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Anesth Analg 2002;94:1434-1440 © 2002 International Anesthesia Research Society
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2-Adrenergic Agonist and 
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Abstract |
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The actions of dexmedetomidine (DEX) on human vascular smooth muscle are unclear. We investigated its effects on isolated, endothelium-denuded human gastroepiploic arteries in vitro and compared them with clonidine (CLO). DEX had little direct effect on resting tension, whereas CLO produced small contractile responses, an effect which is blocked by the
1-adrenergic antagonist prazosin. DEX markedly enhanced the high K+ (40 mmol/L)-induced contraction, and this effect was reversed by the 2-adrenergic antagonists yohimbine and rauwolscine but unaffected by prazosin. However, CLO had little effect on the K+ contractions. Interestingly, larger concentrations (>10-7 mol/L) of both 2-adrenergic stimulants significantly inhibited the contractions elicited by the 1-adrenergic agonist phenylephrine (10-6 mol/L) and, to a lesser extent, those elicited by the 1/2-agonist norepinephrine (10-6 mol/L). These results suggest the possibility that DEX and CLO each have a high affinity for 1-adrenoceptors in human isolated gastroepiploic arteries, resulting in a reduced efficacy of 1-adrenergic activation by -agonists. The differing affinities of the drugs for 1- and 2-adrenoceptors may help explain their additional actions: 1) DEX enhances the high K+-induced contraction presumably through 2-adrenoceptor activation, and 2) CLO acts on 1-adrenoceptors as a partial agonist when present alone.
IMPLICATIONS: Dexmedetomidine may not directly affect smooth muscle in human peripheral resistance vessels within the usual range of plasma concentrations (<10-7 mol/L) achieved in clinical practice. However, in large doses, it could enhance the response to nonadrenergic vasoconstrictor agonists while antagonizing the vasoconstrictor response to 1-adrenoceptor agonists.
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Introduction |
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Dexmedetomidine (DEX), a highly selective
2-adrenergic agonist, is used in clinical practice for its sedative and analgesic actions. DEX use is associated with a reduction in the dose-requirement for anesthetic and analgesic drugs in the perioperative period, and minimal cardiovascular side effects have been reported (1–5). The hemodynamic stability associated with the use of DEX is related in part to the fact that it is more selective than clonidine (CLO) for 2-adrenoceptors (6), which favors a more potent sedative effect without the effects on blood pressure that result from 1-adrenoceptor agonism by CLO. Nevertheless, DEX use has been associated with some modest decreases in blood pressure and heart rate in some studies (7,8), whereas other reports have suggested that an IV administration of large doses can result in acute increases in arterial blood pressure and peripheral vascular resistance (9–11). The range of cardiovascular effects that DEX has been reported to exert may reflect the physiological consequences of activation of peripheral or central 2-adrenergic receptors, or both, as well as the dose and mode of the administration (12,13). To further complicate the picture, 2-adrenoceptor agonists can produce decreases in blood pressure in two ways: 1) by diminishing norepinephrine (NE) release via peripheral prejunctional 2-adrenoceptor stimulation, thereby decreasing locally released and circulating catecholamines (5,13) or 2) by activating 2-adrenoceptors on endothelial cells, thus triggering release of endothelium-derived nitric oxide (10).
To clarify some of the variety of effects seen with DEX in clinical settings, we examined whether or not DEX affects the vasomotor responses to adrenergic and nonadrenergic stimulants in isolated human resistance vessels. In this study, we decided to focus on vascular smooth muscle. We therefore used endothelium-denuded gastroepiploic arteries to compare the actions of DEX with those of CLO, and we tried to determine the extent that 1- and 2-adrenoceptor stimulation plays a role in the effects of DEX.
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Methods |
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With approval from the human ethics committee of Kagoshima University School of Medicine, Japan, the omentum was removed from gastrectomy specimens obtained from 84 patients immediately after surgery and then stored in an oxygenated Krebs buffer. The patients were all <70 yr old (mean, 65.2 yr; range, 43–69 yr), and all were suffering from gastric cancer. None of the patients had any history of vascular disease or other major medical problems. None were smokers, and none had taken aspirin, steroids, nonsteroidal antiinflammatory drugs, or any vasoactive medications before surgery. Within 30 min of resection, the gastroepiploic arteries were isolated from the omentum in a dissecting chamber filled with Krebs solution. Fat and connective tissue were carefully removed under a binocular microscope, and a vascular ring (length, 2–2.5 mm; inner diameter, 500–700 µm) was prepared from each artery for tension recording.
