal denervation.Results: There were significant (P < 0.05) reductions in the renal vasoconstrictor responses to noradrenaline, phenylephrine, methoxamine and Ang II after losartan and carvedilol treatments compared with that in untreated rats (all P < 0.05). However, in renally denervated SHR treated with carvedilol, the vasoconstrictor responses to all the vasoactive agents were enhanced compared with those in SHR with intact renal nerves treated with carvedilol. Intact SHR given both losartan and carvedilol showed greater renal vasoconstrictor responses to the vasoactive agents than when given either losartan or carvedilol alone (all P < 0.05).Conclusion: Carvedilol reduced the vasoconstrictor response to Ang II and all the adrenergic agonists in the presence of the renal nerves, but, following the removal of renal sympathetic activity, carvedilol enhanced the sensitivity of both renal α1-adrenoceptors and AT1 receptors to the vasoactive agents. Co-treatment with losartan and carvedilol reduced the renal vasoconstrictor responses to exogenously administered vasoactive agents but to a lesser extent than losartan or carvedilol alone. The results obtained demonstrate an interaction between Ang II receptors and adrenergic neurotransmission in the SHR.
Renal sympathetic activation from long-term low-dose angiotensin II infusion in rabbits
Journal of Hypertension, 2012
Objective: Activation of renal sympathetic nerve activity (RSNA) has not been observed during long-term infusion of angiotensin II (AngII) which results in marked hypertension, despite activation of hypothalamic autonomic regions. We examined whether the function of central pathways influencing sympathetic activity is altered in conscious rabbits given a low dose of AngII that produces a modest hypertension and, therefore, limited secondary complications.
Hypertension, 2011
Recently, a new derivative of angiotensin (Ang) II, called “Ang A,” has been discovered to be present in plasma of healthy humans and, in increased concentrations, in end-stage renal failure patients. The objectives of the study were to investigate the blood pressure and renal hemodynamic responses to Ang A in normotensive and hypertensive rats and in genetically modified mice and the binding properties of Ang A to Ang II type 1 (AT 1 ) or Ang II type 2 (AT 2 ) receptors. Intravenous and intrarenal administration of Ang A induced dose-dependent pressor and renal vasoconstrictor responses in normotensive rats, which were blocked by the AT 1 receptor antagonist candesartan but were not altered by the AT 2 receptor ligands PD123319, CGP42112A, or compound 21. Similar responses were observed after intravenous administration in spontaneously hypertensive rats. Deletion of AT 1a receptors in mice almost completely abolished the pressor and renal vasoconstrictor responses to Ang A, indicat...
Angiotensin and baroreflex control of the circulation
Brazilian Journal of Medical and Biological Research, 2002
There is a close association between the location of angiotensin (Ang) receptors and many important brain nuclei involved in the regulation of the cardiovascular system. The present review encompasses the physiological role of Ang II in the brainstem, particularly in relation to its influence on baroreflex control of the heart and kidney. Activation of AT 1 receptors in the brainstem by fourth ventricle (4V) administration to conscious rabbits or local administration of Ang II into the rostral ventrolateral medulla (RVLM) of anesthetized rabbits acutely increases renal sympathetic nerve activity (RSNA) and RSNA baroreflex responses. Administration of the Ang antagonist Sarile into the RVLM of anesthetized rabbits blocked the effects of Ang II on the RSNA baroreflex, indicating that the RVLM is the major site of sympathoexcitatory action of Ang II given into the cerebrospinal fluid surrounding the brainstem. However, in conscious animals, blockade of endogenous Ang receptors in the brainstem by the 4V AT 1 receptor antagonist losartan resulted in sympathoexcitation, suggesting an overall greater activity of endogenous Ang II within the sympathoinhibitory pathways. However, the RSNA response to airjet stress in conscious rabbits was markedly attenuated. While we found no effect of acute central Ang on heart rate baroreflexes, chronic 4V infusion inhibited the baroreflex and chronic losartan increased baroreflex gain. Thus, brainstem Ang II acutely alters sympathetic responses to specific afferent inputs thus forming part of a potentially important mechanism for the integration of autonomic response patterns. The sympathoexcitatory AT 1 receptors appear to be activated during stress, surgery and anesthesia.
