Effects of dexmedetomidine on porcine pulmonary artery vascular smooth muscle

doi:10.21203/rs.2.9720/v2

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Effects of dexmedetomidine on porcine pulmonary artery vascular smooth muscle

https://doi.org/10.21203/rs.2.9720/v2

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published 12 Sep, 2019

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Background: The α2-receptor agonists, dexmedetomidine (Dex) have been shown to produce sedative and analgesic effects not only with systemic administration but also when administered in the extradural space and around peripheral nerves. However, the effects and mechanism of action of Dex on pulmonary arteries have not been determined. This study therefore aimed to investigate the effect of Dex on pulmonary arterial vascular smooth muscle by evaluating changes in isometric contraction tension. We then attempted to determine the effects of Dex on depolarization stimulation and receptor stimulation. Methods: Endothelium-denuded porcine pulmonary arteries were sliced into 2- to 3-mm rings. We then exposed them to various substances at various concentrations under different conditions of baseline stimulation (with KCl, adrenaline, caffeine, or histamine) and of the α2-receptor stimulant or antagonists, or α1-receptor antagonist (with imidazoline, yohimbine, rauwolscine, or prazosin), and different conditions of Ca2+ depletion of the intracellular reservoir or extracellular stores, measuring the changes in isometric contraction tension with each addition or change in conditions. The concentration–response relation was determined at Dex concentrations of 10−10, 10−9, 10−8, 10−7, 10−6, 5×10−6, and 10−5 M and for other experiments at 5×10-6 M. Results: Dex enhanced the contraction induced by high KCl stimulation, with the increases reaching significance at Dex concentrations of ≥5×10-6 M. The Dex-induced enhancement of contraction induced by high KCl was completely suppressed by yohimbine and rauwolscine, which are α2-receptor antagonists, but not by prazosin. Dex, imidazoline, yohimbine and rauwolscine reduced the increases in contraction tension induced by the receptor stimulant adrenaline. Dex suppressed the adrenaline-induced increases in contraction tension after depletion of Ca2+ reservoir. In the absence of extracellular Ca2+, Dex suppressed the adrenaline- and histamine-induced increases, and did not affect caffeine-induced increases in contraction tension. Conclusions: Dex-enhanced high KCl-induced contraction was mediated by α2-receptors. Adrenaline-induced contraction was suppressed by the α2-receptor stimulant Dex and α2-receptor antagonists yohimbine and rauwolscine, suggesting that the effect of Dex on adrenaline-induced contraction is attributable to its α2-receptor-blocking action. Dex inhibited receptor-activated Ca2+ channels (RACCs) and phosphatidylinositol-1,4,5-triphosphate-induced Ca2+ release (IICR) but not Ca2+-induced Ca2+ release (CICR).

Anesthesiology & Pain Medicine

porcine pulmonary artery

dexmedetomidine

adrenaline

isometric tension

The α₂-receptor agonists have been shown to produce sedative and analgesic effects not only with systemic administration but also when administered in the extradural space and around peripheral nerves [1–3]. Among them, dexmedetomidine hydrochloride (Dex) is added to local anesthetics to increase their potency and extend their duration of action. For example, administration of Dex 0.5 µg/kg with 0.5% lidocaine to the brachial plexus for brachial nerve block significantly extends the duration of the local anesthetic’s effect [2] and provides postoperative analgesia with a single administration. In dentistry, the current use of local anesthetics containing adrenaline may cause abnormal blood pressure increases, leading to adverse effects such as cerebrovascular disease. To prevent these complications, the adrenaline in local anesthetics should be replaced with an additive that causes smaller fluctuations in the circulation during local anesthesia [4, 5, 6]. The use of Dex-containing lidocaine as a local anesthetic may offer simultaneous prolongation and potentiation of anesthetic effects and may be useful for dental treatment in patients with cardiovascular disease. Dex has thus attracted attention and is being tested in clinical studies as an additive agent for dental local anesthesia. Therefore, the effects and mechanism of action of Dex on the cardiopulmonary vascular system should be clarified. Although several in vivo studies have shown the effects of Dex on aortic or coronary arteries in various animals, there are few reports regarding its effect on other peripheral vessels. The pulmonary artery has been relatively unexplored, even though it is a prominent artery that nourishes the lungs. Although pulmonary vasoconstriction, with its resultant progressive elevation of pulmonary arterial resistance and pressure, plays a central role in pulmonary arterial hypertension, which could be fatal (7, 8), there are only a few reports of the effects of Dex on the pulmonary artery. The diversity of effects of Dex on smooth muscle precludes guessing its effects on any individual smooth muscle.

