(Hypertension. 1996;28:64-75.)
© 1996 American Heart Association, Inc.
Articles |
Role of Prostaglandins in Acetylcholine-Induced Contraction of Aorta From Spontaneously Hypertensive and Wistar-Kyoto Rats
the Department of Pharmacology and Cell Biophysics and Veterans Affairs Medical Center, University of Cincinnati (Ohio) College of Medicine.
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Abstract |
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Evidence in support of prostaglandin (PG) H2 as the endothelium-derived contracting factor released in response to acetylcholine in vessels from adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) is to a large degree indirect. Therefore, the purpose of the present study was to test the hypothesis that a prostaglandin or prostaglandins other than PGH2 may serve as the endothelium-derived contracting factor that mediates acetylcholine-induced contraction in these vessels. Acetylcholine-induced contraction of endothelium-intact aorta from 7- to 12-month-old SHR and WKY in the presence of the nitric oxide synthase inhibitor N
-nitro-L-arginine was abolished by indomethacin and only partially decreased by the thromboxane (Tx) A2/PGH2 receptor antagonist SQ29548. Contraction induced by the TxA2/PGH2 receptor agonist U46619 was abolished by SQ29548. These findings suggest that in endothelium-intact aorta from SHR and WKY, acetylcholine causes the release of a cyclooxygenase product other than PGH2 that induces contraction independently of TxA2/PGH2 receptor activation. To investigate which prostaglandin or prostaglandins could be responsible for the TxA2/PGH2 receptor–independent component, we challenged endothelium-denuded aorta from SHR and WKY with various prostaglandins in the presence of SQ29548. In SQ29548-treated aorta from 7- to 12-month-old rats, maximal contractions to PGF2
, PGE2, and carbacyclin (a PGI2 analogue) were greater than the magnitude of acetylcholine-induced contraction. These findings suggest that PGF2, PGE2, and/or PGI2 could serve as mediators of the TxA2 receptor–independent component of the acetylcholine-induced contraction. However, in studies with SQ29548-treated aorta from 4- to 6-week-old SHR and WKY (an age at which acetylcholine-induced contraction is known to be absent), maximal contraction to PGF2 and PGE2 was also greater or equivalent to that of SQ29548-treated aorta from 7- to 12-month-old rats, whereas carbacyclin induced negligible contraction. Thus, unlike PGE2 and PGF2, the age-dependent pattern of contraction induced by carbacyclin closely resembles the pattern induced by acetylcholine. We also measured the levels of PGI2 released in response to acetylcholine and found that they are sufficient to account for the TxA2 receptor–independent component of the acetylcholine-induced contraction. Thus, we propose that PGI2 released in response to acetylcholine may serve as the endothelium-derived contracting factor that elicits the TxA2/PGH2 receptor–independent and -dependent components of the acetylcholine-induced contraction.
Key Words: aorta • endothelium-derived factor • receptors, thromboxane A2/prostaglandin H2 • prostaglandins • relaxation • rats, inbred SHR
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Introduction |
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An EDCF is released from aorta and other vessels of adult SHR and WKY.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Although it is clear that EDCF is a cyclooxygenase product, because EDCF-induced contraction is prevented by cyclooxygenase inhibitors,2 3 7 8 11 the identity of EDCF has not been established.
