1 Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226; and 2 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235
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ABSTRACT |
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The present study
examined the effects of a series of 20-hydroxyeicosatetraenoic acid
(20-HETE) derivatives on the diameter of renal arterioles to determine
the structural requirements of the vasoconstrictor response to 20-HETE.
The vascular responses to 5-, 8-, 12-, 15-, 19-, 20-, 21-HETEs,
arachidonic acid (AA), and saturated, partially saturated, dimethyl,
carboxyl, and 19-carbon derivatives of 20-HETE
(108 to
10
6 M) were assessed in rat
renal interlobular arteries (65-125 µm). 20-HETE, 21-HETE,
dimethyl-20-HETE, and a partially saturated derivative of 20-HETE,
20-hydroxyeicosa-5(Z),14(Z)-dienoic
acid, reduced vessel diameter by 19 ± 3, 17 ± 3, 16 ± 2, and 28 ± 2%, respectively. In contrast, 5-, 8-, 12-, 15-, and
19-HETE, AA, saturated, partially saturated, carboxyl, and the
19-carbon derivatives of 20-HETE had no effect on vessel diameter.
Pretreatment with 5-, 15-, and 19-HETE, the 19-carbon derivative or
20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (1 µM) completely blocked the vasoconstrictor response to 20-HETE in renal arterioles. Pretreatment with AA, carboxyl, saturated 19-carbon, and saturated 20-HETE derivatives (1 µM) partially blocked
the response, whereas 8- and 12-HETE (1 µM) had no effect on the
vasoconstrictor response to 20-HETE. These findings suggest that
20-HETE agonists and antagonists require a carboxyl or an ionizable
group on carbon 1 and a double bond near the 14 or 15 carbon. 20-HETE
agonists also require a functional group capable of hydrogen bonding on
carbon 20 or 21, whereas antagonists lack this reactive group.
cytochrome P-450; renal arterioles; vasoconstriction; hydroxyeicosatetraenoic acids
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INTRODUCTION |
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RECENT STUDIES HAVE indicated that arachidonic acid (AA) is primarily metabolized by a P-450 4A-dependent pathway to 20-hydroxyeicosatetraenoic acid (20-HETE) in the kidney and the peripheral vasculature (3, 6, 19). 20-HETE serves as a critical second messenger in the regulation of renal and peripheral vascular tone, as well as renal tubular function. In this regard, 20-HETE is a potent vasoconstrictor that inhibits the opening of Ca2+-activated K+ channels in vascular smooth muscle (VSM) cells (12, 32). It promotes Ca2+ entry by depolarizing VSM cells secondary to blockade of Ca2+-activated K+ channels (17) and by increasing the conductance of L-type Ca2+ channels (5). Inhibitors of the formation of 20-HETE block the myogenic response of renal, cerebral, and peripheral arterioles to elevations in transmural pressure and autoregulation of renal and cerebral blood flow in vivo (7, 11, 33, 34). Selective P-450 4A inhibitors attenuate the vasoconstrictor response to endothelin (21), angiotensin II (2, 22), elevations in tissue PO2 (8, 16), and the mitogenic actions of growth factors in VSM and renal mesangial cells (15, 31). They also delay or prevent the development of hypertension in spontaneously hypertensive rats and other experimental models of hypertension (18, 24, 27). In the kidney, 20-HETE is also produced by renal tubular cells, where it participates in the regulation of sodium transport in the proximal tubule and thick ascending limb of the loop of Henle (20, 22, 23). 20-HETE is also produced by the airways in human and rabbit lungs, where it serves as a bronchodilator (13).
Despite the importance of 20-HETE in the regulation of renal function, vascular tone, and airway resistance, little is known about its mechanism of action. Recent studies have indicated that the mitogenic actions of 20-HETE and its effects on vascular tone and sodium transport are associated with activation of protein kinase C and mitogen-activated protein kinase signal transduction cascades (4, 20, 29). Activation of these pathways are usually triggered by receptor-mediated events; however, presently there is no evidence for a 20-HETE receptor. There have been no studies to determine whether 20-HETE binds to membrane proteins or whether the vasoconstrictor properties of 20-HETE can be mimicked by other analogs. Thus the purpose of the present study was to perform structure activity studies with a series of synthetic 20-HETE analogs to evaluate the structural requirements for its vasoconstrictor actions in interlobular arteries microdissected from the kidney of rats.
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METHODS |
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General. Experiments were performed on 10- to 12-wk-old male Sprague-Dawley rats purchased from Harlan Sprague Dawley Laboratories (Indianapolis, IN). The rats were housed in the animal care facility at the Medical College of Wisconsin, which is approved by the American Association for the Accreditation of Laboratory Animal Care. The animals had free access to food and water. All protocols involving animals received approval by the Animal Care Committee of the Medical College of Wisconsin.
