Skip Navigation

Cardiovascular Research 2001 52(3):462-467; doi:10.1016/S0008-6363(01)00390-X
© 2001 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Vila, J. M
Right arrow Articles by Lluch, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vila, J. M
Right arrow Articles by Lluch, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2001, European Society of Cardiology

U-46619-induced potentiation of noradrenergic constriction in the human saphenous vein: antagonism by thromboxane receptor blockade

José M Vilaa,*, Juan B Martínez-Leónb, Pascual Medinaa, Gloria Segarraa, Rosa M Ballestera, Eduardo Oterob and Salvador Llucha

aDepartment of Physiology, University of Valencia School of Medicine, 46010 Valencia, Spain
bDepartment of Surgery, University of Valencia School of Medicine, 46010 Valencia, Spain

vila{at}post.uv.es

* Corresponding author. Departamento de Fisiología, Facultad de Medicina y Odontología, Blasco Ibáñez 17, 46010 Valencia, Spain. Tel.: +34-6-386-4644; fax: 34-6-386-4642

Received 19 April 2001; accepted 28 June 2001


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: We investigated the potentiating effect of U-46619, a synthetic analogue of thromboxane A2 (TXA2), on the adrenergic responses in human saphenous vein. Methods: Saphenous vein rings were obtained from 35 patients undergoing coronary artery bypass surgery. The rings were suspended in organ bath chambers for isometric recording of tension. Results: U-46619 (10–10–3x10–7 mol/l) produced concentration-dependent and endothelium-independent contractile responses. U-46619 (10–10 mol/l) potentiated the contractions elicited by electrical stimulation and potassium chloride, and produced leftward shifts of the concentration–response curve for noradrenaline. The TXA2 receptor antagonist SQ-30741 (10–8 mol/l) prevented the potentiation evoked by U-46619. The dihydropyridine calcium antagonist nifedipine (10–6 mol/l) did not affect the potentiation of electrical stimulation and noradrenaline induced by U-46619, but abolished the potentiation of U-46619 on KCl-induced contractions. Conclusions: U-46619 facilitates sympathetic neurotransmission and potentiates constrictor effects of noradrenaline in human saphenous veins through stimulation of TXA2 receptors. These effects are independent of calcium entry through dihydropyridine calcium channels.

KEYWORDS Adrenergic (ant)agonists; Ca-channel; Receptors; Vasoconstriction/dilation; Veins; Endothelial factors; Vasoactive agents


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Thromboxane A2 (TXA2) is a cyclooxygenase metabolite that has been reported to modulate sympathetic neurotransmission in several preparations. U-46619, a synthetic, metabolically stable analogue of thromboxane A2 [1], enhances sympathetic neurotransmission in human isolated urinary bladder [2], rabbit mesenteric artery [3] and portal vein [4], and the pressor response to nerve stimulation in rat isolated kidney [5]. With regard to human vessels, preliminary experiments have shown that low concentrations of U-46619 enhance contractions elicited by sympathetic nerve stimulation in human saphenous veins [6]. However, the mechanisms involved in the enhancement of adrenergic responses by TXA2 receptor activation are not known. We reasoned that U-46619 could modulate adrenergic responses through stimulation of the same receptor sites that induce smooth muscle contraction. This might have important implications in our understanding of the detrimental effects associated with acute ischemic syndromes after autologous grafts in the arterial circulation or coronary bypass surgery [7–9]. Therefore, we designed this study to determine the influence of concentrations of U-46619 within a range which, while having no direct contractile effects, could amplify adrenergic-mediated contractions of human saphenous veins. Because previous studies have indicated that U-46619 stimulates the opening of voltage-dependent Ca2+ channels to increase Ca2+ influx [10,11], and calcium channel blockers can inhibit the cerebral [12] and coronary [13] vasoconstriction caused by synthetic thromboxane analogues, we also examined whether the enhancing effects of TXA2 on adrenergic contractions could be mediated by Ca2+ entry through dihydropyridine Ca2+ channels.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
Vein segments were taken from portions of human saphenous veins of patients undergoing coronary artery bypass surgery (35 patients, 24 men and 11 women; age range 52 to 71 years). The study was approved by the ethical committee of our institution, and informed consent was obtained from each patient before the study. During surgical preparation of the saphenous vein, the dilation procedure was avoided. The veins were immediately placed in chilled Krebs–Henseleit solution, and rings 3 mm long were cut for isometric recording of tension.