The endothelium was denuded by carefully inserting a small forceps into the lumen and gently rolling the ring back and forth in the dissecting chamber. After a 2-h equilibrium in Krebs solution, the lack of a functional endothelium was confirmed by the absence of relaxation of the NE 10-6 mol/L-induced maximum contraction that is normally induced by the endothelium-dependent vasodilator acetylcholine (Ach; 10-6 mol/L) in such arteries. If our efforts to remove the endothelium failed (i.e., if an ACh-induced relaxation of >5% was observed after attempted denudation), we discarded the rings. In the rings considered to be properly endothelium-denuded, an ACh-induced relaxation was not observed (98.3% ± 4.2%). To exclude any residual effect of ACh still present, the experiments proper were performed 30 min after the ACh trials.
Mechanical activity was measured using a strain gauge (UL-100GR; Minebea, Tokyo, Japan) with the ring in a tissue bath (volume, 1.0 mL) filled with Krebs solution continuously bubbled with 95% O2:5% CO2. The temperature of the solution was maintained at 37°C. The resting tension was set at 20 mN, a value shown by the length-tension relationship to allow a maximal active tension to be induced by NE (10-6 mol/L). During a 2-h equilibrium period, Krebs solution was continuously infused at a rate of 2 mL/min by a pump (Perista pump SJ-1211; ATTO, Tokyo, Japan) from one end of the bath and simultaneously aspirated from the other. Control contractile responses were induced by 40 mmol/L of K+ (Figs. 1
–3) or by an -adrenergic agonist (phenylephrine [PE] or NE; Figs. 4 and 5). After the amplitude of the control contraction induced by one of these drugs had been recorded, the concentration-response relationship for one of the 2-adrenergic agonists (DEX or CLO) was determined by adding it to the Krebs solution or the appropriate contracting solution (K+, PE, or NE) for 5 min every 30 min. During the experiments, the infusion rate was increased to 10 mL/min so that the bath solution was exchanged quickly for new solution. Preliminary experiments showed that the responses reached maximal levels within 30 s after application of the above substances, and a 25-min interval was sufficient for the tension to return to the control level.
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In our study, we tested the direct effects of DEX and CLO and the indirect effects of these drugs on the contractions induced by high K+ and
-adrenergic agonists (PE and NE). To examine the effects of competitive 1- and 2-adrenoceptor antagonists (prazosin, yohimbine, and rauwolscine) on the DEX- and CLO-induced modulations of the high K+-induced contraction, rings were first contracted for 5 min by 40 mmol/L of K+ solution containing 10-6 mol/L of DEX or CLO. After a resting period of 25 min, the same rings were then incubated with prazosin, yohimbine, or rauwolscine for 10 min. They were again contracted using 40 mmol/L of K+ solution containing the same concentrations of the 2-agonist and the antagonist. The reasoning behind the use of 10-6 concentrations of DEX and CLO in the above experiment is explained in the Discussion section. In all experiments, only one 2-agonist was studied in a given ring because it has been suggested that downregulation of 2-adrenoceptors often occurs after prolonged 2-agonist treatment (14).
The Krebs solution had the following composition (mmol/L): Na+ 137.4, HCO3- 15.5, K+ 5.9, Ca2+ 2.6, H2PO4- 1.2, Mg2+ 1.2, H2PO4- 0.34, and glucose 11.5. All solutions were bubbled with 95% O2:5% CO2 throughout the experiment, and the pH value was adjusted to 7.3–7.4 (37°C). The 40 mmol/L of K+ solution was produced by isotonic replacement of saline with potassium chloride. To eliminate any effects related to presynaptic 2-adrenoceptor stimulation by DEX, all the solutions contained 5 µmol/L of guanethidine to prevent NE release from the sympathetic nerve endings present in the tissue (15).
DEX was a gift from the Research Center of the Farmos Group Ltd (Turku, Finland). NE, PE, guanethidine, ACh, CLO, yohimbine, rauwolscine, and prazosin were all obtained from Sigma Chemical Co (St. Louis, MO).
