angiotensin-i and Chronic-Disease

Topics: Angiotensin I; Angiotensin II; Animals; Chronic Disease; Exercise; Humans; Muscle, Skeletal; Weight Loss

Angiotensin type 1 receptors (AT(1)Rs) play a critical role in a variety of physiological functions and pathophysiological states. They have been strongly implicated in the modulation of sympathetic outflow in the brain. An understanding of the mechanisms by which AT(1)Rs are regulated in a variety of disease states that are characterized by sympathoexcitation is pivotal in development of new strategies for the treatment of these disorders. This review concentrates on several aspects of AT(1)R regulation in the setting of chronic heart failure (CHF). There is now good evidence that AT(1)R expression in neurons is mediated by activation of the transcription factor activator protein 1 (AP-1). This transcription factor and its component proteins are upregulated in the rostral ventrolateral medulla of animals with CHF. Because the increase in AT(1)R expression and transcription factor activation can be blocked by the AT(1)R antagonist losartan, a positive feedback mechanism of AT(1)R expression in CHF is suggested. Oxidative stress has also been implicated in the regulation of receptor expression. Recent data suggest that the newly discovered catabolic enzyme angiotensin-converting enzyme 2 (ACE2) may play a role in the modulation of AT(1)R expression by altering the balance between the octapeptide ANG II and ANG- (1-7). Finally, exercise training reduces both central oxidative stress and AT(1)R expression in animals with CHF. These data strongly suggest that multiple central and peripheral influences dynamically alter AT(1)R expression in CHF.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Chronic Disease; Exercise; Heart; Heart Failure; Humans; Medulla Oblongata; Neurons; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Signal Transduction; Sympathetic Nervous System; Transcription Factor AP-1; Transcription, Genetic; Up-Regulation

Angiotensin II (ANG II) is an important factor for the progression of renal diseases. ANG II has many pleiotropic effects on the kidney such as pro-inflammatory and profibrotic actions besides the well-known blood pressure-increasing effect.. Organs have local ANG II-generating systems that work independently from their classic systemic counterpart. Renal proximal tubular cells could generate and secrete ANG II into the urine in concentrations that are 10,000 times higher than those found in serum. These local systems are only incompletely blocked by currently used doses of ACE inhibitors or AT(1) antagonists. There are other enzyme systems besides ACE that contribute to the formation of ANG II. Alternative pathways generate peptides such as angiotensin 1-7 that have antagonistic effect compared with ANG II. Degradation products of ANG II such as angiotensin IV bind at separate receptors and could mediate fibrosis. The discovery of AT(1) receptor dimers and agonistic antibodies against AT(1) receptors contributes to the complexity of the system.. The complexity of the renin-angiotensin-aldosterone system (RAAS) implies that dual blockade with ACE inhibitors and AT(1) receptor antagonists makes sense for pathophysiological reasons. First clinical studies have shown that such as dual therapy reduces progression of chronic renal disease more efficiently that the respective monotherapies in certain risk populations. This shows that novel pathophysiological data could lead to innovative clinical treatment strategies.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Chymases; Clinical Trials as Topic; Diabetic Nephropathies; Disease Progression; Drug Therapy, Combination; Humans; Indoles; Kidney Diseases; Kidney Tubules, Proximal; Losartan; Prospective Studies; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors; Serine Endopeptidases

Plasma aldosterone levels are elevated in patients with chronic heart failure (CHF) taking angiotensin-converting enzyme (ACE) inhibitors. Elevated aldosterone levels may reflect incomplete inhibition of the vascular converting enzyme during long-term ACE inhibition. We simultaneously measured plasma aldosterone levels and the degree of inhibition of the vascular converting enzyme in patients with CHF.. Thirty-four subjects with CHF receiving the maximum recommended doses of ACE inhibitors for a duration of 3 to 105 months were studied. The pressor response to exogenous angiotensin I (AI) was measured and normalized for the pressor response to angiotensin II (AII) to assess inhibition of the vascular converting enzyme (AII/AI ratio). Aldosterone levels were determined by solid-phase radioimmunoassay. Eleven of the 34 subjects had plasma aldosterone levels above the upper limit of normal, ie, >15.0 ng/dL. Seven of these 11 subjects (64%) had an AII/AI ratio < or =0.05, indicating complete inhibition of the vascular converting enzyme. In the entire cohort, the AII/AI ratio did not correlate with the duration of ACE inhibitor therapy.. Plasma aldosterone levels are elevated in patients with CHF during long-term ACE inhibitor therapy despite complete inhibition of the vascular converting enzyme. Complete inhibition of the vascular converting enzyme does not obviate the need for aldosterone receptor blockade in patients with CHF.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Enzyme Activation; Female; Heart Failure; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Radial Artery; Sodium, Dietary; Tonometry, Ocular; Treatment Outcome

This study was designed to fully characterize vascular tissue angiotensin I (AI)/angiotensin II (AII) conversion changes over time in vivo in humans during chronic angiotensin-converting enzyme (ACE) inhibitor therapy.. Plasma AII does not remain fully suppressed during chronic ACE inhibitor therapy. However, the plasma renin angiotensin system (RAS) might be dissociated from the vascular tissue RAS. We therefore set out to characterize the time course of vascular RAS reactivation during chronic ACE inhibitor therapy.. Vascular AI/AII conversion was studied in patients with chronic heart failure (CHF) taking chronic lisinopril therapy by the differential infusion of AI and AII into the brachial artery. A cross-sectional study was done to see whether there were differences in vascular AI/AII conversion according to New York Heart Association (NYHA) class. A second longitudinal study followed 28 patients with NYHA I to II CHF serially over 18 months to see whether vascular ACE inhibition was progressively lost with time despite ACE inhibitor therapy. A third study examined whether increasing the dose of lisinopril affected subsequent vascular ACE inhibition.. In the cross-sectional study, vascular AI-to-AII conversion was significantly reduced in NYHA class III compared with class I/II (p < 0.05). In the longitudinal study, vascular ACE inhibition was significantly reduced at 18 months as compared with baseline (p < 0.001), suggesting gradual reactivation of vascular ACE in CHF over time. In the third study, tissue ACE inhibition could be restored by increasing the ACE inhibitor dose.. Vascular AI/AII conversion reactivates over time during chronic ACE inhibitor therapy even if the CHF disease process is clinically stable. It also occurs as the CHF disease process progresses. Even if vascular AI/AII conversion has reactivated, it can be suppressed by increasing the dose of the ACE inhibitor.

