Gul, Husamettin*; Yildiz, Oguzhan*; Simsek, Abdurrahman†; Balkan, Mujdat†; Ersoz, Nail†; Cetiner, Sadettin†; Isimer, Askin*; Sen, Dervis†
5-Hydroxytryptamine (5-HT, serotonin) has been shown to be a potent vasoconstrictor of the vasculature (1,2). The various effects of 5-HT on the central nervous system and peripheral organs are mediated through activation of multiple types of receptors (1). Although there are seven 5-HT receptor families identified so far, 5-HT2A and 5-HT1B/1D receptor subtypes are almost exclusively responsible for 5-HT–induced vasoconstriction (1,2). In human cerebral arteries, 5-HT1B receptors play a major role in 5-HT–induced vasoconstriction (3,4), whereas in human coronary arteries, 5-HT2A and 5-HT1B/1D receptors mediate serotonin-induced contractions. However, the relative contributions to contraction of these receptor subtypes differ among studies. Connor et al. (5), Toda and Okamura (6), and Bax et al. (7) found that the 5-HT2A receptor was predominant, while Borton et al. (8) and Kaumann et al. (9) identified the 5-HT1B/1D receptor as predominant contractile 5-HT receptors in human coronary artery in vitro. A mixture of 5-HT2A and 5-HT1B/1D receptors also mediates contraction in human saphenous vein (8), human cutaneous hand veins (10), and human pulmonary artery (11). Serotonin acts on human uterine (12,13) and internal mammary arteries (IMAs) (14,15) mainly through 5-HT2A receptors. Previously, Wallerstedt et al. (16) and Nilsson et al. (17) reported that 5-HT–induced contractions in human mesenteric artery were also mediated mainly by 5-HT2A receptors. However, the contribution of the contractile 5-HT receptors, other than 5-HT2A type, has not previously been determined in human mesenteric artery.
Sumatriptan is used to relieve migraine headache by contracting the cranial vessels mainly via 5-HT1B/1D receptors (3,4,18). 5-HT1B/1D receptors also exist in the other vessels such as coronary (5–9) and IMA (19). Experience in clinical practice demonstrated that sumatriptan is generally well tolerated, with an acceptable benefit–risk ratio when used properly (20). Chest pain, coronary vasospasm, and myocardial ischemia with sumatriptan use are rare side effects, but they have been observed (20–22). Recently, it has been reported that sumatriptan may rarely cause mesenteric ischemia and ischemic colitis in patients (23,24). However, there are a few studies on the contractile 5-HT receptors in human isolated mesenteric arteries that reported sumatriptan induced weak (16) or no contraction (17). These studies cannot explain, however, how sumatriptan causes ischemia in human bowels.
The aim of this study is to characterize the contractile serotonergic receptors and to determine the contribution or variability of contractile 5-HT receptors to 5-HT–induced contraction in human isolated mesenteric artery.
Human mesenteric arteries were obtained from extracted specimens of 22 patients with colorectal carcinoma undergoing abdominal surgery. Patients with endocrine tumors, abdominal infections, and previous radiotherapy were excluded. The local Ethics Committee approved the study. The characteristics of the patients are given in Table 1.
Mesenteric arteries were placed in oxygenated Krebs-Henseleit solution (NaCl, 118; KCl, 4.7; CaCl2, 2.5; KH2PO4, 1.2; MgSO4, 1.2; glucose, 10; and NaHCO3, 25 m M; pH, 7.4) at room temperature and transferred immediately into the laboratory. The arteries were dissected from adhering fat and connective tissue and then cut into 3- to 4-mm length rings. The number of segments obtained from each artery (per patient) varied from 3 to 12, depending on the length of the dissected arteries. The outer diameter of the arteries varied from 0.2 to 0.6 mm. The endothelium was removed mechanically by rubbing with a cotton-wrapped fine wood needle in all experiments. Each ring was mounted on an L-shaped brace in an organ bath containing 40 ml of the physiologic solution at 37°C for tension measurement along the former circumferential axis. The solution was gassed with 95% O2 and 5% CO2. Changes in arterial tensions were recorded isometrically using a force-displacement transducer (model FT03, Grass Instruments, Astro-Med Inc, West Warwick, RI, U.S.A.) and recorded continuously on a multichannel recorder polygraph (model P122, Grass Instruments, Astro-Med Inc, West Warwick, RI, U.S.A.) with computer software (Polyview, version 2.0, Grass Instruments, Astro-Med Inc, West Warwick, RI, U.S.A.). The segments were allowed to equilibrate under a previously determined optimum final resting force of 15 mN for at least 2 hours and were washed every 15 minutes.