Some evidence suggests that PGH2 may serve as EDCF.15 However, the evidence is largely indirect. In SHR and WKY aorta, the most widely studied vessel with respect to EDCF, evidence that TxA2 is not EDCF includes the observations that acetylcholine- and ATP-induced contractions were not prevented by TxA2 synthase inhibitors.2 3 5 7 8 10 11 In addition, increased TxA2 release was not detected after exposure to acetylcholine.1 4 7 9
The exclusion of prostaglandins other than PGH2 as possible candidates for the EDCF released by acetylcholine/ATP in SHR and WKY aorta is supported by studies demonstrating that (1) TxA2/PGH2 receptor antagonists block acetylcholine- and ATP-induced contraction5 7 10 11 14 ; (2) PGE2, PGF2, and PGI2, which are released from the endothelium in response to acetylcholine, are much less potent than TxA2/PGH2 receptor agonists in the induction of TxA2/PGH2 receptor–mediated contraction2 7 ; (3) although acetylcholine contracted SHR but not WKY aorta, acetylcholine released similar amounts of PGE2, and PGF2, from the vessels; furthermore, PGE2 and PGF2 contracted both vessels1 2 ; and (4) tranylcypromine, a PGI2 synthase inhibitor,16 17 18 19 did not decrease acetylcholine- and ATP-induced contraction.2 3 7 8
Correlative evidence suggesting that PGH2 is the EDCF responsible for the acetylcholine-induced contraction consists of the following: (1) Similar time courses were observed in SHR aorta for acetylcholine- and PGH2-induced contraction and for the acetylcholine-induced release of 6-keto-PGF1, the stable breakdown product of PGI2.9 6-Keto-PGF1 has been considered an index of PGH2 formation.9 (2) The magnitudes of acetylcholine- and ATP-induced contraction, as well as the amounts of 6-keto-PGF1 release, were greater in aorta from SHR versus WKY and were greater in aorta from adult SHR and WKY versus young rats.1 3 5 6 8 10 11 14
More recently, it was reported that (1) a PGH synthase-1 inhibitor decreased acetylcholine-induced contraction of SHR aorta; (2) PGH synthase-1 expression was greater in endothelium-intact SHR aorta compared with WKY aorta; (3) the contractile potency of PGH2, but not of PGF2 or U46619, a TxA2/PGH2 receptor agonist, was greater in endothelium-intact SHR aorta compared with WKY aorta; and (4) acetylcholine released PGH2 from SHR but not WKY aorta.20 These results also support the suggestion that PGH2 may serve as EDCF but do not eliminate the possible involvement of other prostaglandins. Thus, the present study tests the hypothesis that prostaglandins other than or in addition to PGH2 may serve as possible EDCF mediators of the acetylcholine-induced contraction in SHR and WKY aorta.
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Methods |
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Contractility
Young (4- to 6-week-old [4-6 wk]), young adult (12- to 15-week-old [12-15 wk]), adult (7- to 12-month-old [7-12 mo]), and aged (18- to 23-month-old [18-23 mo]) male SHR, WKY, and Fischer 344 rats (Harlan Sprague Dawley, Indianapolis, Ind, unless specified Charles River Laboratories, Boston, Mass; approximately 25 of each species aged 4-6 wk, 12-15 wk, and 7-10 mo and approximately 10 of each species aged 18-23 mo) were asphyxiated with CO2, and the thoracic aorta was removed, cleaned of extraneous fatty tissue, and cut into helical strips. The endothelium remained intact in tissues exposed to acetylcholine or U46619, but it was removed in tissues exposed to prostaglandin.21
Each strip was mounted under optimal resting tension (5, 10, and 15 mN for aorta from 4-6 wk, 12-15 wk and 7-12 mo, and 18-23 mo rats, respectively) in organ baths containing Krebs-Ringer bicarbonate solution at 37°C. The Krebs-Ringer bicarbonate solution was gassed with 95% O2/5% CO2 and had the following composition (mmol/L): NaCl 118.5, KCl 4.74, MgSO4 1.18, KH2PO4 1.18, CaCl2 2.5, NaHCO3 24.9, glucose 10, and EDTA 0.03. Tissue was allowed to equilibrate for at least 1 hour before drug addition. Tissue was exposed to the cyclooxygenase inhibitor indomethacin (3 or 10 µmol/L), the TxA2/PGH2 receptor antagonist SQ29548 (1 or 10 µmol/L), or the NO synthase inhibitor L-NNA (0.3 or 1 mmol/L) for at least 30, 15, and 60 minutes, respectively, before agonist. In carbacyclin (a stable PGI2 analogue) relaxation experiments, aorta was precontracted with an approximate 80% effective norepinephrine concentration (EC80).
PGI2 Release
For quantification of PGI2 release, aorta from 7-12 mo SHR and WKY was preincubated for 1 hour in Krebs-Ringer bicarbonate solution (gassed with 95% O2/5% CO2; 37°C) and then transferred to Krebs-Ringer bicarbonate solution in the presence of the PGI2 synthase inhibitor tranylcypromine (0.1 mmol/L) or vehicle. Tissue was allowed to incubate for an additional 30 minutes before addition of 1 µmol/L acetylcholine. Aliquots (0.1 mL) of the Krebs-Ringer bicarbonate solution were removed after 30 minutes, and the amount of 6-keto-PGF1 in the aliquot was determined by radioimmunoassay as previously described.22 23
Blood Pressure
Systolic pressure was measured by the tail-cuff method and was determined as the average of three separate measurements. Blood pressures of some rats were not measured.
Statistics
Differences between multiple means were analyzed with ANOVA followed by the Newman-Keuls test. Significance was accepted at the .05 level of probability. Shown are means±SE.
