(Hypertension. 2000;35:244.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
5-Hydroxytryptamine–Induced Potentiation of Endothelin-1– and Norepinephrine-Induced Contraction Is Mitogen-Activated Protein Kinase Pathway Dependent
From the Department of Pharmacology and Toxicology, Michigan State University (East Lansing).
Correspondence to Dr Stephanie W. Watts, B445 Life Sciences Building, Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317. E-mail wattss{at}pilot.msu.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—5-Hydroxytryptamine (5-HT)–induced arterial contraction depends on activation of the tyrosine kinase–dependent extracellular signal-regulated mitogen-activated protein kinase (Erk MAPK) pathway. The importance of 5-HT in the control of peripheral resistance has been questioned because circulating free levels of 5-HT are low (in the nanomolar range). We tested the hypothesis that physiologically relevant concentrations of 5-HT potentiate arterial contraction in response to agonists proved to have importance in blood pressure maintenance (norepinephrine [NE] and endothelin-1 [ET-1]) in a tyrosine kinase– and an Erk MAPK–dependent manner. Strips of endothelium-denuded rat tail artery were used for the measurement of isometric force. The general tyrosine kinase inhibitor genistein (5 µmol/L) and the inhibitor of MAPK/Erk kinase activation PD098059 (10 µmol/L) shifted concentration-response curves to 5-HT (1x10-9 to 3x10-4 mol/L) rightward but did not shift concentration-response curves to NE or ET-1. In separate experiments, 5-HT (10 nmol/L) potentiated contraction in response to NE (20 nmol/L) by
200% to 300% and to ET-1 (0.3 and 1 nmol/L) by 640% and 180%, respectively. Genistein and PD098059 significantly (66% to 100%) reduced 5-HT–induced potentiation of both NE (20 nmol/L)- and ET-1 (0.3 and 1 nmol/L)–induced contraction. Thus, these data support the ability of low physiological concentrations of 5-HT to amplify arterial responses to hormones with bona fide effects on blood pressure in the novel manner of depending on a tyrosine kinase/Erk MAPK pathway. Although these findings were generated in large arteries, we speculate that they may be applicable to vascular functioning in the deoxycorticosterone acetate salt model of hypertension in which all 3 hormones, 5-HT, NE, and ET-1, have been implicated as causal factors.
Key Words: norepinephrine • endothelin • protein kinases • arteries • hormones
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Since its discovery in serum in 1948,1 5-hydroxytryptamine (5-HT [serotonin]) has been of interest to the cardiovascular researcher. 5-HT has been implicated in numerous cardiovascular diseases; vascular reactivity to 5-HT is increased in arteries from animals with different forms of hypertension2 and atherosclerosis.3 However, it has been argued that 5-HT plays an insignificant role in the physiological control of blood vessel tone because uptake of 5-HT by platelets, adrenergic nerves, or both causes circulating levels of 5-HT to be low (estimated to be 15 to 120 nmol/L4 ) and out of a range that can directly cause constriction. One manner by which physiological concentrations of 5-HT may exert an effect on vascular tone is through the potentiation of vascular contraction in response to other vasoactive substances.
5-HT–stimulated potentiation of agonist-induced contraction has classically been studied in the tail artery of the rat.5 6 7 Norepinephrine (NE) was one of the first agonists established to be potentiated by 5-HT. The list of hormones of which contraction can be potentiated by 5-HT has grown and includes diverse agonists such as angiotensin II, vasopressin, prostaglandin F2
, histamine, clonidine, ATP, 15-lipoxygenase, thromboxane A2, and diadenosine polyphosphates.5 6 7 8 9 10 11 12 13 14 15 5-HT–induced potentiation of agonist-induced contraction has also been observed in multiple vascular tissues, including the isolated perfused rat tail artery; rabbit femoral artery, ear artery, and aorta; human coronary artery; the perfused rat mesenteric bed; and mesangial cells.5 6 7 8 9 10 11 12 13 14 15
We tested the hypothesis that a physiologically relevant concentration of 5-HT (10 nmol/L) potentiates arterial contraction in response to agonists of proved importance in blood pressure maintenance (NE and endothelin-1 [ET-1]) and does so in a manner dependent on a signaling pathway inarguably important to vascular smooth muscle cell growth, the tyrosine kinase–dependent extracellular signal-regulated kinase mitogen-activated protein kinase (Erk MAPK) pathway. We and others recently established that this pathway not only is involved in 5-HT vascular smooth muscle cell mitogenesis16 but also is 1 of the pathways used by the 5-HT2A receptor to mediate arterial contraction in response to 5-HT.17 18 19 Here we report the novel and important finding that the robust potentiation of NE- and ET-1–induced arterial contraction in the tail artery by 5-HT is significantly reduced by inhibitors of tyrosine kinases, including MAPK/Erk kinase (MEK), a tyrosine/threonine kinase crucial to functioning of the Erk MAPK pathway.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
All experimental procedures were in accordance with institutional guidelines of Michigan State University.