Topics: Aged; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Vessels; Chronic Disease; Cross-Over Studies; Cross-Sectional Studies; Double-Blind Method; Female; Heart Failure; Humans; Lisinopril; Longitudinal Studies; Male; Middle Aged; Time Factors

[Pro(11)(D)-Ala(12)] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a functionally significant non-ACE angiotensin (Ang) II-generating pathway exists in human dorsal hand veins.. Using a modified Aellig technique, we studied the response to Ang I and [Pro(11)(D)-Ala(12)] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effect of each peptide given before and after a 6.25-mg oral dose of the ACE inhibitor captopril or matching placebo. Placebo or captopril was given in a double-blind, randomized fashion. Ang I induced a mean+/-SEM venoconstrictor response of 45+/-11%, 40+/-10%, 55+/-8%, and 4+/-4% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, the response to Ang I was reproducible and was reduced significantly only after treatment with captopril (P=0.002). [Pro(11)(D)-Ala(12)] Ang I induced a mean venoconstrictor response of 42+/-9%, 49+/-9%, 48+/-10%, and 54+/-11% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [Pro(11)(D)-Ala(12)] Ang I.. We have demonstrated that [Pro(11)(D)-Ala(12)] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacological probe, we have shown that a non-ACE pathway capable of generating Ang II exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase.

Topics: Administration, Oral; Angina Pectoris; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Captopril; Chronic Disease; Chymases; Dose-Response Relationship, Drug; Double-Blind Method; Hand; Humans; Infusions, Intravenous; Irbesartan; Middle Aged; Peptidyl-Dipeptidase A; Reproducibility of Results; Serine Endopeptidases; Substrate Specificity; Tetrazoles; Vasoconstriction; Veins

The RALES study showed that spironolactone, added to conventional therapy for chronic heart failure, dramatically reduced mortality. We tested the hypothesis that this benefit was partially due to improvement in endothelial function and/or to amplified suppression of the vascular renin-angiotensin axis.. We performed a randomized, placebo-controlled, double-blind crossover study on 10 patients with NYHA class II to III chronic heart failure on standard diuretic/ACE inhibitor therapy, comparing 50 mg/d spironolactone (1 month) versus placebo. Forearm vasculature endothelial function was assessed by bilateral forearm venous occlusion plethysmography using acetylcholine and N-monomethyl-L-arginine (L-NMMA), with sodium nitroprusside as a control vasodilator. Also, vascular ACE activity was assessed by use of angiotensin (Ang) I, with Ang II as a control vasoconstrictor. Spironolactone significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [mean+/-SEM], 177+/-29% versus 95+/-20%, spironolactone versus placebo; P<0.001), with an associated increase in vasoconstriction due to L-NMMA (-35+/-6% versus -18+/-4%; P<0.05). The Ang I response was also significantly reduced with spironolactone (P<0.05), with Ang II responses unaltered.. Spironolactone improves endothelial dysfunction, increases NO bioactivity, and inhibits vascular Ang I/Ang II conversion in patients with heart failure, providing novel mechanisms for its beneficial effect on cardiovascular mortality.

Topics: Aged; Angiotensin I; Angiotensin II; Chronic Disease; Cross-Over Studies; Diuretics; Double-Blind Method; Endothelium, Vascular; Enzyme Inhibitors; Forearm; Heart Failure; Humans; Male; Middle Aged; Nitric Oxide; omega-N-Methylarginine; Spironolactone; Vasodilation

This study was designed to compare different proposed methods of assessing adherence with angiotensin-converting enzyme (ACE) inhibitor (ACEI) therapy in chronic heart failure.. The use of ACEIs in chronic heart failure gives us a unique opportunity to assess a patient's adherence by measuring whether the expected biochemical effect of an ACEI is present in the patient's bloodstream. In fact, there are several different ways of assessing ACE in vivo: these are serum ACE activity itself, plasma N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), urine AcSDKP, plasma angiotensin I (AI), plasma angiotensin II (AII), or the AII/AI ratio.. Patients with chronic heart failure (n = 39) were randomized to regimens of ACEI nonadherence for one week, ACEI adherence for one week or two versions of partial adherence for one week, after which the above six tests were performed.. All six tests significantly distinguished between full nonadherence for one week and full or partial adherence. Only plasma AcSDKP produced a significantly different result between partial adherence and either full adherence or full nonadherence for one week. In terms of their ability to distinguish full nonadherence from full adherence, plasma AcSDKP was 89% sensitive and 100% specific with an area under its ROC of 0.95. Corresponding figures for urine AcSDKP were 92%, 97% and 0.95 and for serum ACE they were 86%, 95% and 0.90.. All six tests distinguished full nonadherence from all other forms of adherence. The rank order of performance was plasma AcSDKP, urine AcSDKP, serum ACE, AII/AI ratio and plasma AII followed by plasma AI.

Topics: Aged; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Chronic Disease; Diuretics; Drug Therapy, Combination; Echocardiography; Furosemide; Heart Failure; Humans; Lisinopril; Oligopeptides; Peptidyl-Dipeptidase A; Radionuclide Ventriculography; Treatment Outcome; Treatment Refusal

