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(Hypertension. 1997;29:274.)
© 1997 American Heart Association, Inc.
Arthur C. Corcoran Memorial Lecture |
Cyclooxygenase Inhibition Restores Nitric Oxide Activity in Essential Hypertension
From I Clinica Medica, University of Pisa, Italy.
Correspondence to Stefano Taddei, MD, I Clinica Medica, University of Pisa, Via Roma, 67, 56100 Pisa, Italy
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Abstract |
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To evaluate whether cyclooxygenase constrictor substances can impair nitric oxide-mediated vasodilation in essential hypertension, in seven normotensive subjects (43.3±4.1 years; BP, 117±6/81±2 mm Hg) and seven essential hypertensive patients (47.1±5.2 years; BP, 151±8/98±4 mm Hg) we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15,0.45, 1.5, 4.5, 15 µg·100 mL-1·min-1) in basal conditions, during infusion of NG-monomethyl-L-arginine (L-NMMA; 100 µg·100 mL-1·min-1), a nitric oxide synthase inhibitor, or indomethacin (50 µg·100 mL-1·min-1), a cyclooxygenase inhibitor, or simultaneous indomethacin and L-NMMA. In normotensives, vasodilation to acetylcholine was blunted by L-NMMA (maximum flow increase: 671±64% and 386±42%, respectively; P<.01), and this effect was unchanged by indomethacin. In contrast, in hypertensive patients, vasodilation to acetylcholine (maximum flow increase: 458±33%) was unchanged by L-NMMA. Indomethacin significantly (P<.01) increased the response to acetylcholine (maximum flow increase: 635±53%) and restored the inhibitory effect of L-NMMA (maximum flow increase: 445±36%; P<.01 versus indomethacin alone). In an adjunctive seven normotensives (51.4±4.2 years; BP, 114±5/79±3 mm Hg) and seven essential hypertensives (53.2±7.6 years; BP, 153±9/100±3 mm Hg) we repeated the same protocol by replacing L-NMMA with L-arginine (200 µg·100 mL-1·min-1), the substrate for NO synthase. In normotensives, vasodilation to acetylcholine was increased by L-arginine (maximum flow increase: 539±48% and 806±61%, respectively) and this effect was unchanged by indomethacin. In hypertensive patients, vasodilation to acetyl-choline (maximum flow increase: 339±32%) was unchanged by L-arginine but was significantly (P<.01) increased by indomethacin (maximum flow increase: 592±38%). Moreover, indomethacin restored the facilitatory effect of L-arginine (maximum flow increase: 804±56%; P<.01 versus indomethacin alone). Therefore, cyclooxygenase inhibition restores nitric oxide-mediated vasodilation in essential hypertension, suggesting that cyclooxygenase-dependent substances can impair nitric oxide production.
Key Words: hypertension • endothelium • nitric oxide • endothelium-derived factors • indomethacin
Abbreviations: BP = blood pressure • EDCF = endothelium-derived contracting factor(s) • FBF = forearm blood flow • L-NMMA = NG-monomethyl-L-arginine • NO = nitric oxide • NS = not significant
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Introduction |
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Endothelium plays a major role in the modulation of vascular tone through the production and release of different relaxing and constricting factors acting on the underlying smooth muscle cells.1 The major endothelium-derived relaxing factor is NO,2 a labile substance derived from L-arginine by the activity of the enzyme NO synthase.3 Importantly, this process can be competitively inhibited by L-arginine analogues such as L-NMMA.4,5 Moreover, EDCF are mainly cyclooxy-genase-dependent prostanoids (thromboxane A2 and prostaglandin H2)6–9 or superoxide anions.10
The crucial role of endothelial cells in vascular homeostasis is further emphasized by the evidence of impaired endothelium-dependent responses in cardiovascular disease such as essential hypertension. Thus, in essential hypertensive patients, vasodilation to endothelium-dependent agonists (mainly acetylcholine or bradykinin) is reduced compared with normotensive control subjects.11–15 This abnormality is caused by a defect in NO activity since both L-arginine and L-NMMA, which in normal conditions can increase or reduce the response to acetylcholine, respectively, are ineffective in hypertensive patients.16–18 Moreover, indomethacin, a cyclooxygenase inhibitor, can potentiate the vasodilation to acetylcholine in hypertensive patients but not in normotensive control subjects, indicating the synthesis of cyclooxygenase-dependent EDCF.13 Thus taken together these observations suggest that in essential hypertension endothelial dysfunction is caused by the simultaneous presence of a defect in the L-arginine-NO pathway and production of cyclooxygenase-dependent EDCF.
