Biomedical subjects

M Duriez

Publications and source records attributed to M Duriez.

At least 19 recordsLinked to original sources

PubMed2001

Increased ischemia-induced angiogenesis in the staggerer mouse, a mutant of the nuclear receptor Roralpha.

Ror alpha is an orphan nuclear receptor. In homozygous staggerer mutant mice (Ror alpha(sg/sg)), a deletion within the Ror alpha gene leads to an overexpression of inflammatory cytokines. Because inflammation and hypoxia are 2 key stimuli of ischemia-induced angiogenesis, we studied the role of Ror alpha in this setting. Ischemia was induced by ligation of the right femoral artery in C57BL/6 Ror alpha(+/+) and Ror alpha(sg/sg) mice. After 3 and 28 days, angiogenesis was evaluated by microangiography, measurement of capillary density using immunohistochemistry (anti-CD31), and measurement of blood flow by laser Doppler imaging. At day 3, angiographic score and blood flow were similar in Ror alpha(sg/sg) mice and in Ror alpha(+/+) littermates. Conversely, at day 28, Ror alpha(sg/sg) mice showed a significant 2-fold increase in angiographic score and a 3-fold increase in capillary density within the ischemic hindlimb compared with control. Functionally, this coincided with a significant rise in leg perfusion in Ror alpha(sg/sg) mice (0.83+/-0.05 for ischemic/nonischemic leg perfusion ratio) compared with Ror(+/+) mice (0.66+/-0.04, P<0.05). In addition, more extensive angiogenesis in Ror alpha(sg/sg) mice correlated with an increased expression of eNOS protein by 83+/-12% and 71+/-24% at 3 and 28 days, respectively (P<0.05), whereas the level of the antiangiogenic cytokine IL-12 was significantly reduced by 38+/-10% at day 28 (P<0.05). Conversely, no changes in VEGF expression were observed. Our study identifies for the first time a new role for Ror alpha as a potent negative regulator of ischemia-induced angiogenesis.

Animals↗

PubMed2001

Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B(2) receptor pathway.

Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effect of ACE inhibition may be mediated, in part, by bradykinin (BK) B(2)-receptor pathway. This study therefore examined the neovascularization induced by ACE inhibitor treatment in B(2) receptor-deficient mice (B(2)(-/-)) in a model of surgically induced hindlimb ischemia. After artery femoral occlusion, wild-type and B(2)(-/-) mice were treated with or without ACE inhibitor (perindopril, 3 mg/kg/d) for 28 days. Angiogenesis was then quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. The protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were determined by Western blot. In wild-type animals, vessel density and capillary number in the ischemic leg were raised by 1.8- and 1.4-fold, respectively, in mice treated with ACE inhibitor when compared with the nontreated animals (P<0.01). This corresponded to an improved ischemic/nonischemic leg perfusion ratio by 1.5-fold in ACE inhibitor-treated animals when compared with the untreated ones (0.87+/-0.07 versus 0.59+/-0.05, respectively, P<0.01). Activation of the angiogenic process was also associated with a 1.7-fold increase in tissue eNOS protein level in mice treated with ACE inhibitor (P<0.05 versus control) but not with changes in VEGF protein level. Conversely, ACE inhibition did not affect vessel density, blood flow, and eNOS protein level in ischemic hindlimb of B(2)(-/-) mice. Therefore, proangiogenic effect of ACE inhibition is mediated by B(2)-receptor signaling and was associated with upregulation of eNOS content, independently of VEGF expression.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2001

Regulation of matrix metalloproteinase activity in ischemic tissue by interleukin-10: role in ischemia-induced angiogenesis.