Previous studies in heart failure (CHF) after temporary diuretic withdrawal have suggested that perindopril is associated with no first dose hypotension in comparison with other ACE inhibitors (ACEI) or placebo. The aim of this study was to explore further the profile of perindopril during chronic dosing.. We report the effects of acute and chronic (8 weeks) treatment with the ACE inhibitor perindopril (Per, 2-->4 mg daily) or placebo (P) in a double-blind parallel group study of 24 diuretic treated patients (17M; 67 +/- 8 years, 80 +/- 17 kg) with ischaemic cardiomyopathy (fractional shortening, 19 +/- 5%; radionuclide ejection fraction, 31 +/- 3%). Baseline biochemical, hormonal (ACE, Ang I, Ang II), isotopic renal function (GFR, ERPF, ECFV), pretreatment diuretic dose and heart failure scores were similar between groups. Concomitant cardiac treatments remained unchanged and diuretic withdrawal was not used to introduce treatment.. There were no significant effects on electrolytes, liver function tests, serum or erythrocyte magnesium. There was no significant first dose fall in SBP over 6 h) (P, baseline 137 +/- 18; min 115 +/- 16 mmHg; Per, baseline 137 +/- 15; min 118 +/- 17 mmHg). Neither supine nor erect BP was significantly affected by chronic treatment (P, erect baseline 134 +/- 23/76 +/- 10 to 124 +/- 41/74 +/- 10 mmHg; Per, baseline 135 +/- 21/76 +/- 14 to 128 +/- 22/70 +/- 12 mmHg, P=NS). Active treatment was associated with significant ACE inhibition (P, baseline 47 +/- 17 to 43 +/- 17; Per baseline 49 +/- 15 to 14 +/- 7); aldosterone (P, baseline 337 +/- 179 to 375 +/- 306; Per, baseline 335 +/- 357 to 293 +/- 155 pg ml(-1)) and Ang II suppression (P, baseline 9 +/- 9 to 20 +/- 39; Per baseline 10 +/- 9 to 3 +/- 3 pM). Isotopic renal function was unaffected by either treatment.. At this dose (2-4 mg orally) chronic perindopril therapy has no significant effect on blood pressure or renal function. Sustained neurohormonal suppression of ACE and AII occurred without evidence of AII reactivation. A lack of effect on BP at these doses may make perindopril suitable for study in unstable patients with acute HF or useful in those patients where there are concerns over ACEI induced hypotension.

Topics: Aged; Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiac Output, Low; Chronic Disease; Depression, Chemical; Female; Humans; Indoles; Kidney Function Tests; Male; Middle Aged; Perindopril

Sarcopenia associated with chronic liver disease (CLD) is one of the more common extrahepatic features in patients with these pathologies. Among the cellular alterations observed in the muscle tissue under CLD is the decline in the muscle strength and function, as well as the increased fatigue. Morphological changes, such as a decrease in the fiber diameter and transition in the fiber type, are also reported. At the molecular level, sarcopenia for CLD is characterized by: i) a decrease in the sarcomeric protein, such as myosin heavy chain (MHC); ii) an increase in the ubiquitin-proteasome system markers, such as atrogin-1/MAFbx1 and MuRF-1/TRIM63; iii) an increase in autophagy markers, such as LC3II/LC3I ratio. Among the regulators of muscle mass is the renin-angiotensin system (RAS). The non-classical axis of RAS includes the Angiotensin 1-7 [Ang-(1-7)] peptide and its receptor Mas, which in skeletal muscle has anti-atrophic effect in models of muscle wasting induced by immobilization, lipopolysaccharide, myostatin or angiotensin II. In this paper, we evaluated the effect of Ang-(1-7) on the sarcopenia by CLD in a murine model induced by the 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) hepatotoxin administered through diet. Our results show that Ang-(1-7) administration prevented the decline of the function and strength of muscle and increased the fatigue detected in the DDC-fed mice. Besides, we observed that the decreased fiber diameter and MHC levels, as well as the transition of fiber types, were all abolished by Ang-(1-7) in mice fed with DDC. Finally, Ang-(1-7) can decrease the atrogin-1 and MuRF-1 expression as well as the autophagy marker in mice treated with DDC. Together, our data support the protective role of Ang-(1-7) on the sarcopenia by CLD in mice.

Topics: Angiotensin I; Animals; Autophagy; Biomarkers; Chronic Disease; Fibrosis; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Muscle Proteins; Muscle Strength; Muscle, Skeletal; Muscular Atrophy; Peptide Fragments; Proteasome Endopeptidase Complex; Sarcopenia; SKP Cullin F-Box Protein Ligases; Tripartite Motif Proteins; Ubiquitin; Ubiquitin-Protein Ligases

The effect of the heptapeptide hormone Ang-(1-7) on microvascular fibrosis in rats with Ang II-induced hypertension was investigated, since vascular fibrosis/remodeling plays a prominent role in hypertension-induced end-organ damage and Ang-(1-7) inhibits vascular growth and fibrosis.. Fibrosis of cremaster microvessels was studied in male Lewis rats infused with Ang II and/or Ang-(1-7).. Ang II elevated systolic blood pressure by approximately 40 mmHg, while blood pressure was not changed by Ang-(1-7). Ang II increased perivascular fibrosis surrounding 20-50 μm arterioles as well as interstitial fibrosis; coadministration of Ang-(1-7) prevented the increases in fibrosis. The fibrotic factor CTGF and phospho-Smad 2/3, which upregulates CTGF, were increased by Ang II; this effect was prevented by coadministration of Ang-(1-7). Although TGF-β phosphorylates Smad 2/3, TGF-β was no different among treatment groups. In contrast, Ang II increased the MAP kinase phospho-ERK1/2, which also phosphorylates Smad; p-ERK was reduced by Ang-(1-7). Ang-(1-7), in the presence or absence of Ang II, upregulated the MAP kinase phosphatase DUSP1.. These results suggest that Ang-(1-7) increases DUSP1 to reduce MAP kinase/Smad/CTGF signaling and decrease fibrosis in resistance arterioles, to attenuate end-organ damage associated with chronic hypertension.

Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Arterioles; Blood Pressure; Chronic Disease; Connective Tissue Growth Factor; Dual Specificity Phosphatase 1; Fibrosis; Hypertension; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3; Muscle, Skeletal; Peptide Fragments; Phosphorylation; Rats; Rats, Inbred Lew; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Vasoconstrictor Agents

The midbrain periaqueductal gray (PAG) is an integrative neural site in regulating several physiological functions including cardiovascular activities driven by sympathetic nervous system. Specifically, activation of the dorsolateral PAG (dl-PAG) leads to increases in sympathetic nervous activity and arterial blood pressure. Our recent studies demonstrated that angiotensin-(1-7) [Ang-(1-7)] plays an inhibitory role in neuronal activity of the dl-PAG via a Mas-R [Ang-(1-7) receptor] and neuronal NO dependent signaling pathway (Mas-R-nNOS). Because sympathetic nervous activity is augmented in chronic heart failure (HF), the present study was to determine (1) the levels of Ang-(1-7) and Mas-R-nNOS expression within the dl-PAG of control rats and rats with HF and (2) the role for Ang-(1-7) in modulating activity of dl-PAG neurons in both groups. Results showed that chronic HF decreased the levels of Ang-(1-7) and attenuated Mas-R-nNOS pathways. Also, we demonstrated that the discharge rates of dl-PAG neurons of HF rats (5.52 ± 0.52 Hz, n=21, P<0.05 vs. control) were augmented as compared with control rats (4.03 ± 0.39 Hz, n=28) and an inhibitory role played by Ang-(1-7) in neuronal activity of the dl-PAG was significantly decreased in HF (51 ± 6%, P<0.05 vs. control) as compared with controls (72 ± 8%). Our findings suggest that the inhibitory effects of Ang-(1-7) on dl-PAG neurons are impaired in HF, likely due to attenuated Mas-R-nNOS signaling pathways.