Isolated Tissue Bath Protocol
Rats were euthanized (80 mg/kg pentobarbital IP), and the ventral tail artery was removed. Arteries were dissected into helical strips (1.0x5 mm), and the endothelial cell layer was removed by rubbing the luminal side of the vessel with a moistened cotton swab. Tissues were placed in physiological salt solution (containing [in mmol/L] NaCl 130, KCl 4.7, KH2PO4 1.18, MgSO4 · 7H2O 1.17, CaCl2 · 2H2O 1.6, NaHCO3 14.9, dextrose 5.5, and CaNa2EDTA 0.03) for the measurement of isometric contractile force according to bath procedures. One end of the preparation was attached to a stainless steel rod, and the other was attached to a force transducer (FT03; Grass Instruments) and placed under optimum resting tension (600 mg, determined previously). Muscle baths were filled with warmed (37°C), aerated (95% O2/5% CO2) physiological salt solution. Changes in isometric force were recorded on a Grass Instruments polygraph. After a 1-hour equilibration, arteries were challenged with NE (10-5 mol/L). Tissues were washed, and the status of the endothelium was examined by observing arterial relaxation in response to the endothelium-dependent agonist acetylcholine (1x10-6 mol/L) in tissues contracted by the 1-adrenergic receptor agonist phenylephrine (1x10-8 mol/L). Tissues did not relax in response to acetylcholine and were therefore effectively denuded of endothelial cells. Tissues were washed and used in 1 of 3 protocols.
Protocol for Inhibition of Agonist-Induced Contraction by Inhibitors
Either vehicle (0.5% DMSO), general tyrosine kinase inhibitor genistein (5 µmol/L), inhibitor of MEK activation PD098059 (10 µmol/L), MEK inhibitor U0126 (50 µmol/L), or 5-HT2 receptor antagonist LY53857 (10 nmol/L) was added to the bath and incubated with tissues for 1 hour before the cumulative additions of 5-HT (1x10-9 to 3x10-4 mol/L), NE (1x10-9 to 3x10-4 mol/L), or ET-1 (1x10-11 to 3x10-8 mol/L). Only 1 curve was generated in each tissue.
Protocol for 5-HT/NE Potentiation Experiments
A 20 nmol/L concentration of NE was chosen in these experiments because tail artery strips responded with a similar contraction in response to repeated NE application and because this is a near-threshold concentration of NE. Tissues were first administered NE (20 nmol/L) and washed for 20 minutes to allow arterial tone to return to baseline. Half of the tissues were then administered 5-HT (10 nmol/L) or the vehicle for 5-HT (water). This concentration of 5-HT was chosen because tissues respond with similar contraction in response to repeated application and this is a threshold concentration of 5-HT. Once contraction in response to 5-HT plateaued, NE was added. Tissues were washed for 20 minutes, and half of the tissues were administered a kinase inhibitor or the vehicle (0.5% DMSO) and allowed to incubate for 1 hour before the administration of 5-HT and then NE as described. In this way, tissues could serve as their own control. Thus, there were 4 experimental groups: 1 group challenged with NE in the absence of 5-HT and no kinase inhibitor; 1 group challenged with NE in the presence of 5-HT and no kinase inhibitor; 1 group challenged with NE, no 5-HT, and a kinase inhibitor; and the final group challenged with NE, 5-HT, and a kinase inhibitor. In some experiments, the 5-HT2 receptor antagonist LY53857 (10 nmol/L) was added instead of a kinase inhibitor to examine the dependence of 5-HT–induced potentiation of NE-stimulated contraction on 5-HT receptor activation.