However, the possibility exists that these alterations are not abnormalities which are parallelly associated with hypertensive disease, but, as demonstrated in certain animal models, EDCF can negatively interact with the L-arginine pathway, causing NO destruction.10,15 Thus the present study was designed to evaluate whether cyclooxygenase-dependent EDCF can impair the L-arginine-NO pathway in essential hypertensive patients. Specifically, the investigation focused on assessing whether cyclooxygenase blockade can restore the facilitating or inhibiting effect of L-arginine and L-NMMA, respectively, on the vasodilating response to acetylcholine in essential hypertensive patients.
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Methods |
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Patients
The study population included 14 normotensive control subjects and 14 matched essential hypertensive patients. Subjects with hypercholesterolemia (total cholesterol greater than 5.2 mmol/L), diabetes mellitus, cardiac and/or cerebral ischemic vascular disease, impaired renal function and other major pathologies were excluded from the study. Moreover, subjects or patients smoking more than five cigarettes per day and/or consuming more than 60 g of ethanol (corresponding to half a liter of wine) per day were excluded from the study. In accordance with institutional guidelines, all patients were aware of the investigational nature of the study and gave written consent to it. Any pharmacological treatment was discontinued for at least 2 weeks before performing the study.
Subjects, defined as normal according to the absence of familial history of essential hypertension and BP below 140/90 mm Hg, were characterized by mean age of 47.6±4.3 years and BP values of 115.6±6.1/80.3±2.1 mm Hg. Essential hypertensive patients were recruited from among the newly diagnosed cases in our outpatient clinic if they reported the presence of positive family history of essential hypertension, whenever supine arterial BP (after 10 minutes of rest) measured by mercury sphygmomanometer three times at 1-week intervals was consistently found greater than 140/90 mm Hg. Secondary forms of hypertension were excluded by routine diagnostic procedures. Mean age was 50.6±6.6 years and BP values were 152.5±8.7/ 99.2±3.6 mm Hg. Since the patients were newly diagnosed cases, they were never treated and the known history of hypertension had lasted 2.l±0.4 years. The demographic and clinical characteristics of the two groups are shown in the Table.
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Experimental Procedure
All studies were performed at 08.00 AM after overnight fast with the subjects lying supine in a quiet air-conditioned room (22°C to 24°C). A polyethylene cannula (21 gauge, Abbot) was inserted into the brachial artery under local anesthesia (2% lidocaine) and connected through stopcocks to a pressure transducer (Model MS20, Electromedics) for systemic mean BP (one third pulse pressure+diastolic pressure) and heart rate monitoring (Model VSM1, Physiocontrol) and for intra-arterial infusions. FBF was measured in both forearms (experimental and contralateral forearm) by strain-gauge venous plethysmography (LOOSCO, GL LOOS).20 Circulation to the hand was excluded 1 minute before each sampling or FBF measurement by inflating a pediatric cuff around the wrist at suprasystolic BP. Details concerning the sensitivity and reproducibility of the method as performed in our laboratory have already been published.19
Forearm volume was measured according to the water displacement method and drug infusion rates were normalized to 100 mL tissue by alteration of the drug concentration in the solvent while the pump speed of infusion was kept constant. Drugs were infused at systemically ineffective rates through separate ports via three-way stopcocks.
