In vitro effects of antihypertensive drugs on thromboxane agonist (U46619)-induced vasoconstriction in human internal mammary artery

K. A. Tanaka, F. Szlam, N. Katori, A. Tsuda and J. H. Levy*

Department of Anesthesiology, Emory University School of Medicine, Division of Cardiothoracic Anesthesiology and Critical Care, Emory Healthcare, Atlanta, Georgia, USA

* Corresponding author. E-mail: jerrold_levy{at}emoryhealthcare.org

Accepted for publication March 12, 2004.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Hypertension is a major problem in the perioperative period of cardiac and non-cardiac surgery. The vascular endothelium plays a crucial role in modulating vascular tone by producing vasodilators as well as vasoconstrictors. Thromboxane A2 (TxA2), a prototypical vasoconstrictor produced by endothelium and platelets, may play an important role in the pathogenesis of hypertension and subsequent ischaemic events. Although multiple drugs are currently available to treat perioperative hypertension, there is a paucity of data comparing these agents. Therefore, we examined the in vitro vascular effects of commonly used antihypertensive drugs on human internal mammary artery (IMA) segments.

Methods. Relaxation responses to adenosine (a nucleoside), enalaprilat (a competitive inhibitor of angiotensin-converting enzyme), fenoldopam (a D1-dopamine receptor agonist), hydralazine, labetalol (an {alpha}- and ß-adrenergic blocker), nicardipine (a calcium channel blocker), nicorandil (K+-ATP channel opener), nitroglycerin (GTN, a nitrosovasodilator), and sodium nitroprusside (SNP, a nitrosovasodilator) were studied in IMA segments pre-contracted with the TxA2 analogue (U46619, 1.0x10–8 M). Effects of labetalol were also studied in IMA segments pre-contracted with norepinephrine (1.0x10–6 M). All drugs were added in a cumulative fashion (range 10–10 to 10–3 M).

Results. All agents in the current study, with the exception of enalaprilat, dilated the IMA segments pre-contracted with U46619. Only GTN and SNP induced a complete (90–100%) relaxation. The order of efficacy of the in vitro relaxation was as follows: SNP, GTN, nicardipine, nicorandil, fenoldopam, hydralazine, adenosine, and labetalol. The potency was in the order of GTN, SNP, fenoldopam, nicorandil, hydralazine, adenosine, and nicardipine.

Conclusions. Various antihypertensive agents are effective in attenuating U46619-induced IMA vasoconstriction, but the efficacy and potency differ. The in vitro vasodilation may not be simply extrapolated to the clinical efficacy or outcome of each antihypertensive therapy; however, our data provide additional grounds for the choice of antihypertensive medication. Further clinical studies are needed to help to fully elucidate the use of different antihypertensive agents and clinical outcomes.

Keywords: agonists, thromboxane ; arterial pressure, antihypertensives ; arteries, internal mammary artery ; complications, vasoconstriction


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Hypertension is a major problem in the perioperative period, especially in older patients with atherosclerotic disease, presenting for both cardiac and non-cardiac surgery. Controlling arterial pressure is often a challenging task in the perioperative period, and various antihypertensives are often used as vasodilators in order to reduce myocardial stress.

The vascular endothelium plays a crucial role in modulating vascular tone by producing vasodilators (e.g. prostacyclin (PGI2) and endothelium-derived nitric oxide), as well as vasoconstrictors (e.g. thromboxane A2 (TxA2), endothelin, and superoxide anions).16 Hypertension may be linked to the imbalance in the formation of PG2 and TxA2, and may occur in the perioperative period.7 Elevated levels of TxA2 may well be a causal factor leading to the arterial constriction and vascular events as reported in aspirin-resistant patients who had a higher risk of myocardial infarction and cardiac death.8

Internal mammary artery (IMA) is widely used as a conduit for coronary artery bypass surgery, can be readily obtained, and serves as a useful model to study the effects of pharmacologic agents on human vasculature. Further, systemic arterial pressure control by i.v. antihypertensive agents administered during bypass surgery is highly likely to affect the vascular tone and blood flow in this conduit artery. Previous in vitro studies have described nitrovasodilators, calcium channel blockers, and phosphodiesterase inhibitors on the IMA, but there is a paucity of information on comparing different pharmacologic class of antihypertensive drugs.