Protocol for 5-HT/ET-1 Potentiation Experiments
Because ET-1–induced contraction is so difficult to wash out, tissues could not be used as their own control as was done in the 5-HT/NE experiments. After a 1-hour incubation with either vehicle (0.5% DMSO) or inhibitor, the vehicle for 5-HT (water) or 5-HT (10 nmol/L) was added to the bath. When contraction in response to 5-HT plateaued, ET-1 was added cumulatively with a time period between the 3 concentrations tested (0.1, 0.3, and 1 nmol/L) to allow maximum contraction to be reached at each concentration. Thus, there were 4 experimental groups: 1 group challenged with ET-1 in the absence of 5-HT and no kinase inhibitor; 1 group challenged with ET-1 in the presence of 5-HT and no kinase inhibitor; 1 group challenged with ET-1, no 5-HT, and a kinase inhibitor; and the final group challenged with ET-1, 5-HT, and a kinase inhibitor.
Materials
Drug solutions were prepared fresh daily in water unless specified otherwise. Acetylcholine hydrochloride, 5-HT hydrochloride, NE hydrochloride, and phenylephrine hydrochloride were purchased from Sigma Chemical Co. ET-1 was purchased from Peninsula Laboratories Inc. U0126 (in DMSO) was from Promega. Genistein (in DMSO), LY53857, and PD098059 (in DMSO) were from Sigma/Research Biochemical International.
Data Analyses
Contractions are reported as a percentage of an NE (10 µmol/L)-induced contraction or as a percentage of the first contraction in response to low NE (20 nmol/L). The values for contractions to 5-HT plus NE/ET-1 have had the value of the contraction in response to 5-HT, if observed, subtracted. Apparent antagonist dissociation constants (KB values) were calculated with the use of the equation log(DR-1)=log[B]-logKB, where B is the antagonist concentration, and DR (dose ratio) is the EC50 value of 5-HT in the presence of antagonist divided by the EC50 value of 5-HT in the absence of antagonist. When comparing 2 groups, the appropriate Student’s t test was used. When comparing 3 or more groups, an ANOVA with a Tukey post hoc test was used to determine statistical significance (P<0.05).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Figure 1 demonstrates the effect of the general tyrosine kinase inhibitor genistein, inhibitor of MEK activation PD098059, and MEK inhibitor U0126 in reducing contraction in isolated rat tail arteries stimulated by 5-HT (Figure 1A), NE (Figure 1B), or ET-1 (Figure 1C). Inhibitors have previously been verified to reduce 5-HT–induced activation and tyrosyl-phosphorylation of the Erk MAPKs in aortic smooth muscle,17 19 and we published an examination in arteries, with the exception of U0126, of potential nonselectivities of these compounds.17 At all 5-HT concentrations of
10-8 mol/L, these inhibitors significantly reduced contraction in response to 5-HT. It is unlikely that these compounds are acting as 5-HT receptor antagonists because daidzein (5 µmol/L), the structurally related but inactive isomer of genistein, was unable to shift 5-HT–induced contraction in rat tail artery.17 In contrast, the same concentrations of genistein (5 µmol/L) and PD098059 (10 µmol/L) did not shift or reduce contraction in response to NE or ET-1 (Figures 1B and 1C). U0126 also did not reduce contraction in response to the low concentrations of NE and ET-1 used in the potentiation experiments but did significantly reduce the maximum contraction. In preliminary experiments, we have found that unlike PD098059 and genistein, U0126 can reduce KCl (6 to 100 mmol/L)-induced arterial contraction (data not shown). Because of these data, which are suggestive of nonselectivity, we did not use U0126 in the following experiments.
|
), general tyrosine kinase inhibitor genistein (5 µmol/L; 
), inhibitor of MEK activation PD098059 (10 µmol/L, 
), and MEK inhibitor U0126 (50 µmol/L, 
) on contraction of isolated, endothelium-denuded tail artery to 5-HT (A), NE (B), and ET-1 (C). Values are mean±SEM for number of animals indicated in parentheses. *Statistically significant differences from response of vehicle-incubated tissue. 