Synthesis of 20-HETE agonists and antagonists.
The following compounds: 5(S)-,
8(S)-,
12(S)-,
15(S)-, and
19(S)-HETE, were used to examine the
effect of the position of the hydroxyl group on the vasoconstrictor
response to 20-HETE. All of these analogs are commercially available
(Biomol, Plymouth Meeting, PA) and have the same number of carbons
(20), double bonds (4), and molecular weight as 20-HETE (Fig.
1). The only difference between these
compounds and 20-HETE is the position of the hydroxyl group along the
carbon chain. Additional experiments were also performed with AA
(Sigma, St. Louis, MO) and 20-carboxy-AA, which are structurally
similar to 20-HETE but lack a hydroxyl group on the 20th carbon, and
20-hydroxyeicosa-6(Z),15(Z)-dienoic acid [6(Z),- 15(Z)-20-HEDE],
which has the carboxy and hydroxy moieties on the 1st and 20th
carbon reversed (Fig. 1). The synthesis of 20-HETE and the 20-HETE
analogs are described in detail in the United States patent application
USSN 60/076,091 (25).
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Structural requirements of the vasoconstrictor response to 20-HETE: isolated vessel studies. Interlobular arterioles (65-125 µm inner diameter) were microdissected from the kidneys of rats. The vessels were mounted on glass micropipettes in a perfusion chamber containing physiological saline solution maintained at 37°C and equilibrated with a 95% O2-5% CO2 gas mixture. The vessels were secured to the pipettes with 10-0 silk suture and stretched to its in vivo length using an eyepiece micrometer. This was achieved by stretching the vessel until the inner diameter was close to the initial inner diameter measured in situ before microdissection. The inflow pipette was connected to a pressurized reservoir to control intraluminal perfusion pressure, which was monitored using a transducer (Cobe, Lakewood, CO). The outflow cannula was clamped off, and intraluminal pressure was maintained at 90 mmHg. Vessel diameter was measured with a video system composed of a stereomicroscope (Carl Zeiss), a television camera (KP-130AU, Hitachi), a videocassette recorder (AG-7300, Panasonic), a television monitor (CVM-1271, Sony), and a video measuring system (VIA-100, Boeckeler Instrument, Tucson, AZ). The composition of the perfusate and the bath was (in mM) 119 NaCl, 4.7 KCl, 1.17 MgSO4, 1.6 CaCl2, 12 NaHCO3, 1.18 NaH2PO4, 0.03 EDTA, and 10 glucose, pH 7.4. Indomethacin (5 µM), baicalein (0.5 µM), and 17-octadecynoic acid (17-ODYA, 1 µM) were added to the bath to block the endogenous formation and metabolism of eicosanoids via the cyclooxygenase, lipoxygenase, and cytochrome P-450 pathways (1, 17). After the vessels were mounted and the inhibitors were added to the bath, a 30-min equilibration period was allowed before the cumulative dose-response curves were generated.
After the equilibration period, control inner diameter was measured and a cumulative dose-response curve was generated for each of the 20-HETE analogs (10Drugs and chemicals. All chemicals were of analytic grade. Indomethacin and AA were obtained from Sigma Chemicals. 5(S)-, 8(S)-, 12(S), and 15(S)-HETE, baicalein, and 17-ODYA were purchased from Biomol.
Statistics. Means ± SE are presented. The significance of the differences in mean values between and within groups was determined using an analysis of variance for repeated measures followed by a Duncan's multiple range test. P < 0.05 using a two-tailed test was considered to be significant.
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RESULTS |
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Effect of hydroxyl group position on the vasoconstrictor response to
20-HETE.
The vasoconstrictor responses to the 20-HETE derivatives are presented
in Fig. 2. 20-HETE
(108 to
10
6 M) reduced the diameter
of renal interlobular arteries in a concentration-dependent manner to
19 ± 3% of control (
4.3 ± 0.8 to
22.5 ± 1.5 µm, n = 7). The
threshold concentration of 20-HETE that reduced vascular diameter was
10 nM (P < 0.05). In
contrast, 5(S)-,
8(S)-,
12(S), 15(S), and
19(S)-HETE had no significant effect
on the diameter of renal interlobular arteries even at a concentration
as high as 1 µM (Fig. 2A).
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Importance of other structural features to the constrictor
response to 20-HETE.
The effects of altering the length of the carbon chain on the
vasoconstrictor response to 20-HETE are presented in Fig.
