Anesth Analg 2003;96:539-544
© 2003 International Anesthesia Research Society
OBSTETRIC ANESTHESIA
The Vasodilatory Effects of Hydralazine, Nicardipine, Nitroglycerin, and Fenoldopam in the Human Umbilical Artery
Nobukazu Sato, MD*,
Kenichi A. Tanaka, MD*,
Fania Szlam, MMS*,
Atsushi Tsuda, MD*,
Maria E. Arias, MD
, and
Jerrold H. Levy, MD*
*Department of Anesthesiology, Emory University School of Medicine, Division of Cardiothoracic Anesthesia and Critical Care, Emory Healthcare, Atlanta; and
Atlanta Women’s Specialists, Atlanta, GA
Address correspondence and reprint requests to Jerrold H. Levy, MD, Department of Anesthesiology, Emory University Hospital, 1364 Clifton Rd., NE, Atlanta, GA 30322. Address e-mail to jerrold_levy{at}emoryhealthcare.org
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Abstract
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We studied the effects of hydralazine, nicardipine, nitroglycerin, and fenoldopam (a dopamine D1-agonist) on isolated human umbilical arteries (HUA) from patients classified as normotensive and with pregnancy-induced hypertension (PIH). Umbilical artery rings were contracted with the thromboxane A2 analog (U46619; 10-8 M) and then exposed to cumulative concentrations of fenoldopam, hydralazine, nicardipine, and nitroglycerin. Second, rings were preexposed to prazosin (10-5 M), phenoxybenzamine (10-5 M), or none, and the constriction responses to increasing doses of fenoldopam or dopamine were recorded. Nitroglycerin, hydralazine, and nicardipine produced concentration-dependent relaxation of U46619-preconstricted HUA segments from normotensive and PIH patients. Fenoldopam and dopamine induced umbilical artery constriction in both normal and PIH rings at concentrations 
10-5 M and 10-3 M, respectively. Phenoxybenzamine, but not prazosin, pretreatment irreversibly abolished fenoldopam-induced contraction. In this in vitro study, nitroglycerin was the most potent vasodilator of the HUA constricted with U46619, followed by nicardipine and hydralazine. However, fenoldopam constricted HUA rings only at supratherapeutic concentrations. No significant differences of vascular responses to fenoldopam (P = 0.3534), nitroglycerin (P = 0.7416), nicardipine (P = 0.0615), and hydralazine (P = 0.5514) between rings from normotensive or hypertensive pregnant patients were shown.
IMPLICATIONS: We conclude that currently used drugs to treat acute hypertension have no adverse effects on umbilical artery tone; however, larger concentrations (10-5 M) of fenoldopam may produce contraction of the umbilical artery.
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Introduction
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Hypertensive disorders are common medical complications during pregnancy and a leading cause of increased fetal and maternal morbidity and mortality (1). In maternal and umbilical cord blood, the concentration of both prostacyclin (PGI2) and thromboxane A2 (TxA2) is increased during pregnancy (1). There is a prevailing concept of pregnancy-induced hypertension (PIH) being associated with a functional imbalance between PGI2 and TxA2 with an existing state of relative deficiency of PGI2 and TxA2 dominance (1). Increased TxA2 concentrations are associated with vasoconstriction in the placental circulation (2). Vasodilator therapy is used to reduce maternal and fetal complications associated with hypertensive disorders of pregnancy thus improving perinatal outcome. Hydralazine has been used both orally and IV to control blood pressure in PIH. The oral administration of hydralazine is not associated with significant changes in placental vascular resistance (3). Nicardipine (a calcium channel blocker) and nitroglycerin (a nitrovasodilator) have been used in the management of PIH patients with variable success (4,5). Dopamine has been used to support renal function, which may deteriorate with PIH (6,7). Its peripheral effects are mediated through 
- and ß-adrenergic receptors and dopamine receptors. The potential benefit of dopamine is assumed to occur via D1 receptor stimulation, which tends to increase renal and mesenteric flow including placental flow (8). The existence of D1 receptors in the human umbilical artery (HUA) has been demonstrated by radioligand binding and autoradiographic techniques (9). A more selective dopamine D1-agonist, fenoldopam, is a novel antihypertensive in which the clinical efficacy and effects in parturient and fetus have not yet been studied. There is a paucity of data regarding its use in preeclamptic patients. Additionally, the use of multiple vasodilator drugs in PIH has been described in the literature, but the comparative evaluations of these drugs using human umbilical vessels are few (10). Therefore, we investigated the effects of different classes of vasodilator drugs on HUA preconstricted with a TxA2 analog (U46619). Second, the direct effects of dopamine and fenoldopam on HUA were also investigated.