The control contractile response was taken as the maximum amplitude of the phasic response to an agonist (PE or NE) or 40 mmol/L of K+ (normalized as a relative tension of 1.0 in each ring). Each test response was expressed relative to the control response obtained with a given agonist before any application of DEX, CLO, or antagonist (yohimbine, rauwolscine, or prazosin). The results are expressed as mean ± SEM (n, number of isolated vessels). Statistical analysis was performed using a two-factor factorial analysis of variance followed by an unpaired t-test (Figs. 1, 2, and 4) or a one-factor factorial analysis of variance followed by a paired t-test (Fig. 3). To evaluate the concentration-dependency of the effects of 2-agonists and yohimbine, regression analysis was conducted with replication, and Spearman’s rank correlation coefficients were used (Figs. 1, 2, and 4). P values <0.05 were considered significant.
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Results |
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The direct effects of DEX and CLO on endothelium-denuded human gastroepiploic arterial rings are shown in Figure 1, with representative traces being displayed in Figure 1A. DEX alone had no significant direct constrict effect even at the largest concentration tested (10-5 mol/L) (5% ± 3% of the maximal contraction produced by 40 mmol/L of K+; P > 0.05 versus resting tension). By contrast, CLO elicited significant contractions at concentrations of 10-7 mol/L or more (P < 0.05 versus the resting tension). The contraction induced by CLO (10-6 mol/L) in the absence of high K+ was completely blocked by pretreatment with prazosin (10-6 mol/L) but unaffected by pretreatment with yohimbine (10-6 mol/L) (prazosin, 0.19 ± 0.07 versus 0.01 ± 0.01, P < 0.01; yohimbine, 0.16 ± 0.07 versus 0.14 ± 0.07, P > 0.05; without versus with antagonist treatments, n = 4 in each case).
As shown in Figure 2, DEX increased the response of the rings to 40 mmol/L of K+ at concentrations of 
10-7 mol/L (P < 0.05 or P < 0.01 versus the initial 40 mmol/L of K+-mediated contraction). CLO had no such effect, even at 10-5 mol/L (Fig. 2). Although pretreatment with yohimbine (10-6 mol/L), rauwolscine (10-6 mol/L), or prazosin (10-6 mol/L) did not modify the direct 40 mmol/L of K+-mediated contraction (Fig. 3A), pretreatment with yohimbine (10-6 mol/L) or rauwolscine (10-6 mol/L) significantly attenuated the enhancing effect of DEX (10-6 mol/L) on the K+-mediated contraction (Fig. 3B). However, pretreatment with prazosin (10-6 mol/L) did not affect the enhanced contractions induced by DEX. As can be seen in Figure 3C, CLO (10-6 mol/L) did not modify the high K+ contraction in the absence or presence of these antagonists.
In contrast to its enhancing effect on the high K+-induced contraction, DEX significantly attenuated the contractions induced by PE (10-6 mol/L) and NE (10-6 mol/L) (Fig. 4, A and B). DEX reduced the responses to this concentration of PE and NE in a concentration-dependent fashion. DEX produced significantly more inhibition of the PE than of the NE contractile response (P < 0.01). Similar results were obtained when CLO was used instead of DEX (Fig. 5A). As shown in Figure 5B, the 2-adrenoceptor antagonist yohimbine, which also reduced the contractile responses to both PE and NE, produced significantly greater inhibition of the NE than of the PE response (P < 0.01).
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Discussion |
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In the present study, we explored the effects of DEX on vascular smooth muscle in a human resistance artery (because the vessels were endothelium-denuded). At concentrations less than 10-7 mol/L, DEX had no effect on resting tension or on contractions produced by high K+, PE, or NE. At larger concentrations (10-7–10-5 mol/L), DEX substantially increased tone in high K+-depolarized vessels, an effect that was prevented by pretreatment with a
2-adrenoreceptor antagonist (yohimbine or rauwolscine). DEX significantly relaxed vessels contracted by the 1-adrenergic agonist PE and, to a lesser extent, those contracted by the 1/2 agonist NE. Taken together, these results indicate that DEX has little direct effect on the smooth muscle in human resistance arteries at the steady-state plasma concentrations normally achieved in clinical practice (i.e., <10-7 mol/L), but larger concentrations of DEX have dual 2-agonist and 1-adrenergic antagonist actions.
