Constrictor Factors Research Articles

Pengaruh Fermentasi Serbuk Gergaji oleh Trichoderma viridae terhadap Serat

<p>Availability of potential sawdust can be used as ruminant feeds. However sawdust have constrictor factor that is its low protein content and high harsh fiber. Biology degradation use solid substrate ferment techniques by <em>Trichoderma viridae </em>can be applied to increase assess lignocelluloses feeds materials. This research is conducted for to know <em>Trichoderma viridae </em>inoculums dose influence and ferment 1 time to sawdust fiber composition. Eighteen sawdust sack used in randomized complete block design of factorial 2x3. First factor consist of 2 old level of ferment (10 and 20 day) and second factor consisting of 3 inoculums dose level (2, 3 dan 4%). Variable observed consist of NDF, ADF, lignin and cellulose.</p><p>There are interaction influence from both the factor to degradation of ADF sawdust rate. At all used of inoculums dose, downhill ADF content in line with the increasing of ferment time and improvement of lowest ADF obtained by treatment combination 2%, 4% inoculums and time ferment very significant (P<0.05) to obstetrical degradation of NDF, lignin and cellulose. Inoculums dose excelsior and time ferment hence ever greater also obstetrical degradation of NDF, lignin and cellulose. Highest degradation obtained at time ferment 4,5% inoculums dose and 20 day that is each 10,53%, 20,84% and 28,14%.</p><p>This research can be concluded that more and more inoculums dose and time ferment hence degradation of NDF rate, ADF, excelsior lignin and also cellulose.</p>

Emerging challenges to the existing paradigm of cyclo‐oxygenase pathways in regulating vascular function

Emerging challenges to the existing paradigm of cyclo‐oxygenase pathways in regulating vascular function

Acute vascular effects of the angiotensin II receptor antagonist olmesartan in normal subjects: relation to the renin-aldosterone system

The extent to which the clinical effects of angiotensin receptor blockers (ARB) are related to ambient renin system activity remains poorly defined. Therefore, we measured blood pressure (BP), large (C1) and small (C2) arterial compliance, systemic vascular resistance (SVR), plasma renin activity (PRA), and the 24-h urinary excretion of sodium (UNaV) and aldosterone before and 1, 2, 4, and 24 h after administration of single doses of placebo, and 5, 20, and 40 mg of the ARB olmesartan medoxomil to 12 unmedicated normotensive subjects. In the basal state, SVR was inversely related to UNaV (r=-0,3,p=0,04); the greater the UNaV, the more vasodilated the subject. Indices of arterial compliance, both C1 (r=-0,32,p=0,03) and C2 (r=-0,35,p=0,02) were inversely related to the basal PRA. Renin also predicted olmesartan-induced changes in C1 (r=0,43,p=0,004) and C2r=0,33,p=0,04). The greater the basal PRA, the less the arterial compliance, and the more compliance improved after olmesartan. Both systolic (p=0,003) and diastolic (p<0,0001) BP fell significantly on olmesartan compared with placebo (MANOVA with time), and relations were observed between the basal PRA and olmesartan-induced changes in pressure (systolic BP:r=-0,414,p=0,012; diastolic BP:r=-0.561,p<0,0001) — the greater the initial PRA, the more olmesartan lowered BP. Furthermore, the more pressure fell, the more PRA rose reciprocally (r=-0,44,p=0,007). Finally, aldosterone excretion fell (sig=0,05) on each dose of olmesartan compared with placebo. We conclude that 1) the inverse relation of UNaV and SVR illustrates the reciprocal role of volume versus constrictor factors in maintaining normal BP; and 2) PRA is a physiologic determinant of arterial compliance in normal individuals and of the response to the ARB olmesartan. Measurement of PRA may help to predict clinical ARB responses in individual subjects.