In vessels contracted with prostaglandin in the absence of SQ29548, values of maximal contraction (Emax) and 50% effective concentration (EC50) were derived with an iterative nonlinear least-squares program (Allfit),24 and geometric means of the EC50 values (pD2) were compared. In vessels contracted with prostaglandin in the presence of SQ29548, it was difficult to accurately estimate Emax and pD2 values. These difficulties included the following: (1) WKY and Fischer rat aorta showed a relatively small contraction; (2) in aorta from young SHR and WKY, low prostaglandin concentrations induced transient contractions of a magnitude near the maximal plateau contraction to the prostaglandin in the presence of SQ29548; and (3) the concentration-contraction curves did not all fit accurately. Therefore, Emax and not pD2 values are reported for vessels contracted with prostaglandin in the presence of SQ29548. Furthermore, the Emax values reported are the contractile response elicited by the highest prostaglandin concentration tested in the presence of SQ29548.
Materials
Reagent sources were as follows: acetylcholine chloride, indomethacin, L-NNA, l-norepinephrine-HCl, and tranylcypromine hydrochloride were from Sigma Chemical Co; prostaglandins were from Cayman Chemical Co; and [5,8,9,11,12,14,15-3H(N)]6-keto-PGF1 (210.0 Ci/mmol) was from DuPont–New England Nuclear. U46619 and carbacyclin were gifts from Upjohn, and SQ29548 was a gift from Bristol-Myers Squibb.
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Blood Pressure
Systolic pressures of 4-6 wk SHR, WKY, and Fischer rats did not differ significantly (Fig 1
). At 12-15 wk, SHR blood pressure was greatly elevated, whereas Fischer rat blood pressure was elevated to a much smaller magnitude and WKY blood pressure remained unchanged. SHR, WKY, and Fischer rat blood pressures tended to decrease with aging (18-23 mo), although only the decrease in WKY blood pressure was significant.
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P<.05 vs all other WKY groups; 
P<.05 vs 12-15 wk Fischer; §P<.05 vs 12-15 wk WKY and Fischer; ||P<.05 vs 7-12 mo WKY and Fischer; ¶P<.05 vs 18-23 mo WKY and Fischer.
Acetylcholine Contraction
Acetylcholine (10 µmol/L) in the presence of 0.3 mmol/L L-NNA and 1 to 3 nmol/L norepinephrine contracted endothelium-intact aorta from 7-12 mo SHR obtained from Harlan Sprague Dawley (Fig 2a and 2c). Indomethacin abolished the acetylcholine-induced contraction (Fig 2e), as did endothelium removal (data not shown). SQ29548 partially decreased the acetylcholine-induced contraction and abolished the U46619-induced contraction (Fig 2b and 2d). We previously demonstrated that SQ29548 abolished PGH2-induced contraction of aorta from Sprague-Dawley rats.21
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Acetylcholine (10 µmol/L) in the presence of 0.3 mmol/L L-NNA and 1 to 2 nmol/L norepinephrine also contracted endothelium-intact aorta from 7-12 mo SHR obtained from Charles River Laboratories (Fig 3a and 3c). SQ29548 partially decreased the acetylcholine-induced contraction and abolished the U46619-induced contraction (Fig 3b and 3d).
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Acetylcholine (10 µmol/L) in the presence of 0.3 mmol/L L-NNA and 2 nmol/L norepinephrine also contracted endothelium-intact aorta from 7-12 mo WKY (Fig 4). The magnitude of contraction in WKY aorta was generally less than that of SHR aorta. The acetylcholine-induced contraction was completely inhibited by indomethacin and partially inhibited by SQ29548 (Fig 4). U46619-induced contraction was abolished by SQ29548 (Fig 4).
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Endothelium-intact aorta from 7-12 mo Fischer rats in the presence of 0.3 mmol/L L-NNA and 1 to 5 nmol/L norepinephrine contracted only slightly in response to 10 µmol/L acetylcholine (Fig 5). Indomethacin and SQ29548 abolished the acetylcholine-induced contraction (Fig 5).
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In contrast to the acetylcholine-induced contraction of aorta from 7-12 mo SHR, 10 µmol/L acetylcholine in the presence of 0.3 or 1 mmol/L L-NNA and 10 nmol/L norepinephrine relaxed endothelium-intact aorta from 4-6 wk SHR (Fig 6; data with 0.3 mmol/L L-NNA not shown). The acetylcholine-induced relaxation was still present in aorta exposed to 10 µmol/L indomethacin (Fig 6). These results suggest that acetylcholine may induce relaxation of aorta from 4-6 wk SHR through the release of a non–cyclooxygenase-dependent relaxing factor, such as EDHF (see "Discussion").