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Methods
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After approval by our IRB, human umbilical cords were obtained at delivery (36- to 42-wk gestation) from normotensive (n = 15) and PIH (n = 4) patients. Vessels were placed immediately in chilled modified Krebs-HEPES buffer (pH value of 7.4) of the following composition (mM): NaCl 118, KCl 4.69, CaCl2 3.351, MgSO4 1.175, KH2PO4 1.04, NaHCO3 25, D-glucose 11.1, and HEPES 20. For classification of PIH, we used the criteria of Malatyalioglu et al. (1). None of the PIH patients included in the study had eclampsia. A segment of umbilical cord from the area midway between the fetal and placental insertions was selected. The HUAs were dissected from the cord, and adherent Wharton’s jelly was removed. The vessel was cut into 3-mm-wide rings. Two to three rings were obtained from each vessel. All experiments were performed on the day the samples were collected.
Organ-Chamber Experiments
The rings were suspended between 2 wire hooks in organ chambers filled with 25 mL of Krebs-Henseleit buffer of the following composition (mM): NaCl 118, KCl 4.69, CaCl2 3.351, MgSO4 1.175, KH2PO4 1.04, NaHCO3 25, and D-glucose 11.1. The rings were maintained at 37°C in buffer aerated continuously with 95% O2/5% CO2. The pH value was maintained between 7.35 and 7.45. The upper hook was connected to a force transducer (Kent-Scientific Corporation, Litchfield, CT), and changes in isometric force were recorded (Mac Lab Systems, Milford, MA). A resting tension (3 g), initially defined by preliminary studies, was progressively applied over 45–60 min until a stable baseline was obtained. For the initial contraction experiments, cumulative concentration-response curves were obtained with KCl and U46619. Increasing concentrations of U46619 (10-10 to 10-6 M) and KCl (10-2 to 10-1 M) were added to the organ chamber in 0.5 log-unit steps for U46619 and in 0.2 log-unit steps for KCl. Based on the initial KCl experiments, 60 mM of KCl concentration was chosen as optimal for the maximum contraction and to check the viability of the vessel segments. This KCl concentration was used to precontract all rings at the beginning of each experiment. Once a stable contraction was obtained, the rings were washed two to three times with fresh Krebs buffer, allowed additional 15-min equilibration time, and then contracted with U46619.
The HUA rings were contracted with 10-8 M of U46619. This concentration was determined from the initial cumulative contraction-response curves to achieve 50%–80% of maximum contraction. The HUA contraction was allowed to fully develop for 10 min (the amplitude of contraction produced by 10-8 M of U46619 is stable for at least 75 min), and then cumulative dose-response curves were obtained by adding (a) fenoldopam (10-10 to 10-4 M), (b) hydralazine (10-9 to 10-3.5 M), (c) nicardipine (10-8 to 10-3.5 M), (d) nitroglycerin (10-10 to 10-4.5 M), or (e) dopamine (10-9 to 10-3.5 M) to the organ chamber in 0.5 log-unit increments. Segments of vessels were randomly assigned to one of five treatment groups. Each ring was only exposed to one drug, but different drugs were tested at the same time using separate vascular rings from the same or different patients. Each drug increment was made only after the response had stabilized (the effect had reached a plateau and there was little change on the transducer reading) to the previous drug addition. No more than 75–80 min was required from the time that one of the relaxing drugs was added to the bath until the end of the experiment.
To examine the effects of fenoldopam and dopamine on HUA rings, increasing concentrations of fenoldopam (10-8 to 10-3.5 M) or dopamine (10-9 to 10-3.5 M) were added to tissue baths in 0.5 log-unit steps.
To assess effects of -adrenergic receptors on fenoldopam-induced constriction, rings were pretreated for 30 min with either prazosin (10-5 M) or phenoxybenzamine (10-5 M), and then fenoldopam (10-8 to 10-3.5 M) was added to the organ chamber in 0.5 log-unit steps. Based on published data (11,12), the 10 µM concentration of prazocin and phenoxybenzamine abolishes constriction because of 1 µM of norepinephrine. Additionally, direct effects of prazosin and phenoxybenzamine on vessel segments equilibrated at resting tension were also studied.