The discovery of endothelin: The power of bioassay and the role of serendipity in the discovery of endothelium-derived vasocative substances

Significant discoveries in biology and medicine are rare. The progress in these fields is predominantly incremental, but sometimes new observations revolutionize the field by opening new directions in research for decades to come. Two cornerstone observations in the late 1970s and early 1980s are examples of such “revolutionary” events. The first, by Furchgott and Zawadzki, was the discovery of the “obligatory role of the endothelium in vasorelaxation by acetylcholine”. The other, by Hickey and colleagues, was the first description and characterization of a vasoconstrictor polypeptide produced by endothelial cells in culture. Both of these observations were achieved by the application of bioassay and serendipity played an important role in each of them. They both represent starting points for rapid growth in research activity world-wide leading to the identification of EDRF as nitric oxide, and the polypeptide EDCF as endothelin a few years later. These early observations also raised interest and initiated intensive R&D activity in the pharma industry culminating in the regulatory approval and marketing of novel medicines treating human diseases. This review describes the events leading to the discovery and early characterization of the peptidergic endothelium-derived constrictor factor, and its purification, sequencing and naming it endothelin.

REBUTTAL FROM DR. ROBERTSON

REBUTTAL FROM DR. ROBERTSON

Vascular Smooth Muscle and Endothelial Functions in Aging

Aging is one of the main risk factors for the development of atherosclerosis and, therefore, for coronary artery disease. Age-associated remodeling of the vascular wall includes luminal enlargement, intimal and medial thickening, and increased vascular stiffness. As aging occurs, smooth muscle cells (SMCs) progressively migrate from the tunica media and accumulate into the tunica intima. Aging also associates with changes of SMC proliferative and apoptotic behavior and response to growth factors, such as transforming growth factor-beta1. Aging induces a reduction in the density of the alpha-subunit of Ca(2+)-activated K(+) channels in coronary smooth muscle and increases the response to endothelial constrictor factors and K(+). Accordingly, we have recently shown that the vasodilatory effect of male sex hormone testosterone, which is mediated through large conductance Ca(2+)-activated K(+) channel opening action, decreases with age. Apart from age-associated remodeling of the vascular wall, endothelial function declines with age. This is most obvious from the attenuation of endothelium-dependent dilator responses, which is a consequence of the alteration in the expression and/or activity of the endothelial nitric oxide (NO) synthase, upregulation of the inducible NO synthase, and increased formation of reactive oxygen species. In fact, in the course of aging, there is an alteration in the equilibrium between relaxing and contracting factors released by the endothelium. Hence, there is a progressive reduction in the participation of NO and endothelium-derived hyperpolarizing factor (EDHF) associated with increased participation of oxygen-derived free radicals and cyclooxygenase-derived prostanoids. Also, the endothelin-1 and angiotensin II pathways may play a role in age-related endothelial dysfunction. Aging is also associated with a reduction in the regenerative capacity of the endothelium and endothelial senescence, which is characterized by an increased rate of endothelial cell apoptosis. Thus, aging elicits several changes in the vascular endothelium gradually altering its phenotype from an anti- to a proatherosclerotic one. In conclusion, it becomes increasingly evident that the blood vessel structural and functional disturbances, which characterize vascular aging, make a major contribution to aging-related target organ damage. The use of drugs, including antioxidant therapy, lipid-lowering drugs, and estrogens, seems to be promising.

Multiple effects of diabetes mellitus on the vasomotor responses of human coronary arterioles

In humans, the intrinsic mechanisms regulating coronary arteriolar tone could be affected by diabetes mellitus (DM), which however has not yet been fully elucidated. Thus, we investigated agonist-induced responses of coronary arterioles obtained from patients (N=25) without (non-DM) and with DM. In isolated, pressurized (80 mmHg) coronary arterioles (95±15 μm) acetylcholine (ACh) elicited dilations in non-DM patients (1μM: 82±5%), whereas caused constrictions in arterioles of DM subjects (1μM: −29±7%). In contrast, bradykinin (BK) induced only dilations in both groups, which were greater in arterioles from DM patients (10nM: 77±10%), than in non-DM (10nM: 38±14%). Dilations to NO-donor, sodium nitroprusside were not different in the 2 groups. Inhibition of NO synthesis with L-NAME reduced ACh-induced dilations in controls but did not affect ACh-evoked constrictions in DM patients and BK-induced dilations in both groups. In DM patients enhanced dilations to BK were reduced by the selective cyclooxygenase-2 (COX-2) inhibitor, NS-398; and a marked COX-2 immunostaining was reveled in coronary arterioles of DM subjects. We conclude that in isolated coronary arterioles from humans with DM, in addition to the impairment of NO-mediation, a constrictor factor is released to ACh. In contrast, there is an enhanced dilation to BK, which is likely due to the increased release of COX-2-derived dilator prostaglandins. Supported by AHA NE Aff. 0555897T and Hungarian NSRF/OTKA -T48376 and HSC/ETT 364/2006.