Pharmacology & Pharmacy, 2012
Many agents are known to cause qualitative and quantitative differences in intrarenal blood flow. This study tested the hypothesis that angiotensin II (AII) evokes a differential effect on cortical (CBF) and medullary blood flow (MBF) and that AT 2 receptor mediates AII-induced increase in renal MBF by mechanisms related to nitric oxide (NO) and prostanoids. AII (100, 300 and 1000 ng/kg/min) increased mean arterial blood pressure (MABP) by 24% ± 7% (p < 0.05); decreased CBF by 30% ± 2% (p < 0.05); but increased MBF by 21% ± 8% (p < 0.05). Indomethacin (5 mg/kg), enhanced AII effects on MABP by 154% ± 26% (p < 0.05), MBF by 141% ± 46% but decreased CBF by 74% ± 54% (p < 0.05) indicating the involvement of dilator prostanoids in the systemic and medullary circulation but constrictor prostanoids in the cortex. N G nitro-L-arginine (L-NNA), an inhibitor of NO synthase (100 mg/L in drinking water) enhanced AII effects on MABP (169 ± 75, p < 0.05) and decreased CBF (107% ± 50%, p < 0.05) but blunted the effects of AII on MBF (150% ± 21%, p < 0.05). 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ; 2 mg/kg), a guanylyl cyclase inhibitor, enhanced AII effects on MABP (118% ± 32% , p < 0.05) and decreased CBF(85% ± 47% , p < 0.05) but blunted the effects of AII on MBF (96% ± 15%, p < 0.05). However, glibenclamide (20 µg/kg), a K ATP channel blocker, did not affect intra-renal hemodynamics elicited by AII. Blockade of AT 2 receptors with PD123319 (50 µg/kg/min) did not change basal or AII-induced changes MABP or CBF but blunted AII-induced increase in MBF by 60% ± 11% (p < 0.05). CGP42112 (10 µg/kg/min), an AT 2 receptor agonist, elicited a reduction in MABP and increases in CBF and MBF that were abolished or attenuated by PD123319. These findings demonstrate that AII elicited differential changes in intrarenal blood flow; an AT 1 -mediated reduction in CBF but an AT 2 -mediated increase in MBF. The AT 2 receptor-mediated increase in MBF involves guanylase cyclase, NO and dilator prostanoids but not K ATP channels.
American Journal of Hypertension, 1996
Administered in small doses, angiotensin II (ANG II) potentiates its own pressor responses (autopotentiation). In the present study, we investigated whether potentiation of vasoconstrictor responses in the mesenteric and renal circulation accounted for the autopotentiation of pressor responses. Male Sprague-Dawley rats, 350 to 400 g, were infused with 200 ng/kg/min ANG II intraperitoneally for 7 to 10 days. Control rats were fitted with an osmotic minipump containing vehicle only. Vascular responses to ANG II, norepinephrine (NE), arginine vasopressin (AVP) and nerve stimulation were measured in the mesenteric and renal circulation of rats. In ANG II-treated rats: 1) tail systolic BP was 4 mm Hg higher than in controls (P = NS); 2) mesenteric vascular responses to ANG II (P < .002) and nerve T he administration of angiotensin II (ANG II) to experimental animals is an accepted model for human renovascular and high-renin (ANG II) essential hypertension. 1 Evidence is accumulating, however, that the type of hypertension produced depends on the duration and dose of ANG II administration. The hypertension produced by the administration of pressor doses of ANG stimulation (P = .03) were increased, and those to NE and AVP were unchanged; and 3) renal vascular responses to nerve stimulation were reduced (P < .02), and those to ANG II, NE, and AVP were unchanged. Thus, we demonstrated autopotentiation of vascular responses to ANG II in the mesenteric, but not the renal circulation. An interaction between ANG II and sympathetic activity may explain these differences in regional vascular responses. Regional hemodynamic measurements may provide important clues to pathogenetic mechanisms in hypertension. Am J Hypertens 1996;9:385-392
Kidney International, 2005
