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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vivo studies have previously shown that exogenous angiotensin II (AII) reinforces sympathetic nervous system activity. Conversely, non selective inhibition of endogenous AII by angiotensin I converting enzyme inhibitors (ACEIs) results in sympathoinhibitory effects. The aim of the present study was to examine the influence of selective inhibition of endogenous AII by SR 47436, a non peptide AT1-receptor antagonist, on the sympathetic nervous system. Cardiac, systemic and regional vascular (kidney, mesentery, hindlimb) responses to selective alpha 1- and alpha 2-adrenoceptor agonists and to electrical stimulation of the spinal cord were investigated in the pithed spontaneously hypertensive rat (SHR). Male adults SHRs were orally treated by SR 47436 (10 mg/kg/day for 8 days) or by distilled water. Two hours later, they were anesthetized with pentobarbital (50 mg/kg, i.p.), pithed and artificially ventilated. Blood pressure, heart rate, cardiac output and regional (kidney, mesentery and hindlimb) blood flows (pulsed Doppler technique) were measured. Corresponding vascular resistances were calculated. Three hours after SR 47436--at the time of the drug's maximal effects--or distilled water administration, cardiac, systemic pressor and regional vasoconstrictor responses (a) to increasing i.v. doses of AII, (b) to increasing frequencies of electrical stimulation of the spinal cord, and (c) to increasing i.v. doses of cirazoline, a selective alpha 1-adrenoceptor agonist, and of UK-14,304, a selective alpha 2-adrenoceptor agonist, were investigated. AII systemic pressor, regional vasoconstrictor and tachycardic responses were completely abolished by SR 47436. SR 47436 significantly reduced the systemic pressor responses elicited by spinal cord stimulation, cirazoline and UK-14,304.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Interaction between SR 47436, a new angiotensin II antagonist and sympathetic nervous system in pithed SHR rats]. 812 42

1. The aim of this study was to investigate the contribution of endogenous bradykinin to the vascular sympathoinhibitory effects exerted by angiotensin I converting enzyme inhibitors (ACEIs) in the spontaneously hypertensive rat (SHR). 2. Adult SHRs were treated daily for 8 days with either perindopril (3 mg kg-1), or a selective angiotensin II AT1 receptor antagonist, losartan (10 mg kg-1) both given orally--these two doses being equipotent in inhibiting angiotensin I (AI)-induced vascular responses--or distilled water (controls). After pithing, the animals were instrumented for determination of blood pressure, heart rate, cardiac output, regional (renal, mesenteric, hindlimb) blood flows (pulsed Doppler technique) and corresponding vascular resistances. Afterwards, half of the animals of each group were given the selective bradykinin B2 receptor antagonist, icatibant, used in a dose (10 micrograms kg-1, i.v.) that achieved B2 receptor blockade, the other half received saline (10 microliters kg-1, i.v.). Haemodynamic responses to increasing frequencies of spinal cord stimulation were then measured. 3. Pressor and vasoconstrictor responses to AI were significantly and similarly reduced in both perindopril- and losartan-treated groups. Perindopril and losartan both decreased to a similar extent the pressor and vasoconstrictor responses to electrical stimulation of the spinal cord. 4. In the dose used, icatibant did not affect any of the investigated haemodynamic parameters in any of the experimental groups. Furthermore, icatibant did not affect the stimulation frequency-response curves in the control animals and did not modify the vascular sympathoinhibitory effects exerted by perindopril and by losartan. 5 Taken together, these results demonstrate that endogenous bradykinin does not, through B2 receptor activation, contribute to the vascular sympathoinhibitory effects of ACEIs in SHRs.
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PMID:Lack of involvement of bradykinin in the vascular sympathoinhibitory effects of angiotensin converting enzyme inhibitors in spontaneously hypertensive rats. 856 53

