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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present studies were conducted to examine the roles of angiotensin II, angiotensin IV, and the angiotensin receptor subtypes in the cerebral circulation. The effects of angiotensin II, the selective AT1 receptor antagonist losartan, and the selective AT2 receptor ligands, PD 123319 and CGP 42112, on cerebral blood flow autoregulation, were studied during increases and decreases in blood pressure in normotensive rats. Cerebrocortical blood flow was measured by laser-Doppler flowmetry, while systemic blood pressure was either increased by phenylephrine infusion, or decreased by controlled haemorrhage. The effects of angiotensin II, and AT1 and AT2 receptor ligands on the contractility of rat anterior cerebral artery in vitro, were studied using cannulated, perfused vessel segments. The effect of angiotensin IV on cerebral blood flow after experimental subarachnoid haemorrhage, and possible involvement of nitric oxide, was studied in rat. Subarachnoid haemorrhage was simulated by injecting 0.3 ml arterial blood into the cisterna magna, while cerebral blood flow was measured by laser-Doppler flowmetry. The main findings in the present studies were that angiotensin II, the AT1 antagonist losartan, and the AT2 ligands PD 123319 and CGP 42112, shifted the cerebral blood flow autoregulatory range towards higher blood pressures. PD 123319 and CGP 42112 acted as AT2 receptor agonists. In vitro, angiotensin II elicited an AT1 receptor mediated contraction of rat anterior cerebral artery. Angiotensin IV was able to reverse the acute CBF reduction after subarachnoid haemorrhage. No evidence was found to support the involvement of nitric oxide in this response. In conclusion, there is strong evidence supporting a role for the AT2 receptor in the regulation of cerebral circulation. The role of the AT1 receptor is questionable, and the losartan induced autoregulatory shift is possibly mediated indirectly through AT2 receptor stimulation. Although AT1 receptors mediate the angiotensin II induced contraction of rat anterior cerebral artery in vitro, this effect does not explain the effect of losartan on CBF autoregulation. Angiotensin IV increases cerebral blood flow after experimental subarachnoid haemorrhage possibly by dilating cerebral vessels through stimulation of the AT4 receptor.
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PMID:The role of angiotensin receptor subtypes in cerebrovascular regulation in the rat. 861 May 1

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73 +/- 0.58 micromol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 micromol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 micromol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 micromol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 micromol/L), and PD 123319 (1 micromol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 micromol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2, angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.
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PMID:Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. 861 97

There has been an explosive growth of interest in the multiple interacting paracrine systems that influence renal microvascular function. This review first discusses the membrane activation mechanisms for renal vascular control. Evidence is provided that there are differential activating mechanisms regulating pre- and postglomerular arteriolar vascular smooth muscle cells. The next section deals with the critical role of the endothelium in the control of renal vascular function and covers the recent findings related to the role of nitric oxide and other endothelial-derived factors. This section is followed by an analysis of the roles of vasoactive paracrine systems that have their origin from adjoining tubular structures. The interplay of signals between the epithelial cells and the vascular network to provide feedback regulation of renal hemodynamics is developed. Because of their well-recognized contributions to the regulation of renal microvascular function, three major paracrine systems are discussed in separate sections. Recent findings related to the role of intrarenally formed angiotensin II and the prominence of the AT1 receptors are described. The possible contribution of purinergic compounds is then discussed. Recognition of the emerging role of extracellular ATP operating via P2 receptors as well as the more recognized functions of the P1 receptors provides fertile ground for further studies. In the next section, the family of vasoactive arachidonic acid metabolites is described. Possibilities for a myriad of interacting functions operating both directly on vascular smooth muscle cells and indirectly via influences on endothelial and epithelial cells are discussed. Particular attention is given to the more recent developments related to hemodynamic actions of the cytochrome P-450 metabolites. The final section discusses unique mechanisms that may be responsible for differential regulation of medullary blood flow by locally formed paracrine agents. Several sections provide perspectives on the complex interactions among the multiple mechanisms responsible for paracrine regulation of the renal microcirculation. This plurality of regulatory interactions highlights the need for experimental strategies that include integrative approaches that allow manifestation of indirect as well as direct influences of these paracrine systems on renal microvascular function.
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PMID:Paracrine regulation of the renal microcirculation. 861 62