Experimental Design
Endothelium-dependent vasodilation was estimated by performing a dose-response curve to intra-arterial acetylcholine22 (cumulative increase of the infusion rates: 0.15,0.45, 1.5,4.5, 15 µg/100 mL forearm tissue per minute, for 5 minutes at each dose) while endothelium-independent vasodilation was assessed with a dose-response curve to intra-arterial sodium nitroprusside, a direct smooth muscle cell relaxant compound23 (cumulative increase by 1, 2, and 4 µg/100 mL forearm tissue per minute, for 5 minutes at each dose). These rates were selected to induce vasodilation comparable to that obtained with acetylcholine.
Effect of Cyclooxygenase Inhibition on Response to Acetylcholine in the Presence of L-NMMA
In seven normotensive subjects and seven essential hypertensive patients, after sodium nitroprusside infusion, the dose-response curve to intra-arterial acetylcholine was performed according to the following design: during saline (0.2 mL/min), in the presence of intra-arterial L-NMMA (100 µg/100 mL forearm tissue per minute; started 10 minutes before acetylcholine and continued throughout), in the presence of intra-arterial indomethacin (50 µg/100 mL forearm tissue per minute; started 10 minutes before acetylcholine and continued throughout), and finally in the presence of simultaneous infusion of L-NMMA and indomethacin.
Effect of Cyclooxygenase Inhibition on Response to Acetylcholine in the Presence of L-Arginine
In an adjunctive seven normotensive subjects and seven essential hypertensive patients, the same previously described protocol was performed by replacing L-NMMA with L-arginine infused intrabrachially at 200 µg/100 mL forearm tissue per minute. Thirty minutes of washout was allowed between each dose-response curve in the presence of saline, while 60 minutes was allowed when L-arginine or indomethacin was infused simultaneously.
Data Analysis
Since arterial pressure did not significantly change during the study, all data were analyzed in terms of FBF; FBF increments were taken as evidence of local vasodilation. Differences between two means were compared by paired or unpaired Student’s t test, as appropriate. Responses to acetylcholine and sodium nitroprus-side were analyzed by ANOVA for repeated measures and Scheffé’s test was applied for multiple comparison testing. Results were expressed as mean±SD.
Drugs
Acetylcholine HCl (Farmigea SpA), indomethacin (Liometacen; Chiesi Farmaceutici SpA), L-arginine (Clinalfa AG), L-NMMA (Clinalfa AG), and sodium nitroprusside (Malesci) were obtained from commercially available sources and diluted freshly to the desired concentration by adding normal saline. Sodium nitroprusside was dissolved in glucosate solution and protected from light by aluminum foil.
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Results |
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Response to Intrabrachial Acetylcholine and Sodium Nitroprusside
In the overall population, vasodilation to acetylcholine was significantly (P<.01) blunted in essential hypertensive patients (FBF rose from 3.4±0.5 to a maximum of 17.1±3.2 mL/100 mL forearm tissue per minute with the highest dose) compared with normotensive control subjects (FBF rose from 3.4±0.4 to a maximum of 23.9±5.4 mL/100 mL forearm tissue per minute with the highest dose) (Fig 1). In contrast, the vasodilating effect of the endothelium independent vasodilator sodium nitroprusside was similar in normotensive subjects and essential hypertensive patients (FBF rose from 3.6±0.4 to a maximum of 24.1±2.9 mL/100 mL forearm tissue per minute with the highest dose and from 3.5±0.4 to a maximum of 23.3±3.1 mL/100 mL forearm tissue per minute, respectively; NS) (Fig 1).
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) (n=14) and essential hypertensive patients (•) (n=14). Data are shown as mean±SEM and expressed as absolute values. Asterisks denote a significant difference between normotensive control subjects and hypertensive patients (P<.05).