Reduction in contraction in presence of kinase inhibitor compared with vehicle at Tail arteries responded to a threshold (10 nmol/L) concentration of 5-HT with a minimal contraction (51.78±10.66 mg, or 4.7±0.97% of maximum contraction in response to 10 µmol/L NE; n=50). When compared with a contraction before 5-HT, NE (20 nmol/L)-induced contraction in the presence of 5-HT was enhanced by almost 300% (Figure 2A); such a potentiation was also observed for 10 nmol/L NE. A lower concentration of 5-HT (5 nmol/L) produced a small but statistically insignificant increase in tail artery contraction in response to NE (20 nmol/L). The increase in NE-induced contraction observed in the presence of 5-HT was not due to a time- or response-induced change in sensitivity to NE because in the group that received vehicle and no 5-HT, the second contraction in response to NE was 95.3±4.3% of the first response to NE. Potentiation elicited by 5-HT was receptor dependent because the 5-HT2 receptor antagonist LY53857 (10 nmol/L) reduced 5-HT (10 nmol/L)–induced potentiation of NE (20 nmol/L) contraction by 72.1±3.7% (n=3). Furthermore, LY53857 (10 nmol/L) shifted 5-HT–induced contraction with an apparent antagonist dissociation constant (-logKB, mol/L) of 9.4, a value consistent with interaction with a 5-HT2A receptor. The same concentration of LY53857 did not shift or reduce a NE concentration-response curve (10-9 to 3x10-5 mol/L). Contraction in response to 0.1 nmol/L ET-1 was now observable in the presence of 5-HT, contraction in response to 0.3 nmol/L ET-1 was amplified >10-fold, and contraction in response to 1 nmol/L ET-1 was amplified 2-fold.
|
Activation of a tyrosine kinase–dependent/MEK-dependent pathway by 5-HT to cause potentiation of both NE- and ET-1–induced contraction is supported by the finding that the same concentrations of genistein (5 µmol/L) and PD098059 (10 µmol/L), concentrations that did not alter contraction in response to NE and ET-1 alone, significantly reduced 5-HT–induced potentiation of both NE (Figure 2A)- and ET-1 (Figure 2B)–induced arterial contraction.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Arterial tone results from the summation of stimuli, both relaxant and contractile, within the smooth muscle. Many hormones and neurotransmitters can influence vascular smooth muscle tone, and they do not act singularly. Here we present evidence that the combination of 5-HT with either NE or ET-1 not only significantly potentiates vascular contraction in response to NE or ET-1 but also enables the potentiated contraction in response to NE and ET-1 to become dependent on a pathway that NE and ET-1 do not use to cause contraction individually in the tail artery, a tyrosine kinase/Erk MAPK–dependent pathway. The finding that 5-HT can potentiate vascular contraction in response to NE is not new,5 6 7 8 9 10 but few reports suggest that 5-HT can potentiate the effects of ET-1.20 The importance of this report is to emphasize that the potentiation of arterial contraction in response to important vasoactive hormones can occur at physiologically relevant concentrations of 5-HT and that potentiation may allow a signal transduction pathway not normally used to mediate arterial contraction in response to NE and ET-1. It should be noted that these data were generated in the tail artery, an artery that is not a resistance artery. As such, whether these same events occur in true resistance arteries remains to be seen, and thus the conclusions we make with respect to the involvement of 5-HT–induced potentiation in control of total peripheral resistance must be considered speculative.
The receptors investigated in the tail artery have been characterized. The 5-HT receptor is of the 5-HT2 receptor class21 (supported by inhibition of 5-HT–induced contraction by the 5-HT2 receptor antagonist LY53857), the ET-1 receptor is an ETA receptor,22 and the -adrenergic receptor is a mixture of 1- and 2-adrenergic receptors.23 24 All 3 classes of receptors activate similar, classic signaling pathways (plasma membrane calcium channels and phospholipase C), and all receptors have recently been identified as being able to activate the Erk MAPK pathway in vascular smooth muscle. Several investigators have demonstrated that Erk MAPK can phosphorylate caldesmon and, in doing so, release the calmodulin-mediated inhibition of actinomyosin ATPase and thereby promote smooth muscle contraction.25 26 27 Whether a tyrosine kinase/Erk MAPK pathway–dependent pathway is used for arterial contraction appears to differ among receptors. For example, activation of the Erk MAPK pathway is important to vascular smooth muscle mitogenesis stimulated by 5-HT,16 and 5-HT2A receptor–mediated contraction is clearly tyrosine kinase/Erk MAPK dependent.17 18 19 28 29
In contrast, the involvement of the tyrosine kinase or kinases/Erk MAPK pathway in ET-1–induced contraction is less clear. ET-1 acting at ETA receptors possesses the ability to activate the Erk MAPK pathway in human and rat vascular smooth muscle.30 31 Only a few reports demonstrate that ET-1–induced contraction can be blocked by tyrosine kinase inhibitors,29 and although the MEK inhibitor PD098059 was able to reduce ET-1–induced contraction in the isolated rat uterus,32 no reports specifically implicate the Erk MAPK pathway in arterial contraction in response to ET-1. Interestingly, the ability of ET-1 to act as a direct mitogen is not universally found in that some investigators report that ET-1 could activate the MAPK pathway in smooth muscle but was a poor mitogen.31 33
In vascular smooth muscle cells, NE has been reported to activate the Erk MAPK pathway,34 35 but the literature regarding the dependence of NE-induced contraction on tyrosine kinase or kinases or the Erk MAPK pathway is confusing. Some reports demonstrate that NE-induced contraction can be blocked by tyrosine kinase inhibitors,28 36 whereas others,37 38 including the present study, suggest that NE/-adrenergic receptor–mediated contraction is not dependent on tyrosine kinase(s) or that high concentrations of the tyrphostin family of tyrosine kinase inhibitors and genistein are necessary to only slightly reduce NE-induced contraction.39 These differences likely reflect the differences in species used (and hence, possible receptor subtype), the concentrations of tyrosine kinase inhibitors used, and the possibility that -adrenergic receptors do not routinely use tyrosine kinases to mediate arterial contraction.