To elucidate the effects and mechanism of action of Dex on vascular smooth muscle of the pulmonary artery, we measured isometric contraction tension in the artery. We then attempted to determine the effects of Dex on depolarization stimulation and receptor stimulation. To evaluate Dex’s possible mechanisms of action, we investigated components of the two most important pathways involved in intracellular Ca²⁺fluctuations during vascular smooth muscle contraction—i.e., intracellular influx of extracellular Ca²⁺ and release of stored intracellular Ca²⁺ within the cell.

This study was approved by the Institutional Review Committee on the Ethics of Animal Experiments of Iwate Medical University. All experiments were conducted in accordance with the Institutional Animal Care and Use Committee guidelines (Ethical number 26–010).

Reagents and solutions

All chemicals were obtained from Wako Oure Chemical Industries (Osaka, Japan)

In all experiments, air-equilibrated Hank’s balanced salt solution (HBSS) was used to maintain the arteries under resting conditions. HBSS was composed of 137 mM NaCl, 5.4 mM KCl, 0.8 mM MgSO₄, 1.26 mM CaCl₂, 0.34 mM Na₂HPO₄, 0.44 mM KH₂PO₄, 4.2 mM NaHCO₃, and 5.55 mM glucose (pH 7.34). All other salt solutions used as perfusates were prepared by modifying the HBSS. Isotonic 60 mM KCl solution was prepared by replacing the NaCl in the HBSS solution with an equimolar amount of KCl.

Arterial ring preparation and isometric tension measurement

The pigs are killed as part of a routine procedure in a slaughterhouse, where we obtained the porcine lungs. The one-third of the pulmonary arteries that were 2–3 mm in diameter were excised from the lung of a 6-month-old slaughtered pig and cut into rings 2–3 mm in length. The endothelium, which was rubbed gently against the thin arm of stainless steel tweezers [8, 9], was then denuded and the rings inverted (inner surface facing outward) to prepare specimens of pulmonary arterial vascular smooth muscle. It was confirmed that 3 µM acetylcholine-induced relaxation of the arterial rings disappeared after this procedure. The arterial rings were maintained in HBSS at 5°C until used for assessments.

Specimens were placed in a perfusion chamber (with 3 ml of perfusate), and a resting tension of 4–7 mN was applied. The perfusate, adjusted to 37°C, flowed at a rate of 1.6 ml/min controlled by a peristaltic pump (SMP–23; Tokyo Rikakikai Co., Fujisawa, Japan). After perfusion with HBSS for 30 min, various stimulants were administered, and the resulting contraction tension after each addition was measured, as follows: One end of the specimen in the perfusion chamber was fixed to a manipulator (M–152; Narishige, Tokyo, Japan) and the other end to a tension transducer (UL–2GR; Minebea, Tokyo, Japan) using a tungsten wire. Data were recorded on PowerLab^® (ADInstruments, Bella Vista, Australia) via a pressure amplification unit (N4438; NEC San-ei, Tokyo, Japan).