Topics: Angiotensin I; Animals; Chronic Disease; Heart Failure; Male; Neurons; Nitric Oxide Synthase Type I; Peptide Fragments; Periaqueductal Gray; Rats, Sprague-Dawley; Receptors, Angiotensin; Signal Transduction

Chronic cerebral hypoperfusion (CCH) is associated with cognitive decline in aging, vascular dementia and Alzheimer׳s disease. Recently, angiotensin-(1-7) (Ang-(1-7)), one of the physiological constituents of the brain, was found to protect against cognitive dysfunction and brain ischemia. However, the effects of Ang-(1-7) on CCH-induced cognitive deficits remained unknown. In the present study, Ang-(1-7) significantly alleviated CCH-induced cognitive deficits in rats subjected to permanent bilateral occlusion of the common carotid arteries (a model of CCH). This neuroprotective effect was associated with increased nitric oxide generation, attenuated neuronal loss and suppressed astrocyte proliferation in the hippocampus. These findings demonstrate that Ang-(1-7) is a promising therapeutic agent for CCH-induced cognitive deficits.

Topics: Angiotensin I; Animals; Astrocytes; Blood Pressure; Brain Ischemia; Carotid Artery, Common; Cell Death; Cell Proliferation; Chronic Disease; Cognition Disorders; Disease Models, Animal; Hippocampus; Male; Maze Learning; Neurons; Neuroprotective Agents; Nitric Oxide; Peptide Fragments; Rats, Wistar

AVE 0991 (AVE) is a non-peptide compound, mimic of the angiotensin (Ang)-(1-7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)-induced chronic allergic lung inflammation.. We used BALB/c mice (6-8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 μg·mouse(-1) , i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg(-1) ·per day, s.c.) or saline (100 μL·kg(-1) ·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates.. Treatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL-5 and increased IL-10 levels in the BAL, accompanied by decreased Ang II levels in lungs.. AVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang-(1-7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.

Topics: Airway Remodeling; Angiotensin I; Angiotensin II; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Chronic Disease; Cytokines; Disease Models, Animal; Hypertrophy, Right Ventricular; Imidazoles; Lung; Male; Mice; Mice, Inbred BALB C; Molecular Mimicry; Ovalbumin; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Artery; Pulmonary Veins; Receptors, G-Protein-Coupled; Time Factors

In chronic heart failure (CHF), arterial baroreflex function is impaired, in part, by activation of the central renin-angiotensin system. A metabolite of angiotensin (Ang) II, Ang-(1-7), has been shown to exhibit cardiovascular effects that are in opposition to that of Ang II. However, the action of Ang-(1-7) on sympathetic outflow and baroreflex function is not well understood, especially in CHF. The aim of this study was to determine the effect of intracerebroventricular infusion of Ang-(1-7) on baroreflex control of heart rate and renal sympathetic nerve activity in conscious rabbits with CHF. We hypothesized that central Ang-(1-7) would improve baroreflex function in CHF. Ang-(1-7) (2 nmol/1 μL per hour) or artificial cerebrospinal fluid (1 μL per hour) was infused by an osmotic minipump for 4 days in sham and pacing-induced CHF rabbits (n=3 to 6 per group). Ang-(1-7) treatment had no effects in sham rabbits but reduced heart rate and increased baroreflex gain (7.4±1.5 versus 2.5±0.4 bpm/mm Hg; P<0.05) in CHF rabbits. The Ang-(1-7) antagonist A779 (8 nmol/1 μL per hour) blocked the improvement in baroreflex gain in CHF. Baroreflex gain increased in CHF+Ang-(1-7) animals when only the vagus was allowed to modulate baroreflex control by acute treatment with the β-1 antagonist metoprolol, indicating increased vagal tone. Baseline renal sympathetic nerve activity was significantly lower, and baroreflex control of renal sympathetic nerve activity was enhanced in CHF rabbits receiving Ang-(1-7). These data suggest that augmentation of central Ang-(1-7) inhibits sympathetic outflow and increases vagal outflow in CHF, thus contributing to enhanced baroreflex gain in this disease state.

Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Baroreflex; Chronic Disease; Consciousness; Disease Models, Animal; Heart Failure; Heart Rate; Infusions, Intraventricular; Kidney; Male; Metoprolol; Peptide Fragments; Rabbits; Sympathetic Nervous System; Vagus Nerve

Angiotensin-converting enzyme 2 (ACE2) is expressed at high levels in the kidney and converts angiotensin II (ANG II) to ANG-(1-7). We studied the effects of ACE2 inhibition and ANG-(1-7) in the (5/6) nephrectomy ((5/6) Nx) mouse model of chronic kidney disease (CKD). Male FVB mice underwent sham surgery (Sham) or (5/6) Nx and were administered either vehicle, the ACE2 inhibitor MLN-4760 (MLN), the AT(1) receptor antagonist losartan, MLN plus losartan, or ANG-(1-7) for 4 wk. In (5/6) Nx mice with or without MLN, kidney cortical ACE2 protein expression was significantly decreased at 4 wk, compared with Sham. Inhibition of ACE2 caused a decrease in renal cortical ACE2 activity. Kidney cortical ACE expression and activity did not differ between groups of mice. In (5/6) Nx mice treated with MLN, kidney levels of ANG II were significantly increased, compared with Sham. (5/6) Nx induced a mild but insignificant increase in blood pressure (BP), a 50% reduction in FITC-inulin clearance, and a significant increase in urinary albumin excretion. ACE2 inhibition in (5/6) Nx mice did not affect BP or FITC-inulin clearance but significantly increased albuminuria compared with (5/6) Nx alone, an effect reversed by losartan. Treatment of (5/6) Nx mice with ANG-(1-7) increased kidney and plasma levels of ANG-(1-7) but did not alter BP, FITC-inulin clearance, or urinary albumin excretion, and it increased relative mesangial area. These data indicate that kidney ACE2 is downregulated in the early period after (5/6) Nx. Inhibition of ACE2 in (5/6) Nx mice increases albuminuria via an AT(1) receptor-dependent mechanism, independent of BP. In contrast, ANG-(1-7) does not affect albuminuria after (5/6) Nx. We propose that endogenous ACE2 is renoprotective in CKD.