Detailed knowledge is becoming available on the intrarenal renin-angiotensin system. This paper briefly describes some recent developments on the intrarenal formation and compartmentalization of components of the renin-angiotensin system. Furthermore, renal responses to angiotensin II are reviewed with respect to intraluminal angiotensin II concentrations, and interactions with nitric oxide on the afferent arteriole and the tubuloglomerular feedback system. A main issue is whether angiotensin-converting enzyme inhibitors can block the intrarenal renin-angiotensin system to the same extent as in other tissues. This is particularly interesting in view of the recently discovered polymorphism in the angiotensin-converting enzyme gene, which accounts for substantial variation in plasma angiotensin-converting enzyme levels. AT1 receptor antagonists are now available for clinical use. Although the AT1 receptor has been reported to mediate most, if not all, of the renal actions of angiotensin II, these compounds differ from angiotensin-converting enzyme inhibitors. Firstly, AT1 receptor blockers lack the prostaglandin- and kinin-potentiating effects of angiotensin-converting enzyme inhibitors. Furthermore, they increase angiotensin II, which can activate non-AT1 receptors. Finally, the pharmacodynamics of AT1 receptors may evoke different responses from the sympathetic nervous system than those of angiotensin-converting enzyme inhibitors. Currently, it is unclear whether renin inhibitors will have advantages over angiotensin-converting enzyme inhibitors or AT1 receptor antagonists. From the recent research, it is clear that the classical concept of the renin-angiotensin system cannot be pursued, and is being replaced by detailed schemes in which the intrarenal renin-angiotensin system has an important place.
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PMID:Renal responses to antagonism of the renin-angiotensin system. 883 66

Intrarenal arterial infusion of angiotensin II (4 ng/kg/min) reduced renal blood flow, glomerular filtration rate and urinary Na+ excretion (UNaV) without affecting fractional Na+ excretion (FENa) in anesthetized rabbits. Losartan (10 micrograms/kg/min) abolished these angiotensin II-induced renal responses. The renal blood flow, glomerular filtration rate and UNaV responses were potentiated during intrarenal arterial infusion of N omega-nitro-L-arginine methyl ester (L-NAME, 10 micrograms/kg/min). A high dose of L-NAME (50 micrograms/kg/min) also potentiated the renal blood flow and UNaV responses but not the glomerular filtration rate response. Angiotensin II reduced FENa during L-NAME infusion at either dose. In L-NAME-pretreated rabbits, losartan abolished the angiotensin II-induced renal blood flow and glomerular filtration rate responses, but the reduction in FENa still remained. The present study suggests that in the rabbit kidney (1) nitric oxide attenuates the angiotensin II-induced (angiotensin AT1 receptor-mediated) vasoconstriction and (2) angiotensin II can evoke losartan-resistant tubular Na+ reabsorption, but the tubular action is concealed by nitric oxide.
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PMID:Angiotensin II-induced renal responses in anesthetized rabbits: effects of N omega-nitro-L-arginine methyl ester and losartan. 884 Jan 28

Angiotensin II (Ang II) and nitric oxide (NO) regulate a variety of physiological functions. In this study, we suggest that inhaled Ang II produces an initial bronchodilation apparently by stimulating NO production via AT1 receptors. Also, we demonstrate that following the initial bronchodilation, Ang II causes bronchoconstriction in the guinea pig, also via AT1 receptors. Both of the findings are important for our understanding of airway functions induced by Ang II.
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PMID:Angiotensin II stimulates production of nitric oxide in guinea pig airways via AT1 receptor activation. 884 54

Experiments in inbred strains of normotensive and hypertensive rats have clearly demonstrated circadian rhythms in blood pressure and heart rate. Pre- and postsynaptic signal transduction processes in vitro can, but need not, vary with circadian time, greatly depending on the strain of rats investigated. These data highlight the notion of a strain-dependent, and thus genetic, regulation of the cardiovascular system. Obviously, circadian rhythms in blood pressure cannot be explained by single biochemical parameters, but results from both in vitro and in vivo studies give first evidence that the vascular nitric oxide-cGMP system may be involved in the circadian regulation of blood pressure in WKY and SHR rats. In secondary hypertensive TGR and in their normotensive controls, SPRD, the guanylyl cyclase system does not seem to play a role in circadian blood pressure regulation. In neither of the four strains studied did aortic adenylyl cyclase show any time-dependent variation. Because vascular tissue was taken from the thoracic aorta of the rats, a contribution of adenylyl cyclase to circadian blood pressure regulation in small resistance arteries cannot be ruled out. Further studies in different parts of the vascular tree are needed to definitely answer that question. No data are available on time-dependent variation in the activity of phospholipase C, the second messenger pathway of vascular alpha-adrenoceptors and angiotensin II AT1-receptors, both of which mediate vasoconstriction. Future research into this system will be helpful in identifying mechanisms involved in blood pressure regulation in SPRD and TGR.
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PMID:Signal transduction in animal models of normotension and hypertension. 885 34