At the beginning of each experiment, after approximately 2 min of perfusion with 60 mM KCl solution (Figures 1, 2, 3, 5, 6) or 5 μM adrenaline (Fig. 4), the contraction tension was measured, recorded, and used as the control value. Next, the concentration–response relations for Dex and imidazoline were determined by adding each to HBSS or 60 mM KCl (Figs. 1, 2). The concentration–response relations for Dex, imidazoline, yohimbine, and rauwolscine were determined by adding each to 5 μM adrenaline (Fig. 4) for 2 min and then monitored for almost 20 min. Second, after the amplitude of the control contraction induced by KCl had been recorded, the response for 5×10^–6M Dex was determined by adding it to 60 mM KCl. Those for 10^–6 M yohinbine, rauwolscine, and prazosin were determined by adding each to 60 mM KCl containing 5×10^–5 M Dex (Fig. 3) for 2 min and then monitored for almost 20 min. Third, after depleting the intracellular Ca²⁺, the response to 5×10^–6M Dex was determined by adding it to 5 μM adrenaline (Fig. 5). Also, after depletion of extracellular Ca²⁺, in Ca²⁺-free HBBS, the effect of 5×10^–6M Dex was determined by adding it to 5 μM adrenaline, histamine, or 25 mM caffeine (Fig. 6) for 2 min and then monitored for almost 20 min. The preliminary experiments showed that, after application of these substances, an almost 20-min interval was sufficient for the tension to return to the control level (Figures 1, 2, 3, 4, 6). For all experiments, each new experiment was carried out with fresh preparations because it has been suggested that down-regulation of α₂-adenoreceptors often occurs after prolonged α₂-agonist treatment [10, 11].

Statistical Analysis

Values are presented as means ± SEM. Statistical analysis was performed with SPSS version 11.0 software (SPSS, Chicago, IL, USA). Differences between the means of two groups were evaluated with Student’s ttest. Differences among multiple groups, whose homogeneity of variance was assessed with Levene’s test, were evaluated with repeated measures analysis of variance followed by Scheffe’s multiple comparison procedure. Differences were considered significant at p<0.05.

Direct effects of various concentrations of Dex and imidazoline on pulmonary arterial vascular smooth muscle

No significant changes in contraction tension was observed with the addition of Dex or imidazoline (Fig. 1).

Effects of various concentrations of Dex and imidazoline on high KCl-induced contraction tension

Dex enhanced the contraction induced by high KCl stimulation, with the increases reaching significance at Dex concentrations of ≥5×10^–6 M (Fig. 2).

Effects of yohimbine, rauwolscine, and prazosin on high KCl-induced contraction tension

Yohimbine, rauwolscine, and prazosin had no significant effect on 60 mM KCl-induced contraction tension in the pulmonary arterial vascular smooth muscle. Increases in contraction tension by stimulation with 60 mM KCl containing Dex were significantly suppressed by yohimbine and rauwolscine, which are α₂-receptor antagonists, although there was no significant difference observed with prazocin, also an α₁-receptor antagonist (Fig. 3).

Effects of various concentrations of Dex, imidazoline, yohimbine, and rauwolscine on adrenaline-induced contraction tension

Dex, imidazoline, yohimbine, and rauwolscine each decreased adrenaline-induced increases in contraction tension in a concentration-dependent manner in pulmonary arterial vascular smooth muscle (Fig. 4). The inhibitory concentrations of 50% were 2.083 µM for Dex, 0.8996 µM for imidazoline, 0.376 µM for yohimbine, and 0.5702 µM for rauwolscine.

Effects of Dex on adrenaline-induced contraction tension with Ca²⁺ reservoir depletion

The first administration of caffeine, which caused the intracellular reservoir to release Ca²⁺ during perfusion with Ca²⁺-free HBSS, induced a transient increase in contraction tension. The second and third caffeine doses, which were administered after fixing the Ca²⁺-induced Ca²⁺ release (CICR) channels in the open state with ryanodine, induced no appreciable changes in contraction tension. When Ca²⁺-containing adrenaline was administered in this state, the contraction tension slowly increased and then remained in a steady state (control). The Ca²⁺-containing adrenaline solution containing Dex administered under the same conditions as the control induced changes in contraction tension similar to those in the control, although the maximum value was significantly lower (Fig. 5).