Topics: Albuminuria; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Chronic Disease; Disease Models, Animal; Glomerular Filtration Rate; Hematocrit; Imidazoles; Infusion Pumps; Injections, Subcutaneous; Inulin; Kidney; Kidney Diseases; Leucine; Losartan; Male; Mice; Nephrectomy; Organ Size; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Time Factors

Angiotensin converting enzyme (ACE) 2 is a recently identified homologue of ACE that may counterregulate the actions of angiotensin (Ang) II by facilitating its breakdown to Ang 1-7. The renin-angiotensin system (RAS) has been implicated in the pathogenesis of cirrhosis but the role of ACE2 in liver disease is not known.. This study examined the effects of liver injury on ACE2 expression and activity in experimental hepatic fibrosis and human cirrhosis, and the effects of Ang 1-7 on vascular tone in cirrhotic rat aorta.. In sham operated and bile duct ligated (BDL) rats, quantitative reverse transcriptase-polymerase chain reaction was used to assess hepatic ACE2 mRNA, and western blotting and immunohistochemistry to quantify and localise ACE2 protein. ACE2 activity was quantified by quenched fluorescent substrate assay. Similar studies were performed in normal human liver and in hepatitis C cirrhosis.. ACE2 mRNA was detectable at low levels in rat liver and increased following BDL (363-fold; p < 0.01). ACE2 protein increased after BDL (23.5-fold; p < 0.05) as did ACE2 activity (fourfold; p < 0.05). In human cirrhotic liver, gene (>30-fold), protein expression (97-fold), and activity of ACE2 (2.4 fold) were increased compared with controls (all p < 0.01). In healthy livers, ACE2 was confined to endothelial cells, occasional bile ducts, and perivenular hepatocytes but in both BDL and human cirrhosis there was widespread parenchymal expression of ACE2 protein. Exposure of cultured human hepatocytes to hypoxia led to increased ACE2 expression. In preconstricted rat aorta, Ang 1-7 alone did not affect vascular tone but it significantly enhanced acetylcholine mediated vasodilatation in cirrhotic vessels.. ACE2 expression is significantly increased in liver injury in both humans and rat, possibly in response to increasing hepatocellular hypoxia, and may modulate RAS activity in cirrhosis.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Aorta, Thoracic; Carboxypeptidases; Cell Hypoxia; Cells, Cultured; Chronic Disease; Disease Models, Animal; Female; Hepatitis C, Chronic; Hepatocytes; Humans; Immunoenzyme Techniques; Liver; Liver Cirrhosis; Male; Nitroimidazoles; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation; Vasodilation

The following studies were designed to test the hypothesis that Ang (1-7) contributes to the chronic hypotensive effects of the angiotensin II AT(1)-receptor antagonist, losartan, in normal rats.. We have previously shown a chronic, hypotensive response to the AT(1)-receptor antagonist, losartan, in normotensive rats. The mechanism of this response is not completely understood. Previous studies by others have demonstrated a role for Ang (1-7) in the beneficial antihypertensive effects of angiotensin-converting enzyme (ACE) inhibition. This is thought to be due to vasodilatory effects of increased levels of Ang (1-7) during ACE inhibition. Since it has now been shown that Ang (1-7) levels are also increased during AT(1) antagonism, we designed experiments to test the hypothesis above.. Sprague-Dawley rats were instrumented with venous catheters and radiotelemetric pressure transducers and commenced on a normal (0.4%) NaCl diet. Arterial pressure responses were measured in rats treated with losartan (10 mg/kg/day) (LOS rats, n=8) and compared with those treated with losartan and the Ang (1-7) antagonist, A779 (24 g/kg/hour) (A779/LOS rats, n=11) for 10 days.. By day 7 of treatment, mean arterial pressure had dropped by 27+1 mmHg in LOS rats, in contrast with a decrease of only 21+2 mmHg in A779/LOS rats. This attenuated response in rats treated with A779 became more prominent and continued through day 10 of losartan treatment.. These results support the hypothesis that the chronic hypotensive effects of losartan in normal rats are mediated in part through the actions of Ang (1-7).

Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Chronic Disease; Drug Interactions; Heart Rate; Hypotension; Losartan; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley

The efficacy of ACE inhibitors (ACEIs) in the treatment of chronic heart failures is well documented. However, ACEIs may provide incomplete blockade of the renin-angiotensin system (RAS) because of the alternative pathways for angiotensin II (All) production. We hypothesized that more complete blockade of RAS by adding an AT1 receptor blocker (ARB) may have greater potential to decrease mortality associated with heart failure and improve cardiac function than monotherapy with ACEIs. The objective of this study was to evaluate the effect of combined therapy on cardiac functions and survival in cardiomyopathic hamsters. Male cardiomyopathic hamsters (BIO TO2) were administered either placebo (group C), enalapril (30 mg/kg/day) (group E), or enalapril (30 mg/kg/day) + valsartan (500 mg/ kg/day) (group EV), starting at the age of 6 weeks. Kaplan-Meier analysis was performed to assess the differences in survival. Cardiac functions were evaluated by echocardiogram and cardiac catheterization. Group EV showed significant increases in fractional shortening, LV dP/dTmax, and deceleration time, and showed significant decreases in left ventricular diastolic dimension, LV dP/dTmin, and early diastolic mitral velocity/atrial systolic velocity. Treatment with enalapril resulted in longer survival compared with placebo. Moreover, life expectancy (median probability of survival: 433 days) increased significantly in group EV compared with group E (P<0.05) as well as group C (P<0.001). It is concluded that combined therapy improved cardiac function and survival compared to placebo or enalapril monotherapy.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomyopathy, Dilated; Cell Count; Chronic Disease; Cricetinae; Drug Therapy, Combination; Echocardiography, Doppler; Enalapril; Fibrosis; Hemodynamics; Male; Myocytes, Cardiac; Random Allocation; Receptors, Angiotensin; Renin-Angiotensin System

Medical treatment of chronic heart failure is applied in accordance with the recommendations of the Task Force Report of the European Society of Cardiology [9] adapted to the respective NYHA stage of the cardiac failure. Currently, it includes the use of ACE inhibitors, beta blockers, AT1 receptor antagonists, diuretics including the aldosterone antagonists, and digitalis. While a positive impact on the prognosis has been confirmed for ACE inhibitors, beta blockers and aldosterone antagonists, this is not the case for diuretics and digitalis. These substance groups are used in the treatment of chronic heart failure because of their morbidity-lowering action. The objective of more recent therapeutic concepts is to block neurohumoral achses or local maladaptation processes (e.g. endothelial antagonists, cytokine inhibition, apoptosis inhibition) activated during the heart failure, or to promote protective mechanisms (e.g. endopeptidase inhibition). Here, however, the results of ongoing or planned randomized studies have to be awaited.