Effect of Cyclooxygenase Inhibition on Response to Acetylcholine in the Presence of L-NMMA
In this group of normotensive control subjects, L-NMMA infusion caused a decrement in basal FBF (from 3.4±0.4 to 1.9±0.2 mL/100 mL forearm tissue per minute; P<.01) and significantly blunted the vasodilating effect of acetylcholine (saline: from 3.4±0.4 to 26.2±5.6 mL/100 mL forearm tissue per minute; L-NMMA: from 1.9±0.2 to 8.3±2.1 mL/100 mL forearm tissue per minute; P<.01 versus acetylcholine alone) (Fig 2). Again indomethacin did not change either basal FBF (from 3.4±0.4 to 3.4±0.4 mL/100 mL forearm tissue per minute), the response to acetylcholine (from 3.4±0.4 to 26.8±5.4 mL/100 mL forearm tissue per minute), or the inhibiting effect of L-NMMA on vasodilation to acetylcholine (from 1.9±0.2 to 8.3±2.5 mL/100 mL forearm tissue per minute) (Fig 2).
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In the essential hypertensive patients, L-NMMA infusion caused a decrement in basal FBF (from 3.2±0.6 to 2.3±0.5 mL/100 mL forearm tissue per minute, P<.01) which was significantly smaller than that observed in normotensive control subjects (percent FBF decrease: 44% versus 28%, respectively; P<.01). However, the response to acetylcholine (from 3.2±0.5 to 17.7±4.2 mL/100 mL forearm tissue per minute) was not changed by L-NMMA (from 2.3±0.5 to 12.5±3.2 mL/100 mL forearm tissue per minute, NS versus saline) (Fig 2). Indomethacin infusion did not change basal FBF (from 3.1±0.4 to 3.1±0.6 mL/100 mL forearm tissue per minute). Nevertheless, the cyclooxygenase inhibitor increased the response to acetylcholine (from 3.1±O.4 to 22.0±3.3 mL/ 100 mL forearm tissue per minute; P<.01 versus acetylcholine during saline) (Fig 2). Finally, when the effect of L-NMMA was tested in the presence of indomethacin, the NO synthase inhibitor blunted the vasodilating response to acetylcholine (from 2.3±0.5 to 12.5±3.7 mL/100 mL forearm tissue per minute; P<.01 versus acetylcholine during indomethacin alone) (Fig 2).
In both normotensive subjects and essential hypertensive patients contralateral FBF did not significantly change during the whole study (data not shown).
Effect of Cyclooxygenase Inhibition on Response to Acetylcholine in the Presence of L-Arginine
In this group of normotensive control subjects, acetylcholine-dependent vasodilation (from 3.5±0.5 to 22.3 ±3.3 mL/100 mL forearm tissue per minute) was significantly (P<.01) increased by the simultaneous infusion of L-arginine (from 3.7±0.3 to 33.5±5.8 mL/100 mL forearm tissue per minute) (Fig 3). Indomethacin administration failed to affect either the response to acetylcholine infused alone (from 3.6±0.5 to 22.5±3.5 mL/100 mL forearm tissue per minute, P=NS versus acetylcholine during saline) or the facilitating effect of L-arginine on acetylcholine-induced vasodilation (FBF from 3.5±0.5 to 31.9±5.2 mL/100 mL forearm tissue per minute, P=NS versus acetylcholine during saline+indomethacin) (Fig 2). Of note is that both L-arginine and indomethacin, when infused alone, did not change basal FBF (data not shown).