Point: Release of an endothelium-derived vasoconstrictor and RhoA/Rho kinase-mediated calcium sensitization of smooth muscle cell contraction are/are not the main effectors for full and sustained hypoxic pulmonary vasoconstriction

The ability of an organism, or an organ therein, to respond appropriately to episodes of hypoxia is a key evolutionary determinant. In mammalian lungs, the response to acute hypoxia involves constriction of the intrapulmonary arteries (IPA) in the hypoxic region of the lung. This response, termed

Increase in the sensitivity of the vascular smooth muscle to constrictor factors after denervation and with a decrease in blood pressure

The effect of denervation on the contractile activity of the saphenous artery in normotensive rats and rats with regional hypotension was studied. Hypotension was caused by partial occlusion of the abdominal aorta distally from the renal arteries, and then, in four weeks, to denervate the saphenous artery, a portion of the femoral nerve in one of the limbs was resected. In two more weeks, the contractile responses of ring preparations of the saphenous artery (after removal of the endothelium and block of neuronal uptake and β-adrenoreceptors) were investigated under isometric conditions. In normotensive rats, the denervation led to an increase in the vascular sensitivity to norepinephrine, phenylephrine, serotonin, and KCl. Similar changes in contraction were caused by chronic hypotension; however, rats with hypotension exhibited no additional denervation-induced increase in the vascular sensitivity. After treatment with glyoxylic acid, the fluorescence intensity of the vascular adrenergic fibers adapted to a reduced pressure was lower than that in the norm. It was assumed that the vascular hypersensitivity in hypotension is caused by impairment of sympathetic innervation.

Acute vascular effects of the angiotensin II receptor antagonist olmesartan in normal subjects: relation to the Renin-Aldosterone system

The extent to which the clinical effects of angiotensin receptor blockers (ARB) are related to ambient renin system activity remains poorly defined. Therefore, we measured blood pressure (BP), large (C1) and small (C2) arterial compliance, systemic vascular resistance (SVR), plasma renin activity (PRA), and the 24-h urinary excretion of sodium (UNaV) and aldosterone before and 1, 2, 4, and 24 h after administration of single doses of placebo, and 5, 20, and 40 mg of the ARB olmesartan medoximil to 12 unmedicated normotensive subjects. In the basal state, SVR was inversely related to UNaV ( r = −0.3, P = .04); the greater the UNaV, the more vasodilated the subject. Indices of arterial compliance, both C1 ( r = −0.32, P = .03) and C2 ( r = −0.35, P = .02) were inversely related to the basal PRA. Renin also predicted olmesartan-induced changes in C1 ( r = 0.43, P = .004) and C2 ( r = 0.33, P = .04). The greater the basal PRA, the less the arterial compliance, and the more compliance improved after olmesartan. Both systolic ( P = .003) and diastolic ( P < .0001) BP fell significantly on olmesartan compared with placebo (MANOVA with time), and relations were observed between the basal PRA and olmesartan-induced changes in pressure (systolic BP: r = −0.414, P = .012; diastolic BP: r = −0.561 P < .0001)—the greater the initial PRA, the more olmesartan lowered BP. Furthermore, the more pressure fell, the more PRA rose reciprocally ( r = −0.44, P = .007). Finally, aldosterone excretion fell (sig = 0.05) on each dose of olmesartan compared with placebo. We conclude that 1) the inverse relation of UNaV and SVR illustrates the reciprocal role of volume versus constrictor factors in maintaining normal BP; and 2) PRA is a physiologic determinant of arterial compliance in normal individuals and of the response to the ARB olmesartan. Measurement of PRA may help to predict clinical ARB responses in individual subjects.