We have previously shown that deficiency in the anti-inflammatory cytokine interleukin-10 (IL-10) is responsible for enhanced angiogenesis after hindlimb ischemia. This study examined the putative involvement of matrix metalloproteinase (MMP) activation in this process. Ischemia was produced by artery femoral occlusion in both C57BL6 IL-10(+/+) and IL-10(-/-) mice. Angiographic vessel density and laser Doppler perfusion data at day 28 showed significant improvement in ischemic/nonischemic leg ratio by, respectively, 1.8-fold and 1.4-fold in IL-10(-/-) mice compared with IL-10(+/+) mice. This was associated with an increase in vascular endothelial growth factor (VEGF) protein content in the ischemic hindlimb. Three days after ischemia, gelatin zymography showed a significant increase in both pro- and active forms of MMP-2 and MMP-9 in ischemic hindlimbs of IL-10(-/-) mice compared with IL-10(+/+) mice (P<0.01). This increase in MMP activity in IL-10(-/-) mice was completely inhibited by treatment with BB-94 (5 mg/kg IP), a specific MMP inhibitor. Furthermore, increases in both vessel density and blood perfusion indexes at day 28 in IL-10(-/-) mice were abolished after treatment with BB-94 (0.78+/-0.06 versus 1.17+/-0.09 and 0.62+/-0.02 versus 0.88+/-0.04, for vessel density and blood perfusion ratio, respectively, in IL-10(-/-) mice treated with BB-94 versus untreated IL-10(-/-) mice, P<0.05). In contrast, BB-94 treatment did not affect the rise in VEGF protein content. These findings in IL-10(-/-) mice underscore the critical role of MMP activation, in a context of increased VEGF expression, in promoting ischemia-induced angiogenesis.

Angiography↗

PubMed2001

Flow (shear stress)-induced endothelium-dependent dilation is altered in mice lacking the gene encoding for dystrophin.

BACKGROUND: Dystrophin has a key role in striated muscle mechanotransduction of physical forces. Although cytoskeletal elements play a major role in the mechanotransduction of pressure and flow in vascular cells, the role of dystrophin in vascular function has not yet been investigated. Thus, we studied endothelial and muscular responses of arteries isolated from mice lacking dystrophin (mdx mice). METHODS AND RESULTS: Carotid and mesenteric resistance arteries 120 micrometer in diameter were isolated and mounted in vitro in an arteriograph to control intraluminal pressure and flow. Blood pressure was not affected by the absence of dystrophin. Pressure-induced (myogenic), phenylephrine-induced, and KCl-induced forms of tone were unchanged. Flow (shear stress)-induced dilation in arteries isolated from mdx mice was decreased by 50% to 60%, whereas dilation to acetylcholine or sodium nitroprusside was unaffected. NG-nitro-L-arginine methyl ester-sensitive flow dilation was also decreased in arteries from mdx mice. Thus, the absence of dystrophin was associated with a defect in signal transduction of shear stress. Dystrophin was present in vascular endothelial and smooth muscle cells, as shown by immunolocalization, and localized at the level of the plasma membrane, as seen by confocal microscopy of perfused isolated arteries. CONCLUSIONS: -This is the first functional study of arteries lacking the gene for dystrophin. Vascular reactivity was normal, with the exception of flow-induced dilation. Thus, dystrophin could play a specific role in shear-stress mechanotransduction in arterial endothelial cells. Organ damage in such diseases as Duchenne dystrophy might be aggravated by such a defective arterial response to flow.

Acetylcholine↗

PubMed2001

Coronary microvasculature alteration in hypertensive rats. Effect of treatment with a diuretic and an ACE inhibitor.