Two stainless steel L-shaped pins 200 µm in diameter were introduced through the lumen of the vein ring. One pin was fixed to the wall of the organ bath, and the other was connected to a force-displacement transducer (Grass FT03). Changes in isometric force were recorded on a Grass polygraph (model 7). Each vein ring was set up in a 4 ml bath that contained modified Krebs–Henseleit solution of the following millimolar composition: NaCl, 115; KCl, 4.6; MgCl2·6H2O, 1.2; CaCl2, 2.5; NaHCO3, 25; glucose, 11.1; and disodium EDTA, 0.01. The solution was equilibrated with 95% oxygen and 5% carbon dioxide to give a pH of 7.3 to 7.4. Temperature was held at 37°C. Resting tension was set to the optimal level for development of active force [14]. The optimal resting tension was 3 g. The vein rings were allowed to attain a steady level of tension during a 2–3 h accommodation period before testing. Functional integrity of the endothelium was confirmed routinely at the beginning of the experiment by the presence or absence of relaxation induced by acetylcholine (10–7–10–6 mol/l) or substance P (10–9 mol/l) during contraction obtained with noradrenaline (10–7–3x10–7 mol/l).

Electrical field stimulation was provided by a Grass S88 stimulator via two platinum electrodes positioned on each side and parallel to the axis of the vein ring. To assess the nature of the contractile responses and avoid direct stimulation of the smooth muscle, frequency–response relationships were determined on a group of veins in the presence and absence of 10–6 mol/l tetrodotoxin following procedures previously described [15]. In summary, the protocol was designed to find the optimal stimulation parameters (15 V, 0.2 ms duration) causing a contractile response that was completely eliminated by 10–6 mol/l tetrodotoxin. Frequency–response relationships were determined with 15-s trains of pulses at 1, 2 and 4 Hz. A period of 10 min was allowed between stimulations. The preparations were allowed to equilibrate for at least 10 min before they were incubated with tetrodotoxin (10–6 mol/l) or prazosin (10–6 mol/l). After 10–15 min incubation with the antagonist, a second set of stimulations was performed. In each experiment, a second frequency–response relationship in untreated vein rings was run in parallel.

To study the effects of U-46619 on electrical field stimulation-induced responses, frequency–response relationships were determined in a separate group of experiments. After an initial set of stimulations, the vein rings were consecutively incubated with increasing concentrations of U-46619 (10–11 to 10–10 mol/l) for 10 min before another set of stimulations was given. As a control, four consecutive sets of stimulations were given to a group of untreated vein rings at identical intervals. Less than 10% variability in the magnitude of electrical field stimulation-induced contractions was observed for a given ring during four consecutive sets of control stimulations.

In another series of experiments, after a first frequency–response relationship was obtained, the preparations were incubated with either the TXA2 receptor antagonist SQ-30741 (10–8 mol/l), the TXA2 receptor antagonist (10–8 mol/l) plus U-46619 (10–10 mol/l), the reuptake blocker cocaine (10–6 mol/l) plus U-46619 (10–10 mol/l), or the dihydropyridine calcium antagonist nifedipine (10–6 mol/l) plus U-46619 (10–10 mol/l). After 10–15 min incubation with the corresponding drugs, a second set of stimulations was then performed. In each group of experiments, stimulations without any treatment were run in parallel.

Concentration–response curves for noradrenaline (10–9–10–5 mol/l) and KCl (5–100 mmol/l) were determined in a cumulative manner. Control (in the absence of U-46619) and experimental (in the presence of U-46619) data were obtained from separate vascular preparations. Another group of vein rings was incubated with the TXA2 receptor antagonist SQ-30741 (10–8 mol/l) plus U-46619 (10–10 mol/l) before exposure to noradrenaline or KCl.

In a separate group of veins, noradrenaline (10–9–10–5 mol/l) and KCl (5–100 mmol/l) were applied in the presence of either nifedipine (10–6 mol/l) or nifedipine plus U-46619 (10–10 mol/l), and the data were compared with those obtained from untreated (control) segments.

2.1 Drugs
The following drugs were used: tetrodotoxin, nifedipine, prazosin, noradrenaline hydrochloride, acetylcholine chloride, U-46619 [9,11-dideoxy-11{alpha},9{alpha}-epoxy-methanoprostaglandin F2{alpha}, substance P acetate salt (Sigma, St. Louis, MO, USA), SQ-30741 [1S-[1{alpha},2{alpha}(Z),3{alpha},4{alpha}]]-7-[3-[[[[(1-oxoheptyl)amino] acetyl] amino]methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid (Bristol-Myers Squibb, Princeton, USA) and cocaine chlorhydrate (Abelló, Madrid, Spain). All drugs were dissolved in Krebs–Henseleit solution except nifedipine, which was dissolved initially in ethanol and further diluted in Krebs solution to the proper final concentration. Drugs were added to the organ bath in volumes of less than 70 µl. Stock solutions of the drugs were freshly prepared every day, and kept on ice throughout the experiment.