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Prostaglandin Contraction in the Presence of SQ29548
To identify which prostaglandins released from SHR and WKY aorta in response to acetylcholine (PGF2, PGE2, and PGI21 5 7 ) could be responsible for the acetylcholine-induced contraction in the presence of SQ29548 (Figs 2 through 4
), we tested whether the magnitude of PGF2-, PGE2-, or carbacyclin-induced contraction in the presence of SQ29548 was (1) at least equivalent to that induced by acetylcholine in the presence of SQ29548, (2) greater in aorta from 7-12 mo SHR compared with aorta from 7-12 mo WKY, (3) greater in aorta from older compared to younger SHR and WKY, and (4) not greater in aorta from older compared with younger Fischer rats (negative control).
PGF2
Maximal PGF2 contraction of SHR aorta decreased with rat age (Figs 7A and 8A). Maximal PGF2 contraction of aorta from 4-6 wk, 12-15 wk, 7-12 mo, and 18-23 mo SHR was 100%, 50%, 50%, and 30%, respectively, of the contraction with 0.3 µmol/L norepinephrine. In contrast, maximal PGF2 contraction of WKY aorta did not change significantly with rat age (Figs 7A and 8A). Maximal PGF2 contraction of WKY aorta was significantly less than that of SHR aorta and was approximately 10% of the contraction with 0.3 µmol/L norepinephrine. Fischer rat aorta contracted 1% or less of the contraction with 0.3 µmol/L norepinephrine in response to PGF2 (Figs 7A and 8A).
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PGE2
Maximal PGE2 contraction of aorta from 4-6 wk, 12-15 wk, and 7-12 mo SHR was not significantly different and was approximately 50% to 60% of the contraction with 0.3 µmol/L norepinephrine (Figs 7B and 8B). Maximal PGE2 contraction of aorta from 18-23 mo SHR tended to be less than that of aorta from younger SHR (30% of the contraction with 0.3 µmol/L norepinephrine), although the decrease was not significant. In WKY aorta, maximal PGE2 contraction changed relatively little with rat age (Figs 7B and 8B). Maximal PGE2 contraction of WKY aorta was significantly less than that of aorta from age-matched SHR and ranged between 10% and 20% of the contraction with 0.3 µmol/L norepinephrine. Fischer rat aorta contracted less than 5% of the contraction with 0.3 µmol/L norepinephrine in response to PGE2 (Figs 7B and 8B).
Carbacyclin
The relationship between maximal carbacyclin contraction of SHR aorta and rat age was strikingly different from the relationships observed with PGF2 and PGE2. Carbacyclin induced only 10% of the contraction with 0.3 µmol/L norepinephrine in aorta from 4-6 wk SHR, whereas it contracted aorta from 12-15 wk and 7-12 mo SHR to 30% and 50%, respectively, of the contraction with 0.3 µmol/L contraction (Figs 7C and 8C). Maximal carbacyclin contraction of aorta from 18-23 mo SHR was only 7% of the contraction with 0.3 µmol/L norepinephrine.
In contrast to the greater maximal carbacyclin contraction of aorta from 12-15 wk and 7-12 mo SHR compared with aorta from 4-6 wk SHR, maximal carbacyclin contractions of aorta from 4-6 wk, 12-15 wk, and 7-12 mo WKY did not differ significantly (Figs 7C and 8C). Furthermore, maximal carbacyclin contraction of aorta from 12-15 wk and 7-12 mo WKY (10% and 20% of the contraction with 0.3 µmol/L norepinephrine, respectively) was significantly less than that of aorta from age-matched SHR.
Fischer rat aorta contracted less than 2% of the contraction with 0.3 µmol/L norepinephrine in response to carbacyclin (Figs 7C and 8C).
Carbacyclin Relaxation
To test whether the apparent increased maximal contraction to carbacyclin in the presence of SQ29548 of aorta from 12-15 wk and 7-12 mo SHR (Figs 7C and 8C) was actually due to decreased carbacyclin relaxation,21 we investigated whether carbacyclin relaxation in the presence of SQ29548 was decreased in aorta from older compared with younger SHR and WKY. As a negative control, we investigated whether these changes also occurred in Fischer rat aorta.
Absence of SQ29548
In aorta from 4-6 wk SHR, 0.3 µmol/L carbacyclin induced a small amount of relaxation, and higher concentrations reversed the relaxation and further contracted the tissue (Fig 9). In aorta from older SHR, the relaxation response was absent, and only concentration-dependent contraction was observed. In aorta from 4-6 wk and 12-15 wk WKY, carbacyclin elicited a clear biphasic response: concentration-dependent relaxation at carbacyclin concentrations less than 3 µmol/L, and reversal of the relaxation at higher carbacyclin concentrations (Fig 9). In aorta from 7-12 mo and 18-23 mo WKY, the relaxation response was absent, and only concentration-dependent contraction was observed. Aorta from Fischer rats of all age groups responded biphasically to carbacyclin: concentration-dependent relaxation at carbacyclin concentrations less than 3 µmol/L, and reversal of the relaxation at higher carbacyclin concentrations (Fig 9).