The development of hypertension is accompanied by rarefaction of arterioles and capillaries in both animal models and humans. Although many studies have examined the effects of antihypertensive therapies on hemodynamics, cardiac hypertrophy, and large vessel structure, the question of whether changes in microvascular density induced by hypertension can be restored by pharmacologic treatment has yet to be answered. We report a series of experiments performed in rats with renovascular hypertension induced by unilateral nephrectomy and renal artery stenosis (Goldblatt one-kidney, one-clip model). Animals were treated for 4 weeks, after renal artery clipping, either with an angiotensin converting enzyme inhibitor (perindopril [PER], 0.76 mg/kg/day), or with an indol derivative diuretic with specific vascular properties (indapamide [IDP], 0.24 mg/kg/day) or with the combination of both drugs at the same doses as during monotherapy. Coronary microvessel densities (arterioles and capillaries) were evaluated by double immunolabeling in nonserial cryostat sections of the left ventricular inner myocardium. After 4 weeks of hypertension (mean arterial pressure, 174+/-11 v 124+/-5 mm Hg in normotensive (NT) controls, P < .01), cardiac hypertrophy (+59%, P < .001) was associated with a significant increase in myocardial arteriolar density (+27%, P < .01), and a decrease in capillary density (-12%, P < .05). Treatment with PER prevented the increase in arterial pressure, heart weight, and arteriolar density, but did not significantly affect the low coronary capillary density in comparison with that measured in untreated hypertensive (HT) rats. Treatment with IDP preserved normal capillary myocardial density but did not significantly lower the blood pressure (BP) (169+/-9 mm Hg) and only slightly reduced the cardiac ventricular hypertrophy: - 14% v untreated HT (P < .05) and +37% v NT (P < .01). In the same way, IDP normalized the left ventricular capillary density in spontaneously HT rats (+18% v untreated rats, P < .01). The combination of both drugs, PER and IDP, at the same low doses as during monotherapy, resulted in normal levels of arterial pressure and complete normalization of cardiac hypertrophy and arteriolar and capillary myocardial densities. In conclusion, the results observed after PER suggest that blockade of the renin-angiotensin system could inhibit large coronary vessel growth but minimally affects the capillary density despite complete normalization of BP. Indapamide could have beneficial effect on myocardial capillary density. The combination of IDP and PER has additional effects and prevents the increase in BP and cardiac weight, and reverses microvascular rarefaction, specifically arteriolar and capillary densities.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2001

Chronic blockade of endothelin receptors improves ischemia-induced angiogenesis in rat hindlimbs through activation of vascular endothelial growth factor-no pathway.

This study investigated in vivo the putative angiogenic role of endothelin (ET)-1 in a model of ischemia-induced angiogenesis. Ischemia was produced by unilateral femoral artery occlusion in Wistar rats submitted to either chronic ET-1 infusion (2 nmol. kg(-1). min(-1)) or to a dual ET(A)/ET(B) receptor antagonist (bosentan, 100 mg. kg(-1). d(-1)) for 3 and 28 days. Arterial density was evaluated by microangiography and measurement of capillary and arteriolar density in hindlimb muscles. ET-1 infusion had no effect on ischemia-induced angiogenesis and was associated with a slight decrease in vascular endothelial growth factor (VEGF) content measured by Western blot analysis. Conversely, bosentan induced a marked increase in vessel density at 3 and 28 days (1.4-fold and 1.7-fold, respectively, compared with no treatment; P<0.05), which was associated with an increase in VEGF and endothelial NO synthase levels in ischemic legs (by 31+/-8% and 45+/-23%, respectively, at 3 days and by 65+/-13% and 55+/-15%, respectively, at 28 days; P<0.05 versus nontreated rats). At day 28, the proangiogenic effect of bosentan was abolished when NO synthesis inhibitor N(G)-nitro-L-arginine methyl ester (10 mg. kg(-1). d(-1)) or VEGF-neutralizing antibody (2.5 micro/kg twice a week) were coadministered with bosentan. Those results provide the first evidence of an early and sustained proangiogenic effect of endothelin antagonism associated with an upregulation of VEGF and endothelial NO synthase in vivo.

Animals↗

PubMed2000

Antiangiogenic effect of interleukin-10 in ischemia-induced angiogenesis in mice hindlimb.