The selection of DEX and CLO at a concentration of 10-6 mol/L (Fig. 3) was based on the following reasoning. Although we do not know whether these agonists compete in a one-for-one manner at the receptor, we thought that we should compare agonist and antagonist effects at the same concentration. Moreover, the use of different concentrations would have made it difficult to compare efficacies. We avoided using 10-5 mol/L of yohimbine in these experiments because at that concentration it affects 1- as well as 2-adrenoceptors (see Fig. 5, which shows that this concentration of yohimbine strongly inhibited the contraction induced by the 1-agonist PE). Consequently, we chose 10-6 mol/L as the concentration for both agonist and antagonist. Figure 5 also suggests that, although 10-6 mol/L of yohimbine exerted a strong antagonizing effect on the 2-adrenoceptor, it also exerted a modest, but significant, antagonizing effect at the 1-adrenoceptor (as revealed by an examination of the PE- and NE-mediated contractions). Based on those results, a concentration of 10-6 mol/L as a perfect selectivity of -adrenoceptor antagonists should not be assumed. However, an alternative explanation is that 10-6 mol/L of PE may not be entirely selective for the 1-adrenoceptor. At present, we cannot determine which of these alternatives is more likely.
Circulating and locally released catecholamines play a crucial role in cardiovascular homeostasis and the regulation of blood pressure, and the postjunctional 1- and 2-adrenoceptors present on vascular smooth muscle cells are generally responsible for the production of vasoconstriction (12). DEX is reportedly a potent, selective, and specific 2-adrenoceptor agonist (6), but it produced no significant effect on resting vascular smooth muscle tone in our study. In contrast, the 2-agonist CLO produced a significant increase in resting tone, as previously reported by a number of other investigators (16,17). In fact, CLO is less selective in terms of 2- over 1-adrenoceptor binding (6) and produces a 1-adrenoceptor-mediated vasoconstriction (16,17). Indeed, in our experiments, CLO-induced direct contractile responses were inhibited by the 1-adrenoceptor antagonist prazosin. Thus, the already well-characterized differences between DEX and CLO in terms of selectivity for 1- or 2-adrenoceptors in vascular smooth muscle (6) most likely account for the differences we observed in the contractile potencies of DEX and CLO in the endothelium-denuded human gastroepiploic artery.
Whereas DEX had no significant effect on resting tone in the endothelium-denuded human gastroepiploic artery in our study, it did produce a marked dose-dependent enhancement of the high K+-induced contraction. Inhibition of this contracting effect of DEX was obtained with high efficacy using yohimbine or rauwolscine, suggesting that DEX produces a significant contraction of high K+-depolarized vascular smooth muscle through 2-adrenoceptor-coupling mechanisms. In general, high K+-induced contractions in vascular smooth muscle result from membrane depolarization, which activates L-type voltage-dependent Ca2+ channels (VDCC), resulting in Ca2+ influx and consequent activation of the contractile machinery. Previous investigators have shown that 2-adrenoceptor-induced tone in human subcutaneous resistance arteries is also dependent, at least in part, on Ca2+ influx through L-type VDCC (18), and 2-adrenoceptor agonists have been reported to directly increase VDCC by a G protein-dependent mechanism linked to activation of protein kinase C (19). In addition, 2-adrenoceptor stimulation has been reported to result in membrane depolarization in rat saphenous vein smooth muscle (20), which could indirectly activate VDCC, and 2-adrenergic agonists may also enhance contractions independently of Ca2+, an effect termed Ca2+ sensitization (21). Given these well-described effects of 2-adrenoceptor stimulation on vascular smooth muscle, we are not surprised that DEX had the synergistic effect on the high K+-induced smooth muscle contraction observed in our study. Unexpectedly, however, CLO produced little or no change in the high K+-induced contraction, suggesting that it may have a smaller effect on membrane-depolarized human gastroepiploic arteries than DEX. This observation is in good agreement with previous in vitro data showing that CLO lacks vasomotor activity in high K+-depolarized dog and monkey lingual arteries (17). As noted previously, DEX is a potent and selective 2-adrenoceptor agonist with a high binding affinity for 2-adrenergic, compared with 1-adrenergic, receptors (2 to 1 ratio, 1620:1) (6). CLO is a similar drug, albeit with a somewhat smaller 2/1-adrenergic receptor specificity (2 to 1 ratio, 220:1) (6). Thus, the different selectivities of these drugs for 2/1-adrenoceptors in vascular smooth muscle may account for their different contractile potencies in the human depolarized arteries examined here. However, further pharmacological and biochemical experiments will be required to establish the extent that the administration of DEX leads to stimulation of VDCC in human vascular tissues.