2.2 Data analysis
All values are expressed as mean±S.E.M. Contractions are reported as a percentage of the maximal tension developed by 100 mmol/l of KCl. EC50 values (concentrations of agonist producing half-maximal contraction) were determined from individual concentration–response curves by non-linear regression analysis, and from these values the geometric means were calculated. The EC50 values were compared by an unpaired t-test and an analysis of variance with Scheffe’s test as post-hoc test. The number of rings taken from each patient varied from eight to 16. Concentration–response curves of the tested agonists or frequency–response relationships were obtained in the presence and absence of either U-46619 or the antagonists in rings obtained from the same patient; the responses obtained in each patient were averaged to yield a single value. Therefore, all n values are presented as the number of patients from whom the blood vessels were obtained. For electrical stimulation experiments, in which the same veins were stimulated in the absence and presence of U-46619, a paired t-test was used. Statistical significance was accepted at P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Effects of the thromboxane analogue U-46619
U-46619 (10–10–3x10–7 mol/l) caused concentration-dependent contractions with an EC50 of 3.7x10–9 mol/l. These contractions were endothelium-independent (Fig. 1). The presence of the TXA2 antagonist SQ-30741 (10–8 mol/l) induced a parallel rightward shift (about 27-fold) (P<0.05) of the response to U-46619, but differences in the maximal tensions developed were not significant (P>0.05). Increasing the concentration of the antagonist to 10–7 mol/l further displaced (127-fold) the control curve for U-46619. The {alpha}-1 adrenoceptor blocker prazosin (10–6 mol/l) did not affect the concentration–response curve to U-46619 (Fig. 1).


Figure 1
View larger version (25K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Concentration–response curves for U-46619 in the presence (bullet, n=7) and absence ({circ}, n=7) of endothelium, in the presence of the {alpha}1 adrenoceptor blocker prazosin ({bigtriangleup}, n=3), the TXA2 antagonist SQ-30741 at a concentration of 10–8 mol/l ({square}, n=4) and 10–7 mol/l ({blacksquare}, n=5). Values are mean±S.E.M.

 
3.2 Effects of U-46619 on electrical stimulation-induced responses
Electrical stimulation induced frequency-dependent contractions which were abolished by tetrodotoxin (10–6 mol/l) and prazosin (10–6 mol/l), thus indicating that the effect was due to the release of noradrenaline from perivascular adrenergic nerves acting on {alpha}-1 adrenoceptors (results not shown).

U-46619 (3x10–11–10–10 mol/l) enhanced in a concentration-dependent manner the contractions to electrical stimulation (Fig. 2A). This effect was observed at all the frequencies used (Fig. 2B). In the presence of the TXA2 receptor antagonist SQ-30741 (10–8 mol/l), U-46619 failed to enhance the responses to electrical stimulation (Fig. 2B). Blockade of neuronal catecholamines reuptake by cocaine (10–6 mol/l) or treatment with nifedipine (10–6 mol/l) did not change significantly the frequency–response curve to electrical stimulation nor did it inhibit the enhancement of neurogenic responses by U-46619 (Fig. 2C and D)


Figure 2
View larger version (35K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 (A) Contractile responses to electrical stimulation (2 Hz) in human saphenous veins under control conditions and after incubation with increasing concentrations of U-46619. (B) Effects of U-46619 on frequency-dependent contractile responses to electrical stimulation in the absence and presence of the TXA2 receptor antagonist SQ-30741. (C) Contractile responses to electrical stimulation in the absence and presence of cocaine or cocaine plus U-46619. (D) Frequency–response relationship in control veins and in veins treated with nifedipine or nifedipine plus U-46619. Values are mean±S.E.M. *Significant difference from control value, P<0.05.