Ca2+ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent.

The main aim of this study was to determine the effects of endothelium removal on tension and intracellular Ca(2+) ([Ca(2+)](i)) during hypoxic pulmonary vasoconstriction (HPV) in rat isolated intrapulmonary arteries (IPA). Rat IPA and mesenteric arteries (MA) were mounted on myographs and loaded with the Ca(2+)-sensitive fluorophore fura PE-3. Arteries were precontracted with prostaglandin F(2alpha), and the effects of hypoxia were examined. HPV in isolated IPA consisted of a transient constriction superimposed on a second sustained phase. Only the latter phase was abolished by endothelial denudation. However, removal of the endothelium had no effect on [Ca(2+)](i) at any point during HPV. The endothelin-1 antagonists BQ-123 and BQ-788 did not affect HPV, although constriction induced by 100 nM endothelin-1 was abolished. In MA, hypoxia induced an initial transient rise in tension and [Ca(2+)](i), followed by vasodilatation and a fall in [Ca(2+)](i) to (but not below) prehypoxic levels. These results are consistent with sustained HPV being mediated by an endothelium-derived constrictor factor that is distinct from endothelin-1 and that elicits vasoconstriction via Ca(2+) sensitization.

Acute effects of 17β-estradiol on left internal mammary graft after coronary artery bypass grafting

Background. Vasospasm of arterial conduits used for coronary surgical procedures is an important cause of postoperative graft failure. Mounting experimental evidence suggests that estrogen reverses acetylcholine-induced vasospasm of the coronary arteries in animals and humans. Estrogen also affects endothelium-derived constrictor factors. We therefore investigated the in vivo vasomotor responses to transdermal 17β-estradiol of the left internal mammary artery (LIMA) grafted on the anterior descending coronary artery. Methods. We studied 20 women, mean age of 62 ± 7.2 years (range, 48 to 73 years), who had undergone cardiopulmonary bypass for coronary artery bypass grafting. They received transdermal 17β-estradiol on the fifth day after operation. The diameter, cross-sectional area, and blood flow of the LIMA graft were measured by transthoracic color Doppler echography before (basal values) and after the transdermal administration of 50 μg of 17β-estradiol (control). Results. LIMA graft vasodilation after the administration of 17β-estradiol was observed. A significant increase in diameter (2.06 ± 0.4 mm versus 2.37 ± 0.28 mm; p = 0.035) and cross-sectional area (3.45 ± 1. 2 mm 2 versus 4.24 ± 1 mm 2; p = 0.039) was registered. The LIMA graft mean flow increased by 49% (44.76 ± 27.19 mL/min versus 56.62 ± 27.69 mL/min), but this increase was not statistically significant ( p = 0.06). Conclusions. The acute postoperative transdermal administration of 17β-estradiol induced a significant increase of LIMA graft diameter and cross-sectional area in postmenopausal women who underwent coronary artery bypass grafting. The LIMA graft vasodilation was also associated with an improvement in LIMA blood flow.

Signaling pathways of mechanotransduction in arteriolar endothelium and smooth muscle cells in hypertension.

Hypertension, a disease with a high incidence in the population, affects all parts of the cardiovascular system. Studying the alteration of vasomotor responses of microvessels of hypertensive animals or responses of vessels following short-term increases in hemodynamic forces helps us to better understand the underlying cellular signaling events responsible for their functional adaptation. These adaptations are likely to precede the structural remodeling of arterioles, resulting in irreversible increases in peripheral vascular resistance in hypertension. Although malfunction of several mechanisms can lead to the development of hypertension, hemodynamic forces (such as pressure and shear stress) are increased in all forms of hypertension. Thus, local mechanisms that sense the level of these forces and transduce the signals into vasomotor responses must be affected in all forms of hypertension. The endothelium has a central role in the early functional adaptations. Pressure-induced myogenic constriction is enhanced due to the augmented release of endothelium-derived constrictor factors that modulate arteriolar smooth muscle sensitivity to Ca(2+). In contrast, flow/shear stress-induced dilation of arterioles is reduced in hypertension, due to the impaired mediation of the response by nitric oxide (NO). The magnitude of impairment is gender specific, primarily due to an estrogen-dependent enhancement of NO release in females. It is proposed that the elevated hemodynamic forces present in hypertension may themselves initiate these alterations, probably by enhancing the release of reactive oxygen species (ROS; produced by xanthine oxidase, NAD(P)H oxidoreductase, eNOS, etc.), which then interfere with the synthesis and/or action of endothelium-derived mediators. Interfering early on with these mechanisms may prevent the development of irreversible structural changes of the microcirculation observed in hypertension.