In contrast to the constrictor effect of DEX seen in high K+-contracted rings, CLO had a marked relaxing action in PE-contracted rings. Thus, DEX may antagonize constrictions mediated by stimulation of 1-adrenoceptors. Interestingly, a similar inhibition of a PE-induced constriction can also be seen with CLO [(16,17,22) and the present study]. This blocking action of CLO has previously been explained by a partial 1-adrenergic agonist action (16,17,22). As shown by both Schümann and Endoh (22) (cardiac muscle) and Ruffolo et al. (23) (vascular smooth muscle), a similar phenomenon is seen with a number of imidazoles (a class to which both CLO and DEX belong), and drugs of this class can bind 1-receptors with substantially higher affinities than the full agonist (PE), but their 1-receptor binding is associated with a decreased efficacy of agonists at the receptor. However, according to Daniel et al. (24), agonists selective for 2-adrenoceptors can also inhibit contractions initiated by 1-selective agonists (in rat mesenteric arteries), indicating that in this situation, even though the affinity of these 2-adrenergic agonists for the 1-receptors might be high, their efficacy is low or zero. Thus, the maximum physiological response to -receptor occupation by these partial agonists is lower than that seen with a full 1-agonist such as PE. CLO seems to display a competitive dualism at the 1-adrenoceptor. It can act either as an agonist (in the absence of PE) or as an antagonist (in the presence of PE) (17). Although our data are not conclusive, the inhibition of PE contractions produced by DEX could reflect a similar phenomenon. If so, DEX will need to be viewed as a partial 1-adrenoceptor agonist.
DEX also blocked NE-induced contractions to some extent. However, DEX had a greater inhibitory effect on the contractions induced by the 1-adrenoceptor selective agonist PE than on those induced by the 1/2-adenoceptor agonist NE. Similar results were obtained in the experiments in which CLO was used instead of DEX. These results suggest that imidazoline derivatives showing pronounced agonism for 2-adrenoceptors may antagonize the 1-adrenoceptor but have relatively weak effects on the 2-adrenoceptor during stimulation by an 1/2-adenoceptor agonist. In our experiments, the 2-selective antagonist yohimbine also attenuated both NE- and PE-induced contractions. However, in contrast to the 2-agonists, yohimbine had much more effect on NE contraction than on PE contraction, indicating a more powerful antagonism of the 2-adrenoceptor than of the 1-adrenoceptor. Taken together, these results suggest that the effects of DEX on NE-induced contractions could be accounted for by a 1-adrenoceptor blocking action without the need to propose a competitive dualism of DEX at the 2-adrenoceptor. However, this remains to be clarified in future investigations.
The blood concentrations of DEX and CLO required to maintain a sedative effect in humans are reported to be very similar at 1.0 x 10-9 g/mL, i.e., 4.0 x 10-9 mol/L (4,5,25). The present results demonstrate a lack of effect of DEX when applied in clinically effective concentrations on vasoconstrictor responses in human gastroepiploic arteries. Based on our results, the reported systemic effects of DEX observed in the clinical setting, including decreases in blood pressure, may not be the result of direct actions on vascular smooth muscle but possibly because of decreases in central and peripheral sympathetic nervous system activity. A biphasic effect on blood pressure (an initial increase followed by a decrease) has been reported with IV DEX in humans (5). One clinical report also suggested that at large doses (>10-8 mol/L), DEX produces an increase in peripheral vascular resistance leading to an increase in blood pressure (9). Although the mechanisms underlying the increase in blood pressure are uncertain, we cannot exclude the possibility that some of the vasoconstrictor effects of DEX demonstrated in the present study (i.e., those that may be mediated by VDCC activation) may be relevant in such cases.
In conclusion, DEX did not have direct effects on endothelium-denuded human gastroepiploic arterial rings in vitro. However, large doses markedly enhanced high K+-induced contractions in such preparations, and this action was completely blocked by both yohimbine and rauwolscine. Thus, the enhancing (vasoconstrictor) action of this sedative on nonadrenergically induced contractions seems to be largely due to a 2-adrenoceptor–agonist action. In contrast, DEX had a direct vasorelaxing effect on both PE- and NE-contracted vessels. This action may be related to a 1-antagonist effect produced via a weak partial 1-agonist action similar to that seen with CLO.
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Acknowledgments |
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The authors thank the Departments of Surgery and Pathology in Kagoshima Medical Association Hospital, Japan, (K. Sakoda, director of the hospital) for providing the samples. We also thank R.J. Timms, MD, for his help in preparing the manuscript.
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