AT-1 receptor antagonism modifies the mediation of endothelin-1, thromboxane A 2, and catecholamines in the renal constrictor response to angiotensin II. Objective. The present study investigated the consequences of partial AT 1 receptor blockade on the participation of catecholamines, thromboxane A 2 (TXA 2), and endothelin-1 (ET-1) in the renal vasoconstriction induced by angiotensin II (Ang II). Methods. For this purpose, the increase in renal perfusion pressure (RPP) produced by Ang II was studied in isolated kidneys from untreated or irbesartan-treated Wistar Kyoto and spontaneously hypertensive rats (SHR), in absence or presence of the alfa-1 receptor antagonist, prazosin, the TXA 2 receptor antagonist, ifetroban, or the ET A /ET B receptor antagonist, PD145065. Results. Systolic arterial pressure (SAP) was higher (P < 0.05) in SHR than in WKY. Increases in RPP produced by Ang II were comparable in kidneys from both untreated groups. Treatment with irbesartan reduced SAP and RPP in both strains in a comparable extent. Presence of prazosin, ifetroban, or PD145065 in perfusion media reduced (P < 0.05) Ang II maximal response in all groups. Maximal inhibition of Ang II-induced vasoconstriction produced by the 3 antagonists was comparable in untreated WKY, but that of ifetroban and PD145065 was lower (P < 0.05) than that of prazosin in untreated SHR. Maximal inhibition of Ang II-induced vasoconstriction produced by the 3 antagonists was comparable in WKY treated with irbesartan, and not different to that observed in untreated WKY. Maximal inhibitory effect of the 3 antagonists was higher (P < 0.05) in treated than in untreated SHR. Conclusion. The study further supports the importance of catecholamines, TXA 2 , and ET-1 as mediators of the renal vasoconstriction induced by Ang II in both normotensive and hypertensive rats. Hypertensive conditions appeared to reduce the participation of TXA 2 and ET-1 in Ang II-induced vasoconstriction when compared with normotensive conditions. Chronic partial blockade of AT 1 receptors did not affect the participation of catecholamines, TXA 2 , and ET-1 in normotensive rats, but increased the participation of the 3 mediators in SHR.
Hypertension, 1982
Male albino rabbits received continuous (24 hr/day) infusions of angiotensin II (AH) at doses of 1 or 3 Mg/hr into a lateral cerebral ventricle (i.v.t.) for 10 consecutive days. Infusions were preceded by a 5day control period and followed by a 5-day recovery period. Water intake, urine output, water "balance" (water intake minus urine output), urinary sodium and potassium excretions were determined daily. Arterial pressure, heart rate, plasma electrolytes (sodium and potassium), plasma volume, and extracellular fluid volume were determined at 5-day intervals. Chronic i.v.t. infusion of AH resulted in reversible, dose-dependent increases in arterial pressure, water intake, and urinary sodium excretion, and decreases in plasma sodium, plasma potassium, and water balance. Infusions of normal saline i.v.t. (n = 5) did not significantly alter any of the above values. Intravenous infusion of the same doses of AH raised arterial pressure to a similar degree as that from i.v.t. administration, but did not significantly affect any of the other measured variables. In an additional group of 10 rabbits, AH was infused at 3 Mg/ nr '•*•*• for 5 days, and the acute cardiovascular actions of i.v. i.v. saralasin (4 Mg/kg/min), and "total" autonomic blockade were compared to the effects of these treatments in five saline-infused rabbits. No significant differences in responses of the two groups were found. In another series of 10 rabbits, 5-day i.v.t. infusion of All (3 Mg/hr) was shown to be associated with increased pressor sensitivity to norepinephrine, but not to AH or vasopressin. A similar experiment in four additional rabbits revealed that plasma vasopressin concentration was not altered by i.v.t. infusion of AH. We conclude that chronic i.v.t. infusion of AH in rabbits can cause a sustained hypertension that is not dependent on salt or water retention, "leak" of AH into the peripheral vasculature, increased release of vasopressin in the circulation, or increased autonomic nervous system activity.