In our in vitro study we investigated the relaxation responses of different classes of antihypertensive agents on human IMA pre-contracted with TxA2 analogue in order to elucidate differences in potency and efficacy of the different agents routinely used in clinical practice.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Vessel preparation
Following approval by our institutional review board, segments of right and left IMA were collected from 60 patients undergoing CABG. The cardiovascular risk factors and the preoperative drug therapy of these patients are listed in Table 1. The discarded distal end was carefully removed and placed in chilled modified Krebs–HEPES buffer of the following composition (mmol litre–1): NaCl 118, KCl 4.69, CaCl2 2.5, MgSO4 1.04, NaHCO3 25, D-glucose 11.1, and HEPES 21.8, pH 7.40 (0.05). The vessels were transferred to the laboratory and then cleaned of adherent connective tissue. The time delay between vessel harvest and preparation was less than 15 min. The IMA segments were cut into 3-mm rings. Two to four rings were obtained from each vessel. Active endothelial function was confirmed by acetylcholine-induced vasodilation.


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Table 1 The cardiovascular risk factors and preoperative drug therapy of the patients included in the study.

 
Experiments with isolated vascular rings
The rings were suspended between two wire hooks in organ chambers filled with 25 ml Krebs–Henseleit solution (37°C, pH 7.40) aerated with oxygen 95%/carbon dioxide 5%. The upper hook was connected to a force transducer (Kent-Scientific Corporation, Litchfield, CT), and changes in isometric force were recorded (MacLab® system, ADI Instruments; Milford, MA). A resting tension (4 g) initially defined by preliminary studies was progressively applied, and the rings were allowed to stabilize for 45 min (until a stable baseline was obtained).9 The IMA segments were then pre-contracted with 60 mM potassium chloride. The contraction was allowed to plateau for 10 min and then acetylcholine was (10–6 M) added to assess endothelial function. Only rings that exhibited more than 30% relaxation were used in the subsequent experiments.10 The vascular segments were then washed twice with fresh buffer solution and pre-contracted with the TxA2 analogue U46619 (10–8 M). Additionally, when labetalol was used as the relaxing agent, some of the rings were pre-contracted with norepinephrine (10–6 M). The concentrations of pre-contracting agents (U46619 and norepinephrine) were determined from the cumulative contraction–response curves to achieve 50–80% of the maximum contraction as described previously.9 After 10–15 min equilibration (time needed for the development of stable contraction), segments of IMA were randomly assigned to one of 10 groups (adenosine, enalaprilat, fenoldopam, hydralazine, labetalol, labetalol/norepinephrine, nicardipine, nicorandil, nitroglycerin (GTN), and sodium nitroprusside (SNP)) and exposed to increasing concentrations (range 10–10 to 10–3 M) (in 0.5 log unit steps) of relaxants. Each IMA ring was exposed to only one drug, which was added cumulatively every 5 min. Control, U46619, and norepinephrine contracted rings not challenged with any antihypertensive agent were run in parallel as time controls. No more than 75–80 min was required from the time the relaxing agent was added to the bath until the end of the experiment.

Drugs
All drugs were obtained from commercial sources as follows: adenosine diphosphate (Fujisawa USA, Inc., Deerfield, IL), enalaprilat (Merck, Rahway, NJ), fenoldopam (Neurex Corporation, Menlo Park, CA), hydralazine (American Regent Laboratories, Shirley, NY), labetalol (Glaxo-Wellcome, Inc., Reseach Triangle Park, NC), nicardipine (Wyeth Laboratories, Inc., Philadelphia, PA), nitroglycerin (Solopack Laboratories, Elk Grove Village, IL), nicorandil (Chugai Pharmaceutical Co. Ltd, Japan), norepinephrine (Abbott Laboratories, Chicago, IL), TxA2 analogue (U46619) (Upjohn Company, Kalamazoo, MI), SNP and KCl (Sigma Chemical Company, St Louis, MO). An aliquot of TxA2 analogue (U46619) was evaporated to dryness under nitrogen and re-dissolved in absolute ethanol to 10–3 M and then serially diluted in distilled water. All other drugs were serially diluted in distilled water. Drugs were prepared before each experiment and stored on ice. Drug concentrations are expressed as final molar concentrations in the bath solution.