2B. 21-HETE and 20,20-dimethyl-20-HETE
were just as potent vasoconstrictors as 20-HETE. 21-HETE reduced vessel
diameter in a dose-dependent manner to a maximum of 17 ± 3% of
control (4.8 ± 0.9 to
21.1 ± 2.4 µm,
n = 6). Dimethyl-20-HETE reduced
vessel diameter to a maximum of 15 ± 2% of control (
4.2 ± 0.8 to
18.4 ± 1.2 µm, n = 6). In contrast, AA, which lacks a
hydroxyl group on the 20th carbon,
C19 analog, and 20-carboxy-AA had
no significant effect on vessel diameter. Similarly, the saturated
20-HETE derivative 20-HE, in which the double bonds were eliminated,
had no effect on vessel diameter (Fig.
2B). The partially saturated 20-HETE derivative
5(Z),14(Z)-20-HEDE,
in which two of the four double bonds were removed, was as potent a
constrictor as 20-HETE. The 5(Z),14(Z)-20-HEDE
produced a concentration-dependent fall in vascular diameter to a
maximum of 28 ± 2% of control (
6.4 ± 1.2 to
29.1 ± 0.7 µm, n = 3). Interestingly,
6(Z),15(Z)-20-HEDE
in which the positions of the hydroxy and carboxy groups on the 1st and
20th carbon are reversed, had no effect on vascular diameter (Fig.
2B).
Determinants of 20-HETE antagonist activity.
We also studied whether the inactive analogs of 20-HETE could serve as
antagonists of the vasoconstrictor response to 20-HETE. Concentration
response curves to 20-HETE were generated in isolated perfused renal
interlobular arteries before and after adding 0.5-1 µM of the
various inactive 20-HETE derivatives to the bath. Under control
conditions, 20-HETE (108 to
10
6 M) produce a
dose-dependent fall in vessel diameter to a maximum of 25.5 ± 4.4%
of control (
5.4 ± 0.9 to
20.6 ± 1.4 µm,
n = 9). Addition of
5(S)- (0.5 µM,
n = 5) or
15(S)-HETE (1 µM,
n = 5) to the bath completely blocked
the vasoconstrictor response to 20-HETE (Fig.
3A).
Similarly, addition of 19(S)-HETE
(n = 5, 1 µM), the
C19 analog (n = 5, 1 µM), or
6(Z),15(Z)-2-HEDE
(n = 3, 1 µM) to the bath, eliminated the
vasoconstrictor response to 20-HETE (Fig.
3B).
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DISCUSSION |
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The present study examined the effects of a series of 20-HETE analogs on the diameter of renal interlobular arteries to determine the structural requirements for the vasoconstrictor response to this compound. Our results indicate that AA, which differs from 20-HETE by the lack of a hydroxyl group on the 20th carbon, does not constrict renal interlobular arteries. Similarly, 5(S)-, 8(S)-, 12(S)-, 15(S)-, and 19(S)-HETE, in which the hydroxyl group is located on other carbons, have no effect on vascular diameter. Moreover, a C19 analog of 20-HETE, which is one carbon shorter, has no effect on vascular tone. In contrast, 21-HETE and dimethyl-20-HETE are just as potent constrictors as 20-HETE. These results indicate that the vasoconstrictor response to 20-HETE is critically dependent on the presence of a hydroxyl group on the 20th or 21st carbon.
We also examined the importance of double bonds to the vasoconstrictor response to 20-HETE analogs in renal arterioles. One could speculate that the interactions between the double bonds in the 20-HETE molecule might induce some secondary structure that is required for constrictor activity. Therefore, the vascular responses to saturated and partially saturated analogs of 20-HETE were compared with that of the native compound. We found that 20-HE, the saturated 20-HETE analog, had no effect on vascular tone, whereas the partially saturated analog 5(Z),14(Z)-20-HEDE with double bonds between the 5,6- and 14,15- carbons retained agonist activity. These findings indicate that these double bonds are an important structural requirement for the vasoconstrictor response to 20-HETE.
The most exciting finding of the present study is that analogs of 20-HETE that lack vasoconstrictor activity can serve as antagonists. In this regard, AA, 5(S)-, 15(S)-, 19(S)-HETE, and the C19 analog were all effective antagonists of the vasoconstrictor response to 20-HETE. We also found that there are predictable structural determinants of antagonist activity. Thus it appears that preserving the hydrophobic nature of 20-HETE is critical to retain antagonist activity. For example, molecules such as 12(S)- or 8(S)-HETE, which have a hydroxyl group near the head of the molecule, could not interact with the putative 20-HETE binding site and did not antagonize the vasoconstrictor response to 20-HETE. From these findings, one would predict that 11(S)- and 7(S)-HETE as well as 8,9- and 11,12-epoxyeicosatrienoic acid (8,9-EET and 11,12-EET) and dihydroxyeicosatrienoic acid (Di-HETEs) would probably be ineffective as 20-HETE antagonists.