Effects of Dex on adrenaline-, caffeine- and histamine-induced contraction tension in the absence of extracellular Ca²⁺

When Ca²⁺ was present in the intracellular reservoir but absent in the extracellular fluid, contraction tension transiently increased with administration of adrenaline, caffeine, and histamine and then rapidly decreased (control). Dex-containing adrenaline, caffeine, and histamine administered under the same conditions as the control induced changes in contraction tension similar to those in the control. Dex-containing adrenaline and histamine produced significantly lower maximum values, whereas Dex-containing caffeine had no effect on contraction tension (Fig. 6).

This study had two major findings. First, in porcine pulmonary arterial vascular smooth muscle, Dex increased contraction tension that had been induced by depolarization stimulation with high KCl and reduced the increases in contraction tension induced by adrenaline receptor stimulation. These effects were concentration-dependent in both cases. Second, Dex suppressed receptor-activated Ca²⁺ channels (RACCs), which allow extracellular Ca²⁺into the cells, and phosphatidylinositol–1,4,5-triphosphate (IP₃)-induced Ca²⁺ release (IICR), which releases intracellular Ca²⁺ within the cells. Dex did not suppress CICR.

In porcine pulmonary arterial vascular smooth muscle, Dex enhanced the contraction induced by high KCl stimulation. Conversely, the Dex-induced enhancement of contraction induced by high KCl was completely suppressed by yohimbine and rauwolscine, which are α₂-receptor antagonists, but not by prazosin, also an α₁-receptor antagonist (Fig. 2. 3). These results suggest that Dex’s enhancing effect on vascular smooth muscle contraction induced by high KCl depolarization is mediated by an α₂-receptor mechanism.

A study of endothelium-denuded human gastroepiploic arteries showed that the enhancement of high KCl-induced vascular smooth muscle contraction induced by adding Dex was completely antagonized by the α₂-receptor antagonists yohimbine and rauwolscine, leading the authors to conclude that the enhancing effect of Dex is mediated by α₂ receptors [11]. Another study, on the human forearm, showed that the vasoconstriction effect of Dex after administration of a β- or α₂-receptor antagonist was completely antagonized by the α₂-receptor antagonist yohimbine [12].

In general, high KCl-induced contraction of vascular smooth muscle is mediated by increased Ca²⁺ brought about by an influx of extracellular Ca²⁺ via voltage-dependent Ca²⁺ channels (VDCCs). These channels open in response to cell membrane depolarization, resulting in intracellular CICR via ryanodine receptors on endoplasmic reticulum (ER) [13]. Dex-induced increases in high KCl-induced contraction tension (Fig. 2) may promote VDCC-mediated influx of extracellular Ca²⁺ and/or CICR. Stimulation with caffeine activates ryanodine receptors on the ER and promotes CICR to increase Ca²⁺, resulting in contraction. In the present experiment, Dex had no effect on caffeine-induced increases during contraction tension in the Ca²⁺-free HBBS solution (Fig. 6). Therefore, the mechanism by which Dex increases depolarization-induced contraction of the pulmonary arterial vascular smooth muscle is not facilitation of CICR from the Ca²⁺ reservoir. Rather, the increase is likely to result from facilitated influx of extracellular Ca²⁺ via VDCCs. α₂-Receptor-induced contraction of human subcutaneous resistance arteries depends, at least in part, on Ca²⁺ influx via L-type VDCCs [14]. α₂-Receptor stimulants directly promote VDCC by a mechanism that depends on a G protein associated with protein kinase C activation [15]. It has also been reported that α₂-receptor stimulation in rat saphenous vein vascular smooth muscle results from depolarization of the cell membrane, which indirectly enhances Ca²⁺-dependent contraction and Ca²⁺ sensitivity through VDCC activation [16]. Because Dex has an imidazole group, it is believed to act not only on the α_2-receptor but also on imidazoline receptors [17]. We therefore administered imidazoline, which is an imidazoline-receptor stimulant, and compared its effects with those of Dex. Imidazoline did not increase the contraction resulting from depolarization with high KCl (Fig. 2).