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Different results were obtained in essential hypertensive patients. Again acetylcholine infusion caused a dose-dependent vasodilation (from 3.6±0.5 to 16.4±2.9 mL/100 mL forearm tissue per minute) which was statistically lower (P<.01) than that observed in normotensive control subjects. L-Arginine administration changed neither basal FBF ( from 3.6±0.5 to 3.7±0.4 mL/100 mL forearm tissue per minute) or the vasodilating effect of acetylcholine (from 3.7±0.4 to 16.5±3.1 mL/100 mL forearm tissue per minute, NS versus saline) (Fig 3). Indomethacin did not change basal FBF (from 3.3±0.5 to 3.4±0.4 mL/100 mL forearm tissue per minute), but significantly increased the response to acetylcholine (from 3.4±0.4 to 23.6±3.4 mL/ 100 mL forearm tissue per minute, P<.01 versus saline) (Fig 2). It is worth noting, finally, that when L-arginine was coinfused with indomethacin the vasodilating effect of acetylcholine was further increased (from 3.4±0.5 to 31.1±4.1 mL/100 mL forearm tissue per minute; P<.01 versus acetylcholine in the presence of indomethacin) (Fig 3).
In both normotensive subjects and essential hypertensive patients contralateral FBF did not significantly change during the whole study (data not shown).
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Discussion |
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Essential hypertension is characterized by endothelial dysfunction.11–18 This alteration is further confirmed in the present study since the response to acetylcholine, an endothelium-dependent vasodilator,1,5,22 but not to sodium nitroprusside, a direct smooth muscle cell relaxant,23 was blunted in essential hypertensive patients compared with matched normotensive control subjects. The mechanisms responsible for the impaired endothelium-dependent vasodilation include an alteration in the L-arginine-NO pathway and production of cyclooxygenase-dependent EDCF. That these mechanisms can operate in essential hypertensive patients is confirmed by the present results. Thus, in agreement with previous observations,16 administration of L-arginine, the substrate for NO synthase,3 can increase the vasodilating effect of acetylcholine in normotensive subjects while the amino acid is ineffective in essential hypertensive patients. Moreover, L-NMMA, an antagonist for NO synthase,4,5 can blunt the response to acetylcholine in control subjects, but not in hypertensive patients.15 Taken together these results clearly confirm the presence of a defect in the endothelium-derived NO system in essential hypertension, since neither activation nor inhibition of the NO pathway can lead to modifications of the vascular response to the endothelium-dependent vasodilator. It is important to observe that the lack of effect of these compounds on acetylcholine-induced vasodilation is not linked to insufficient infusion rates of either L-arginine or L-NMMA, as already demonstrated by previous evidence obtained in similar experimental conditions.16,17
Moreover, this abnormality does not totally account for the impaired vasodilation to acetylcholine observed in essential hypertension. Thus in hypertensive patients, but not in normotensive subjects, indomethacin indreased the response to the endothelium-dependent vasodilator, confirming that, in agreement with previous evidence,13 the production of cyclooxygenase derivatives can curtail endothelial responses in essential hypertension. It is worth noting that for the first time the alteration in the endothelium-derived NO system and production of cyclooxygenase-dependent EDCF has been demonstrated in the same patients, supporting the possibility that these endothelial alterations coexist in essential hypertension.
However, the main finding of the present study is the demonstration that in essential hypertensive patients cyclooxygenase inhibition by indomethacin administration restores the potentiating and inhibiting effect of L-arginine and L-NMMA, respectively, on acetylcholine-induced vasodilation. In contrast, in normotensive control subjects, indomethacin does not change the effect of L-arginine and L-NMMA on endothelium-dependent vasodilation to acetylcholine. Taken together these findings suggest that in essential hypertension, cyclooxygenase activity causes endothelial dysfunction by producing cyclooxygenase-dependent substances which, at least partially, can inactivate the L-arginine-NO system. There is experimental evidence indicating that in vessels from hypertensive animals a close relationship exists between the L-arginine-NO pathway and cyclooxygenase activity. Thus in primary hypertension, cyclooxygenase activity is increased to produce not only vasoconstrictor prostanoids,6–9,24 but also superoxide anions, which cause NO breakdown.10,25,26 Moreover, it has been demonstrated in canine basilar arteries that an increased production of superoxide anions can destroy NO produced by the activity of the L-arginine pathway, thus causing full expression of vasoconstrictor prostanoids.25 This negative interaction between the NO system and cyclooxygenase activity could be a likely explanation for the impaired endothelium-dependent vasodilation, which is characteristic of essential hypertensive patients. Therefore, in our experimental conditions, in essential hypertensive patients the stimulation of endothelial cells could cause the activation of two parallel pathways involving both NO synthase and cyclooxygenase. Cyclooxygenase activity could lead to the production of NO-inactivating substances (endoperoxides? superoxide anions?), thus explaining the absence of effects of L-arginine and L-NMMA on vasodilation to acetylcholine. When cyclooxygenase is blocked by indomethacin and NO break-down no longer occurs or is at least decreased, it is therefore possible to demonstrate the activity of L-arginine and L-NMMA as observed in normotensive control subjects.
