(Hypertension. 1996;27:1149-1152.)
© 1996 American Heart Association, Inc.
Articles |
Platelet Lipoxygenase in Spontaneously Hypertensive Rats
From the Institute of Endocrinology, Tel Aviv–Elias Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv (Israel) University.
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Abstract |
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Abstract We have previously reported that the nonselective lipoxygenase inhibitor phenidone is a potent hypotensive agent in the spontaneously hypertensive rat (SHR). In the present study, we examined the relationship between production of platelet 12-hydroxyeicosatetraenoic acid (12-HETE) and intra-arterial blood pressure in SHR and Wistar-Kyoto rats (WKY) using both a cross-sectional analysis and an acute pharmacological intervention. Basal generation rate of 12-HETE by platelets collected from the SHR was approximately 3.7-fold higher than in the WKY (0.86±0.24 versus 0.23±0.05 nmol/mL per 10 minutes, respectively; P<.01). Systolic arterial pressure was positively related to platelet 12-HETE formation rate when the entire rat population was considered (r=.70, P<.001). The specific 12-lipoxygenase inhibitor cinnamyl-3,4-dihydroxycyanocinnamate induced lowering of both arterial blood pressure and platelet 12-lipoxygenase activity in SHR. At 15 mg/kg, cinnamyl-3,4-dihydroxycyanocinnamate elicited a marked hypotensive effect in SHR but not in WKY. This reduction in arterial pressure was accompanied by an approximate 70% inhibition in platelet 12-HETE production rate. The return of high blood pressure to basal levels was associated with a significant rise in the production of platelet 12-HETE toward control values (baseline, 0.97±0.33 nmol/mL per 10 minutes; nadir of blood pressure, 0.19±0.03; resumption of basal pressure, 0.42±0.14). In contrast, captopril (15 mg/kg) induced a quantitatively similar decrease in blood pressure but had no effect on platelet 12-HETE generation rate. Thus, hypertension in SHR is linked to increased production rate of platelet 12-HETE. Acute blood pressure reduction attained during lipoxygenase inhibition but not by angiotensin converting enzyme inhibition leads to a concomitant reduction in the production of platelet 12-HETE. We speculate that since rat arterial tissue produces 12-HETE, increased 12-lipoxygenase activity in SHR may contribute to the maintenance of elevated arterial pressure in this strain.
Key Words: arachidonate 12-lipoxygenase • lipoxygenase • hydroxyeicosatetraenoic acids • rats, inbred SHR • blood pressure
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Introduction |
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We have previously reported that the nonselective LO blocker phenidone lowers arterial blood pressure in the SHR and two-kidney, one clip (2K1C) renovascular hypertensive rat but not in the volume-dependent, deoxycorticosterone acetate–salt hypertensive rat.1 2 Presumably, the mechanism underlying the hypotensive effect of LO inhibition in both SHR and 2K1C rats was increased LO activity. Increased 12-HETE production has been thus far demonstrated in the angiotensin II–dependent phase of 2K1C hypertension.2 This finding is consistent with reports that angiotensin II increases 12-LO activity in adrenal glomerulosa cells3 and cultured vascular smooth muscle cells.4 In the case of angiotensin II–induced aldosterone secretion, we provided evidence that 12-LO activation is an important mediator of steroidogenesis.3 In cultured smooth muscle cells5 and glomerulosa cells,6 12-HETE generation apparently contributes to the rise in cytosolic calcium observed during cell activation by angiotensin II by an as yet unexplored mechanism.
The pronounced hypotensive effect of LO inhibition in SHR strongly suggested that LO activity may be increased in this form of hypertension. However, direct proof for enhanced 12-LO activity in SHR has not yet been provided. In the present study, we examined 12-HETE production in platelets obtained from SHR and WKY. Additionally, we investigated the effects of the specific 12-LO inhibitor CDC7 on platelet 12-HETE generation and intra-arterial blood pressure. The results are consistent with the concept that increased 12-LO activity in SHR contributes to the maintenance of high blood pressure and renders rats with this form of genetically determined hypertension particularly susceptible to the hypotensive effect of LO blockade.