After the equilibration period, arterial strips were exposed to 80 m M KCl. Two consecutive contractions to 80 m M KCl were obtained to establish reproducible KCl responses. After a 30-minute equilibration period, with repeated washing every 10 minutes, tissues were challenged with either 5-HT or sumatriptan. Agonists were added to the bath in a cumulative fashion in 0.5 log10 units. Adjacent segments obtained from the same patient were used in antagonist experiments. Each preparation was used only for one experimental protocol. In figures, n represents the number of patients.
GR127935, as a selective 5-HT1B/1D receptor antagonist, and ketanserin, as a selective 5-HT2A receptor antagonist, were used. Cumulative concentration–response curves to 5-HT and sumatriptan were then performed. To determine the possible contribution of 5-HT3 receptors and α1-adrenoceptors to 5-HT–induced contractions, tropisetron (10−6M, 5-HT3 receptor antagonist) and prazosin (10−6M, a selective α1-adrenoceptor antagonist) were used. All antagonists were incubated for at least 30 minutes before a concentration–response curve for an agonist was begun.
Successful removal of endothelium was assessed with the relaxation caused by acetylcholine (10−6M) administered in the presence of submaximal effective concentration of phenylephrine (10−6M). The arterial rings, which were relaxed more than 10% of phenylephrine submaximal contraction, were excluded from the experiments.
Analysis of data
Agonist-evoked contractile responses are expressed as arithmetic mean ± SEM of the percentage of the 80 m M KCl response in each corresponding tissue. The EC50 values (the concentrations of agonists required to produce 50% of the calculated maximum response for the agonist) were used to determine pD2 values (the negative log10 of the EC50 value). The pA2 value for ketanserin was calculated according to Arunlakshana and Schild (25). Statistical comparisons were made by using paired or unpaired Student t test where appropriate or by one-way analysis of variance (ANOVA) and post hoc Duncan multiple range test. A p value < 0.05 was considered significant.
5-HT, creatinine sulfate, phenylephrine, and acetylcholine were purchased from Sigma (St Louis, MO, U.S.A.). Sumatriptan was a gift of Glaxo (Ware, U.K.). GR127935 (N-[4-methoxy-3-(4-methyl-piperazinyl)phenyl]-2”-methyl-4-(5-methyl-1,2,4,-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide) was a gift from Pfizer Research (Sandwich, Kent, U.K.). Ketanserin tartrate, prazosin, and tropisetron were obtained from RBI Inc. (Natick, MA, U.S.A.). GR127935 was dissolved in 1% w/v citric acid diluted in distilled water. The maximum bath concentration of citric acid was 0.1 n M. At this concentration, citric acid did not change the control responses to 5-HT and sumatriptan. All other drugs were dissolved in distilled water and diluted in Krebs solution.
Effects of 5-HT and sumatriptan
5-HT (1 n M–300 μM) caused concentration-dependent contractions in human mesenteric artery rings (Emax, 127.37 ± 7.61% of 80 m M KCl maximal contraction; pD2, 6.73 ± 0.09, n = 22). Sumatriptan (1 n M–30 μM) induced concentration-dependent contraction in isolated mesenteric arteries of nine patients (Emax, 61.82 ± 10.04%; pD2, 6.56 ± 0.21), and the concentration–response curve to sumatriptan seemed biphasic. However, mesenteric arteries from the remaining 13 patients either responded weakly (Emax, < 5%) or they did not respond to sumatriptan at all (Fig. 1). The maximal contractile response to 5-HT was significantly higher than that of sumatriptan (p < 0.05, ANOVA and post hoc Duncan multiple range test). In these arteries, pD2 value of sumatriptan was not significantly different from that of 5-HT (p > 0.05). The maximal contractions to 80 m M KCl were not different in arterial rings that responded or did not respond to sumatriptan (58.0 ± 10.7 and 58.1 ± 8.7 mN, respectively; p > 0.05, unpaired Student t test).