 
3.3 Effects of U-46619 on noradrenaline- and KCl-induced contractions
U-46619 (10–10 mol/l) produced a significant potentiation of the noradrenaline-induced contractions (Fig. 3A). The EC50 shifted significantly from 2.6x10–7 to 7.5x10–8 mol/l in the presence of U-46619 (P<0.05). The maximal response to noradrenaline was not altered. The TXA2 antagonist SQ-30741 (10–8 mol/l) completely reversed the U-46619-induced potentiation of the noradrenaline response curve. The EC50 increased to 1.7x10–7 mol/l, a value similar to that obtained when noradrenaline was given alone (P>0.05). The presence of nifedipine (10–6 mol/l) diminished maximal responses to noradrenaline, but EC50 was not altered (2.6x10–7 versus 3.1x10–7 mol/l) (Fig. 3B). In addition, the enhancement of the contractile responses to noradrenaline by U-46619 was identical to that observed in the absence of nifedipine (Fig. 3B).


Figure 3
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 (A) Concentration–response curves for noradrenaline in the absence (bullet, n=10) and in the presence of either U-46619 (10–10 mol/l) ({circ}, n=10) or SQ-30741 (10–8 mol/l) plus U-46619 (10–10 mol/l) ({square}, n=7). (B) Concentration–response curves for noradrenaline in the absence (bullet, n=10) and in the presence of nifedipine (10–6 mol/l) ({bigtriangleup}, n=3) or nifedipine together with U-46619 (10–10 mol/l) ({blacktriangleup}, n=3). (C) Concentration–response curves for KCl in the absence (bullet, n=8) and in the presence of U-46619 (10–10 mol/l) ({circ}, n=8), SQ-30741 (10–8 mol/l) plus U-46619 (10–10 mol/l) ({square}, n=7), nifedipine (10–6 mol/l) ({bigtriangleup}, n=5) or nifedipine plus U-46619 (10–10 mol/l) ({blacktriangleup}, n=5). Contractions to 100 mmol/l KCl were 5167±586 mg in venous rings with endothelium and 5318±637 in venous rings without endothelium. Values are mean±S.E.M.

 
The contractions to KCl were significantly potentiated by U-46619 (10–10 mol/l) (Fig. 3C). The EC50 of the concentration–response curve changed from 28±2 mmol/l (control) to 21±2 mmol/l (U-46619) (P<0.05). The maximal response to KCl was not changed. Previous addition of SQ-30741 (10–8 mol/l) inhibited the potentiation by U-46619 on the KCl-response curve (EC50=28±2 mmol/l). In the presence of nifedipine, KCl-induced contractions were significantly reduced and U-46619 failed to enhance the constrictor responses to KCl (Fig. 3C)

The antagonistic action of SQ-30741 was specific since it did not inhibit contractions induced by noradrenaline or KCl, even at concentrations as high as 10–6 mol/l (results not shown).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The results of this study demonstrate that low concentrations of the thromboxane A2 analogue U-46619 enhance the contractile effects of electrical stimulation and noradrenaline in the human saphenous vein. The potentiating effects occur at U-46619 concentrations substantially lower than those required to produce a clear direct contractile response. The thromboxane receptor antagonist SQ-30741 inhibited the amplifying effects of U-46619 on electrical stimulation and noradrenaline-induced contractions in a concentration-dependent manner. The results are consistent with the hypothesis that stimulation of TXA2 receptors in the absence of direct contraction is followed by enhancement of responses to both endogenous and exogenous noradrenaline.

It might be conceived that the effects of U-46619 on electrical stimulation contractions could involve an effect of adrenergic nerves, leading to release of noradrenaline, or, alternatively, U-46619 could act with noradrenaline at postjunctional receptor sites. Because noradrenaline release was not measured in this study, a contribution of presynaptic facilitating effects cannot be excluded. The fact that the concentration–response curve to U-46619 was not modified by prazosin, an {alpha}1 adrenoceptor blocker, suggests that the action of U-46619 does not involve release of noradrenaline. Additional support comes from experiments in strips of human saphenous vein showing that the thromboxane analogue U-46619 did not modify electrically-evoked (3H)-noradrenaline release unless it was used at concentrations higher than 1 µmol/l [16]. The possibility that U-46619 could block the reuptake of noradrenaline and therefore enhance the contractile responses is unlikely because the potentiating effects were still evident in the presence of cocaine. Alternatively, U-46619-induced potentiation could be due to alterations at the receptor level, leading to an increased affinity of noradrenaline for its receptor. This may be a likely explanation because U-46619 increased the contractions to exogenously applied noradrenaline. However, this suggestion cannot account entirely for the present observations because contractions to KCl, which are mediated by voltage-dependent calcium channels, were also potentiated by U-46619, an effect completely reversed by SQ-30741. Thus the potentiating effects of thromboxane-receptor activation are not restricted to events triggered by {alpha}-adrenergic stimulation but seem to reflect a general modification of vascular smooth muscle. Thus we also considered the possibility that the enhancing effects of TXA2 could be due to a facilitation of Ca2+ entry through dihydropyridine-sensitive calcium channels. Nifedipine did not affect the contractile response induced by electrical stimulation. We have previously reported that nifedipine diminished the maximal responses to noradrenaline by 25% without changing the EC50 values [17]. The present results show that nifedipine did not affect the potentiating action of TXA2 on noradrenaline- and electrical stimulation-induced contractions, thus indicating that an influx of extracellular Ca2+ through dihydropyridine-sensitive calcium channels does not importantly contribute to the potentiating effects of U-46619 on adrenergic contractions. Other mechanisms of calcium handling such as an increase in inositol phosphate metabolism and/or increase calcium release from intracellular reservoirs may be involved in the potentiating effects of U-46619 on adrenergic stimulation [18,19].

