Propofol was introduced into clinical anaesthesia some 25 yr ago  and has become the world's leading short-acting intravenous anaesthetic. However, hypotension is a common problem with propofol, especially when administered rapidly and in the elderly. The underlying mechanisms are poorly understood. Both a direct vascular dilating effect [2,3] and a reduction of sympathetic activity [4,5] have been proposed. There is a wealth of evidence that propofol directly reduces smooth muscle tone. Both endothelium-dependent and -independent effects have been described. The underlying mechanisms, by which propofol mediates peripheral vasodilation, are still not completely understood. We have shown earlier that propofol acts as a direct vasodilator both in porcine and in human coronary artery segments, and that this effect is independent of an intact endothelium . The aim of the present study was to investigate the mechanisms by which propofol relaxes vascular segments. Potential pathways propofol may interfere with include nitric oxide formation, prostanoid synthesis (i.e. formation of prostacyclin, PGI2), Ca2+ and different K+ channels. To this end we performed different experiments in the presence and absence of inhibitors of the synthesis or action of nitric oxide (NO), prostanoids and endothelium-derived hyperpolarizing factors.
Materials and vessel preparation
Materials. The following compounds were used: Propofol 1% (Disoprivan®; AstraZeneca, Wedel, Germany), potassium chloride (KCl), prostaglandin F2α (PGF2α, Dinoprost, Minprostin F2α, Pharmacia & Upjohn, Erlangel, Germany) (thromboxane A2 analogue), diltiazem (Dilzem®; Gödecke, Karlsruhe, Germany). All other compounds were obtained from Sigma Chemicals: Bradykinin, sodium indomethacin (inhibitor of cyclo-oxygenase), glibenclamide (inhibitor of ATP-sensitive K+ channels), Nω-nitro-L-arginine (L-NNA, inhibitor of NO synthase), tetraethylammonium chloride (TEA, non-selective inhibitor of K+ channels, with preference for the high conductance Ca2+-sensitive K+ channel, BKCa), sucrose. The Krebs-Ringer solution contained (mmol L−1): NaHCO3 25.0, glucose 11.1, titriplex III 0.026, MgSO4.7 H2O 1.2, KH2PO4 1.2, KCl 4.7, CaCl2 1.9 and NaCl 118.2.
Vessel preparation. This study was performed in porcine coronary artery segments. Hearts of adult pigs were obtained immediately post-mortem from a nearby slaughterhouse and stored in ice-cold Krebs-Ringer solution. Left anterior descending coronary arteries were dissected from the hearts, flushed with Krebs-Ringer solution, cleaned of surrounding fat and cut into 3 mm wide rings (n = 4-12 per vessel). Artery rings were placed in organ chambers filled with 10 mL of Krebs-Ringer solution at 37°C and bubbled with a O2 (95%)-CO2 (5%) gas mixture. The vessel segments were suspended between two stainless steel hooks, one of which was anchored in the organ chamber and the other connected with a high fidelity force transducer (Hugo Sachs Elektronik, March, Germany), allowing continuous isotonic measurement of vessel tension and display on a printer.
Artery rings were progressively stretched to optimal tension (20 mN) and then allowed to equilibrate for 45 min. A standard contractile response to 8 × 10−2 mol KCl was obtained first. After the segments had been flushed, a prolonged contraction was obtained with 3.5 × 10−5 mol PGF2α. Endothelial integrity was assessed by exposing the rings to 10−6 mol bradykinin. In rings with a dilation of more than 60% of the PGF2α contraction an intact endothelial function was supposed, preparations failing to meet this criterion were excluded. We studied the influence of propofol (0.5-1000 μg mL−1) on contractions obtained with KCl (8 × 10−2 mol) or PGF2α (3.5 × 10−5 mol). First, a stable contraction was established in different sets of experiments either by KCl or PGF2α, then propofol was added cumulatively. The resulting relaxation was measured, and concentration-response curves were constructed. After the rings had been allowed to rest for 90 min, they were again contracted in the presence of one of the following compounds: L-NNA 0.1 mmol, indomethacin 10 μmol, a combination of L-NNA 0.1 mmol and indomethacin 10 μmol, glibenclamide 5 μmol and 100 μmol, TEA 3, 50 and 100 mmol, diltiazem 0.1 μmol and sucrose 100 mmol. Then propofol was again added in a cumulative manner. Two rings not exposed to any of the substances mentioned above served as controls.
Relaxation after adding propofol was expressed as relative value of precontraction induced by KCl or PGF2α. All values are given as mean ± standard error of mean (SEM). Statistical analysis was performed with the analysis of variance (ANOVA). The differences between groups were considered significant when P < 0.05.
One-hundred-and-eighteen rings were precontracted with KCl, 47 with PGF2α. The numbers of rings in each group are given in Table 1. Propofol-induced concentration-dependent relaxation of both KCl and PGF2α-mediated contractions. Characteristic S-shaped concentration-response curves were constructed for propofol. In the presence of propofol 1000 μg mL−1 almost complete relaxation of the precontraction was recorded. The response to propofol was not affected by L-NNA, indomethacin, by a combination of both compounds, glibenclamide 5 and 100 μmol, diltiazem, TEA 3 mmol and sucrose 100 mmol (Fig. 1). TEA 50 mmol reduced propofol-induced relaxation in KCl precontracted rings significantly (P < 0.001). TEA 100 mmol produced a marked reduction of propofol-induced relaxation in rings precontracted with both mediators (P < 0.001) (Fig. 1).