We also found that the double bonds of the 20-HETE analogs influence
antagonist activity. In this regard, saturated
C19
(sC19 analog) and
C20 analogs of 20-HETE (20-HE)
were not as effective as the parent compounds in antagonizing the
vasoconstrictor response to 20-HETE. Similar to our findings with
20-HETE derivatives possessing agonist activity, we found that only one
pair of double bonds (between the 5,6- and 14,15- carbons) is required
to fully preserve antagonist activity. In this regard, the partially
saturated analog 6(Z),15(Z)-20-HEDE
completely blocked the vasoconstrictor response to 20-HETE. This
compound is particularly interesting since it might be more
biologically stable than the other analogs because removal of the
double bonds across the 8,9- and 11,12-carbons would block metabolism
of this compound by cyclooxygenase and lipoxygenase enzymes. Stability
of this compound could also be enhanced by adding an ionizable
sulfonimide group to the carboxyl group to block metabolism by
-oxidation and esterification. It is likely that addition of a
sulfonimide group would not alter the biological properties of this
compound since addition of this group does not alter the effects of
20-HETE, EETs, and mechanism-based inhibitors of the synthesis of
20-HETE (1, 10).
The present findings demonstrating the structural requirements for the vasoconstrictor actions of 20-HETE and the fact that closely related, inactive analogs serve as 20-HETE antagonists provide the first evidence for a 20-HETE receptor. The nature of this receptor or binding site, however, remains to be determined. Classic receptors are generally associated with the extracellular side of the membrane and are members of the seven or more transmembrane domain family of proteins. The effects of 20-HETE on K+ channel activity, vascular tone and growth, as well as sodium transport in renal tubules are associated with activation of protein kinase C and mitogen-activated protein kinase signal transduction cascades (4, 20, 29). However, there is also evidence that 20-HETE (30) and epoxyeicosatrienoic acids (14) can inhibit K+ channel activity in detached membrane patches, suggesting that they may act as intracellular lipid activators of various kinases rather than as a hormone or paracrine factor acting on an extracellular receptor.
In summary, the present structure activity studies suggest that 20-HETE
agonists and antagonists both require a carboxyl or other ionizable
group at one end of the molecule to serve as an anchor point with the
putative receptor or binding site. They also require a double bond at a
distance equal to 14 or 15 carbons from this carbon (the carboxyl or
ionizable group) capable of forming a bond to stabilize the
molecule in the acceptor site. A 20-HETE agonist also requires a
hydroxyl or other ionizable or functional group capable of hydrogen
bonding to interact with the receptor at a distance equivalent to 20 or
21 carbons from the ionizable group on the 1st carbon. A 20-HETE
antagonist has a similar structure as an agonist, but it lacks a
reactive group on the 20th or 21st carbon.
Perspectives
Recent studies have indicated that 20-HETE plays an important role as a second messenger in autoregulation of renal blood flow, tubuloglomerular feedback, renal sodium transport, pulmonary function, and the mitogenic and vasoconstrictor responses to numerous vasoactive hormones and growth factors (2, 6-8, 11, 13-18, 21-25, 29-34). The formation of cytochrome P-450 metabolites of AA is altered in genetic and experimental models of hypertension, diabetes, hepatorenal syndrome, and toxemia of pregnancy (6, 18, 22, 24-28). 20-HETE also contributes to the vasoconstrictor actions of angiotensin II, endothelin, and nitric oxide synthase inhibitors and the inhibitory effects of parathyroid hormone, dopamine, angiotensin II, bradykinin, endothelin, and vasopressin on sodium transport in the kidney (1, 2, 20, 23). Given the critical role of this substance in the regulation of renal and pulmonary function, vascular tone, and the control of arterial pressure, it is likely that stable 20-HETE antagonists and analogs may have therapeutic potential in the treatment of some of these diseases. At the very least, these analogs should provide researchers with important, new tools to investigate 20-HETE signaling pathways and the role of this substance in the control of renal and cardiovascular function. ![]() |
ACKNOWLEDGEMENTS |
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This work was support in part by the National Heart, Lung, and Blood Institute Grants HL-29587 and HL-36279. M. Alonso-Galicia was a recipient of a Post-Doctoral Fellowship from the National Kidney Foundation.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. J. Roman, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226-0509 (E-mail: rroman{at}mcw.edu).
Received 1 April 1999; accepted in final form 30 June 1999.
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