Aging, ion channel expression, and vascular function

Cardiovascular disease remains the leading cause of death in the United States, and aging is one of the main risk factors for its development. Coronary arteries nurture the heart, but as age progresses, they suffer changes that make them stiffer, thicker, and with higher spontaneous contractile activity. Even in the absence of pathological atherosclerotic lesions, these changes make the coronary arteries at risk for vasospasm and the individual at risk for myocardial ischemia and heart failure. Thus, knowledge of the molecular mechanisms involved in the vascular physiology, disease, and aging of the coronary circulation is required to develop strategies to preserve the quality of life of an increasingly aging population. One of the key factors that regulate coronary arterial tone is the activity of K + channels in the vascular smooth muscle cells (SMCs). In particular, voltage-dependent and Ca 2+-activated K + (BK Ca) channels, which are abundant in the coronary SMCs, are targets of vasoconstrictors and vasorelaxants, and play a key role in determining arterial tone and diameter. Aging induces a reduction in the density of the α-subunit of BK Ca channels in coronary smooth muscle, lowers baseline endothelial release of the relaxant nitric oxide (NO), and increases the response to endothelial constrictor factors and K +. Thus, aging induces the remodeling of important proteins involved in the excitability and contractility of the coronary circulation. Altogether, these changes increase the risk of coronary artery vasospasm, myocardial ischemia, and infarct in the elderly.

Hypoxia induces the release of a pulmonary-selective, Ca(2+)-sensitising, vasoconstrictor from the perfused rat lung.

Sustained hypoxic pulmonary vasoconstriction is dependent upon the presence of an intact endothelium, strongly suggesting that an endothelium-derived constrictor factor is involved in this response. In the present study we have attempted to determine whether hypoxia induces the release of a vasoconstrictor(s) from the lung, and whether this vasoconstrictor shares mechanistic features with the hypoxic constrictor response. The salt-perfused rat lung, coupled with a simple solid-phase extraction process, and a rat intrapulmonary artery functional bioassay were utilised in this study. Hypoxic, but not normoxic, perfusion of the isolated lung of the rat induced the release of a vasoconstrictor(s) which appeared to be selective for pulmonary over mesenteric arteries of the rat. The vasoconstriction observed was unaffected by inhibition of voltage-gated Ca(2+) channels, and was not associated with a rise in intracellular [Ca(2+)], suggesting Ca(2+)-sensitisation of the contractile apparatus. The vasoconstriction was also unaffected by the protein kinase C (PKC) inhibitor Ro-31-8220, or the endothelin-1 antagonists BQ123/BQ788 but was markedly potentiated in the presence of prostaglandin F(2alpha). We conclude that hypoxic perfusion of the rat lung results in the release of a vasoconstrictor(s) which shares some of the facets of the sustained hypoxic constriction of isolated intrapulmonary arteries of the rat, since it involves PKC-independent Ca(2+) sensitisation, is independent of voltage-gated Ca(2+) entry, and is potentiated by the presence of preconstriction.