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Methods |
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Experimental Protocols
All experimental protocols were approved by the animal research committee of Elias Sourasky Tel Aviv Medical Center.
We used 12-week-old male SHR (mean weight, 257±11 g) and WKY (mean weight, 265±9 g) for this study. After 1 week of equilibration in our animal research facility, the rats were anesthetized with a phenobarbital solution (50 mg/kg body wt IP). The carotid artery was cannulated as previously described1 2 with polyethylene tubing (PE-50) via an incision in the ventral surface of the neck. The cannulas were filled with a solution containing 0.9% saline and 1000 U/mL heparin (Abbott Laboratories) and were passed under the skin laterally and posteriorly to emerge at the base of the neck. Intra-arterial pressure was measured directly 24 hours later via these catheters, which were connected to a pressure transducer (Statham P23 Db) and strain-gauge amplifier and recorder (TR 2000 N recorder, TSC-820 signal conditioner, Gulton). For the determination of platelet 12-LO activity, 3 mL of blood was rapidly collected into prechilled tubes containing acid citrate/dextrose anticoagulation solution at a ratio of 9 parts blood to 1 part anticoagulation solution. Intra-arterial blood pressure was continuously recorded as of 15 minutes before and up to 2 hours after drug administration. CDC dissolved in 0.2 mL dimethyl sulfoxide (or vehicle alone) was injected intraperitoneally at doses of 3 to 30 mg/kg (one dose per rat).
12-HETE Production in Platelets
To obtain platelet-rich plasma, we centrifuged
freshly collected blood at 200g for 20 minutes.
Platelet-rich plasma was aspirated and
recentrifuged at 500g for 15 minutes. Plasma was
then removed and the platelet pellet resuspended in a platelet
buffer containing (mmol/L) HEPES 10, NaCl 145, KCl 5, MgSO4
1, NaH2PO4 0.5, and dextrose 6, at pH 7.4
(37°C). One milliliter of the platelet solution was then
transferred to 1.5-mL microcentrifuge tubes and incubated
at 37°C for 10 minutes. 12-HETE generated under these conditions
reflects basal platelet 12-LO activity.1 Platelets
were removed by spinning in a microcentrifuge for 5
minutes. Plasma proteins were removed by the addition of 2 mL
acetonitrile, followed by pelleting the precipitated proteins by
centrifugation. For determination of circulating
12-HETE levels, ethanol was added to plasma (4:1 vol/vol), and 20
minutes later plasma proteins were precipitated by
centrifugation. The supernatant was acidified by the
addition of 450 µL glacial acetic acid and further diluted with 7 mL
water. Samples were subsequently loaded into Bond Elut C18
solid-phase extraction columns (Analytichem International) and
washed, and HETE fractions were eluted with 70%
acetonitrile/H2O. Samples were then lyophilized and
reconstituted in a 66% methanol/water solution for HPLC
analysis. The HPLC determination was modified from our
previously published methods.1 2 3 4 Extracted samples were
separated by reverse-phase HPLC with an HPLC system (Milton-Roy)
equipped with a C18 column (Shandon, Keystone Scientific; 3 µm, 15 cm
length). The chromatography solvent consisted of an
isocratic mobile phase containing 80% methanol, 19.15% water, 0.75%
acetic acid, and 0.1% triethylamine at 1 mL/min for 20 minutes.
Effluent was monitored at 247 nm with a Spectro-Monitor 3100 UV
detector (Milton-Roy). Data were quantified by integrating peak area
with standard curves generated under the same conditions. For further
validation of the HPLC determination, 12-HETE in extracted samples was
also measured by radioimmunoassay (Advanced Magnetics) as previously
described.2 3 Data are expressed as nanomoles of
12-HETE per milliliter of platelet-rich plasma per 10 minutes,
after adjustment for platelet number.
Results were assessed by Student's t test for single between-group comparisons or by ANOVA for the time course and dose-response curves. Results are expressed as mean±SE.