Renin-like activity (RLA), angiotensin I converting enzyme-like (ACELA), and kallikrein-like activity (KLA), activities of the key enzymes of renin-angiotensin and kallikrein-kinin systems, were sought in the kidney of the African lungfish Protopterus annectens during the aquatic phase. RLA, examined by RIA (using porcine angiotensinogen as substrate), was 0.38 +/- 0.05 ng angiotensin I/mg protein/hr. ACELA and KLA were investigated in assays spectrophotometrically. ACELA, measured at 37 and at 20 degrees , was, respectively, 1.55 +/- 0.55 and 0.61 +/- 0.23 nmol hippurate/min/mg protein. KLA was 7.34 +/- 0.93 mU/mg protein in the crude kidney extract and 31.05 +/- 7.50 mU/mg protein after electrophoretic purification. Renal kininogenase activity was inhibited by 100% by D-Phe-Phe-Arg-chloromethyl ketone (10 microM), 98% by phenylmethylsulfonyl fluoride (2 nM), and 91% by aprotinin (1000 kIU). The apparent molecular weight of the renal kininogenase on SDS-PAGE was 27,000 Da. Both the renal enzyme and the purified glandular kallikrein, used as a control, have the same mobility on polyacrylamide gel electrophoresis. Immunoreactivities toward angiotensin II and bradykinin were localized by double immunostaining in the same cells of the proximal tubules. Putative angiotensin II receptors were demonstrated immunohistochemically, in the supranuclear region of proximal tubular cells, using an antibody to the sequence between amino acids 225 and 237 of the mammalian AT1 receptor.
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PMID:The kallikrein-kinin and renin-angiotensin systems in the kidney of an African lungfish, Protopterus annectens. 881 41

The present study was undertaken to determine whether trandolaprilat, an active form of angiotensin I converting enzyme (ACE) inhibitor, may improve ischemia/reperfusion-induced contractile dysfunction and metabolic derangement of isolated rat hearts. Ischemia (25 min) and subsequent 60-min reperfusion resulted in a small recovery of post-ischemic left ventricular developed pressure (LVDP), a sustained increase in left ventricular end-diastolic pressure, an increase in the release of creatine kinase and ATP metabolites from the perfused heart, and changes in myocardial sodium, potassium, calcium and magnesium contents. Treatment with 10-100 microM of trandolaprilat for the last 10 min of pre-ischemia recovered approximately 50-90% of pre-ischemic LVDP during reperfusion, whereas that with 30-100 microM of enalaprilat restored approximately 55-65% of the pre-ischemic LVDP. Treatment with either trandolaprilat or enalaprilat at these concentrations attenuated the release of creatine kinase and ATP metabolites into the perfusate during reperfusion. Treatment with 30 microM trandolaprilat suppressed ischemia/reperfusion-induced changes in myocardial ion content. Treatment with bradykinin during the last 10 min of pre-ischemia also resulted in a post-ischemic contractile recovery with a degree similar to that of the trandolaprilat-treated hearts. E4177, an AT1-antagonist, showed no effect on ischemia/reperfusion-induced changes in cardiac parameters. The enhancement of post-ischemic contractile recovery by the ACE inhibitor was abolished by treatment with either Hoechst 140, a bradykinin (BK2) antagonist, or diclofenac, a cyclooxygenase inhibitor. These results suggest that trandolaprilat is capable of attenuating ischemia/reperfusion injury of isolated perfused hearts and altered BK metabolism is, at least in part, involved in this effect.
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PMID:Beneficial effects of angiotensin I converting enzyme inhibitor on post-ischemic contractile function of perfused rat heart. 887 76