Data and statistical analysis
Contraction responses to norepinephrine, and the TxA2 analogue (U46619) were expressed in gain of tension (in grams). Relaxation responses were calculated as percentage of norepinephrine or U46619 induced contraction. Data were averaged for each patient in all experiments. For curves that saturated, the effective concentration of vasodilator agent that caused 50% relaxation (EC50) was determined for each IMA (responses from vascular segments were averaged for one IMA) by the logistic curve fitting the equation:

where E is the response, Emax is the maximal relaxation, C is the concentration, and {gamma} is the slope parameter (Sigma Plot®, SPSS, Inc., San Rafael, CA). Results are expressed as mean (SD). Statistical analysis (STATVIEW (Macintosh OS9)) was performed with Kruskal–Wallis H-test followed by Mann–Whitney U-test with Bonferroni correction. A probability value <0.05 was considered significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Concentration–response curves
There were no differences in baseline pre-contraction and maximum contraction levels between the groups (Table 2), and the maximum contraction achieved by U46619 and norepinephrine in control IMA rings was stable for the duration of the relaxation experiments. The Emax and EC50 values for nicorandil, nicardipine, and adenosine were not calculated as the respective concentration–response curves had not saturated at the highest concentration achieved during the study (Figs 1Go3). GTN and SNP were the only two agents, which allowed maximum relaxation (Emax) of 90–100% of IMA segments pre-contracted with U46619 (Fig. 1). The EC50 for relaxation was higher for nitroglycerin (4.51 (3.4)x10–8 mol litre–1) than for SNP (3.90 (1.6)x10–8 mol litre–1), but the difference was not significant. Nicardipine, a calcium channel blocker, caused a concentration-dependent relaxation of IMA, but its efficacy and potency were lower than GTN or SNP (Fig. 1, Table 2). Nicorandil also caused a concentration-dependent relaxation of IMA, however, it was as efficacious but less potent than nicardipine (Fig. 2, Table 2). Fenoldopam caused slightly, but not statistically significant less relaxation of IMA when compared with nicorandil (54.3 vs 70.7%, respectively; P=0.231) (Fig. 2, Table 1). Emax value for fenoldopam was lower that those of SNP and GTN (P<0.01 vs SNP and GTN). EC50 value for fenoldopam was higher than those of GTN and SNP (Table 2). Adenosine and hydralazine caused only a small concentration-dependent relaxation of IMA segments (37.7 (14.5) and 39.0 (14.8)%), respectively, which were significantly less than the responses to GTN, SNP, nicardipine, and nicorandil (Fig. 3 and Table 2). Labetalol minimally relaxed U46619 constricted IMA at the highest concentration used; therefore, its EC50 was not calculated (Fig. 4). However, it caused an almost 90% relaxation when the vessel was pre-contracted with norepinephrine (Fig. 4). Enalaprilat was ineffective in reversing TxA2 analogue induced contraction, even at the highest concentration used (10–3 M); therefore, its Emax and EC50 were not calculated (Fig. 4). The overall efficacy of the antihypertensive drugs used in the current in vitro evaluation, based on U46619 pre-constriction was as follows:


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Table 2 Summary of resting and contracted tensions along with potency and efficacy estimates.

 


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Fig 1 Concentration–response curves for nitroglycerin (n=6), nitroprusside (n=6), and nicardipine (n=7) in human IMA contracted with the TxA2 analogue U46619. Data are expressed as mean (SD), n=number of vessel segments. M=concentration of drugs in mol litre–1.

 


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Fig 2 Concentration–response curves for fenoldopam (n=6) and nicorandil (n=6) in human IMA contracted with the TxA2 analogue U46619. The curve for SNP was also shown as a reference. Data are expressed as mean (SD), n=number of vessel segments. M=concentration of drugs in mol litre–1.

 


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Fig 3 Concentration–response curves for adenosine (n=6) and hydralazine (n=6) in human IMA contracted with the TxA2 analogue U46619. The curve for SNP was also shown as a reference. Data are expressed as mean (SD), n=number of vessel segments. M=concentration of drugs in mol litre–1.