Gender Difference in the Contribution of an Indomethacin-Sensitive Constrictor Factor to Phenylephrine Responsiveness in Rat Mesenteric Arteries

P22 The mechanism for gender differences in cardiovascular disease may be due, in part, to differences in vascular function. Based on previous studies from our laboratory, we hypothesized that there is enhanced production of a vasoconstrictor cyclooxygenase product in arteries from males when compared to those from females. We studied three month-old male and female Sprague-Dawley rats (n=6 in each group). Small mesenteric arteries (∼400 μm) were isolated, pressurized, and the outer diameter was measured. Arteries from each rat were paired: one had intact endothelium (ENDO +) and the other was mechanically denuded (ENDO -). Dose-response curves to the α 1 -adrenergic agonist, phenylephrine (PE), were performed in the absence and presence of the cyclooxygenase inhibitor, indomethacin (INDO; 10 μM). Negative log EC 50 values were calculated as an index of PE sensitivity and compared between groups using ANOVA and lsd. There were no differences in the sensitivity to PE in ENDO + arteries from males (6.07±0.07) and females (6.12±0.10, p=0.93). In ENDO + arteries from females, the PE sensitivity was unchanged in the presence of INDO (6.11±0.13, p=0.94 when compared to control). However, INDO significantly decreased PE sensitivity in ENDO + arteries from males (5.70±0.08, p=0.01 when compared to control). Endothelium denudation had no significant effect on PE sensitivity in males or females. In denuded arteries from females, INDO produced no change in PE sensitivity (denuded female: 6.08±0.09, denuded + INDO: 5.88±0.13, p=0.23). In contrast, INDO produced a significant decrease in sensitivity in denuded arteries from males (denuded male: 6.33±0.14, denuded + INDO (5.94±0.09, p=0.03). The magnitude of the shift in PE sensitivity produced by INDO (Δ EC 50 )in males was equivalent in ENDO + (0.37±0.07) and ENDO - (0.39±0.09, p=0.9, Student’s t-test) arteries. In conclusion, arteries from male rats produce more of an indomethacin-sensitive vasoconstrictor factor than arteries from female rats. The site of enhanced production of this cyclooxygenase product in males is not the endothelium, but may be vascular smooth muscle.

Gender Difference in the Contribution of an Indomethacin-Sensitive Constrictor Factor to Phenylephrine Responsiveness in Rat Mesenteric Arteries

P22 The mechanism for gender differences in cardiovascular disease may be due, in part, to differences in vascular function. Based on previous studies from our laboratory, we hypothesized that there is enhanced production of a vasoconstrictor cyclooxygenase product in arteries from males when compared to those from females. We studied three month-old male and female Sprague-Dawley rats (n=6 in each group). Small mesenteric arteries (∼400 μm) were isolated, pressurized, and the outer diameter was measured. Arteries from each rat were paired: one had intact endothelium (ENDO +) and the other was mechanically denuded (ENDO -). Dose-response curves to the α 1 -adrenergic agonist, phenylephrine (PE), were performed in the absence and presence of the cyclooxygenase inhibitor, indomethacin (INDO; 10 μM). Negative log EC 50 values were calculated as an index of PE sensitivity and compared between groups using ANOVA and lsd. There were no differences in the sensitivity to PE in ENDO + arteries from males (6.07±0.07) and females (6.12±0.10, p=0.93). In ENDO + arteries from females, the PE sensitivity was unchanged in the presence of INDO (6.11±0.13, p=0.94 when compared to control). However, INDO significantly decreased PE sensitivity in ENDO + arteries from males (5.70±0.08, p=0.01 when compared to control). Endothelium denudation had no significant effect on PE sensitivity in males or females. In denuded arteries from females, INDO produced no change in PE sensitivity (denuded female: 6.08±0.09, denuded + INDO: 5.88±0.13, p=0.23). In contrast, INDO produced a significant decrease in sensitivity in denuded arteries from males (denuded male: 6.33±0.14, denuded + INDO (5.94±0.09, p=0.03). The magnitude of the shift in PE sensitivity produced by INDO (Δ EC 50 )in males was equivalent in ENDO + (0.37±0.07) and ENDO - (0.39±0.09, p=0.9, Student’s t-test) arteries. In conclusion, arteries from male rats produce more of an indomethacin-sensitive vasoconstrictor factor than arteries from female rats. The site of enhanced production of this cyclooxygenase product in males is not the endothelium, but may be vascular smooth muscle.