The following drugs were used: TxA2 analog U46619 (10 mg/mL in methyl acetate; Upjohn Company, Kalamazoo, MI), fenoldopam (Neurex Corporation, Menlo Park, CA), hydralazine (American Regent Laboratories Inc, Shirley, NY), nicardipine (Wyeth Laboratories Inc, Philadelphia, PA), nitroglycerin (Solopack Laboratories, Elk Grove Village, IL), dopamine HCl (American Regent Laboratories), prazosin (Sigma Chemical Co, St Louis, MO), and phenoxybenzamine HCl (ICN Biochemicals Inc, Aurora, OH). An aliquot of U46619 was evaporated to dryness under nitrogen, re-dissolved in absolute ethanol to a concentration of 10-3 M, and diluted to 10-5 M in distilled water. Prazosin 1 mg/mL was diluted in 5% ethanol/water (vol/vol). All other drugs were diluted in distilled water. Drugs were prepared 5 min before each experiment and kept on ice for the duration of the experiment. The concentrations of the drugs are expressed as final molar concentration in the organ chamber.
Results are expressed as mean ± SD. Contraction responses to U46619, KCl, fenoldopam, and dopamine were expressed in gain of tension (in grams). Relaxation responses were calculated as a percentage of U46619-induced contraction. For the relaxation study, responses to each drug were obtained in two to three rings and averaged for each patient if the results of the individual rings were within 10%–15%. The effective concentration of vasodilator drug that caused 50% of relaxation is expressed as 50% effective concentration (EC50) and was determined by the logistic curve fitting equation: E = (Emax x C
)/(C + EC50) where E is the response, Emax is the maximal relaxation, C is the concentration, and is the slope variable. EC50 was calculated for each HUA (responses from rings were averaged for one HUA) using sigma plot software (SPSS Inc., San Rafael, CA). Unpaired t-test or analysis of variance were used to test statistical significance among different dilators regarding the maximal responses or EC50. To compare the influence of prazosin or phenoxybenzamine on fenoldopam-induced vasoconstriction, two-way analysis of variance followed by Scheffé test was used. A value of P < 0.05 was considered statistically significant.
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Results
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The HUA segments exhibited constriction in the presence of U46619 and KCl in a dose-dependent manner (Fig. 1). Maximal contraction for U46619 and KCl were 8.57 ± 2.52 g and 2.49 ± 1.41 g, respectively.
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Figure 1. Contraction response curves for the thromboxane A2 (TxA2) analog U46619 (closed circles) and KCl (closed triangles) in human umbilical artery (HUA). Data are expressed in gain of tension (grams), mean ± SD.
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Nitroglycerin, hydralazine, and nicardipine produced a concentration-dependent relaxation of the HUA segments preconstricted with U46619 (Figs. 2 and 3). In both the normotensive and PIH group, the Emax (percent) response to nitroglycerin was greater than the Emax of hydralazine and nicardipine, with the EC50 (M) values following the same order (Table 1). Emax values for nitroglycerin and hydralazine were comparable between normal and PIH groups (Table 1). The Emax of nicardipine tended to be lower in the PIH group than in the normotensive group, but this did not reach statistical significance (P = 0.0654). However, EC50 values for nitroglycerin (P = 0. 128), hydralazine (P = 0.193), and nicardipine (P = 0.103) tended to be higher in PIH than in the normotensive group, but again a statistically significant difference was not reached.
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Figure 2. Concentration response curves for fenoldopam (open circles), hydralazine (closed circles), nicardipine (open squares), and nitroglycerin (closed squares) in the human umbilical artery (HUA) (normotensive patients) preconstricted with the thromboxane A2 (TxA2) analog (U46619; 10-8 M). Data are expressed as mean ± SD.
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Figure 3. Concentration response curves for fenoldopam (open circles), hydralazine (closed circles), nicardipine (open squares), and nitroglycerin (closed squares) in the human umbilical artery (HUA) (pregnancy-induce hypertensive [PIH] patients) preconstricted with the thromboxane A2 (TxA2) analog (U46619; 10-8 M). Data are expressed as mean ± SD.
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In comparison, fenoldopam caused a constriction of HUA at the dose of 10-5.0 M or larger in both normotensive and PIH groups (Fig. 2 and 3).