 


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Fig 4 Concentration–response curves for labetalol (n=6), enalaprilat (n=6), and SNP (n=6, reference) in human IMA contracted with the TxA2 analogue U46619. Relaxation response to labetalol (n=5) in human IMA contracted with norepinephrine was also shown (Labetalol-NE). Data are expressed as mean (SD), n=number of vessel segments. M=concentration of drugs in mol litre–1.

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In the current in vitro study of antihypertensive drugs on the reversal of U46619-induced vascular contraction, we observed three broad patterns of responses: (i) clear dose–response relationship in the therapeutic range (SNP and GTN); (ii) obtunded response requiring concentration greater than therapeutic range (adenosine, fenoldopam, hydralazine, nicardipine, and nicorandil); (iii) no response (labetalol and enalaprilat).

Perioperative stress along with vascular injury and platelet activation cause vasoconstriction presenting as systemic hypertension. Understanding the efficacy and potency of antihypertensive drugs on IMA should be useful because it is widely used as a conduit for coronary artery bypass surgery, and antihypertensive therapy may be potentially useful in preventing vasospasm-related myocardial ischaemia after surgery. TxA2 agonist, U46619, and other vasopressors (e.g. phenylephrine) cause vasoconstriction by increasing intracellular inositol phosphate turnover via G-protein (Gq/11) coupled TP receptors. We tested whether antihypertensive drugs could reverse U46619-induced vasoconstriction in vitro. All of the agents used are important clinically and represent the major classes of i.v. drugs with antihypertensive properties.

Both nitrodilators cause nitric oxide-mediated vasodilation of systemic artery in a dose-dependent manner (Fig. 1). Their clear potency and efficacy are a result of a nitric oxide-mediated mechanism of action. SNP and GTN were the most potent and efficacious agents from all the antihypertensive drugs that we evaluated in the current study. Nicardipine, a dihydropyridine calcium channel inhibitor, exerted moderate vasodilatory effect (79.2%) at 10–4 M, but this was only achieved at much higher than the therapeutic plasma concentrations (0.5–1.0 10–7 M) (Fig. 1).11 We have reported previously a similar difference between GTN and a short-acting calcium channel blocker, clevidipine.12 Nicorandil, an ATP sensitive K+ channel opener, also exerted vasodilation (71.7%) of human IMA, which is in agreement with others,13 and its potency was similar to nicardipine. Increased K+ efflux by ATP channel opening causes hyperpolarization of the vascular smooth muscle and subsequent relaxation, and nicorandil is also presumed to increase cGMP levels.14 Although its vasodilatory effect was less potent than nitrovasodilators, nicorandil is more effective in reversing vasoconstriction in human IMAs than in radial artery pre-constricted with U46619;13 pointing to the variability in relaxation responses among different systemic vessels. Additionally, nicorandil has been shown to relax vasospasm of radial artery resistant to conventional Ca2+ antagonists.15 It is also notable that K+ channel openers and Ca2+ channel antagonists are generally more efficient in reversing the vessel contraction mediated by a voltage-dependent mechanism (i.e. KCl) rather than by a receptor-dependent mechanism (i.e. TxA2).16 Less complete relaxation of TxA2-induced vasoconstriction by nicardipine, nicorandil, and hydralazine may be, in part, explained by the mode of vasoconstriction.

Fenoldopam is a novel D1-dopamine receptor agonist. D1-Dopamine receptor stimulation leads to increased intracellular cAMP, resulting in vasodilation. Our results suggest the existence of D1-dopamine receptors in IMA (Fig. 2). EC50 value for the relaxant effect of fenoldopam (1.73x10–7 M) (Table 1) was higher than the therapeutic concentrations reported in plasma (0.20–6.7x10–7 M).11 D1-Dopamine receptors are located at various systemic sites, such as renal, mesenteric, coronary, and cerebral arteries. We have reported previously that fenoldopam could induce {alpha}-adrenergic stimulation and cause vasoconstriction of human umbilical artery.11 In the current study, however, we did not observe vasoconstriction at comparable concentrations. In the study by Hughes and colleagues, fenoldopam effectively reversed norepinephrine- or prostaglandin F2{alpha}-induced contraction on renal, gastric/splenic artery, and colic artery with EC50 (1.4–2.9x10–6 M).17 Similar relaxation occurred in brachial and cerebral arteries but at higher concentrations with EC50 (12–22x10–6 M). It is obvious from Hughes' data and ours that the vasodilatory response is heterogeneous among systemic arteries. This underlies clinical safety and efficacy of fenoldopam in maintaining mesenteric and renal blood flow at low doses (0.03 µg kg–1 min–1) as well as at antihypertensive doses (0.1–0.3 µg kg–1 min–1) without causing non-selective systemic vasodilation associated with SNP.18