We have shown recently that propofol attenuates the contractile response to different vasoconstrictors . These experiments, carried out with three concentrations of propofol, produced indirect evidence for the vasorelaxing effect of this substance. In the present study, a stable contraction was achieved by two different vasoconstrictors, namely KCl and PGF2α, the first acting by depolarization of the membrane, the latter acting as a thromboxane A2 analogue in the vessel wall. In both sets of experiments, propofol directly and dose-dependently relaxed precontracted vessels. The concentrations of propofol showing significant relaxing effect are higher compared with those used in clinical practice. Blood concentrations of propofol 2-10 μg mL−1 (1-5 × 10−5 mol) are regarded as clinically effective . Taking into consideration that 97-98% of the substance is bound to plasma proteins , the free fraction is probably even lower. However, in vivo and in vitro concentrations are not easy to compare, as the in vivo situation cannot be mimicked completely in organ baths. Hence, the relevance of the finding, that the vasorelaxing effect of propofol in low concentrations is fairly weak is not completely clear. The lowest concentration of propofol that produced relaxation was 10−5 mol and in the same range as reported for human omental vessels .
These investigators also described that propofol relaxed omental arteries and veins in an endothelium-independent manner . This is in accordance with our own results in coronary arteries . It is also reported in the rat aorta [10,11], canine  and porcine  coronary artery. In contrast, propofol has also been found to have endothelium-dependent effects, for example in bovine  and in rat  coronary artery rings. Other workers showed that propofol stimulates NO release from cultured endothelial cells . On the other hand, propofol seems to attenuate acetylcholine-induced, endothelium-dependent relaxation in pulmonary  and mesenteric  arteries. Although our own results  and those presented by Wallerstedt and colleagues  suggest an endothelium-independent relaxing effect of propofol on isolated vessels, we felt it was necessary to look more intensively at endothelial function.
As the endothelium is known to produce an abundance of vasoconstricting and relaxing factors, a more distinct differentiation of the mechanisms contributing to the vasoactive properties of propofol is needed. In our experiments, L-NNA, a specific inhibitor of NO synthase did not affect the vasodilating effect of propofol, indicating that NO formation is not involved in propofol-induced relaxation of coronary arteries. This obviously also occurs in omental arteries . Prostanoid synthesis does not play a role in the vasodilating activity of propofol, either. This is documented by the fact that indomethacin, an inhibitor of prostanoid synthesis, failed to influence the dilating effect of propofol. This rules out that PGI2, a potent vasodilator produced by the endothelium, is involved in the mechanisms by which propofol acts at the vessel wall. Consequently, the combination of the blockade of NO formation and of prostanoid synthesis failed to influence the relaxant effect of propofol.
Diltiazem, an inhibitor of voltage-sensitive Ca2+ channels, did not affect the vasorelaxing effect of propofol. The curves depicting vessel contraction at different propofol concentrations, adjusted to 100% contraction before adding propofol, are nearly congruent. The problem with the diltiazem group is that the absolute value of contraction in the presence of the Ca2+ antagonist is only 50% of the value for the first contraction. However, starting from this level the propofol-induced relaxation was not affected by preincubation with the Ca2+ channel blocking compound.
On the other hand, it is a matter of debate whether K+ channels are involved in the mechanisms discussed here. Glibenclamide, an inhibitor of ATP-sensitive K+ channels, did not affect propofol-induced vasodilation, even when administered in high concentrations. This rules out that these channels play an important role in this experimental setting. However, in the presence of TEA, an inhibitor of the BKCa channel, the vasodilating action of propofol was reduced. This effect was concentration dependent with no effect at TEA 3 mmol, a weak action at TEA 50 mmol, and a strong inhibiting effect at TEA 100 mmol. The latter concentration is 10 fold higher than that reported by other investigators working with omental vessels . In canine coronary arteries, no such influence of TEA could be demonstrated . The selectivity for the BKCa channnel may be questioned, as TEA is said to have antimuscarinic effects, as well . The suspicion that muscarinic receptors may be involved in the mechanisms discussed here was ruled out by blocking these receptors with atropine . The effect of TEA remained unchanged. On the other hand, the concentration of TEA needed to affect the vasodilating effect of propofol is very high, so that an unspecific osmotic effect may be discussed. As sucrose 100 mmol had no effect on the effectiveness of TEA administration, this suspicion can be ruled out. The fact that the vasodilating effect of propofol is obviously reduced in the presence of TEA gives rise to the suspicion that the BKCa may contribute to the relaxant effect of this anaesthetic drug. Propofol may activate this channel, hereby increasing K+ efflux and hyperpolarizing of the membrane. The result would be a reduction in smooth muscle tone, explaining the vasodilating effect of propofol. As the membrane potential was not recorded, however, this conclusion is speculative and suggests at best a potential contribution of this mechanism to the vasodilating effect of propofol.
In summary, propofol relaxed coronary arteries concentration dependently. This effect was shown to be independent of NO and prostanoid formation, but may be caused by hyperpolarization, possibly resulting from activation of the BKCa channel.
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