The influence of the renin-angiotensin system (RAS) on the aortic wall mechanical properties under angiotensin I converting enzyme inhibition (enalaprilat, 0.3 mg/kg iv) or angiotensin II receptor (AT1) blockade (E-3174, 1 mg/kg iv) was examined in eight normotensive and eight renovascular hypertensive conscious dogs. Aortic diameter (D; sonomicrometry)-pressure (P; microtransducer) hysteresis loops during steady state and during rapid distal aortic occlusion allowed (after hysteresis elimination) calculation of the aortic wall viscosity index, the purely elastic P-D relationship, and derivation into compliance-pressure curves. At the early stage ofrenovascular hypertension when activation of RAS is more pronounced, aortic wall stiffness and wall viscosity were increased as compared with normotensive states. Blood pressure remained unchanged in normotensive animals and was reduced during hypertension after antihypertensive treatments. In hypertensive animals, enalaprilat and E-3174 decreased viscosity index and shifted the compliance-pressure curve upward with respect to pretreatment conditions. In normotensive dogs, whereas E-3174 did not change the compliance-pressure curve and viscosity index, enalaprilat increased compliance and reduced viscosity index. We concluded that in normotensive dogs converting enzyme inhibition modifies arterial viscoelastic parameters by angiotensin-independent mechanisms that contribute to the modulation of the buffering function of large arteries.
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PMID:In vivo angiotensin II receptor blockade and converting enzyme inhibition on canine aortic viscoelasticity. 912 49

RENIN-ANGIOTENSIN ANTAGONISTS: The renal effects of angiotensin II receptor antagonists (AT1 blockers) can be compared with another class of drugs inhibiting the renin-angiotensin-aldosterone system, i.e. the angiotensin I converting enzyme inhibitors (ACE1). SIMILAR BUT SPECIFIC EFFECTS: The renal effects of these two classes of drugs are similar but each class has specific effects explained by several mechanisms. i) The system includes a large number of active peptides (angiotensin II, angiotensin III, angiotensin 1-7) which exert various effects according to their specific receptor(s): ii) several types of angiotensin II receptors have been identified (AT1, AT2, AT4 ...). Only AT1 blockers are available in clinical practice. iii) Receptor or enzyme blockade can produce varying effects; ACE inhibition is not specific since increased bradykinin activity is associated with the suppression of angiotensin peptide generation. EXPERIMENTAL AND CLINICAL TRIALS: Experimental and recent clinical studies have shown that AT1 blockers can induce, like ACE1, hypotension, renal vasodilation and natriuresis. The definite effects on discrete renal structures (vessels, glomeruli, tubules) differ however in magnitude which may suggest specific indications according to the pathophysiological background (renal disease, congestive heart failure, etc.).
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PMID:[Renal effects of AT1 angiotensin receptor antagonists (AT1ra)]. 953 2

The angiotensin II receptor blockers (ARBs), are highly selective for the AT1 subtype and will block the effects of angiotensin II on peripheral vessels. Several short- and long-term studies have shown these agents to be safe and effective antihypertensive drugs. Since monotherapy of hypertension may be ineffective in lowering the blood pressure to goal, the use of an ARB, especially in combination with a diuretic or another medication, is frequently necessary to bring the blood pressure <140/90 mm Hg (<130/80 mm Hg among people with diabetes mellitus or chronic renal failure), according to JNC 7 guidelines. Besides hypertension, the ARBs have been shown to reduce left ventricular hypertrophy in hypertensive patients. Other benefits of these medications, as well as the angiotensin I converting enzyme inhibitors (ACEIs), include a decrease in cardiovascular morbidity and mortality in patients with heart failure, or hypertensive diabetic nephropathy with proteinuria. Some of the beneficial effects noted with the ACEIs and ARBs (congestive heart failure, left ventricular hypertrophy), have also been demonstrated with the use of b blockers alone and in combination with a diuretic. These drugs, i.e., b blockers, ARBs, and ACEIs, seem to exert their beneficial action through the blockade of the renin-angiotensin-aldosterone system. The role of this system in cardiovascular remodeling and its blockade will be discussed in this review, which will specifically summarize data with the ARB, valsartan.
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PMID:Clinical experience with angiotensin receptor blockers with particular reference to valsartan. 1530 83