The relationship between cyclooxygenase-dependent EDCF and primary hypertension is of interest. It must be noted that these substances, while causing endothelial dysfunctions, do not seem to contribute to an increase in BP values. Thus, in the spontaneously hypertensive rat,27 treatment by ifetroban, a thromboxane A2/prostaglandin endoperoxide-receptor blocker, normalized endothelium-dependent relaxations to acetylcholine in isolated segments of aorta but produced no reduction in BP values. In agreement with experimental data, in human hypertension the acute administration of ridogrel, a combined thromboxane synthase inhibitor and thromboxane A2 receptor antagonist, did not lower BP values in essential hypertensive patients.28 In addition, the lack of relationship between cyclooxygenase-dependent EDCF and BP values in humans is further confirmed by recent evidence indicating that production of such substances seem to be mainly relating to the aging process.29 Thus in normotensive subjects it is possible to detect production of EDCF when aging increases over 60 years, and this phenomenon is anticipated in essential hypertensive patients (starting from the fourth decade of life). However, it is worth noting that in young essential hypertensive patients production of cyclooxygenase-dependent EDCF does not seem to occur. Therefore, the dissociation between EDCF production and elevated BP values underlines the possibility that EDCF do not participate in the development of hypertension. However, it is well documented that whatever is the nature of EDCF (endoperoxide or superoxide anions), they can increase vascular tone and stimulate platelet aggregation or smooth muscle cell proliferation by direct mechanisms or by inducing NO breakdown.30 It is therefore conceivable that EDCF production, although not important as a causal mechanism responsible for the development of hypertension, probably plays a role in the vascular damage associated with aging and hypertension itself.
As regards the important issue of the relationship between the duration of essential hypertension and EDCF production, no data are available to understand whether the degree of synthesis of these substances is in some way dependent on the length of the hypertensive process. In the present study, unfortunately the recruited hypertensive population shows a quite short duration of hypertension and no conclusion can be drawn.
Finally, it is worth noting that these endothelial mechanisms operate mainly when endothelial cells are stimulated by acetylcholine. Thus, in agreement with previous observations, neither L-arginine16 nor indomethacin13 (nor the combination of both compounds) can influence basal blood flow in either normotensive subjects or essential hypertensive patients. In contrast, L-NMMA infusion can decrease basal FBF, confirming that NO is basally released in human vasculature5 and this mechanism is defective in essential hypertension since, as previously demonstrated,17,18 L-NMMA-induced vasoconstriction is blunted in hypertensive patients compared with control subjects. However, the simultaneous infusion of indomethacin with L-NMMA does not change the vasoconstrictor effect of the NO synthase inhibitor suggesting that cyclooxygenase activity does not participate in NO-mediated local regulation of basal flow.