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Presence of SQ29548
In aorta from 4-6 wk SHR, WKY, and Fischer rats, the carbacyclin contraction observed in the absence of SQ29548 was reversed to relaxation in the presence of SQ29548 (Fig 9 and Table 1). Maximal relaxation and sensitivity to carbacyclin were not significantly different in aorta from 4-6 wk SHR, WKY, and Fischer rats. In contrast to the relaxant effect of carbacyclin in aorta from 4-6 wk SHR, carbacyclin had no effect on aorta from 12-15 wk SHR (Fig 9 and Table 1). Maximal relaxation and sensitivity to carbacyclin in aorta from 12-15 wk WKY and Fischer rats were not significantly different from values in aorta from 4-6 wk SHR, WKY, and Fischer rats. In aorta from 7-12 mo SHR, carbacyclin elicited a small amount of contraction (Fig 9 and Table 1). Carbacyclin also contracted aorta from 8-9 mo SHR obtained from Charles River Laboratories (data not shown). Carbacyclin had no effect on aorta from 7-12 mo WKY.
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The sensitivity of aorta from 7-12 mo Fischer rats was not significantly different from the sensitivity of aorta from 4-6 wk and 12-15 wk Fischer rats, whereas maximal carbacyclin relaxation was decreased by 20% compared with aorta from 4-6 wk and 12-15 wk Fischer rats (Fig 9 and Table 1).
In aorta from 18-23 mo SHR, carbacyclin elicited a small amount of contraction (Fig 9 and Table 1). Carbacyclin had no effect on aorta from 18-23 mo WKY. The sensitivity of aorta from 18-23 mo Fischer rats was threefold less than that of aorta from 4-6 wk, 12-15 wk, and 7-12 mo Fischer rats. Maximal carbacyclin relaxation of aorta from 18-23 mo Fischer rats was not significantly different from maximal relaxation of aorta from 7-12 mo Fischer rats and was almost twofold less than maximal relaxation of aorta from 4-6 wk and 12-15 wk Fischer rats.
Prostaglandin Contraction in the Absence of SQ29548
Since concentrations of PGF2, PGE2, and carbacyclin in the micromolar range elicited contractions of the magnitude caused by acetylcholine in the presence of SQ29548 (compare Figs 2 through 4 with Fig 7), we investigated whether micromolar concentrations of the prostaglandins could also account for the magnitude of acetylcholine-induced contraction in the absence of SQ29548.
PGF2
Maximal PGF2 contraction of aorta from all age groups of SHR, WKY, and Fischer rats ranged between 100% and 150% of the contraction with 0.3 µmol/L norepinephrine (Figs 7A and 10A).
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The PGF2 sensitivity of aorta from 4-6 wk SHR, WKY, and Fischer rats was greater than the PGF2 sensitivity of aorta from 12-15 wk, 7-12 mo, and 18-23 mo rats of the respective strains (Figs 7A and 10A, Table 2). In aorta from 4-6 wk SHR, the PGF2 EC50 was 0.08 µmol/L, whereas PGF2 EC50 values in aorta from 12-15 wk, 7-12 mo, and 18-23 mo SHR were 0.21, 1.2, and 2.4 µmol/L, respectively (Fig 10A, Table 2). In aorta from 4-6 wk WKY and Fischer rats, the PGF2 EC50 values were 0.23 and 1.0 µmol/L, respectively, and the EC50 values of aorta from 12-15 wk, 7-12 mo, and 18-23 mo WKY and Fischer rats ranged from 1.1 to 5.8 µmol/L (Fig 10A, Table 2).
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PGE2
Maximal PGE2 contraction of aorta from all age groups of SHR, WKY, and Fischer rats ranged between 100 and 160% of the contraction with 0.3 µmol/L norepinephrine (Figs 7B and 10B).
The PGE2 sensitivity of aorta from 4-6 wk and 12-15 wk SHR was fourfold greater than the PGE2 sensitivity of aorta from 7-12 mo SHR (EC50=1.0, 0.8, and 3.5 µmol/L, respectively; Figs 7B and 10B; Table 2). The PGE2 sensitivities of aorta from 7-12 mo and 18-23 mo SHR, and from all age groups of WKY and Fischer rats, were similar (EC50 range=1.6-7.2 µmol/L; Figs 7B and 10B; Table 2).