The results issued from experimental models and randomized controlled clinical trials have shown that the more intense is the blockade of the renin-angiotensin system (RAS), the more effective is the prevention of target organ damage. Combined inhibition of the RAS is aimed at more complete blockade of the system through action at two different sites, angiotensin I converting enzyme (ACE) and AT1 receptors. This is achieved either by neutralizing the rise in renin and angiotensin (Ang) I, which follows the interruption of the Ang II-renin negative feed-back loop, or by directly antagonizing Ang II, whose synthesis is in part independent of the RAS. By comparison with higher doses of single site RAS blockers, a combination of an ACE inhibitor and an AT1 receptor antagonist block more effectively the RAS. After the demonstration of its synergistic or additive blood pressure lowering effects in sodium depleted normotensive subjects and animal models, combined blockade of the RAS was shown to be more efficient than single site RAS blockade: 1. in lowering blood pressure in hypertensive patients; 2. in lowering proteinuria and possibly retarding progression of renal failure in patients with diabetic and non-diabetic nephropathy; 3. finally, in improving left ventricular remodelling, cardiac function status and cardiovascular morbidity and mortality in patients with congestive heart failure. The advantage offered by combining two RAS blockers is to increase the beneficial effect of cardioprotection and nephroprotection which are currently demonstrated with the highest doses of an ACE inhibitor or an AT1 receptor antagonist.
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PMID:[Blockade of the renin-angiotensin system by a combination of ACE inhibitors and AT1 receptor antagonists]. 1549 22

The recent discovery of the angiotensin II (Ang II)-breakdown enzyme, angiotensin I converting enzyme (ACE) 2, suggests the importance of Ang II degradation in hypertension. The present study explored the signaling mechanism by which ACE2 is regulated under hypertensive conditions. Real-time PCR and immunohistochemistry showed that ACE2 mRNA and protein expression levels were high, whereas ACE expression levels were moderate in both normal kidney and heart. In contrast, patients with hypertension showed marked ACE up-regulation and ACE2 down-regulation in both hypertensive cardiopathy and, particularly, hypertensive nephropathy. The inhibition of ACE2 expression was shown to be associated with ACE up-regulation and activation of extracellular regulated (ERK)1/2 and p38 mitogen-activated protein (MAP) kinases. In vitro, Ang II was able to up-regulate ACE and down-regulate ACE2 in human kidney tubular cells, which were blocked by an angiotensin II (AT)1 receptor antagonist (losartan), but not by an AT2 receptor blocker (PD123319). Furthermore, blockade of ERK1/2 or p38 MAP kinases by either specific inhibitors or a dominant-negative adenovirus was able to abolish Ang II-induced ACE2 down-regulation in human kidney tubular cells. In conclusion, Ang II is able to up-regulate ACE and down-regulate ACE2 expression levels under hypertensive conditions both in vivo and in vitro. The AT1 receptor-mediated ERK/p38 MAP kinase signaling pathway may be a key mechanism by which Ang II down-regulates ACE2 expression, implicating an ACE/ACE2 imbalance in hypertensive cardiovascular and renal damage.
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PMID:Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. 1840 95

The role of the renin-angiotensin-aldosterone system (RAAS) on the development of insulin resistance and type 2 diabetes (T2DM) is an area of growing interest. Most of the deleterious actions of the RAAS on insulin signals appear to be mediated through activation of the serine/threonine kinase, oxidative stress and tissue-inflammation in insulin-sensitive organs. Both experimental and clinical studies demonstrated that angiotensin II (Ang II) and aldosterone could play a role in the development of insulin resistance, diabetes and cardiovascular diseases. Large randomized clinical trials revealed that blockade of the RAAS with either angiotensin I converting enzyme inhibitors or AT1 receptor blockers results in decreased T2DM incidence, with a minor attenuation of markers for insulin resistance. This review focuses on the role of RAAS in the pathogenesis of insulin resistance, as well as on clinical relevance of RAAS blockade in the prevention and treatment of the metabolic syndrome and pre-diabetes.
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PMID:[RAAS and insulin resistance]. 2301 1


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