So why are these studies important, and what do the results mean? Activation of the Erk MAPK pathway is not the only mechanism mediating 5-HT–induced potentiation. Xiao and Rand6 demonstrated in the isolated perfused rat tail artery that ketanserin and the L-type calcium channel antagonist diltiazem (10 µmol/L) abolished 5-HT–mediated potentiation of NE- and phenylephrine-induced contraction. The 5-HT2A receptor has long been associated with activation of calcium channels and phospholipase C, but we recently recognized that the Erk MAPK pathway is a third, parallel pathway of signaling that is used by arterial 5-HT2A receptors.17 18 19 Importantly, this study demonstrates that because 5-HT involves the Erk MAPK pathway in contraction, 5-HT enables contraction in response to NE and ET-1, more specifically, that potentiated by 5-HT, to become dependent on the tyrosine kinase/Erk MAPK pathway. The mechanism by which this occurs is unclear, and it is difficult to determine whether it is just 5-HT and its receptor interacting with the Erk MAPK pathway in the potentiated state or whether 5-HT provides NE and ET-1 with the opportunity to independently stimulate the Erk MAPK pathway.
We can speculate as to the importance of potentiation in the control of blood pressure. The finding that physiologically relevant concentrations of 5-HT can potentiate arterial contraction in response to low concentrations of hormones, NE and ET-1, with undisputed effects on total peripheral resistance suggests that this may occur in vivo and modulate not only contractility but possibly vascular smooth muscle growth as well. Does this mean that 5-HT is involved in the control of total peripheral resistance or the increased total peripheral resistance observed in hypertension? This is debatable. As many studies demonstrate that 5-HT receptor antagonists can reduce blood pressure in a hypertensive model40 as do argue that 5-HT receptor antagonists are ineffective as antihypertensive agents41 or that the reduction in blood pressure caused by 5-HT receptor antagonists such as ketanserin is due to nonselective blockade of 1-adrenergic receptors.42 This question remains intriguing, especially in light of the fact that NE, ET-1, and 5-HT have been implicated as causal factors in a model of hypertension that displays both increased peripheral vascular resistance and growth: the deoxycorticosterone acetate-salt hypertensive rat.43 44
In summary, we present evidence that a low, physiological concentration of 5-HT (10 nmol/L) can significantly potentiate rat tail artery contraction in response to NE and ET-1, and we present the novel finding that potentiation is dependent on activation of a tyrosine kinase/Erk MAPK pathway.
|
Acknowledgments |
|---|
This work was supported by NIH grant HL-58489.
Received September 13, 1999; first decision October 8, 1999; accepted October 20, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Rapport MM. Serum vasoconstrictor (serotonin) V: the presence of creatinine in the complex: a proposed study of the vasoconstrictor principle. J Biol Chem. 1949;180:961–969.
2. Turla MB, Webb RC. Vascular responsiveness to 5-hydroxytryptamine in experimental hypertension. In: Fozard JR, ed. The Peripheral Actions of 5-Hydroxytryptamine. Oxford, UK: Oxford University Press; 1989:327–353.
