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.
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Abstract |
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Methods. Relaxation responses to adenosine (a nucleoside), enalaprilat (a competitive inhibitor of angiotensin-converting enzyme), fenoldopam (a D1-dopamine receptor agonist), hydralazine, labetalol (an - 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, 1.0x108 M). Effects of labetalol were also studied in IMA segments pre-contracted with norepinephrine (1.0x106 M). All drugs were added in a cumulative fashion (range 1010 to 103 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 (90100%) 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
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Introduction |
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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.
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Methods |
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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 103 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:
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Results |
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Discussion |
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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 104 M, but this was only achieved at much higher than the therapeutic plasma concentrations (0.51.0 107 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 (1.73x107 M) (Table 1) was higher than the therapeutic concentrations reported in plasma (0.206.7x107 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 -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
-induced contraction on renal, gastric/splenic artery, and colic artery with EC50 (1.42.9x106 M).17 Similar relaxation occurred in brachial and cerebral arteries but at higher concentrations with EC50 (1222x106 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 kg1 min1) as well as at antihypertensive doses (0.10.3 µg kg1 min1) 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 (0.61.5 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 kininangiotensin 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.
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