In conclusion, the present results indicate that endothelial dysfunction which is characteristic of essential hypertension is determined by the simultaneous presence of an alteration in the L-arginine-NO pathway and production of cyclooxygenase derivatives. These alterations do not seem to be independent since in essential hypertensive patients, but not in normotensive control subjects, the dysfunctioning NO system seems to be restored or at least improved by cyclooxygenase blockade. Which cyclooxy-genase-dependent substances could be responsible for inhibition of the L-arginine NO pathway is, at the present time, under investigation.
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L. A. Holowatz and W. L. Kenney Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans J. Physiol., June 1, 2007; 581(2): 863 - 872. [Abstract] [Full Text] [PDF]
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W. G. Schrage, J. H. Eisenach, and M. J. Joyner Ageing reduces nitric-oxide- and prostaglandin-mediated vasodilatation in exercising humans J. Physiol., February 15, 2007; 579(1): 227 - 236. [Abstract] [Full Text] [PDF]
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 I. Sudano, A. Virdis, S. Taddei, L. Spieker, R. Corti, G. Noll, A. Salvetti, and T. F. Luscher Chronic Treatment With Long-Acting Nifedipine Reduces Vasoconstriction to Endothelin-1 in Essential Hypertension Hypertension, February 1, 2007; 49(2): 285 - 290. [Abstract] [Full Text] [PDF]
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 S. Taddei, N. Caraccio, A. Virdis, A. Dardano, D. Versari, L. Ghiadoni, E. Ferrannini, A. Salvetti, and F. Monzani Low-Grade Systemic Inflammation Causes Endothelial Dysfunction in Patients with Hashimoto's Thyroiditis J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 5076 - 5082. [Abstract] [Full Text] [PDF]
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 A. Z. Kalea, D. A. Schuschke, P. D. Harris, and D. J. Klimis-Zacas Cyclo-Oxygenase Inhibition Restores the Attenuated Vasodilation in Manganese-Deficient Rat Aorta J. Nutr., September 1, 2006; 136(9): 2302 - 2307. [Abstract] [Full Text] [PDF]
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 M. Feletou and P. M. Vanhoutte Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture) Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H985 - H1002. [Abstract] [Full Text] [PDF]
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 P. C. Williams, M. J. Coffey, B. Coles, S. Sanchez, J. D. Morrow, J. R. Cockcroft, M. J. Lewis, and V. B. O'Donnell In vivo aspirin supplementation inhibits nitric oxide consumption by human platelets Blood, October 15, 2005; 106(8): 2737 - 2743. [Abstract] [Full Text] [PDF]
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F. A Dinenno, S. Masuki, and M. J Joyner Impaired modulation of sympathetic {alpha}-adrenergic vasoconstriction in contracting forearm muscle of ageing men J. Physiol., August 15, 2005; 567(1): 311 - 321. [Abstract] [Full Text] [PDF]
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W. G. Schrage, N. M. Dietz, J. H. Eisenach, and M. J. Joyner Agonist-dependent variablity of contributions of nitric oxide and prostaglandins in human skeletal muscle J Appl Physiol, April 1, 2005; 98(4): 1251 - 1257. [Abstract] [Full Text] [PDF]
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L. A Holowatz, C. S Thompson, C. T Minson, and W. L. Kenney Mechanisms of acetylcholine-mediated vasodilatation in young and aged human skin J. Physiol., March 15, 2005; 563(3): 965 - 973. [Abstract] [Full Text] [PDF]
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F. A. Dinenno and M. J. Joyner Combined NO and PG inhibition augments {alpha}-adrenergic vasoconstriction in contracting human skeletal muscle Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2576 - H2584. [Abstract] [Full Text] [PDF]
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S. C. Newcomer, U. A. Leuenberger, C. S. Hogeman, B. D. Handly, and D. N. Proctor Different vasodilator responses of human arms and legs J. Physiol., May 1, 2004; 556(3): 1001 - 1011. [Abstract] [Full Text] [PDF]