Adenosine only mildly reversed IMA contraction induced by TxA2 analogue (Fig. 3). This low in vitro efficacy of adenosine seems not to be a result of its short half-life (0.6–1.5 s) as according to the previous study, addition of dipyridamole, an inhibitor of adenosine metabolism, does not change the degree of the maximal relaxation.19 Luscher and colleagues showed that adenosine caused only a partial reversal (Emax 39 (8)%) of norepinephrine-induced IMA contraction.20 Labetalol and enalaprilat lacked vasodilatory effects in our in vitro study. The critical difference of our vascular model from in vivo model is the lack of autonomic influences that is noradrenergic nerve supply, and the kinin–angiotensin system. Labetalol effectively reversed norepinephrine-induced IMA contraction in vitro (Emax 97%, Fig. 4), suggesting a different intracellular pathway of TP receptor stimulation, as U46619 has been shown to potentiate the constrictor effects of norepinephrine in human saphenous veins through stimulation of TP receptors.21 With regard to enalaprilat, the absence of plasma kinins and angiotensins resulted in lack of IMA vasodilation to enalaprilat. Mombouli showed that ACE inhibitors augmented vasodilation caused by exogenously administered bradykinin, but did not produce vasodilation in the absence of bradykinin.22

Limitations
Because IMA segments were obtained from patients undergoing CABG, varying degrees of atherosclerosis are likely to be reflected in our results. Although we only used TxA2 as a vasoconstrictive agent (except for labetalol), the result of our study may have implications for the choice or combination of antihypertensive agents to be used in the perioperative period, when TxA2 levels are likely to be elevated. The perioperative period poses a tremendous challenge to anaesthesiologists in treating hypertensive patients, already on chronic antihypertensive therapy. The vessels that were used in our study came from those patients; hence we cannot totally discount the possibility that these preoperative drug treatments listed in Table 1 have had any effects on the results of the current study, although we pre-tested vascular endothelial function. In a recent paper by Hamilton and colleagues the authors reported that acute in vitro pre-treatment of human IMA with amlodipine, nifedipine (calcium channel blockers), and nicorandil (nitrovasodilator/ATP-dependent potassium channel opener) attenuated constriction responses to KCl and PE (phenylephrine).13 Whether the same results would be obtained in IMAs from patients on chronic antihypertensive, statin, antidiabetic, or combination therapy using TxA2 analogue, U46619, as the constrictor remains to be elucidated.

In summary, we have demonstrated that most commonly used antihypertensive drugs cause vasodilation in human IMA pre-contracted with TxA2 analogue U46619. The efficacy of relaxation was in the order of SNP, GTN, nicardipine, nicorandil, fenoldopam, hydralazine, adenosine, and labetalol. The in vitro vasodilation may not be simply extrapolated to clinical efficacy or outcome of each antihypertensive therapy. Nevertheless, our current data provide grounds for the choice of the antihypertensive medication. Further clinical studies are needed to fully elucidate the use of different antihypertensive agents and clinical outcomes.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Belhassen L, Pelle G, Dubois-Rande JL, Adnot S. Improved endothelial function by the thromboxane A2 receptor antagonist S 18886 in patients with coronary artery disease treated with aspirin. J Am Coll Cardiol 2003; 41: 1198–204[CrossRef][ISI][Medline]

2 Hayakawa H, Raij L. Relationship between hypercholesterolaemia, endothelial dysfunction and hypertension. J Hypertens 1999; 17: 611–9[CrossRef][ISI][Medline]