Ischemia induces both hypoxia and inflammation that trigger angiogenesis. The inflammatory reaction is modulated by production of anti-inflammatory cytokines. This study examined the potential role of a major anti-inflammatory cytokine, interleukin (IL)-10, on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by artery femoral occlusion in both C57BL/6J IL-10(+/+) and IL-10(-/-) mice. After 28 days, angiogenesis was quantified by microangiography, capillary, and arteriole density measurement and laser Doppler perfusion imaging. The protein levels of IL-10 and vascular endothelial growth factor (VEGF) were determined by Western blot analysis in hindlimbs. IL-10 was markedly expressed in the ischemic hindlimb of IL-10(+/+) mice. Angiogenesis in the ischemic hindlimb was significantly increased in IL-10(-/-) compared with IL-10(+/+) mice. Indeed, angiographic data showed that vessel density in the ischemic leg was 10.2+/-0.1% and 5.7+/-0.4% in IL-10(-/-) and IL-10(+/+) mice, respectively (P:<0.01). This corresponded to improved ischemic/nonischemic leg perfusion ratio by 1.4-fold in IL-10(-/-) mice compared with IL-10(+/+) mice (0.87+/-0. 05 versus 0.63+/-0.01, respectively; P:<0.01). Revascularization was associated with a 1.8-fold increase in tissue VEGF protein level in IL-10(-/-) mice compared with IL-10(+/+) mice (P:<0.01). In vivo electrotransfer of murine IL-10 cDNA in IL-10(-/-) mice significantly inhibited both the angiogenic process and the rise in VEGF protein level observed in IL-10(-/-) mice. No changes in vessel density or VEGF content were observed in the nonischemic hindlimb. These findings underscore the antiangiogenic effect of IL-10 associated with the downregulation of VEGF expression and suggest a role for the inflammatory balance in the modulation of ischemia-induced angiogenesis.

Animals↗

PubMed2000

Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure.

BACKGROUND: We hypothesized that, in compensated heart failure (HF), hemodynamic perturbations and their consequences exist in pulmonary artery (PA) despite the absence of any perturbation in thoracic aorta (TA). METHODS AND RESULTS: The left coronary artery was ligated in 20 male Wistar rats with compensated HF. Four months after ligation, these rats were compared with 20 sham-operated control rats. Blood pressure, velocity, viscosity, luminal diameter, and wall tensile and shear stresses were determined in PA and TA. Arterial rings were mounted in a myograph for ex vivo study. Endothelial nitric oxide synthase (eNOS) mRNA expression was determined in lung and aorta. Sections of PA and TA were used for histomorphometric study. In PA from rats with compensated HF, (1) blood pressure and wall tensile stress increased, whereas blood velocity and wall shear stress decreased; (2) contractions to KCl were not altered, but maximal contraction to phenylephrine and EC(50) decreased; (3) endothelium-dependent relaxation to acetylcholine and basal NO activity were blunted, whereas endothelium-independent relaxation was preserved; (4) eNOS mRNA levels and eNOS transcription in lung nuclei decreased; and (5) medial cross-sectional area, thickness, smooth muscle cell number, elastin, and collagen contents increased. Conversely, no such changes were found in TA from rats with compensated HF. CONCLUSIONS: In compensated HF induced by small myocardial infarction, hemodynamics, vascular wall function, and structure are altered in PA but preserved in TA. These results indicate that the pulmonary vascular bed is an early target of regional circulatory alterations in HF.

Animals↗

PubMed2000

[Is there agreement on the determination of public health priorities in Europe?].

Inspired by the WHO document, "Health for All in the Year 2000", and by the WHO European office's definition of 38 health objectives, several European countries have begun defining their health priorities. An analysis of the definition of these priorities shows that there exist common points among them. However, each country constructed its own process for decision making that was unique to its situation and implemented different strategies for engaging its citizens in their processes.

Decision Making, Organizational↗

PubMed1999

Protective role of interleukin-10 in atherosclerosis.