3. Henry PD, Yokoyama M. Supersensitivity of atherosclerotic rabbit aorta to ergonovine. J Clin Invest. 1980;66:306–313.
4. Martin GR. Vascular receptors for 5-hydroxytryptamine: distribution, function and classification. Pharmac Ther. 1994;62:283–324.[Medline] [Order article via Infotrieve]
5. Szabo C, Hardebo JE, Owman C. An amplifying effect of exogenous and neurally stored 5-hydroxytryptamine on the neurogenic contraction in rat tail artery. Br J Pharmacol. 1991;102:401–407.[Medline] [Order article via Infotrieve]
6. Xiao XH, Rand MJ. Amplification by serotonin of responses to other vasoconstrictor agents in the rat tail artery. Clin Exp Pharmacol Physiol. 1989;16:725–736.[Medline] [Order article via Infotrieve]
7. Medgett IC, Fearn HJ, Rand MJ. Serotonin enhances sympathetic vasoconstrictor responses in rat isolated perfused tail artery by activation of postjunctional serotonin-2 receptors. Clin Exp Pharmacol Physiol. 1984;11:343–346.[Medline] [Order article via Infotrieve]
8. Yildiz O, Smith JR, Purdy RE. Serotonin and vasoconstrictor synergism. Life Sci. 1998;62:1723–1732.[Medline] [Order article via Infotrieve]
9. Van Neuten JA, Janssen PAJ, deRidder W, Vanhoutte PM. Interaction between 5-hydroxytryptamine and other vasoconstrictor substances in the isolated femoral artery of the rabbit: effect of ketanserin (R 41 468). Eur J Pharmacol. 1982;77:281–287.[Medline] [Order article via Infotrieve]
10. De la Lande IS. Evidence for a 5-HT1-like receptor mediating the amplifying action of 5-HT in the rabbit ear artery. Br J Pharmacol. 1992;107:550–555.[Medline] [Order article via Infotrieve]
11.
Purdy RE, Murray D. Serotonin-induced vasoconstriction and contractile synergism with noradrenaline: role of -adrenoceptors. In: Mylecharane EJ, Angus JA, de la Lande IS, Humphrey PP, eds. Serotonin: Actions, Receptors, Pathophysiology. London, UK: Macmillan Press Ltd; 1989:130–135.
12. Takiguchi Y, Hashimoto H, Nakashima M. Reciprocal potentiation of a vasoconstrictor response between 5-hydroxytryptamine and clonidine in the perfused mesenteric vascular bed of the rat. Arch Int Pharmacodyn. 1987;287:16–30.
13. Van Diest MJ, Verbeuren TJ, Herman AG. Vascular interactions between 5-hydroxytryptamine and 15-lipoxygenase metabolites of arachidonic acid. Eur J Pharmacol. 1993;231:267–274.[Medline] [Order article via Infotrieve]
14.
Chester AH, Allen SP, Tadjkarimi S, Yacoud MH. Interaction between thromboxane A2 and 5-hydroxytryptamine receptor subtypes in human coronary arteries. Circulation. 1993;87:874–880.
15.
Schulze-Lohoff E, Zanner S, Ogilvie A, Sterzel RB. Vasoactive diadenosine polyphosphates promote growth of cultured renal mesangial cells. Hypertension. 1995;26:899–904.
16.
Lee SL, Wang WW, Lanzillo JJ, Fanburg BL. Regulation of serotonin-induced DNA synthesis of bovine pulmonary artery smooth muscle cells. Am J Physiol. 1994;266:L53–L60.
17.
Watts SW. Serotonin activates the mitogen activated protein kinase pathway in vascular smooth muscle: use of the mitogen activated protein kinase kinase inhibitor PD098059. J Pharmacol Exp Ther. 1996;279:1541–1550.
18. Watts SW. Activation of the mitogen-activated protein kinase pathway via the 5-HT2A receptor. Ann N Y Acad Sci. 1998;861:162–168.[Medline] [Order article via Infotrieve]
19.
Florian JA, Watts SW. Integration of mitogen activated protein kinase kinase activation of vascular 5-hydroxytryptamine2A receptor signal transduction. J Pharmacol Exp Ther. 1998;284:346–355.
20.
Yang BC, Nichols WW, Lawson DL, Mehta JL. 5-Hydroxytryptamine potentiates vasoconstrictor effect of endothelin-1. Am J Physiol. 1992;262:H931–H936.