In addition, we obtained large and small branches of the mesenteric arteries from five patients at the same time. The responses to sumatriptan did not differ between the large and small branches of mesenteric arteries of these five patients. Namely, sumatriptan responses were weak (Emax, < 5%) in the large and small arterial branches from three of the five patients. However, sumatriptan responses were strong in the large and small branches of the arteries from the remaining two patients without significant differences in the potency and maximum of sumatriptan (data not shown).
We did not find any differences between the characteristics (i.e., age, gender, hypertension, ischemic heart disease, diabetes, and smoking) of the patients who responded or did not respond to sumatriptan (Table 1).
Effects of GR127935 to responses of 5-HT
Lower concentration of GR127935 (3 n M) caused a rightward shift of the concentration–response curve to 5-HT without a reduction in the maximum response. Whereas in the presence of GR127935 (3 n M), pD2 value of 5-HT increased from 6.54 + 0.18 to 6.27 + 0.09 with no significance (p > 0.05) and the higher concentration of GR127935 (10 n M) caused a rightward shift of the concentration–response curve significantly (pD2, 5.93 ± 0.11; p < 0.05 vs. 5-HT control curve, ANOVA, and post hoc Duncan multiple range test;Fig. 2). GR127935 (10 n M) had no significant effect on the maximal contractions elicited by 5-HT.
Exploration of the presence of 5-HT1B/1D receptors: responses to sumatriptan
GR127935 (3 n M) antagonized sumatriptan-induced contractions in an insurmountable manner and caused a significant reduction in the maximum response to sumatriptan (p < 0.05;Fig. 3).
Proof of the presence of 5-HT2A receptors: effects of ketanserin on 5-HT responses
Ketanserin (10 n M, 100 n M, and 1 μM) caused concentration-dependent rightward shifts of the concentration–response curve to 5-HT (Fig. 4). There was no change in the maximum response. Ketanserin (0.01–1 μM) produced displacements to the right of the 5-HT concentration–response curve, without significant reduction in the maximum response. The pA2 value of ketanserin was 8.40 ± 0.25. The slope of Schild plots was significantly different from unity (slope, 1.43 ± 0.18; r2, 0.98, Schild plots are not shown).
Antagonism of responses to 5-HT by GR127935, ketanserin, and the combination of GR127935 and ketanserin
Neither GR127935 nor ketanserin alone was able to antagonize 5-HT responses fully. Additional experiments were carried out with a combination of GR127935 (10 n M) and ketanserin (100 n M). In the presence of 100 n M ketanserin, 10 n M GR127935 caused a rightward shift in the concentration–response curve to 5-HT with no significant difference from ketanserin alone and with no significant reduction in the maximum response. We did not use GR127935 at a concentration of 100 n M because of its relative high affinity (pKi, 7.40 ± 0.20) to 5-HT2A (25). The pD2 value of 5-HT control curve (6.50 ± 0.13) and pD2 value in the presence of GR127935 (10 n M) (5.75 ± 0.14) were significantly lower than that in the presence of ketanserin (100 n M; 4.63 ± 0.08) and that in the presence of the combination (4.37 ± 0.11; p < 0.05, ANOVA and post hoc Duncan multiple range test). However, the pD2 value of 5-HT in the presence of ketanserin was slightly but not significantly lower than that in the presence of the combination (Fig. 5).
Effects of tropisetron and prazosin on the responses of 5-HT
The contraction elicited by 5-HT was not affected by the 5-HT3 receptor antagonist tropisetron and α1-adrenoceptor antagonist prazosin (Fig. 6). The pD2 values for 5-HT alone and in the presence of tropisetron and prazosin were 6.84 ± 0.21, 6.71 ± 0.28, and 6.62 ± 0.26, respectively.
In the current study, we identified the receptors mediating contractile responses to 5-HT in human mesenteric artery. We found that while 5-HT had a potent vasoconstrictor effect in all arterial preparations used, sumatriptan, a selective 5-HT1B/1D receptor agonist, was a potent vasoconstrictor agent only in some of them (9 of 22). This finding showed the presence of functional 5-HT1B/1D receptors in these patients. However, in the other 13 patients, sumatriptan induced very weak contractions (Emax, < 5% of 80 m M KCl) or no contraction at all. This finding showed the variability of sumatriptan-induced and 5-HT1B/1D receptor mediated responses among the patients.