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M. E. Widlansky, D. T. Price, N. Gokce, R. T. Eberhardt, S. J. Duffy, M. Holbrook, C. Maxwell, J. Palmisano, J. F. Keaney Jr, J. D. Morrow, et al. Short- and Long-Term COX-2 Inhibition Reverses Endothelial Dysfunction in Patients With Hypertension Hypertension, September 1, 2003; 42(3): 310 - 315. [Abstract] [Full Text] [PDF]
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S. Taddei, A. Virdis, L. Ghiadoni, D. Versari, G. Salvetti, A. Magagna, and A. Salvetti Calcium Antagonist Treatment by Lercanidipine Prevents Hyperpolarization in Essential Hypertension Hypertension, April 1, 2003; 41(4): 950 - 955. [Abstract] [Full Text] [PDF]
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 D. Behr-Roussel, P. Chamiot-Clerc, J. Bernabe, K. Mevel, L. Alexandre, M. E. Safar, and F. Giuliano Erectile dysfunction in spontaneously hypertensive rats: pathophysiological mechanisms Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R682 - R688. [Abstract] [Full Text] [PDF]
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 M. Annuk, B. Fellstrom, and L. Lind Cyclooxygenase inhibition improves endothelium-dependent vasodilatation in patients with chronic renal failure Nephrol. Dial. Transplant., December 1, 2002; 17(12): 2159 - 2163. [Abstract] [Full Text] [PDF]
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 G. Jackson and F. Giuliano Moderators' introduction Eur. Heart J. Suppl., December 1, 2002; 4(suppl_H): H1 - H6. [Abstract] [PDF]
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C. A DeSouza, C. M Clevenger, J. J Greiner, D. T Smith, G. L Hoetzer, L. F Shapiro, and B. L Stauffer Evidence for agonist-specific endothelial vasodilator dysfunction with ageing in healthy humans J. Physiol., July 1, 2002; 542(1): 255 - 262. [Abstract] [Full Text] [PDF]
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 S. T. Davidge Prostaglandin H Synthase and Vascular Function Circ. Res., October 12, 2001; 89(8): 650 - 660. [Abstract] [Full Text] [PDF]
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 M. Imamura, S. Biro, T. Kihara, S. Yoshifuku, K. Takasaki, Y. Otsuji, S. Minagoe, Y. Toyama, and C. Tei Repeated thermal therapy improves impaired vascular endothelial function in patients with coronary risk factors J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1083 - 1088. [Abstract] [Full Text] [PDF]
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V. B. O'Donnell and B. A. Freeman Interactions Between Nitric Oxide and Lipid Oxidation Pathways : Implications for Vascular Disease Circ. Res., January 19, 2001; 88(1): 12 - 21. [Abstract] [Full Text] [PDF]
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 S. P. Didion, C. D. Sigmund, F. M. Faraci, and Z. S. Katusic Impaired Endothelial Function in Transgenic Mice Expressing Both Human Renin and Human Angiotensinogen • Editorial Comment Stroke, March 1, 2000; 31(3): 760 - 765. [Abstract] [Full Text] [PDF]
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R. Busse and I. Fleming A critical look at cardiovascular translational research Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1655 - H1660. [Full Text] [PDF]
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M.-S. Zhou, Y. Nishida, Q.-H. Chen, and H. Kosaka Endothelium-Derived Contracting Factor in Carotid Artery of Hypertensive Dahl Rats Hypertension, July 1, 1999; 34(1): 39 - 43. [Abstract] [Full Text] [PDF]
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 C. Cardillo and J. A Panza Impaired endothelial regulation of vascular tone in patients with systemic arterial hypertension Vascular Medicine, May 1, 1998; 3(2): 138 - 144. [Abstract] [PDF]
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K. M. Gauthier-Rein and N. J. Rusch Distinct Endothelial Impairment in Coronary Microvessels from Hypertensive Dahl Rats Hypertension, January 1, 1998; 31(1): 328 - 334. [Abstract] [Full Text] [PDF]
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