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Results |
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The platelet generation rate of 12-HETE in vitro was approximately 3.7-fold higher in SHR than WKY. Likewise, plasma 12-HETE, which represents predominantly 12-HETE released from circulating platelets, was also significantly higher in SHR (Fig 1
). Fig 2 depicts the relationship
between platelet 12-HETE production in vitro and
systolic pressure in SHR and WKY. Systolic pressure was
positively related to platelet 12-LO production in SHR
(r=.57, P<.02) but not in WKY. When the entire
rat population of WKY and SHR was pooled, there was an overall linear
correlation between platelet 12-LO activity and systolic
pressure (r=.70, P<.001, Fig 2).
Diastolic pressure was also positively related to
platelet 12-HETE generation when SHR and WKY were pooled
(r=.41, P<.02), although this correlation was
considerably weaker than the overall correlation of systolic
pressure with 12-HETE.
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) rat population represented in Fig 1
The administration of 3, 15, and 30 mg/kg CDC was associated with
approximately 30%, 70%, and 80% inhibition of platelet 12-HETE
generation in SHR and approximately 25%, 55%, and 80% inhibition in
WKY, respectively (Table). The effects of three doses of
the specific 12-LO inhibitor CDC on systolic
pressure in SHR and WKY are shown in Fig 3. In SHR, 15
and 30 mg/kg CDC elicited a marked hypotensive response. In fact, some
of the hypertensive rats became hypotensive (systolic pressure
<90 mm Hg) after the administration of 30 mg/kg CDC. In contrast, CDC
(15 mg/kg) had little effect on blood pressure in WKY, and only
the highest dose used (30 mg/kg) lowered blood pressure by 30±2 mm Hg
(n=6, P<.04). At this dose, however, the relative
hypotensive effect was similar to that observed in SHR.
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The relationship between the effect of CDC (15 mg/kg) on blood
pressure and its effects on platelet 12-HETE generation is shown in
Fig 4. In preliminary experiments,
intra-arterial pressure was recorded continuously
to establish the time course and range of the hypotensive effect. A
decrease in blood pressure was evident within 3 to 5 minutes, reaching
nadir levels by 10 to 12 minutes. A gradual increase in pressure was
recorded after 10 minutes at nadir levels, and in most rats blood
pressure returned to basal levels by 90 to 120 minutes. In the next set
of experiments, blood pressure was monitored continuously and blood
samples were collected at times determined by the recorded pressure
and the time course and response patterns established in the
preliminary experiments. To avoid sampling-related activation of
platelets, we collected only one blood sample per rat, ie, a sample
representing basal 12-HETE production, a sample for
the determination of 12-HETE generation rate during the lowest
pressure, or a sample obtained after the return of arterial
pressure to basal levels. In SHR receiving 15 mg/kg CDC, reduction of
arterial pressure was associated with a marked inhibition
of platelet 12-HETE generation rate. When blood pressure returned
to the initial levels, platelet 12-HETE generation rate rose
significantly toward the basal range. However, 12-HETE
production was still depressed compared with preinjection
activity. Although CDC at 15 mg/kg was also effective in reducing
platelet 12-LO activity in WKY, CDC did not affect
arterial pressure in the normotensive rats.