Figure 4 shows the effects of dopamine and fenoldopam on the resting tension of the HUA segment from normotensive patients. Fenoldopam induced HUA constriction at the concentration of 10-5 M or larger, but dopamine caused it only at the largest concentration (10-3.5 M). The Emax, induced by fenoldopam was significantly higher than the Emax of dopamine (11.7 ± 5.72 g versus 3.02 ± 2.29 g, respectively; P < 0.05). The pretreatment of HUA with a noncompetitive -adrenergic blocker, phenoxybenzamine (10 µM), completely inhibited a fenoldopam-induced vasoconstriction (Fig. 4). The HUA constriction was only partially inhibited by the pretreatment with a competitive -adrenergic blocker, prazosin (10 µM). Fenoldopam induced HUA constriction only at the concentration of 10-4.5 M or larger in the presence of prazosin (Fig. 4) thus shifting the dose response curve to the right. The Emax induced by fenoldopam was comparable before and after the prazosin pretreatment (11.7 ± 5.72 g versus 10.7 ± 5.21 g; Fig. 4). Prazosin and phenoxybenzamine had no effect on the resting tension of HUA segments from PIH and normotensive controls.
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Figure 4. Contraction response curves for fenoldopam (open circles), fenoldopam pretreatment with 10-5 M of prazocin (closed circles), fenoldopam pretreatment with 10-5 M of phenoxybenzamine (open squares), and dopamine (closed squares) in human umbilical artery (HUA) from normotensive patients. Data are expressed as mean ± SD.
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Discussion
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These data demonstrate that conventional vasodilators including nitroglycerin, hydralazine, and nicardipine effectively reverse U46619-induced contraction of HUAs. We also demonstrated that fenoldopam, a D1 dopamine receptor agonist, was ineffective and actually produced vasoconstriction at concentrations 10-5 M.
Nitroglycerin has been extensively studied in humans and animals during pregnancy. Its vasodilatory action is mediated by nitric oxide (13). Nitric oxide and PGI2 are released from the endothelium of human umbilical vessels and play an important role in the regional regulation of the vascular smooth muscle tone, platelet function, and in the maintenance of umbilical arterial tone. The imbalance of PGI2 and TxA2 production occurs in preeclamptic patients where the placental circulation is hindered by the dominance of TxA2, which constricts microvessels and activates platelets (1).
David et al. (14) reported that the fetal-maternal venous nitroglycerin concentration ratio was between 1:400 and 1:160, and after one minute of IV injection (0.25 mg), the plasma concentrations of nitroglycerin in the maternal venous blood, umbilical arterial blood, and umbilical venous blood were 1.7 x 10-7 M, 3.5 x 10-11 M, and 4.2 x 10-10 M, respectively. The levels in fetal circulation were less than the nitroglycerin concentration used in our current experiments (10-10 M or larger). IV administration of nitroglycerin to the maternal circulation may have less direct vasodilatory effects on HUA than in vitro. Doppler study has shown that IV nitroglycerin administration decreased the abnormally high placental resistance, as evidenced by normalized HUA velocity ratio in PIH patients (5). Although this improvement may be secondary to the change in placental blood flow, direct vasodilatory effect cannot be excluded. In in vitro vasodilatory responses in HUA, a conductance artery cannot be simply inferred to describe the in vivo response to nitroglycerin. The difference between conductance and resistance vessels may explain the requirement for supratherapeutic concentrations for its vasodilatory action. It should also be noted that the concentration of parent molecule in plasma might not directly reflect the therapeutic effect because nitroglycerin is inactive without metabolism (13).
We found that hydralazine and nicardipine caused only a moderate reversal of the U46619-induced HUA constriction. Hydralazine has been used orally and IV for the management of hypertension secondary to preeclampsia or eclampsia. Hydralazine maintains uterine blood flow, uterine tone, and fetal heart rate (15). A Doppler study has shown that IV administration of hydralazine decreases HUA resistance and improves placental circulation in hypertensive pregnancies (15), although orally administered hydralazine has no effect on placental vascular resistance (4). IV administered hydralazine crosses the placental barrier, and the umbilical blood concentration could reach the maternal blood level (16). Our data showed that hydralazine induced a moderate reversal of a U46619-induced HUA constriction in a concentration-dependent manner. Thus, IV hydralazine may directly reverse the increased resistance of fetal umbilical vessels.
Nicardipine, a 1,4-dihydropyridine calcium channel blocker, has been introduced in the management of hypertensive patients with preeclampsia. It produces a dilation of the peripheral arterioles with minimal negative inotropic effects (16). Therapeutic concentrations of nicardipine in plasma range from 54 to 97 nM (
28–50 ng/mL). Carbonne et al. (17) showed that the IV infusion of nicardipine <1 µg · kg-1 · min-1 was safe in hypertensive pregnant patients, reporting maternal and fetal plasma levels of 106 nM and 8 nM, respectively. In the present study, nicardipine from 10-8 to 10-4 M induced mild dilation of isolated HUA preconstricted with U46619. A Doppler study suggested that IV nicardipine did not affect the HUA resistance (17). Hence, the IV nicardipine in PIH does not affect umbilical vascular tone.