Topics: Adrenergic beta-Antagonists; Angiotensin I; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiac Glycosides; Chronic Disease; Controlled Clinical Trials as Topic; Diuretics; Drug Therapy, Combination; Heart Failure; Humans; Placebos; Prognosis; Risk Factors

The present study was undertaken to clarify the role of intrarenal angiotensin (Ang) II and its generating pathways in clipped and nonclipped kidneys of 4-week unilateral renal artery stenosis in anesthetized dogs. After 4 weeks, renal plasma flow (RPF) decreased in clipped and nonclipped kidneys (baseline, 59+/-3; clipped, 16+/-1; nonclipped, 44+/-2 mL/min; P<0.01, n=22). Renal Ang I levels increased only in clipped, whereas intrarenal Ang II contents were elevated in both clipped (from 0.7+/-0.1 to 2.0+/-0.2 pg/mg tissue) and nonclipped kidneys (from 0.6+/-0.1 to 2.5+/-0.3 pg/mg tissue). Intrarenal ACE activity was increased in nonclipped kidneys but was unaltered in clipped kidneys. An angiotensin receptor antagonist (olmesartan medoxomil) given into the renal artery markedly restored RPF, and dilated both afferent and efferent arterioles (using intravital videomicroscopy). Furthermore, in clipped kidneys, the elevated Ang II was suppressed by a chymase inhibitor, chymostatin (from 2.1+/-0.6 to 0.8+/-0.1 pg/mg tissue; P<0.05), but not by cilazaprilat. In nonclipped kidneys, in contrast, cilazaprilat, but not chymostatin, potently inhibited the intrarenal Ang II generation (from 2.4+/-0.3 to 1.5+/-0.2 pg/mg tissue; P<0.05). Finally, [Pro11-D-Ala12]Ang I (an inactive precursor that yields Ang II by chymase but not by ACE; 1 to 50 nmol/kg) markedly elevated intrarenal Ang II in clipped, but not in nonclipped, kidneys. In conclusion, renal Ang II contents were elevated in both clipped and nonclipped kidneys, which contributed to the altered renal hemodynamics and microvascular tone. Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE-mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.

Topics: Angiotensin I; Angiotensin II; Animals; Chronic Disease; Chymases; Cilazapril; Dogs; Hemodynamics; Hypertension, Renal; Imidazoles; Ischemia; Kidney; Male; Oligopeptides; Olmesartan Medoxomil; Peptidyl-Dipeptidase A; Renal Circulation; Renin-Angiotensin System; Serine Endopeptidases; Tetrazoles

1. Inhibition of the renin-angiotensin system (RAS) improves symptoms and prognosis in heart failure. The experimental basis for these benefits remains unclear. We examined the effects of inhibition of ACE or blockade of angiotensin II type 1 (AT1) receptor on the haemodynamics, cardiac G-proteins, and collagen synthesis of rats with coronary artery ligation (CAL), a model in which chronic heart failure (CHF) is induced. 2. Rats were orally treated with the ACE inhibitor trandolapril (3 mg kg(-1) day(-1)) or the AT1 receptor blocker L-158809 (1 mg kg(-1) day(-1)) from the 2nd to 8th week after CAL. CAL resulted in decreases in the left ventricular systolic pressure and its positive and negative dP/dt, an increase in the left ventricular end-diastolic pressure, and the rightward shift of the left ventricular pressure-volume curve. Long-term treatment with either drug improved these signs of CHF to a similar degree. 3. Cardiac Gsalpha and Gqalpha protein levels decreased, whereas the level of Gialpha protein increased in the animals with CHF. Long-term treatment with trandolapril or L-158809 attenuated the increase in the level of cardiac Gialpha protein of the animals with CHF without affecting Gsalpha and Gqalpha protein levels. Cardiac collagen content of the failing heart increased, whose increase was blocked by treatment with either drug. 4. Exogenous angiotensin I stimulated collagen synthesis in cultured cardiac fibroblasts, whose stimulation was attenuated by either drug. 5. These results suggest that blockade of the RAS, at either the receptor level or the synthetic enzyme level, may attenuate the cardiac fibrosis that occurs after CAL and thus affect the remodelling of the failing heart.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Chronic Disease; Collagen; Dose-Response Relationship, Drug; Fibroblasts; GTP-Binding Proteins; Heart; Heart Failure; Heart Septum; Heart Ventricles; Hemodynamics; Imidazoles; Indoles; Lung; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Tetrazoles