The α₂-receptor stimulant Dex, imidazoline-receptor stimulant imidazoline, and α₂-receptor antagonists yohimbine and rauwolscine produced concentration-dependent decreases in contraction induced by the α₁α₂-receptor stimulant adrenaline. Dex and imidazoline suppressed contraction resulting from adrenaline, suggesting that receptor stimulants containing an imidazoline group inhibit receptor stimulation involving both α₁ and α₂. In the present study, adrenaline-induced contraction was suppressed by the α₂-receptor stimulant Dex, the imidazoline-receptor stimulant imidazoline, and the α₂-receptor antagonists yohimbine and rauwolscine. These findings suggest that the effect of Dex on adrenaline-induced contraction is attributable to its α₂-receptor-blocking action.

Dex inhibited RACC and IICR but not CICR. Cell membrane Ca²⁺ channels regulated by receptor stimulation include RACCs, which are receptors that have a channel function coupled with receptor stimulants and that mediate the influx of extracellular Ca²⁺. Receptor stimulants activate phospholipase C by activating G protein-coupled receptors on the cell membrane, resulting in the production of IP₃ from phosphatidylinositol, a lipid component of the cell membrane. IP₃ production leads to activation of IICR from the intracellular reservoir [18]. Influx of extracellular Ca²⁺ and IP₃ activate ryanodine receptors on the ER, causing CICR from the Ca²⁺ reservoir. Both IP₃ and ryanodine receptors, which are present on the ER, play an important role in the regulation of Ca²⁺ release [19]. Vascular smooth muscle contraction is regulated by changes in the Ca²⁺ sensitivity of contraction proteins through phospholipase C activation by receptor stimulation [20].

The present study showed that Dex reduced the increases in contraction tension induced by the receptor stimulant adrenaline, suggesting that it suppressed RACC-mediated influx of extracellular Ca²⁺, IICR, and/or CICR (Fig. 4). Dex’s suppression of adrenaline-induced increases in contraction tension after depletion of Ca²⁺ suggest that Dex reduces the RACC-mediated influx of extracellular Ca²⁺ (Fig. 5). Dex’s suppression of adrenaline-induced increases in contraction tension in the absence of extracellular Ca²⁺ suggest that Dex suppresses IICR and/or CICR (Fig. 6). In the absence of extracellular Ca²⁺, Dex did not affect caffeine-induced increases in contraction tension (Fig. 6). Caffeine stimulation activates ryanodine receptors on the ER and promotes CICR to induce contraction [13]. This mechanism suggests that Dex suppresses IICR because it did not suppress CICR.

We also conducted experiments with histamine to confirm that Dex suppresses IICR. Receptor stimulation by histamine is coupled with phospholipase C via Gq, a G protein-mediated, seven-transmembrane receptor. Ca²⁺ is recruited via IP₃ as a second messenger. Contraction then occurs via diacylglycerol-mediated activation of protein kinase C [21]. Thus, histamine is believed to act specifically on IICR [22].

Our previous study showed that receptor stimulation in the absence of Ca²⁺ in the extracellular fluid, and following depletion of the Ca²⁺ reservoir with caffeine and ryanodine, did not cause any changes in contraction tension [18]. This finding indicates that IP₃ receptor stimulation results in no Ca²⁺ release from the Ca²⁺ reservoir when ryanodine receptors are fixed in the open state. The experiment showed that the histamine-induced increase in contraction tension was reduced in the absence of extracellular Ca²⁺, suggesting that Dex suppresses IICR (Fig. 6).