Carbacyclin
Maximal carbacyclin contractions of aorta from all age groups of SHR and WKY, and from 4-6 wk and 18-23 mo Fischer rats, ranged between 50 and 110% of the contraction with 0.3 µmol/L norepinephrine (Figs 7C and 10C). In contrast, maximal carbacyclin contraction of aorta from 12-15 wk and 7-12 mo Fischer rats was 20% of the contraction with 0.3 µmol/L norepinephrine.
The carbacyclin sensitivities of aorta from all age groups of SHR and WKY were similar (EC50 range=1.4-4.3 µmol/L; Figs 7C and 10C; Table 2). In contrast, the carbacyclin sensitivity of aorta from 4-6 wk Fischer rats (EC50=9.1 µmol/L; Table 2) was less than that of aorta from SHR and WKY.
Tranylcypromine
To further test the possible involvement of PGI2 in the acetylcholine-induced contraction, we attempted to investigate whether tranylcypromine, a PGI2 synthase inhibitor,16 17 18 19 decreased the acetylcholine-induced contraction. We used 0.1 mmol/L tranylcypromine because this was the concentration other researchers used to investigate the potential role of PGI2 in acetylcholine-induced contraction of SHR and WKY aorta.2 3 7 However, control experiments demonstrated that 0.1 mmol/L tranylcypromine inhibited norepinephrine-induced contraction and potentiated carbacyclin-induced contraction elicited in the presence of 10 µmol/L SQ29548 in deendothelialized aorta from 7-9 mo SHR (Fig 11). Tranylcypromine (0.1 mmol/L) slightly increased basal tone (data not shown).
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We then tested whether 0.1 mmol/L tranylcypromine decreased the amount of acetylcholine-induced PGI2 release. Tranylcypromine did not alter 1 µmol/L acetylcholine-induced or basal PGI2 (6-keto-PGF1) release from endothelium-intact aorta from 7-12 mo SHR and WKY (Fig 12). Acetylcholine-induced PGI2 release from SHR aorta was greater than from WKY aorta and was approximately threefold and twofold greater than basal release, respectively. Basal PGI2 release was greater in SHR aorta compared with WKY aorta.
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Discussion |
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This study suggests that acetylcholine-induced contraction of 7-12 mo SHR and WKY aorta is composed of two components: one resulting from activation of the TxA2/PGH2 receptor and the other from activation of an additional prostaglandin receptor or receptors (Fig 13
). This suggestion is based on the observations that in the presence of an NO synthase inhibitor, the cyclooxygenase inhibitor indomethacin abolished the acetylcholine-induced contraction, whereas the TxA2/PGH2 receptor antagonist SQ29548 only partially inhibited the contraction.
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In contrast to the present results, Satake's group (Ito et al9 and Iwama et al10 ) demonstrated that a TxA2/PGH2 receptor antagonist prevented acetylcholine-induced contraction of SHR and WKY aorta exposed to an NO synthase inhibitor. These previous results9 10 would suggest that acetylcholine-induced contraction is entirely due to TxA2/PGH2 receptor activation and thus are consistent with the proposal that PGH2 may mediate the contraction.15 Although the explanation for these contrasting results cannot be deduced from the present study, differences in methodology, including the use of different TxA2/PGH2 receptor antagonists and NO synthase inhibitors as well as the presence of norepinephrine (1 to 3 nmol/L)–induced tone during the acetylcholine challenge (present study), may account for the contrasting observations. It should be noted, however, that a small TxA2/PGH2 receptor–independent component of acetylcholine-induced contraction was apparently observed in the presence of an NO synthase inhibitor in resting aorta from 12-14 wk SHR, although this observation was not discussed.14 More recently, a small but significant acetylcholine-induced contraction was observed in the presence of a TxA2/PGH2 receptor antagonist and an NO synthase inhibitor in resting mesenteric resistance arteries from 74-week-old SHR25 and in the presence of a TxA2/PGH2 receptor antagonist in resting aorta from NO synthase inhibitor–induced hypertensive rats.26
It is difficult to obtain direct evidence as to the identity of the prostaglandin or prostaglandins responsible for the TxA2/PGH2 receptor–independent component of the acetylcholine-induced contraction because of the lack of selective prostaglandin synthase inhibitors and receptor antagonists.27 Potential candidates for the prostaglandins mediating the TxA2/PGH2 receptor–independent component of contraction include PGF2, PGE2, and PGI2, as these prostaglandins are released from SHR and WKY aorta in response to acetylcholine (see References 1, 5, and 7 and the present results).