To produce a chronical thyrotoxicosis model in rat, and to evaluate, using spectral analysis, the involvement of the renin-angiotensin system (RAS) in short-term variability of blood pressure (BP) in experimental hyperthyroidism.. Thyrotoxicosis was produced by a daily intraperitoneal (i.p.) injection of L-thyroxine (T4: 0.1 mg/kg for 15 days) in Wistar rats. Control (euthyroid) rats received i.p. daily injection of the thyroxine solvent. Two series of experiments were performed in conscious and unrestrained rats. In the first series, 10 euthyroid and 14 hyperthyroid rats were surgically prepared with a femoral artery catheter to measure BP and heart rate (HR) and to collect blood samples on the last day of treatment. In the second series of experiments (n = 12 in each group), on the fifteenth day of treatment, BP and HR were recorded by telemetry in control conditions and after a specific blockade of the RAS by the angiotensin type I receptors antagonist: valsartan (10 mg/kg, i.p.). BP recordings were analysed by the Fast Fourier Transform on consecutive 204.8-s stationary periods.. The dose and duration of T4 treatment was sufficient to induce a significant degree of hyperthyroidism with characteristic features including: tachycardia, systolic hypertension, myocardial hypertrophy, hyperthermia, and weight loss. In addition, we measured an increase in free fractions of thyroid hormones, and a 3 fold-increase of plasma renin activity. Hyperthyroidism modified systolic BP (SBP) variability profiles. An amplification of low frequency (LF) oscillations (2.37 +/- 0.12 mmHg vs 1.78 +/- 0.11 mmHg, p < 0.01) was observed after T4 treatment. In hyperthyroid rats, valsartan diminished the slow fluctuations of SBP (p < 0.001) and increased the mid-frequency oscillations (2.44 +/- 0.20 mmHg vs 1.32 +/- 0.18 mmHg, p < 0.001).. The cardiovascular alterations of hyperthyroidism are reproduced with thyroid hormone injections in rats. Activation of the RAS in hyperthyroid rats was accompanied by increased SBP variability in the LF range. Using the angiotensin type I receptors antagonist, valsartan, we demonstrated that the RAS impinged on the LF oscillations of the SBP in our experimental hyperthyroidism model.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Cardiomegaly; Chronic Disease; Disease Models, Animal; Fever; Fourier Analysis; Heart Rate; Hypertension; Hyperthyroidism; Injections, Intraperitoneal; Male; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; Signal Processing, Computer-Assisted; Tachycardia; Tetrazoles; Thyroid Hormones; Thyrotoxicosis; Thyroxine; Valine; Valsartan; Weight Loss

We tested the hypothesis that a combination of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor antagonist (AT1-ant) may have an additive cardioprotective effect in mice with heart failure (HF), because these two agents could have other mechanisms of action besides interrupting the renin-angiotensin system. ACEi prevent degradation of bradykinin. During treatment with AT1-ant, increased angiotensin II could activate AT2 receptors, with an antitrophic effect. To test this hypothesis, we used a mouse model of HF induced by myocardial infarction. Seven days after surgery, mice were divided into six groups and treated for 23 weeks: (a) sham ligation; (b) HF-vehicle; (c) HF-ACEi; (d) HF-AT1-ant; (e) HF-ACEi + AT1-ant (half dose of each); and (f) HF-ACEi + AT1-ant (full dose of each). Cardiac function was evaluated in conscious mice during the treatment period. The HF-vehicle group showed significantly decreased left ventricular (LV) ejection fraction (EF), shortening fraction (SF), and cardiac output (CO) and increased LV dimensions, interstitial collagen, and myocyte cross-sectional area (MCSA) compared with controls. Treatment with ACEi or AT1-ant significantly increased EF, SF, and CO and decreased LV dimensions and MCSA in mice with HF. However, a combination of these drugs did not improve cardiac function more than ACEi or AT1-ant alone. We concluded that ACEi and AT1-ant have similar cardioprotective effects and may reach maximal effect when given individually; thus no further improvement can be achieved with combined therapy in mice with HF.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiac Output; Chronic Disease; Echocardiography; Female; Heart; Heart Failure; Imidazoles; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Organ Size; Ramipril; Stroke Volume; Tetrazoles; Ventricular Remodeling

Five patients with chronic pulmonary diseases (3 pulmonary emphysema, 1 chronic respiratory failure caused by old tuberculosis, 1 diffuse panbronchiolitis) showed a marked increase of plasma angiotensin-I and PRA level, which was accompanied by an increase of angiotensin-II level, however, whose systemic blood pressure was not elevated. The intravenous infusion of angiotensin-II-analogue (1-Sarcosine, 8-Isoleucine-Angiotensin-II) elicited an antagonistic blood pressure response resembling Bartter's syndrome.

Topics: 1-Sarcosine-8-Isoleucine Angiotensin II; Angiotensin I; Angiotensin II; Blood Pressure; Chronic Disease; Female; Humans; Lung Diseases; Male; Renin

We compared the reactivity of pulmonary vessels to bradykinin (BK) and angiotensin I (AI) in normal and chronically hypoxic rats; the latter have pulmonary hypertension and muscularized pulmonary arterioles. These peptides are respectively inactivated and activated by the angiotensin converting-enzyme (ACE) on pulmonary endothelium. Isolated lungs were perfused at a constant flow rate when changes in pulmonary artery pressure (Ppa) reflect changes in vascular resistance. Dose-response curves to BK (1 ng-10 micrograms) were derived during normoxia and pre-constriction by hypoxia; BK both decreased and increased vascular resistance, i.e. vasodilation and vasoconstriction. In normal rats only constriction was seen in normoxia, which reflected low basal vascular tone, whereas in chronically hypoxic rats there was only dilatation which reflected high basal vascular tone. In hypoxia in normal rats, low doses caused dilatation, high doses constriction; in chronically hypoxic rats there was again only dilatation which was larger than in controls. After the ACE-inhibitor captopril, constriction was exaggerated in control rats in both normoxia and hypoxia and took place in chronically hypoxic rats after high doses in both normoxia and hypoxia; oedema often followed. Dose-response curves to AI (1 ng-micrograms) in normoxia showed greatly enhanced pressor responses in chronically hypoxic compared with normal rats, probably attributable to increased sensitivity to angiotensin II (AII) rather than enhanced conversion of AI to AII. Captopril caused a proportionate reduction in responses in both groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin I; Animals; Blood Pressure; Bradykinin; Captopril; Chronic Disease; Dose-Response Relationship, Drug; Hypoxia; Male; Pulmonary Artery; Rats; Rats, Inbred Strains; Vasoconstriction; Vasodilation

1. The effects of heart failure due to chronic myocardial infarction on the responsiveness to injected angiotensin I and ACE inhibition by intravenous cilazapril (1 mg kg-1) were evaluated. 2. For this purpose one group of 17 rats with a 4-week old myocardial infarction was compared with a group of 10 sham operated rats. 3. Heart failure increased markedly the responsiveness of the renal and mesenteric vascular beds to ACE inhibition which produced a vasodilation in these two vascular beds. 4. This increased responsiveness was most likely due to a stimulation of the renin-angiotensin system without any change of sensitivity to angiotensin I of the renal and mesenteric vascular beds. 5. Cilazapril produced the same level of ACE inhibition in both groups of rats.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Cilazapril; Heart Failure; Hemodynamics; Myocardial Infarction; Myocardium; Pyridazines; Rats; Rats, Inbred Strains; Vascular Resistance