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To address the possibility that the reduction in arterial pressure per se led to decreased platelet 12-LO activity, we administered the converting enzyme inhibitor captopril (15 mg/kg) intraperitoneally to SHR. Systolic pressure declined from 187±11 to 145±12 mm Hg. However, in vitro platelet 12-HETE generation remained unaffected (basal, 347±45 ng/mL per 10 minutes; after captopril, 362±51; n=10 in each group).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In a previous communication we reported that the nonselective LO blocker phenidone acutely lowered blood pressure in SHR. Although phenidone also decreased blood pressure in the normotensive WKY, the hypotensive effect was much larger in SHR. Furthermore, chronic administration of phenidone attenuated the evolution of hypertension in SHR.1
In the present study, we demonstrate that platelet 12-HETE
production is considerably increased in SHR compared with WKY
and that SHR display greater sensitivity to the hypotensive effect of
the specific 12-LO inhibitor CDC. These results suggest
that increased 12-LO activity may contribute to the pathogenesis and/or
maintenance of elevated arterial blood pressure in
SHR. Observations in the present study that acute reduction in
platelet 12-HETE generation induced by CDC is associated with
lowering of intra-arterial blood pressure and that
resumption of hypertension is observed along with a significant
recovery in platelet 12-HETE production further reinforce a
putative role for an abnormally activated 12-LO system in
hypertension in SHR. Our study does not clarify why the 12-HETE
generation rate did not fully recover once arterial
pressure returned to preinjection levels. There may be differences in
enzyme kinetics and/or CDC clearance between platelets and the
arterial tissue. Also, a close examination of Fig 2
suggests that at a higher 12-HETE production rate, the
relationship between the generated HETE and blood pressure may be
weakened such that once a certain level has been exceeded, blood
pressure no longer correlates with the 12-HETE generation rate.
Finally, the possibility that CDC lowers arterial pressure
by additional unknown, LO-independent biological effects cannot be
excluded.
The results of the present study must be interpreted in the context of previously identified alterations in SHR platelets. Increased cytosolic calcium concentration under basal conditions and in response to agonists has been observed in SHR platelets8 9 10 as well as in platelets of human hypertensive patients.11 12 Similar observations in vascular smooth muscle cells of SHR13 14 have suggested that high intracellular calcium levels might reflect relative activation of the signal transduction cascade that contributes to the altered contractility in hypertension. This concept gained further support by recent reports of increased phospholipase C activity in platelets and vascular smooth muscle cells of SHR.15 16
Diacylglycerol, a product of phospholipase C activity, can be metabolized by diacylglycerol lipase, which releases arachidonic acid from its Sn position. Arachidonic acid thus formed may be rapidly oxidized via several metabolic routes, including the 12-LO pathway, resulting in the generation of 12-HETE. Indeed, it has been shown that inhibition of diacylglycerol lipase activity reduces 12-HETE formation.17 Thus, increased 12-LO activity in SHR may reflect increased substrate availability secondary to increased phospholipase C activity and/or constitutive overexpression of the 12-LO enzyme.
Despite some earlier disagreement as to whether HETEs can be produced by vascular smooth muscle cells, Natarajan et al4 have recently demonstrated the presence of leukocyte–type 12–LO protein and mRNA in porcine vascular smooth muscle cells. Products of the 12- and 15-LO pathways have been identified in coronary vessels and shown to be powerful constrictors of coronary arteries.18
The present study, which demonstrates both enhanced formation of 12-HETE in SHR platelets and a marked hypotensive effect of the 12-LO inhibitor CDC associated with a reduction in 12-HETE production, raises the possibility that increased 12-LO activity in SHR may be a feature shared by platelets and vascular smooth muscle cells. Indeed, Gesce et al19 reported that in arterial tissue obtained from SHR, arachidonate metabolism is gradually shifted from predominantly cyclooxygenase-dependent metabolism toward the LO pathway as hypertension evolves. However, no reference was made in that study to the specific vascular LO metabolite presumably increased in SHR. Thus, the hypothesis that 12-LO activity is increased in the arterial contractile cells in SHR, as it is in platelets, presently awaits direct proof.
In summary, the hypotensive effect of CDC in SHR is consistent with our previous report of the blood pressure–lowering effect of the nonselective LO inhibitor phenidone. That the hypotensive effect of CDC is seen in SHR that display enhanced formation of 12-HETE suggests a role for 12-LO in the maintenance of this form of hypertension. LO enzyme blockade provides a novel tool for manipulating vascular tone and blood pressure in experimental hypertension.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors wish to thank Rivka Morris for her expert assistance in the preparation of this manuscript.
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Footnotes |
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Reprint requests to N. Stern, MD, Institute of Endocrinology, Tel Aviv–Elias Sourasky Medical Center, Ichilov Hospital, 6 Weizman St, Tel-Aviv 64239, Israel.
Received October 4, 1995; first decision November 11, 1995; accepted December 27, 1995.
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References |
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