21. Pertz H, Elz S. In vitro pharmacology of sarpogrelate and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT contractions in rat tail artery. J Pharm Pharmacol. 1995;47:310–316.[Medline] [Order article via Infotrieve]
22.
Adner M, Uddman E, Cardell LO, Edvinsson L. Regional variation in appearance of vascular contractile endothelin-B receptors following organ culture. Cardiovasc Res. 1998;37:254–262.
23.
Xiao XH, Rand MJ. 2-Adrenoceptor agonists enhance responses to certain other vasoconstrictor agonists in the rat tail artery. Br J Pharmacol. 1989;96:539–546.[Medline]
[Order article via Infotrieve]
24.
Medgett IC, Langer SZ. Heterogeneity of smooth muscle alpha adrenoceptors in rat tail artery in vitro. J Pharmacol Exp Ther. 1984;229:823–830.
25. Adam LP, Hathaway DR. Identification of mitogen-activated protein kinase phosphorylation sequences in mammalian h-caldesmon. FEBS Lett. 1993;322:56–60.[Medline] [Order article via Infotrieve]
26.
Khalil RA, Menice CB, Wang CLA, Morgan KG. Phosphotyrosine-dependent targeting of mitogen-activated protein kinase in differentiated contractile vascular cells. Circ Res. 1995;76:1101–1108.
27.
Katoch SS, Moreland RS. Agonist and membrane depolarization induced activation of MAP kinase in swine carotid artery. Am J Physiol. 1995;269:H222–H229.
28. DiSalvo J, Steusloff A, Semenchuk L, Satoh S, Kolquist K, Pfitzer G. Tyrosine kinase inhibitors suppress agonist-induced contraction in smooth muscle. Biochem Biophys Res Commun. 1993;190:968–974.[Medline] [Order article via Infotrieve]
29. Epstein AM, Throckmorton D, Brophy CM. Mitogen-activated protein kinase activation: an alternate signaling pathway for sustained vascular smooth muscle contraction. J Vasc Surg. 1997;26:327–332.[Medline] [Order article via Infotrieve]
30. Koide M, Kawahara Y, Tsuda T, Ishida Y, Shii K, Yokoyama M. Endothelin-1 stimulates tyrosine phosphorylation and the activities of two mitogen-activated protein kinases in cultured vascular smooth muscle cells. J Hypertens. 1992;10:1173–1182.[Medline] [Order article via Infotrieve]
31.
Yang Z, Krasnici N, Luscher TF. Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade. Circulation. 1999;100:5–8.
32.
Kimura A, Ohmichi M, Takeda T, Kurachi H, Ikegami H, Koike K, Masuhara K, Hayakawa J, Kanzaki T, Kobayashi M, Akabane M, Inoue M, Miyake A, Murata Y. Mitogen-activated protein kinase cascade is involved in endothelin-1-induced rat puerperal uterine contraction. Endocrinology. 1999;140:722–731.
33.
Irons CE, Flynn MA, Mok LM, Reynolds EE. Endothelin and PDGF enhance arachidonic acid release and DNA synthesis in vascular smooth muscle cells. Am J Physiol. 1996;270:C1642–C1646.
34.
Hu ZW, Shi XY, Lin RZ, Chen J, Hoffman BB. 1-Adrenergic receptor stimulation of mitogenesis in human vascular smooth muscle cells: role of tyrosine protein kinases and calcium in activation of mitogen-activated protein kinase. J Pharmacol Exp Ther. 1999;290:28–37.
35.
Uddin MR, Muthalif MM, Karzoun NA, Benter IF, Malik KU. Cytochrome P-450 metabolites mediate norepinephrine-induced mitogenic signaling. Hypertension. 1998;31:242–247.
36. Abebe W, Agrawal DK. Role of tyrosine kinases in norepinephrine-induced contraction of vascular smooth muscle. J Cardiovasc Pharmacol. 1995;26:153–159.[Medline] [Order article via Infotrieve]
37. Merkel LA, Rivera LM, Colussi DJ, Perrone MH. Inhibition of EGF-induced vasoconstriction in isolated rabbit aortic rings with the tyrosine kinase inhibitor RG50864. Biochem Biophys Res Commun. 1993;192:1319–1326.[Medline] [Order article via Infotrieve]
38.
Sauro MD, Thomas B. Tyrphostin attenuates platelet-derived growth factor-induced contraction in aortic smooth muscle through inhibition of protein tyrosine kinase(s). J Pharmacol Exp Ther. 1993;267:1119–1125.