If sumatriptan caused contractions without prior precontraction with other vasoconstrictor substances in arteries, the 5-HT1B/1D receptors mediating to the contraction were referred to as “active, functional” receptors, indicating that these receptors were considered to be coupled to signal transduction events mediating contraction. Conversely, in arteries in which sumatriptan caused contraction only after precontraction with another agent, the 5-HT1B/1D receptors were referred to as “inactive, silent,” indicating that precontraction was required to cause these receptors to become coupled to signal transduction events (2,26–28). The current study uniquely shows strong 5-HT1B/1D receptor-mediated contractions in some of the human isolated mesenteric arteries. Previously, Chester et al. (29) reported that 5-HT1B/1D and 5-HT2 receptors were involved in the contraction of human epicardial coronary arteries and that the effects mediated by 5-HT1B/1D receptors but not 5-HT2 receptors were preserved in patients with ischemic heart disease. Kaumann et al. (9) showed that the contribution of the 5-HT2 and 5HT1B/1D receptors to the 5-HT–induced contractions varied greatly in human isolated coronary arteries. However, other studies did not report variable participation of 5-HT receptors in 5-HT–induced contractions in human coronary arteries (5–7) and in other human vessels (10–17).
Our findings indicated that some of the human mesenteric arteries (9 of 22) responded strongly to sumatriptan, whereas previous studies reported that sumatriptan-induced contractions were very weak (Wallerstedt et al., Emax, < 6% of 60 m M KCl) (16) or there was no contraction in human isolated mesenteric arteries (17). The discrepancy between the present and the previous studies may be attributed to some factors, i.e., pretension, size, and anatomic localization of the arteries, endothelium, and the characteristics of the patients.
Pretension in our study was about 15 mN as opposed to 2 mN in the study of Nilsson et al. (17), where no contraction to sumatriptan was detected. Wallerstedt et al. (16) only reported the initial tension as 25 mN, but it was possible that their final tension was considerably lower. In the current study, a higher pretension may have unmasked contractile responses to sumatriptan. However, our final resting tension was the same (15 mN) for all arteries, but only some of them responded to sumatriptan strongly. Thus, our resting tension did not seem to be responsible for this variation.
In our study, anatomic localization of the arteries seemed not to be different from the previous studies. According to our observations, the diameter of the arteries may not be the factor that influences sumatriptan responses as mentioned in the results.
Endothelium might also be a factor that influenced our results. In the current study, endothelium was removed, while in the previous studies it was not (16,17). It was previously shown that the removal of the endothelium did not affect the responses to 5-HT and sumatriptan in rabbit mesenteric artery (30). In the current study, sumatriptan-induced contractions were also similar in the absence or presence of endothelium (data not shown).
In a cohort study on adverse reactions to sumatriptan, young age, hypertension, general complaints of abdominal pain, and a family history of myocardial infarction were found to be associated with an increased risk of chest pain attributed to sumatriptan (31). Yildiz et al. (19) showed that sumatriptan-induced contractions were higher in IMAs of the hypertensive patients than in those of normotensive patients. In the current study, hypertension was relatively greater in patients who exhibited strong sumatriptan responses (4 of 9) than in those in the weak-response group (1 of 13).
Sumatriptan-induced contractions suggest involvement of two cloned 5-HT1 receptor subtypes, 5-HT1B and 5-HT1D, which have a similar pharmacology (32,33). Sumatriptan has also affinity for 5-HT1F receptors (1,33). But the contribution of 5-HT1F receptors to sumatriptan-induced contractions in various vessels seems little or negligible (34,35). Human 5-HT1B and 5-HT1D receptors have different affinity for ketanserin, with KD values around 100 n M for 5-HT1D and 10 μM for 5-HT1B receptors (9,32). We observed initial phasic contractions at the lower concentrations of sumatriptan in some of the arterial preparations. Therefore, the concentration–response curve to sumatriptan seemed biphasic, as if two receptors were involved. In the current study, ketanserin (100 n M) had no effect on sumatriptan responses in the arteries that responded to sumatriptan, but it inhibited the initial phasic contractions (data not shown). We could not further evaluate the antagonistic effect of the higher concentration of ketanserin on sumatriptan responses because of unavailability of the arterial preparations.