3 Ungvari Z, Koller A. Endothelin and prostaglandin H(2)/thromboxane A(2) enhance myogenic constriction in hypertension by increasing Ca(2+) sensitivity of arteriolar smooth muscle. Hypertension 2000; 36: 856–61[Abstract/Free Full Text]

4 Luscher TF, Noll G. The pathogenesis of cardiovascular disease: role of the endothelium as a target and mediator. Atherosclerosis 1995; 118 (Suppl.): S81–90[CrossRef][ISI][Medline]

5 Kritz H, Schmid P, Keiler A, O'Grady J, Sinzinger H. Isradipine increases vascular prostaglandin I2-formation while the thromboxane B2-synthesis is diminished. Thromb Res 1995; 80: 483–9[CrossRef][ISI][Medline]

6 Munzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG. Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest 1995; 95: 187–94[ISI][Medline]

7 Watkins WD, Peterson MB, Kong DL, et al. Thromboxane and prostacyclin changes during cardiopulmonary bypass with and without pulsatile flow. J Thorac Cardiovasc Surg 1982; 84: 250–6[Abstract]

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9 Huraux C, Makita T, Montes F, Szlam F, Levy JH. A comparative evaluation of the effects of multiple vasodilators on human internal mammary artery. Anesthesiology 1998; 88: 1654–9[CrossRef][ISI][Medline]

10 Hamu Y, Kanmura Y, Tsuneyoshi I, Yoshimura N. The effects of vasopressin on endotoxin-induced attenuation of contractile responses in human gastroepiploic arteries in vitro. Anesth Analg 1999; 88: 542–8[Abstract/Free Full Text]

11 Sato N, Tanaka KA, Szlam F, Tsuda A, Arias ME, Levy JH. The vasodilatory effects of hydralazine, nicardipine, and fenoldopam in the human umbilical artery. Anesth Analg 2003; 96: 539–44[Abstract/Free Full Text]

12 Huraux C, Makita T, Szlam F, Nordlander M, Levy JH. The vasodilator effects of clevidipine on human internal mammary artery. Anesth Analg 1997; 85: 1000–4[Abstract]

13 Hamilton CA, O'Dowd G, McIntosh L, et al. Vasorelaxant properties of isolated human radial arteries: comparison with internal mammary arteries. Atherosclerosis 2002; 160: 345–53[CrossRef][ISI][Medline]

14 The IONA study group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet 2002; 359: 1269–75[CrossRef][ISI][Medline]

15 Sadaba JR, Mathew K, Munsch CM, Beech DJ. Vasorelaxant properties of nicorandil on human artery. Eur J Cardiothorac Surg 2000; 17: 319–24[Abstract/Free Full Text]

16 He GW, Acuff TE, Ryan WH, et al. Inhibitory effects of calcium antagonists on alpha-adrenoceptor-mediated contraction in the human internal mammary artery. Br J Clin Pharmacol 1994; 37: 173–9[ISI][Medline]

17 Hughes AD, Sever PS. Action of fenoldopam, a selective dopamine (DA1) receptor agonist, on isolated human arteries. Blood Vessels 1989; 26: 119–27[ISI][Medline]

18 Gretler DD, Elliott WJ, Moscucci M, Childers RW, Murphy MB. Electrocardiographic changes during acute treatment of hypertensive emergencies with sodium nitroprusside or fenoldopam. Arch Int Med 1992; 152: 2445–8[CrossRef][ISI]

19 Jett GK, Guyton RA, Hatcher CR,jr, Abel PW. Inhibition of human internal mammary artery contractions. An in vitro study of vasodilators. J Thorac Cardiovasc Surg 1992; 104: 977–82[Abstract]

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21 Vila JM, Martinez-Leon JB, Medina P, et al. U-46619-induced potentiation of noradrenergic constriction in the human saphenous vein: antagonism by thromboxane receptor blockade. Cardiovasc Res 2001; 52: 462–7[CrossRef][ISI][Medline]

22 Mombouli JV, Illiano S, Nagao T, Scott-Burden T, Vanhoutte PM. Potentiation of endothelium-dependent relaxations to bradykinin by angiotensin I converting enzyme inhibitors in canine coronary artery involves both endothelium-derived relaxing and hyperpolarizing factors. Circ Res 1992; 71: 137–4[Abstract]





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