The high pressure muscular pulmonary circulation of chronically hypoxic (CH) rats was compared with the low pressure circuit in control (C) rats; differences were found in the effects of lung inflation, in pressure/flow relations during lung inflation, in reactivity to autocoids, and in responses to pulmonary dilator drugs. Isolated blood-perfused lungs of CH rats (2 to 3 wk in 10% O2) were compared with those of C rats kept in air. High inflation (alveolar) pressure (Palv) caused a rise in pulmonary artery pressure (Ppa) close to delta Palv in both groups; in CH rats, Ppa continued to rise, whereas it adapted to a lower level in C rats. Pressure-flow (P/Q) lines were measured at high and low Palv, all in Zone 2 state. In normoxia, high Palv caused a parallel shift in the P/Q line close to delta Palv in both C and CH rats. However, during hypoxic pulmonary vasoconstriction (HPV), high Palv caused a shift in the P/Q line less than delta Palv in C rats and greater than delta Palv in CH rats. Similar differences between C and CH rats were seen during constriction caused by almitrine, a drug that simulates HPV. Thus, these stimuli affect vessels that are functionally "extra-alveolar" in C rats but functionally "alveolar" in CH rats. We consider whether vasoconstriction by hypoxia and almitrine moves peripherally to the newly muscularized alveolar arterioles that are found in CH rats. Reactivity of lung vessels to bradykinin, angiotensin-1, and platelet-activating factor was greater in CH than in C rats, possibly also associated with muscularization of arterioles in the former.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Almitrine; Angiotensin I; Animals; Bradykinin; Chronic Disease; Hypoxia; Male; Platelet Activating Factor; Pulmonary Circulation; Pyrazines; Rats; Rats, Inbred Strains; Reference Values; Respiration; Vasoconstriction; Vasodilator Agents; Vasomotor System

This study tested the hypothesis that interactions of endogenous angiotensin II (AII) with the noradrenergic neuroeffector junction are important in renin-dependent hypertension. In the in situ blood-perfused rat mesentery, in normal rats exogenous AII potentiated mesenteric vascular responses to periarterial (sympathetic) nerve stimulation (PNS) more than vascular responses to exogenous norepinephrine (NE). In 2-kidney-1-clip (2K-1C) rats with renovascular hypertension mesenteric vascular responses to PNS and NE were greater than in sham-operated rats, and renovascular hypertension mimicked the effects of exogenous AII with respect to enhancing responses to PNS more than responses to NE. In 2K-1C rats, but not in sham-operated rats, 1-Sar-8-Ile-AII markedly suppressed vascular responses to PNS, without influencing responses to NE. Finally, 1-Sar-8-Ile-AII attenuated sympathetic nerve stimulation-induced neuronal spillover of NE in 2K-1C rats, but not in sham-operated rats. These data indicate that renovascular hypertension enhances noradrenergic neurotransmission, and that this enhancement is mediated in part by AII-induced facilitation of NE release.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Chronic Disease; Electric Stimulation; Hypertension, Renovascular; Norepinephrine; Rats; Renal Artery; Renin; Sympathetic Nervous System; Vascular Resistance

The effects of exposing rats to hypoxia at normal atmospheric pressure for periods of 21-24 days on intrapulmonary conversion of angiotensin I (ANG I) to angiotensin II (ANG II) were examined using an isolated rat lung preparation perfused at constant flow. 125I-ANG I (160 fmol) was injected alone and with graded doses (0.1, 1.0, and 100 nmol) of unlabeled ANG I into the pulmonary artery, and the effluent was collected for measurement of ANG I, ANG II, and metabolites. At low doses of injected ANG I (125I-ANG I alone or with 0.1 or 1.0 nmol unlabeled ANG I), the percent conversion of ANG I to ANG II was 67.5 +/- 2.1 (SE), 65.1 +/- 2.0, and 62.5 +/- 1.6 in 21-day hypoxia-exposed animals and 83.8 +/- 2.7, 81.4 +/- 3.9, and 79.6 +/- 2.3 (P less than 0.01) in control rats maintained under normoxic conditions. At the highest dose (100 nmol) of injected ANG I, percent conversion was reduced in both hypoxic and control groups to 46.8 +/- 5.0 and 64.0 +/- 6.0, respectively (P less than 0.05). Mean transit times of labeled material through the pulmonary circulation were not significantly different in hypoxic vs. normoxic lungs at any ANG I load, suggesting that the decreased conversion seen in hypoxic lungs was not related to altered kinetics of substrate exposure. Thus chronic hypoxia is associated with significant inhibition of transpulmonary ANG I conversion that is independent of perfusate flow. We postulate that this phenomenon is due to alterations at the endothelial membrane level.

Topics: Angiotensin I; Angiotensin II; Angiotensins; Animals; Chronic Disease; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Lung; Male; Peptidyl-Dipeptidase A; Perfusion; Pulmonary Circulation; Rats; Rats, Inbred Strains

In nine patients with severe, treatment-resistant heart failure (stages IV in the NYHA classification) the acute and long-term effect of captopril were studied. In the acute experiment, peripheral resistance fell by 27% after administration of 25 mg captopril, cardiac index rose by 25%, arterial pressure, pulmonary arterial pressure and mean right atrial pressure fell by a similar amount. This haemodynamic improvement increased slightly in the course of longterm treatment (cardiac index +30%, peripheral resistance -30%, mean pulmonary arterial pressure -42%). The fall in heart rate by 15% and 25%, respectively, was an expression of haemodynamic improvement and reduction in angiotensin II. The fall in peripheral vascular resistance coincided with a 50% reduction in angiotensin II concentration. Over the longer term, 2-42 weeks, the renin system stimulation regressed with the improvement in haemodynamics. Four of the nine patients in stage IV improved to stage II, while the remaining five patients improved from IV to III.

Topics: Adult; Aged; Angiotensin I; Angiotensin II; Captopril; Chronic Disease; Drug Evaluation; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Proline; Time Factors

Topics: Aldosterone; Angiotensin I; Angiotensins; Chronic Disease; Humans; Hypertension; Hypertension, Pulmonary; Lung Diseases; Male; Middle Aged