39. Laniyonu AA, Saifeddine M, Yang SG, Hollenberg MD. Tyrosine kinase inhibitors and contractile action of G-protein linked vascular agonists. Can J Physiol Pharmacol. 1994;72:1075–1085.[Medline] [Order article via Infotrieve]
40. Balasubramaniam G, Lee HS, Mah SC. Differences in the chronic hypotensive mechanism of action of ketanserin in spontaneously hypertensive and Wistar-Kyoto rat. J Hypertens. 1994;12:7–14.[Medline] [Order article via Infotrieve]
41.
Docherty JR. An investigation of the effects of intravenous injection of the 5-hydroxytryptamine2 receptor antagonists ketanserin and LY53857 on blood pressure in anesthetized spontaneously hypertensive rats. J Pharmacol Exp Ther. 1989;248:736–740.
42. Cohen ML. Vascular serotonin receptors and blood pressure regulation. Drug Dev Res. 1984;4:301–313.
43. Lariviere R, Sventek P, Thibault G, Schiffrin EL. Endothelin-1 expression in blood vessels of DOCA-salt hypertensive rats treated with the combined ETA/ETB endothelin receptor antagonist bosentan. Can J Physiol Pharmacol. 1995;73:390–398.[Medline] [Order article via Infotrieve]
44. Watts SW, Fink GD. 5-HT2B receptor antagonist LY272015 is antihypertensive in DOCA-salt hypertensive rats. Am J Physiol. 1999;276:H944–H952.
This article has been cited by other articles:
 |
|
 |
|
  T. Matsumoto, K. Ishida, N. Nakayama, T. Kobayashi, and K. Kamata Involvement of NO and MEK/ERK pathway in enhancement of endothelin-1-induced mesenteric artery contraction in later-stage type 2 diabetic Goto-Kakizaki rat Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1388 - H1397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Diaz, W. Ni, J. Thompson, A. King, G. D. Fink, and S. W. Watts 5-Hydroxytryptamine Lowers Blood Pressure in Normotensive and Hypertensive Rats J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 1031 - 1038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Escano Jr., L. B. Keever, A. A. Gutweiler, and B. T. Andresen Angiotensin II Activates Extracellular Signal-Regulated Kinase Independently of Receptor Tyrosine Kinases in Renal Smooth Muscle Cells: Implications for Blood Pressure Regulation J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 34 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Linder, W. Ni, J. L. Diaz, T. Szasz, R. Burnett, and S. W. Watts Serotonin (5-HT) in Veins: Not All in Vain J. Pharmacol. Exp. Ther., November 1, 2007; 323(2): 415 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zhang and L. Zhang Regulation of {alpha}1-Adrenoceptor-Mediated Contractions of the Uterine Artery by Protein Kinase C: Role of the Thick- and Thin-Filament Regulatory Pathways J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1253 - 1260. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Ni, K. Lookingland, and S. W. Watts Arterial 5-Hydroxytryptamine Transporter Function Is Impaired in Deoxycorticosterone Acetate and N{omega}-Nitro-L-Arginine But Not Spontaneously Hypertensive Rats Hypertension, July 1, 2006; 48(1): 134 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A. Rufanova and A. Sorokin CrkII Associates with BCAR3 in Response to Endothelin-1 in Human Glomerular Mesangial Cells. Experimental Biology and Medicine, June 1, 2006; 231(6): 752 - 756. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sorokin and D. E. Kohan Physiology and pathology of endothelin-1 in renal mesangium Am J Physiol Renal Physiol, October 1, 2003; 285(4): F579 - F589. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Matrougui, L. B. Tanko, L. Loufrani, D. Gorny, B. I. Levy, A. Tedgui, and D. Henrion Involvement of Rho-Kinase and the Actin Filament Network in Angiotensin II-Induced Contraction and Extracellular Signal-Regulated Kinase Activity in Intact Rat Mesenteric Resistance Arteries Arterioscler Thromb Vasc Biol, August 1, 2001; 21(8): 1288 - 1293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Matrougui, Y. E. G. Eskildsen-Helmond, A. Fiebeler, D. Henrion, B. I. Levy, A. Tedgui, and M. J. Mulvany Angiotensin II Stimulates Extracellular Signal-Regulated Kinase Activity in Intact Pressurized Rat Mesenteric Resistance Arteries Hypertension, October 1, 2000; 36(4): 617 - 621. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||