The potential role of anti-inflammatory cytokines in the modulation of the atherosclerotic process remains unknown. Interleukin (IL)-10 has potent deactivating properties in macrophages and T cells and modulates many cellular processes that may interfere with the development and stability of the atherosclerotic plaque. IL-10 is expressed in human atherosclerosis and is associated with decreased signs of inflammation. In the present study, we show that IL-10-deficient C57BL/6J mice fed an atherogenic diet and raised under specific pathogen-free conditions exhibit a significant 3-fold increase in lipid accumulation compared with wild-type mice. Interestingly, the susceptibility of IL-10-deficient mice to atherosclerosis was exceedingly high (30-fold increase) when the mice were housed under conventional conditions. Atherosclerotic lesions of IL-10-deficient mice showed increased T-cell infiltration, abundant interferon-gamma expression, and decreased collagen content. In vivo, transfer of murine IL-10 achieved 60% reduction in lesion size. These results underscore the critical roles of IL-10 in both atherosclerotic lesion formation and stability. Moreover, IL-10 appears to be crucial as a protective factor against the effect of environmental pathogens on atherosclerosis.

Animals↗

PubMed1999

Enalapril improves arterial elastic properties in rats with myocardial infarction.

Systemic arterial elastic properties, important determinants of left ventricular function and coronary blood flow, are compromised in myocardial infarction (MI). The cardiac effect of angiotensin-converting enzyme inhibitors (ACEIs) has been extensively studied, whereas their arterial effect has been poorly reported in MI. The aim of this work was to study the effect of prolonged ACEI enalapril treatment on systemic arterial structure and elastic properties in rats with MI. One week after the induction of an MI, 40 male Wistar rats received either no treatment (n = 20) or ACEI enalapril (2 mg/kg; n = 20) for 17 weeks. At the end of the treatment period, blood pressure, cardiac output, total peripheral resistance, systemic arterial compliance, characteristic impedance, and left ventricular power were measured in anesthetized rats. Then the rats were killed for infarct-size determination and aortic histomorphometric study. Infarct size, heart, and left and right ventricular weights were similar in the ACEI-treated and untreated infarcted rats. Prolonged ACEI enalapril treatment reduced blood pressure by 17% (p < 0.001), total peripheral resistance by 22% (p < 0.01), and characteristic impedance by 26% (p < 0.03), and increased systemic arterial compliance by 35% (p < 0.01), in comparison with untreated infarcted rats. Enalapril reduced aortic media wall thickness by 9% (p < 0.02) and increased elastin content by 22% (p < 0.03) and elastin-to-collagen content ratio by 42% (p < 0.01). Enalapril did not affect cardiac output and left ventricular power. Smooth muscle cell nuclei number and size and collagen content of aortic wall were similar in the ACEI-treated and untreated infarcted rats. These results indicate that long-term treatment with ACEI enalapril improves arterial elastic properties through structural modifications of arterial wall in rats with MI. This vascular effect may contribute to improve the left ventricular function and the coronary perfusion of infarcted myocardium, and added to the cardiac effect, may explain the prevention of left ventricular remodeling observed with ACEI in this model.

Anesthesia↗

PubMed1998

Aminoguanidine prevents age-related arterial stiffening and cardiac hypertrophy.

Aging is associated with cardiac hypertrophy and arterial stiffening possibly associated with accumulation of advanced glycation end products (AGEs). We evaluated the effect of aminoguanidine, an inhibitor of AGE production, on end-stage alterations of renal and cardiovascular systems. Normotensive WAG/Rij rats were treated from 24 to 30 mo with aminoguanidine and compared with a control group. Aminoguanidine did not modify body and kidney weights but prevented the age-related cardiac hypertrophy (heart weight: 1276 +/- 28 mg and 1896 +/- 87 mg in 24- and 30-mo-old control animals and 1267 +/- 60 mg in 30-mo-old treated rats, P < 0.01). The increase in mesangial surface in aging rats was reduced by 30% by aminoguanidine. Collagen content of the arterial wall increased between 24 and 30 mo whereas elastin content, media thickness, and smooth muscle cell number remained unchanged. Aminoguanidine did not affect these parameters; however, the age-related increase in aortic impedance (12.4 +/- 1.4 and 18.2 +/- 1.9 10(3).dyne.sec.cm-5 in control 24- and 30-mo-old rats, P < 0.01) and the decrease in carotid distensibility (0.79 +/- 0.11 and 0.34 +/- 0. 07 mm Hg-1 in control 24- and 30-mo-old rats, P < 0.01) were prevented by aminoguanidine. The prevention of arterial stiffening and cardiac hypertrophy in the absence of changes in collagen and elastin content suggests that the effect of aminoguanidine is related to a decrease in the AGE-induced cross-linking of the extracellular matrix.