In addition, our results show that TXA2 potentiated KCl contractions, an effect completely reversed by thromboxane-receptor blockade. This suggests, in agreement with previous reports [20], that thromboxane-receptor stimulation may also bring about a facilitation of extracellular Ca2+ entry by KCl through voltage-dependent Ca2+ channels.

Thromboxane A2 has long been involved in platelet aggregation and vasospasm [21–24]. Our experiments show that TXA2 not only produces a marked constriction of human saphenous vein but also potentiates contractions elicited by electrical stimulation and noradrenaline through stimulation of specific receptors. This raises the possibility that TXA2 may act synergistically with the adrenergic neurotransmitter and contribute to mechanisms involved in acute ischemic syndromes associated with venous grafts. The human saphenous vein can undergo spasm immediately after autologous grafts in the arterial circulation or coronary bypass surgery [7–9]. In view of the specificity and potency of SQ-30741, our results give functional evidence that drugs that antagonize the actions of thromboxane A2 by blocking its receptors may have potential clinical use providing protection against possible increases in TXA2 levels. Moreover, if the compound is sufficiently specific, the effect of endogenous protective mediators such as prostacyclin would be retained in the absence of the action of TXA2 [25].

Time for primary review 22 days.


   Acknowledgements
 
This work was supported by the Comisión Interministerial de Ciencia y Tecnología, Ministerio de Sanidad and Generalitat Valenciana. G. Segarra was a recipient of a Fellowship of the Instituto de Salud Carlos III (99/9016).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Coleman R.A., Humphrey P.P.A., Kennedy I., Levy G.P., Lumley P. Comparisons of the actions of U-46619, a stable prostaglandin H2 analogue, with those of prostaglandin H2 and thromboxane A2 on some isolated smooth muscle preparations. Br J Pharmacol (1981) 73:773–778.[ISI][Medline]
  2. Palea S., Toson G., Pietra C., et al. Pharmacological characterization of thromboxane and prostanoid receptors in human isolated urinary bladder. Br J Pharmacol (1998) 124:865–872.[CrossRef][ISI][Medline]
  3. Trachte G.J., Stein E. Platelet-generated thromboxane A2 enhances norepinephrine release from adrenergic nerves. J Pharmacol Exp Ther (1988) 247:1139–1145.[Abstract/Free Full Text]
  4. Stein E.A., Trachte G.J. Thromboxane mimetics enhance adrenergic neurotransmission in the rabbit-isolated portal vein. J Cardiovasc Pharmacol (1989) 14:469–474.[ISI][Medline]
  5. Rump L.C., Schollmeyer P. Effects of endogenous and synthetic prostanoids, the thromboxane A2 receptor agonist U-46619 and arachidonic acid on [3H]-noradrenaline release and vascular tone in rat isolated kidney. Br J Pharmacol (1989) 97:819–828.[ISI][Medline]
  6. Fabi F., Argiolas L., Ruvolo G., Del Basso P. Neuropeptide Y-induced potentiation of noradrenergic vasoconstriction in the human saphenous vein: involvement of endothelium generated thromboxane. Br J Pharmacol (1998) 124:101–110.[CrossRef][ISI][Medline]
  7. Vlodaver Z., Edwards J.E. Pathologic changes in aortic-coronary arterial saphenous vein grafts. Circulation (1971) 69:719–728.
  8. Hamaker W.R., O’Connel T.J., Gomez A.C. Subintimal obliterative proliferation in saphenous vein grafts: a cause of early failure of aorta-to-coronary artery bypass grafts. In: Ann Thorac Surg (1972) 488–493.
  9. Grondin C.M., Campeau L., Lesperance J., Enjalbert M., Bourassa M.G. Comparison of late changes in internal mammary artery and saphenous vein grafts in two consecutive series of patients 10 years after operation. Circulation (1984) 70(suppl_I):I208–I212.[Medline]