When the 6-month-old pig whose tissues were used in the present experiments was euthanized, the major stress of the animal could have produced depletion of the Ca²⁺ reservoir. All pigs at that location are euthanized routinely with an electrical method. Hence, the euthanasia protocol did not introduce bias in the results.

The selection of Dex at a concentration of 10^–6M was based on the following data. We considered that the inhibitory concentration of 50% of Dex was 2.083 µM according to the dose-dependent curve (Fig. 4). We therefore needed to have 60–70% maximum inhibition. Figure 2 shows that Dex increased the 60 mM KCl-induced contraction tension, with the observed increases reaching significance at a Dex concentration of ≥5×10^–6 M. Hence, we decided to use 5 µM. Dex at high doses activates the α₂β-receptors distributed in vascular smooth muscle, causing hypertension resulting from contraction of vascular smooth muscle. At low doses, Dex causes hypotension resulting from vasodilation and bradycardia due to parasympathetic dominance [19]. The blood concentrations of Dex required to maintain a sedative effect in humans are reported to be similar, at 1.0 ×10^–9 g/mL (i.e., 4.0 × 10^–9 mol/L) [23, 24]. The present results show that Dex had no effect on vasoconstrictor responses in porcine pulmonary arteries when applied in clinically effective concentrations. The previous reported systemic effects of Dex observed in the clinical setting, including decreased blood pressure, may not be the result of direct actions on vascular smooth muscle but possibly due to decreases in central and peripheral sympathetic nervous system activity [11]. One clinical report also suggested that, at large doses (>10^–8 mol/L), Dex increases peripheral vascular resistance, leading to increased blood pressure [13]. Although the mechanism of blood pressure increase is unclear, it cannot be ruled out that the vasoconstrictor effects of Dex shown in this study (i.e., those mediated by VDCC activation or in case of accidental intravenous administration) may be relevant in such cases.

To elucidate the effects and mechanism of action of Dex on vascular smooth muscle of the pulmonary artery, we measured isometric contraction tension in the artery. Dex increased the contraction tension resulting from depolarization stimulation by high KCl. The enhancement of high KCl-induced contraction when adding Dex was completely antagonized by the α₂-receptor antagonists yohimbine and rauwolscine. Thus, Dex’s enhancing effect was mediated by α₂-receptors. Adrenaline-induced contraction was suppressed by the α₂-receptor stimulant Dex and imidazoline, and the α₂-receptor antagonists yohimbine and rauwolscine, suggesting that the effect of Dex on adrenaline-induced contraction is attributable to its α₂-receptor-blocking action. Dex suppressed the adrenaline-induced increases in contraction tension after depletion of Ca²⁺reservoir. In the absence of extracellular Ca²⁺, Dex suppressed the adrenaline- and histamine-induced increases, and did not affect caffeine-induced increases in contraction tension. Also, Dex inhibited RACC and IICR, but not CICR.

CICR, Ca²⁺-induced Ca²⁺ release; HBSS, Hank’s balanced salt solution; ER, endoplasmic reticulum; IICR, IP₃-induced Ca²⁺ release; IP₃, phosphatidylinositol–1,4,5-triphosphate; RACC, receptor-activated Ca²⁺ channel; VDCC: voltage-dependent Ca²⁺ channel

Ethics approval and consent to participate

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

There was no funding for this manuscript.

Authors’ contributions

MC contributed to data collection, data analysis, and manuscript preparation; approved the final manuscript; and attests to the integrity of the original data and the analysis reported in this manuscript. KS contributed to study design, data collection, data analysis, and manuscript preparation; approved the final manuscript, and attests to the integrity of the original data and the analysis reported in this manuscript.

Acknowledgment

None.

Authors’ details

Division of Dental Anesthesiology, Department of Reconstructive Oral and Maxillofacial Surgery, School of Dentistry, Iwate Medical University, 1–3–27 Chuo-dori, Morioka, Iwate 020–8505, Japan

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