Effect of atorvastatin on endothelium-dependent constrictor factors in dyslipidemic rabbits

Relaxations to acetylcholine and contractions to acetylcholine in the presence of the nitric oxide (NO) synthesis inhibitor ( l- N G-nitroarginine methyl ester, l-NAME) were studied in aortic rings from rabbits fed either a control or a diet containing 0.5% cholesterol+14% coconut oil for 14 weeks and treated or not with atorvastatin (2.5 mg kg −1 day −1). Rings were incubated with the endothelin (ET A) receptor antagonist BQ123, and/or the thromboxane A 2 (TXA 2)/prostaglandin H 2 (PGH 2) receptor antagonist ifetroban. In rabbits, high cholesterol and triglyceride plasma levels were associated with intimal thickening and blunted acetylcholine-relaxation as compared with controls. By contrast, acetylcholine+ l-NAME response was higher. Incubation with either ifetroban or BQ123 increased acetylcholine-relaxation in both diet groups and it reduced the constrictor response only in dyslipidemic rabbits. Removal of endothelium reduced acetylcholine+ l-NAME contraction in dyslipidemic rabbits, although increased it in control animals. Atorvastatin treatment reduced plasma lipid levels and lesion size in dyslipidemic animals. Likewise, it prevented acetylcholine-relaxation reduction. In addition, atorvastatin reduced constrictor response in dyslipidemic rabbits but only in rings with endothelium. Incubation with either ifetroban or BQ123 did not further modify these responses in atorvastatin-treated animals in any group. These data suggest that ET and TXA 2 availabilities seem to participate in the endothelial dysfunction associated with dyslipidemia. Atorvastatin treatment reduces intimal thickening and improves endothelial dysfunction in rabbits. This effect seems to be a consequence of its ability to act on ET and TXA 2 systems.

Chronic blockade of endothelin ETA receptors improves flow dependent dilation in resistance arteries of hypertensive rats.

Flow (shear stress)-induced dilation (FD) is attenuated in hypertension. Flow triggers the release by endothelial cells of dilators, such as NO or cyclo-oxygenase (COX) derivatives and constrictor factors such as endothelin-1 (ET-1) which might be involved in several cardiovascular diseases. We hypothesized that ET-1 might play a functional role in FD and participate in the endothelial dysfunction in hypertension. We investigated the effect of chronic treatment with the ETA receptor blocker LU135252 (50 mg/kg/day) for 2 weeks on the dilator response to flow in normotensive (Wistar-Kyoto; WKY) or hypertensive (SHR, n = 7 or 8 per group) rats. Systolic arterial pressure was not significantly affected by chronic ETA receptor blockade in both strains. In mesenteric resistance arteries (diameter: approximately 100 microns), isolated in vitro, FD was lower and myogenic tone higher in SHR than in WKY rats. Chronic ETA receptor blockade increased FD by 73% (7.5 +/- 1.5 to 13.0 +/- 2.7 microns dilation with a flow-rate of 150 microliters/min) in SHR (no effect in WKY). The participation of NO to FD was increased in SHR and the participation of dilator COX product(s) (blocked by indomethacin 10 mumol/l) to FD was significantly increased in SHR and in WKY. In control rats FD was improved by acute ETA receptor blockade in WKY rats (18.5 +/- 2.0 to 23.2 +/- 1.8 microns dilation to flow-rate of 150 microliters/min) and significantly more in SHR (6.0 +/- 1.8 to 15.1 +/- 1.6 microns). Acetylcholine-induced dilation was also improved by chronic ETA receptor blockade (no effect of an acute blockade). Myogenic and phenylephrine-induced tone were not affected by chronic or acute ETA receptor blockade. The improvement of endothelium-dependent dilation was not related to a change in blood pressure. Chronic ETA receptor blockade increased flow-induced dilation in SHR possibly by suppressing flow-induced ETA stimulation and by improving the release of dilator products by the endothelium.

Role of endothelium-derived constrictor factors in regulation of venular tone

Role of endothelium-derived constrictor factors in regulation of venular tone