Aging↗

PubMed1997

Impaired flow-induced dilation in mesenteric resistance arteries from mice lacking vimentin.

The intermediate filament vimentin might play a key role in vascular resistance to mechanical stress. We investigated the responses to pressure (tensile stress) and flow (shear stress) of mesenteric resistance arteries perfused in vitro from vimentin knockout mice. Arteries were isolated from homozygous (Vim-/-, n = 14) or heterozygous vimentin-null mice (Vim+/-, n = 5) and from wild-type littermates (Vim+/+, n = 9). Passive arterial diameter (175+/-15 micron in Vim+/+ at 100 mmHg) and myogenic tone were not affected by the absence of vimentin. Flow-induced (0-150 microl/min) dilation (e. g., 19+/-3 micron dilation at 150 mmHg in Vim+/+) was significantly attenuated in Vim-/- mice (13+/-2 micron dilation, P < 0.01). Acute blockade of nitric oxide synthesis (NG-nitro- L-arginine, 10 microM) significantly decreased flow-induced dilation in both groups, whereas acute blockade of prostaglandin synthesis (indomethacin, 10 microM) had no significant effect. Mean blood pressure, in vivo mesenteric blood flow and diameter, and mesenteric artery media thickness or media to lumen ratio were not affected by the absence of vimentin. Thus, the absence of vimentin decreased selectively the response of resistance arteries to flow, suggesting a role for vimentin in the mechanotransduction of shear stress.

Animals↗

PubMed1997

Failure of preconditioning to improve postcardioplegia stunning of minimally infarcted hearts.

BACKGROUND: Ischemic preconditioning is an effective means of reducing myocardial infarct size, but its ability to attenuate stunning after an episode of surgically relevant global ischemia remains elusive. Likewise, the role played by adenosine in this setting has not been established conclusively. This study was designed to address these two issues. METHODS: Thirty isolated, crystalloid-perfused rabbit hearts were subjected to 60 minutes of normothermic potassium arrest and 60 minutes of reperfusion. They were divided into three equal groups. The first group had no prearrest intervention and served as a control. In the second group, ischemic preconditioning was achieved with 5 minutes of zero-flow ischemia followed by 5 minutes of buffer reperfusion before arrest. In the third group, the hearts were first infused for 5 minutes with the nucleoside transport inhibitor draflazine (10(-6) mol/L), the efficacy of which was demonstrated by reversal of the normally high inosine to adenosine ratio in the coronary effluent. These hearts subsequently were given 2 additional minutes of ischemic (zero-flow) preconditioning followed by 5 minutes of reperfusion before arrest. During reperfusion, function was measured serially under isovolumic conditions. Myocardial necrosis was estimated from the release of creatine kinase after the initial 5 minutes of reflow, and the planimetrically determined extent of infarction was determined by triphenyltetrazolium chloride staining. RESULTS: Baseline hemodynamic data were comparable among the three groups. Neither ischemic preconditioning alone nor ischemic preconditioning with draflazine-induced enhancement of endogenous adenosine levels improved postischemic recovery of function over that seen in control, untreated hearts. These results correlated with a minimal amount of infarction in the control group (on average, <10% of the left ventricle), which was not reduced further by either preconditioning regimen. CONCLUSIONS: These data support the idea that, in the absence of substantial necrosis, ischemic preconditioning does not ameliorate postischemic stunning, which leads to the question of its usefulness in clinical cardiac operations. Although, in this model, protection was not potentiated by increasing endogenous concentrations of adenosine, it remains a worthwhile goal to identify the final effectors of the signaling pathway accounting for the otherwise demonstrated cardioprotective effects of preconditioning because of the potential for these mediators to act as effective antiischemic agents.