Fenoldopam is a selective postsynaptic D1 dopamine receptor agonist that has been successfully used IV for hypertensive emergencies requiring rapid reduction in blood pressure because of its rapid onset of action and short half-life (5 min) (18,19). Our data establish that fenoldopam augments U46619-induced constriction of HUA at the concentration 10-5.0 M (Emax, 11.7 ± 5.72 g). We attributed these constrictive responses to -adrenergic stimulation by fenoldopam because the pretreatment of HUA with a nonselective -adrenergic blocker, phenoxybenzamine (10 µM), completely inhibited a fenoldopam-induced vasoconstriction (Fig. 4). Because the HUA constriction was only partially inhibited by the pretreatment with a competitive -adrenergic blocker, prazosin (10 µM), fenoldopam seemed to be a competitive agonist of -adrenergic receptors (Fig. 4). There are adrenergic receptors of both 1 and 2 subtypes in the HUA (20). Fenoldopam is a competitive -adrenergic antagonist with a higher affinity to 2-receptors than to 1-adrenergic receptors (21,22). However, our data suggest that fenoldopam may exert a partial agonist/antagonist effect on -adrenergic receptors, and further studies with specific 1 and 2 antagonists are required to help elucidate the type of receptors involved in the vascular responses elicited by fenoldopam. In this study, an -adrenergic effect of fenoldopam was seen at a supratherapeutic level (therapeutic range, 10-8 to 10-7 M [4–64 ng/mL]). Because of the placental barrier, the drug concentration in HUA would be much smaller than the maternal plasma level. Therefore, HUA constriction is unlikely when fenoldopam is administered to pregnant patients in a therapeutic dose.
The difference in the HUA vascular responses between dopamine and fenoldopam was extremely clear in our study. Fenoldopam increased the tension of the HUA segments, whereas dopamine did not except at the largest concentration (10-3.5 M). Therefore, fenoldopam is a more potent constrictor than dopamine of HUA. Nonselectivity of dopamine, which stimulates adrenergic and dopaminergic receptors, and the relative paucity of dopamine D1 receptors on HUA may have contributed to the difference in vascular responses to fenoldopam and dopamine.
We were not able to show significant differences of HUA vascular responses between normal and PIH groups. Possibly, the mechanisms of action of the vasodilators we studied were not endothelium-dependent. Chambers et al. (23) showed that vascular endothelial function is impaired in women with previous preeclampsia compared with uncomplicated pregnancy. Nitroglycerin (24) and hydralazine (10) caused endothelium-independent vasodilation, however Ghaleh et al.(25) reported that nicardipine induced the endothelium-dependent vasodilation in canine large coronary arteries and human internal mammary artery, respectively. In the current study, nicardipine caused the Emax of 52.2% ± 13.3% in the HUA rings of the normotensive group and 33.3% ± 19.0% in the PIH group (P = 0.0615). We hypothesized that nicardipine would have caused more prominent relaxation in the normal HUA than in the impaired HUA of the PIH group. It is possible that statistical significance was not reached because of the small number of PIH patients included in the study and the variable degree of endothelial impairment in PIH. Second, the reactivity of the HUA may be significantly variable among samples. Coexisting disease of the mother, maturity of fetus, different muscularity along the HUA, manipulation during delivery, and physiological condition may all affect reactivity of the vessel. Although we pretested the viability of the rings by constricting them with KCl, these previously outlined factors may have contributed to a wide range of EC50 values.
In summary, we have demonstrated that nitroglycerin, nicardipine, and hydralazine caused vasodilation in HUA, which was precontracted with TxA2 analog U46619. Emax was as follows: nitroglycerin > hydralazine = nicardipine. Second, our study showed that fenoldopam, a novel dopamine D1-agonist, caused a constriction of HUA at supratherapeutic concentrations. The constrictive responses of HUA to fenoldopam are mediated by -adrenergic receptors because they are obtunded by phenoxybenzamine, a noncompetitive -adrenergic antagonist. Further in vivo study is required to evaluate maternal and fetal hemodynamic effects of fenoldopam during pregnancy.
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Accepted for publication October 8, 2002.
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Abstract
Introduction