Ketanserin had a potent antagonistic effect on the contractile response to 5-HT. Ketanserin caused a right displacement of the 5-HT concentration–response curve at higher concentrations of 5-HT; therefore, the concentration–response curve appeared biphasic, which might suggest that 5-HT1 receptors were involved in the first phase (at lower concentrations of 5-HT) and 5-HT2 receptors were involved in the second phase (at higher concentrations of 5-HT) of the 5-HT concentration–response curve. Previously, similar biphasic concentration–response curves to 5-HT were observed in rabbit mesenteric and femoral arteries (27,36,37). The lowest concentration of ketanserin (10 n M) was ineffective against the responses to lower concentrations of 5-HT. Ketanserin (at 100 n M and 1 μM) reduced the contractions to 5-HT not only at the higher concentrations but also partly at the lower concentrations of 5-HT. The antagonistic effect of ketanserin (1 μM) at the lower concentrations of 5-HT was striking. This raises the possibility of 5-HT1D receptor involvement in the responses to 5-HT since ketanserin, at micromolar concentrations, exhibits significant selectivity for the human 5-HT1D but not 5-HT1B receptors (9,32). Human 5-HT1D receptors have nearly 100-fold more affinity (pKi, 7.0–7.5) for ketanserin than 5-HT1B receptors (pKi, < 5) (32,38). The pA2 value of ketanserin in the current study was lower than the values determined for other tissues containing 5-HT2A receptors (32,39,40), although a rather wide variation in pA2 values of ketanserin for the 5-HT2A receptor was reported in functional models (41). This pA2 value of ketanserin did not fit with its reported affinity for the various 5-HT1 binding sites as well (42). In addition, the slope of Schild plots was high (1.43 ± 0.18) and different from unity. Thus, higher concentrations of ketanserin provided a greater than expected degree of inhibition. These results suggested that ketanserin antagonized more than one 5-HT receptor subtype, namely 5-HT2A receptors at high and 5-HT1D receptors at low concentrations of 5-HT, in human isolated mesenteric artery.
GR127935, a selective 5-HT1B/1D receptor antagonist (43), antagonized 5-HT– and sumatriptan-induced responses. GR127935 (3 n M) antagonized the sumatriptan responses in an insurmountable manner in human mesenteric artery. Consistent with our finding, GR127935 has a high affinity (at nanomolar concentration) for human 5-HT1B and 5-HT1D receptors (pKi, 9.9 ± 0.1 and 8.9 ± 0.1, respectively) (43). But it did not seem possible to discriminate functionally the 5-HT1B and the 5-HT1D receptors using different concentrations of GR127935 because it has high affinity for both receptors.
The potency and efficacy of 5-HT3 receptor antagonists exhibit species and regional-dependent variation. It was previously shown that tropisetron antagonized 5-HT–induced vasodilatation in the human forearm (44). Therefore, it may be expected the 5-HT3 receptors exist in arteries and mediate some vascular effects of 5-HT. In the current study, the contractions induced by 5-HT were not significantly affected by the 5-HT3 receptor antagonist tropisetron. On the other hand, Purdy et al. (45) reported 5-HT to be an agonist at α1-adrenoceptors. Some studies indicate that α1-adrenoceptors mediate to the response to higher concentrations of 5-HT (45,46). Ogawa et al. (47) and Shaw et al. (48) reported the involvement of an α1-adrenoceptor in the contractile response to 5-HT in pulmonary artery of the rat. In the current study, α1-adrenoceptors seemed unlikely to be involved in responses to 5-HT because the concentration–response curve to 5-HT was not affected by α1-adrenoceptor antagonist prazosin (10−6M) in a concentration enough for α1-adrenoceptor blockade. Therefore, a possible involvement of 5-HT3 receptors and α1-adrenoceptors in 5-HT responses can be excluded in human mesenteric artery.
The present data provide evidence for the presence of functional 5-HT1B/1D and 5-HT2A receptors that mediate the contractile effects of 5-HT in human mesenteric artery. 5-HT1B/1D receptor-mediated responses varied greatly among patients.
The authors thank Professors Meral Tuncer and Ralph E. Purdy for providing helpful comments and suggestions.
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