Adenosine↗

PubMed1997

Sodium, survival, and the mechanical properties of the carotid artery in stroke-prone hypertensive rats.

BACKGROUND: Reduction in sodium intake improves the survival of stroke-prone spontaneously hypertensive rats (SHR-SP) without causing any change in their blood pressure. OBJECTIVE: To investigate whether the diuretic indapamide improves survival of SHR-SP and whether changes in the structure and the function of large arteries are associated with survival. EXPERIMENTAL DESIGN: Forty-eight hypertensive rats aged 6 weeks were divided into three groups: a control SHR-SP group (n = 24) and a control spontaneously hypertensive rat (SHR) group (n = 12), with 1% saline drinking water; and an indapamide-treated SHR-SP group (n = 12) with 1% saline drinking water administered 1 mg/kg per day indapamide via their food. At the end of a 12-week follow-up period, pulsatile changes in blood pressure and common carotid artery diameter (measured by high-resolution echo-tracking techniques) were determined and aortic histomorphometry was performed. RESULTS: By the end of the study 58% of the SHR-SP control group rats had died. There were no deaths in the other two groups. In these two groups the mean blood pressure (217+/-10 and 212+/-7 mmHg), carotid diameter and distensibility (0.48+/-0.09 and 0.61+/-0.22 mmHg[-1]), arterial thickness (116+/-4 and 116+/-3 microm), and collagen content of the arterial wall were identical. In the SHR-SP control group the mean blood pressure was significantly lower (168+/-9 mmHg), the carotid distensibility was higher (1.47+/-0.35 mmHg[-1]), and the arterial thickness (138+/-5 microm) and collagen content were substantially higher than those in the other two groups. In the study population as a whole, for a given mean arterial pressure the carotid distensibility was identical in the three groups, although the arterial thickness was substantially greater in the SHR-SP control group rats. CONCLUSIONS: The study provides evidence that the diuretic compound indapamide improved the survival of SRH-SP even though their blood pressure was higher than that of untreated animals, and that genetic sensitivity to sodium, rather than blood pressure, influences the changes in arterial structure.

Animals↗

PubMed1997

Role of angiotensin II and bradykinin on aortic collagen following converting enzyme inhibition in spontaneously hypertensive rats.

We previously showed that chronic angiotensin-converting enzyme (ACE) inhibition prevented the increase in aortic collagen in spontaneously hypertensive rats (SHRs) independently of blood pressure reduction. The aim of the present study was to determine whether the effects of ACE inhibition on aortic fibrosis were due to inhibition of angiotensin II formation, preservation of bradykinin, or a combination of both. Four week-old SHRs were treated for 4 months with the ACE inhibitor quinapril, quinapril with the bradykinin B2 receptor antagonist Hoe 140, or the angiotensin II AT1 receptor antagonist CI996. Control SHR and Wistar-Kyoto (WKY) rats received a placebo for the same period of time. At the end of the treatment, as compared to conscious SHR and WKY controls, quinapril completely prevented the development of hypertension, whereas quinapril-Hoe 140 and the AT1 receptor antagonist produced only a partial reduction of blood pressure. In relation with blood pressure changes, aortic hypertrophy was significantly prevented by quinapril but not by quinapril-Hoe 140 or CI996. In contrast, aortic collagen accumulation was completely prevented by all three treatments. The study provides evidence that in young live SHRs, the prevention of aortic collagen accumulation is independent of blood pressure changes and bradykinin preservation and involves exclusively angiotensin II inhibition through AT1 receptors.

Angiotensin II↗

PubMed1996

Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure.