PGF2 and PGE2
The possibility that PGF2 and/or PGE2 may mediate the TxA2 receptor–independent component of the acetylcholine-induced contraction is supported by the following observations, all seen in the presence of SQ29548: (1) The magnitude of PGF2- and PGE2-induced contraction can account for the magnitude of acetylcholine-induced contraction in aorta from 7-12 mo SHR and WKY; (2) the magnitude of PGF2- and PGE2-induced contraction of aorta from 7-12 mo SHR was greater than that of aorta from 7-12 mo WKY, which was the pattern of contraction elicited by acetylcholine; and (3) PGE2 and PGF2 did not contract Fischer rat aorta, a vessel that did not contract in response to acetylcholine.
However, the lack of correlation between rat age and acetylcholine-induced contraction, as well as the reported pattern of PGF2/PGE2 release from the aorta,28 suggests that neither PGF2 nor PGE2 could serve as the EDCF mediator of the TxA2/PGH2 receptor–independent component of the acetylcholine-induced contraction.
Nonetheless, it should also be considered that the apparent lack of correlation between rat age and acetylcholine-induced contraction of and PGF2/PGE2 release from the aorta may have resulted from acetylcholine-induced release of a relaxant factor not dependent on cyclooxygenase or NO synthase activity in aorta from young rats. In this regard, we demonstrated that acetylcholine relaxed endothelium-intact aorta from young SHR in the presence of L-NNA and indomethacin. It is likely that this factor is EDHF, as EDHF is released from rat aorta in response to acetylcholine.29 30 31 Furthermore, the relaxant effects of EDHF are decreased in mesenteric artery from SHR compared with that from WKY and are decreased with SHR and WKY age.32 33 34 Thus, the exclusion of PGF2 and PGE2 as EDCF requires the elimination of EDHF-induced relaxation as well as the development of selective prostaglandin synthesis inhibitors and receptor antagonists.
PGI2
We also considered that PGI2 may mediate the TxA2 receptor–independent component of the acetylcholine-induced contraction. This suggestion is supported by correlative relationships between rat age, acetylcholine- and carbacyclin-induced contraction in the presence of SQ29548, and PGI2 release from the aorta: (1) Carbacyclin and acetylcholine did not elicit contraction in aorta from young SHR, whereas significant contraction was observed in aorta from adult SHR. In addition, contractions to carbacyclin and acetylcholine in aorta from adult SHR were greater than those in aorta from age-matched WKY. The differences in carbacyclin contractility most likely reflect both decreased carbacyclin relaxant efficacy with SHR and WKY age and weaker contractile efficacy of carbacyclin in WKY aorta compared with SHR aorta. In this regard, the present results represent the first demonstration, to our knowledge, of decreased PGI2-induced relaxation in the vasculature of SHR and WKY with maturation and aging. (2) The capacity for PGI2 release increases with rat age, as arachidonic acid–induced PGI2 release increased from aorta of young (prehypertensive) through mature SHR and WKY.28 35 36 Furthermore, arachidonic acid– and acetylcholine-induced PGI2 release from SHR aorta was greater than from WKY aorta (see References 5, 10, 28, 35, and the present results; although also see Reference 1).
In apparent conflict with our suggestion that PGI2 mediates the TxA2 receptor–independent component of the acetylcholine-induced contraction are reports that 0.1 mmol/L tranylcypromine, a PGI2 synthase inhibitor,16 17 18 19 did not inhibit acetylcholine-induced contraction of SHR and WKY aorta.2 3 7 However, the present study demonstrated that 0.1 mmol/L tranylcypromine did not inhibit acetylcholine-induced PGI2 release from aorta of adult SHR and WKY. The inability of 0.1 mmol/L tranylcypromine to inhibit acetylcholine-induced PGI2 release is consistent with the reported IC50 of 1.0 mmol/L for inhibition of PGX (PGI2) synthase in rabbit aorta microsomes.17 Furthermore, the only reports of tranylcypromine inhibition of PGI2 release demonstrated that 1.0 mmol/L tranylcypromine inhibited arachidonic acid–induced PGI2 release in rabbit mesenteric artery19 and 0.6 mmol/L tranylcypromine inhibited mechanical stimulation–induced PGI2 release in cultured human pulmonary artery cells.18 Tranylcypromine concentrations greater than 0.1 mmol/L were not presently studied because of the 0.1 mmol/L tranylcypromine–induced relaxation of the norepinephrine contraction (see also References 8 and 19) and potentiation of the carbacyclin contraction (present results).