Angiotensin II (A II), the active component of the renin-angiotensin system, plays a major role in the regulation of blood pressure and renal function. A II actions are mediated by the interaction of this peptide with specific receptors that have been classified into two major types. AT1 and AT2. AT1 receptors have been associated with all of the known cardiovascular and renal effects of A II. Losartan, the first nonpeptide A II-receptor antagonist, exerts its antihypertensive action through the inhibition of A II binding to AT1 receptors. However, additional mechanisms seem to be involved in the actions of losartan in the rat. Administration of the nitric oxide (NO)-synthase inhibitor, NG-nitro-L-arginine methyl ester (LNAME), prevented the hypotensive effect induced by losartan in spontaneously hypertensive rats (SHR). Similarly, pretreatment with LNAME reduced the increases in renal plasma flow and glomerular filtration rate produced by this AT1-receptor antagonist in SHR. Furthermore, concurrent administration of the prostaglandin (PG)-synthesis inhibitor indomethacin attenuated vasodepressor, diuretic, and natriuretic effects of losartan in SHR. Finally, it should be mentioned that losartan was able to reduce the "ex vivo" vasoconstriction induced by phenylephrine in aortic rings from SHR. This effect was not observed in endothelium-denuded rings, suggesting a mediatory role of an endothelium-derived factor in this effect of losartan. Consequently, these data suggest a contributory role of NO and PGs in the vasodepressor and renal actions of AT1-receptor antagonists in SHR.
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PMID:The potential role of nitric oxide in angiotensin II-receptor blockade. 891 37

Angiotensin receptor antagonists represent a new class of drugs for the treatment of patients with hypertension. Reduction of blood pressure in patients with essential hypertension requires increased activity of the renin-angiotensin system. Losartan, the first orally active, nonpeptide angiotensin antagonist, specifically competes with angiotensin II (Ang II) for the AT1 receptor and reversibly alters the receptor. Maximum blood pressure reductions occur after doses of approximately 50 mg, although some patients will require 100 mg; the parent compound and a metabolite are responsible for a smooth 24-hour effect on blood pressure. Once-daily dosing with losartan has been documented to be safe. The drug's safety has been evaluated in 4,058 patients; of these patients, more than 1,200 were treated for longer than 6 months and more than 800 were treated for longer than 1 year with doses of 10 mg to 150 mg. Overall, no hypertensive patients were withdrawn from treatment because of elevated serum creatinine or potassium levels, and there were no reports of angioedema. In addition, some reductions in plasma uric acid levels were noted. Cough occurred significantly less often in patients treated with losartan than in those treated with hydrochlorothiazide or lisinopril. In contrast to angiotensin-converting enzyme (ACE) inhibitors, losartan does not activate bradykinin-nitric oxide-prostanoid vasodilation.
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PMID:Losartan: first of a new class of angiotensin antagonists for the management of hypertension. 893 38

1. The aim of this study was to investigate, by use of spectral analysis, (1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME); (2) the involvement of the renin-angiotensin system in these modifications, by use of the angiotensin II AT1-receptor antagonist losartan. 2. Blockade of NO synthesis was achieved by infusion for 1 h of a low-dose (10 micrograms kg-1 min-1, i.v., n = 10) and high-dose (100 micrograms kg-1 min-1, i.v., n = 10) of L-NAME. The same treatment was applied in two further groups (2 x n = 10) after a bolus dose of losartan (10 mg kg-1, i.v.). 3. Thirty minutes after the start of the infusion of low-dose L-NAME, systolic BP (SBP) increased (+10 +/- 3 mmHg, P < 0.01), with the effect being more pronounced 5 min after the end of L-NAME administration (+20 +/- 4 mmHg, P < 0.001). With high-dose L-NAME, SBP increased immediately (5 min: +8 +/- 2 mmHg, P < 0.05) and reached a maximum after 40 min (+53 +/- 4 mmHg, P < 0.001); a bradycardia was observed (60 min: -44 +/- 13 beats min-1, P < 0.01). 4. Low-dose L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7 +/- 1.7 mmHg2 vs 3.4 +/- 0.5 mmHg2, P < 0.05), whereas the high dose of L-NAME not only increased the LF component (40 min: 11.7 +/- 2 mmHg2 vs 2.7 +/- 0.5 mmHg2, P < 0.001) but also decreased the mind frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14 +/- 0.3 mmHg2 vs 1.7 +/- 0.1 mmHg2, P < 0.05) of SBP. 5. Losartan did not modify BP levels but had a tachycardic effect (+45 beats min-1). Moreover, losartan increased MF oscillations of SBP (4.26 +/- 0.49 mmHg2 vs 2.43 +/- 0.25 mmHg2, P < 0.001), prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose of L-NAME. Losartan also prevented the amplification of the LF oscillations of SBP induced by L-NAME; the decrease of the MF oscillations of SBP induced by L-NAME was reinforced after losartan. 6. We conclude that the renin-angiotensin system is involved in the increase in variability of SBP in the LF range which resulted from the withdrawal of the vasodilating influence of NO. We propose that NO may counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.
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PMID:Contribution of the renin-angiotensin system to short-term blood pressure variability during blockade of nitric oxide synthesis in the rat. 893 9


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