Angiotensin II (Ang II) is both a vasoactive and a potent growth-promoting factor for vascular smooth muscle cells. Little is known about the in vivo contribution of AT1 and AT2 receptor activation to the biological action of Ang II. Therefore, we investigated the effect of AT1 or AT2 subtype receptor chronic blockade by losartan or PD123319 on the vascular hypertrophy in rats with Ang II-induced hypertension. Normotensive rats received for 3 wk subcutaneous infusions of Ang II (120 ng/kg per min), or Ang II + PD 123319 (30 mg/kg per d), or Ang II + losartan (10 mg/kg per d) or PD 123319 alone, and were compared with control animals. In normotensive animals, chronic blockade of AT2 receptors did not affect the plasma level of angiotensin II and the vascular reactivity to angiotensin II mediated by the AT1 receptor. Chronic blockade of AT1I in rats receiving Ang II resulted in normal arterial pressure, but it induced significant aortic hypertrophy and fibrosis. Chronic blockade of AT2 receptors in Ang II-induced hypertensive rats had no effect on arterial pressure, but antagonized the effect of Ang II on arterial hypertrophy and fibrosis, suggesting that in vivo vasotrophic effects of Ang II are at least partially mediated via AT2 subtype receptors.

Angiotensin II↗

PubMed1996

Vascular reactivity in mesenteric resistance arteries following chronic nitric oxide synthase inhibition in Wistar rats.

1. Chronic inhibition of nitric oxide synthase (NOS) induces a sustained hypertension in rats. We studied the effects of chronic inhibition on the in vitro vasoreactivity of mesenteric resistance arteries in Wistar rats. We also investigated the effects of acute in vitro NOS inhibition in these vessels. 2. Acute NOS inhibition (N omega-nitro-L-arginine, L-NOARG, 10 microM) had no effect on the contractile response to KCl (125 mM), enhanced the response to the phorbol ester, phorbol dibutyrate (1 microM; 69 +/- 9% of KCl response, n = 6; 38 +/- 7% control, n = 6, P < 0.05), increased sensitivity to phenylephrine (EC50: 1.68 +/- 0.14 microM, n = 5; 2.35 +/- 0.23 microM control, n = 5, P < 0.05) and sodium nitroprusside (SNP; EC50 1.79 +/- 0.61 nM, n = 6; 20.44 +/- 6.87 nM control, n = 6, P < 0.05) and decreased sensitivity to acetylcholine (EC50 123 +/- 12 nM, n = 6; 45 +/- 10 nM control, n = 13, P < 0.05). 3. In contrast, contractile responses to KCl (125 mM; 170 +/- 12 mN mm-3, n = 10; 257 +/- 21 mN mm-3 in control, n = 13, P < 0.005) and phenylephrine (maximum response, 30 microM: 169 +/- 24 mN mm-3, n = 10; 295 +/- 19 mN mm-3 in control, n = 13, P < 0.001) were significantly reduced in magnitude following chronic NOS inhibition. Sensitivity to phenylephrine was not significantly altered. 4. The effects of chronic NOS inhibition (N omega-nitro-L-arginine methyl ester, L-NAME, 10 mg kg-1 daily for 3 weeks) were similar to those of acute NOS blockade with respect to the relaxant responses to SNP and acetylcholine, and also the contraction in response to protein kinase C activation. 5. Chronic inhibition of NOS significantly increased medial cross sectional area of mesenteric resistance arteries (0.013 +/- 0.002 mm2, n = 7; 0.009 +/- 0.0005 mm2 control, n = 15, P < 0.05). 6. Thus, in contrast to the acute effects of NOS inhibition, chronic NOS inhibition results in a down-regulation of the contractile responses to KCl and phenylephrine in mesenteric resistance arteries, despite an increase in medial cross sectional area. However protein kinase C-dependent contraction remains relatively enhanced. Endothelium-dependent relaxation is reduced and endothelium-independent relaxation is enhanced in a manner similar to the effects of acute NOS blockade.

Animals↗