For PGI2 to serve as the EDCF that mediates the TxA2 receptor–independent component of the acetylcholine-induced contraction, the local PGI2 concentration after acetylcholine exposure must be great enough to account for the observed contraction. A concentration of PGI2 in the micromolar range would be required, as micromolar concentrations of carbacyclin were required to elicit a magnitude of contraction similar to the one caused by acetylcholine in SHR and WKY aorta in the presence of SQ29548.
Although it is difficult to determine the local PGI2 concentration after acetylcholine exposure, the concentration can be approximated on the basis of our recent study in which the local PGI2 concentration achieved after exposure of the rat aorta to phorbol myristate acetate (0.1 to 1 µmol/L) was estimated to be in the micromolar range.37 This estimate corresponded to the release of approximately 280 pg 6-keto-PGF1/mg dry wt aorta per minute.37 Thus, since (1) 30-minute exposure of SHR and WKY aorta to 1 µmol/L acetylcholine released approximately 75 and 25 pg 6-keto-PGF1/mg dry wt aorta per minute, respectively (present results), and (2) acetylcholine release of 6-keto-PGF1 from SHR aorta occurred over a 7-minute period,9 the local PGI2 concentration achieved after 1 µmol/L acetylcholine would likely be in the micromolar range. Furthermore, 10 µmol/L acetylcholine, the concentration presently shown to elicit contraction in the presence of SQ29548, would presumably result in an even greater local PGI2 concentration. These results would also suggest that PGI2 may serve as mediator of the TxA2/PGH2 receptor–independent contraction induced by acetylcholine in aorta from SHR and WKY.
Working Model
As shown in the working model of Fig 13, we speculate that in aorta from young SHR and WKY, PGI2 released in response to a high acetylcholine concentration fully activates the PGI2 receptor and only partially activates the TxA2/PGH2 receptor and an additional prostaglandin receptor or receptors, such as the PGF2 and/or PGE2 receptor. In this regard, we demonstrated that PGI2 has a relatively low affinity for the TxA2/PGH2 receptor.21 Thus, the relaxation observed after acetylcholine in aorta from young SHR and WKY may represent PGI2-induced maximal relaxation mediated through the PGI2 receptor, with possible minimal involvement of PGI2-induced contraction mediated through the TxA2/PGH2 and PGF2/PGE2 receptors. The role of EDHF-mediated relaxation in the acetylcholine-induced relaxation of aorta from young rats also needs to be considered (see above).
Fig 13 also illustrates the possible events leading to the acetylcholine-induced contraction observed in aorta from adult SHR and WKY. In these vessels, the amount of PGI2 released in response to a high acetylcholine concentration may be greater than 10-fold that released from aorta of young rats.28 35 36 The released PGI2, however, does not induce relaxation, possibly because of the absence of PGI2 receptor and/or a lesion postreceptor activation. In contrast, the greater release of PGI2 would result in activation of the TxA2/PGH2 receptor and an additional prostaglandin receptor or receptors, such as the PGF2/PGE2 receptors, to a greater extent than in aorta from young rats. Thus, the contraction observed after acetylcholine in aorta from adult versus young SHR and WKY could result from both greater activation of the TxA2/PGH2 and PGF2/PGE2 receptors, which are coupled to contraction, and loss of PGI2 receptor–mediated relaxation.
In addition, in the presence of TxA2/PGH2 receptor blockade, acetylcholine induced a greater magnitude of contraction in aorta from adult SHR compared with that from WKY. This difference can be explained by increased acetylcholine-induced release of PGI2 and the greater contractile efficacy of PGF2 and PGE2 in aorta from adult SHR versus WKY.
Conclusion
The present results suggest that acetylcholine-induced contraction of SHR and WKY aorta can be mediated at least in part or possibly entirely by a prostaglandin other than PGH2. Furthermore, although the identity of the prostaglandin or prostaglandins is not known, the contractile effects of PGI2 are consistent with the characteristics of the EDCF contraction. The potential role of PGI2 in EDCF contraction of SHR and WKY aorta, as well as other blood vessels and in additional pathophysiological models, needs to be considered further. However, it is also important to keep the present observations in perspective given the relative lack of evidence in support of a major role for the local production of prostaglandins in blood pressure regulation.38
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a VA Merit Review Award. Thanks to Anita K. Campbell, Gerald Frank, Darren Hurst, Charlotte Mayfield, and Gilbert A. Newman for technical support; Dr Leslie Myatt for the antibody against 6-keto-PGF1
; Rita Eveleigh for manuscript preparation; and Dr Carl Johnson for helpful discussion. |
Footnotes |
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Reprint requests to Robert M. Rapoport, PhD, Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Bethesda Ave, PO Box 670575, Cincinnati, OH 45267-0575.
Received June 23, 1995;
first decision February 27, 1996;
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References |
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