  10. Han S.Z., Karaki H., Ouchi Y., Akishita M., Orimo H. 17 Beta-estradiol inhibits Ca2+ influx and Ca2+ release induced by thromboxane A2 in porcine coronary artery. Circulation (1995) 91:2619–2626.[Abstract/Free Full Text]
  11. Liu F., Wu J.Y., Beasley D., Orr J.A. TXA2-induced pulmonary artery contraction requires extracellular calcium. Respir Physiol (1997) 109:155–166.[CrossRef][ISI][Medline]
  12. Towart R., Perzborn E. Nimodipine inhibits carbocyclic thromboxane-induced contractions of cerebral arteries. Eur J Pharmacol (1981) 69:213–215.[CrossRef][ISI][Medline]
  13. Smith E.F., Lefer A.M., Nicolaou K.C. Mechanism of coronary vasoconstriction induced by carbocyclic thromboxane A2. Am J Physiol (1981) 240:H493–H497.[ISI][Medline]
  14. Aldasoro M., Medina P., Vila J.M., et al. Endothelium-dependent relaxation of human saphenous veins in response to vasopressin and desmopressin. J Vasc Surg (1997) 25:696–703.[CrossRef][ISI][Medline]
  15. Aldasoro M., Martínez C., Vila J.M., Flor B., Lluch S. Endothelium-dependent component in the contractile responses of human omental arteries to adrenergic stimulation. Eur J Pharmacol (1993) 250:103–107.[CrossRef][ISI][Medline]
  16. Molderings G. Modulation of noradrenaline release from the sympathetic nerves of the human saphenous vein and pulmonary artery by presynaptic EP3 and DP-receptors. Br J Pharmacol (1994) 111:733–738.[ISI][Medline]
  17. Medina P., Acuña A., Martínez-León J.B., et al. Arginine vasopressin enhances sympathetic constriction through the V1 vasopressin receptor in human saphenous vein. Circulation (1998) 97:865–870.[Abstract/Free Full Text]
  18. Uski T.K., Andersson K.-E. Effects of prostanoids on isolated feline cerebral arteries. II. Roles of extra- and intracellular calcium for PGF2{alpha} induced contraction. Acta Physiol Scand (1984) 120:197–205.[ISI][Medline]
  19. Furci L., Fitzgerald D.J., Fitzgerald G.A. Heterogeneity of prostaglandin H2/thromboxane A2 receptors: distinct subtypes mediate vascular smooth muscle contraction and platelet aggregation. J Pharmacol Exp Ther (1991) 258:74–81.[Abstract/Free Full Text]
  20. Tosun M., Paul R.J., Papoport R.M. Role of extracellular Ca++ influx via L-type and non-L-type Ca++ channels in thromboxane A2 receptor-mediated contraction in rat aorta. J Pharmacol Exp Ther (1998) 284:921–928.[Abstract/Free Full Text]
  21. Green K., Vesterqvist O. In vivo synthesis of thromboxane and prostacyclin in man in health and disease: data from GC–MS measurements of major urinary metabolites. Adv Prostaglandin Thromboxane Leukotriene Res (1986) 16:309–324.[Medline]
  22. Lorenz R.L., Schacky C.V., Weber M., et al. Improved aortocoronary bypass patency by low-dose aspirin (100 mg daily): effects on platelet aggregation and thromboxane formation. Lancet (1984) 1:1261–1264.[CrossRef][ISI][Medline]
  23. Lewis H., Davis J.W., Archibald D.G., et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. New Engl J Med (1983) 309:396–403.[Abstract]
  24. Cairns J.A., Gent M., Singer J., et al. Aspirin, sulfinpyrazone, or both in unstable angina: results of a Canadian multicenter trial. New Engl J Med (1985) 313:1369–1375.[Abstract]
  25. Aiken J.W., Shebuski R.J., Miller O.V., Gorman R.R. Endogenous prostacyclin contributes to the efficacy of a thromboxane synthetase inhibitor for preventing coronary artery thrombosis. J Pharmacol Exp Ther (1981) 219:299–308.[Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Vila, J. M
Right arrow Articles by Lluch, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vila, J. M
Right arrow Articles by Lluch, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?