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(Hypertension. 1998;31:194.)
© 1998 American Heart Association, Inc.

Arthur C. Corcoran Memorial Lecture

The Role of Eicosanoids in Angiotensin-Dependent Hypertension

Alberto Nasjletti, MD

From the Department of Pharmacology, New York Medical College, Valhalla, New York, NY.

Correspondence to Alberto Nasjletti, MD, Department of Pharmacology, New York Medical College, Valhalla, NY 10595

	Abstract

Top Abstract Introduction Vascular and Renal Eicosanoids:... Influence of Cyclooxygenase- and... Cyclooxygenase-Derived... Lipoxygenase-Derived Eicosanoids Vascular and Renal Eicosanoids... Contribution of Cyclooxygenase... Summary and Conclusions References

 
Many eicosanoids produced in vascular and renal structures are endowed with the ability to influence vascular and renal mechanisms of blood pressure regulation. Eicosanoids subserve both prohypertensive and antihypertensive mechanisms. The development of angiotensin-dependent hypertension in rats is accompanied by increased vascular production of thromboxane A₂ (TXA₂) and of lipoxygenase-derived products with the ability to inhibit prostacyclin synthase. As a result of these abnormalities, the activity of pressor mechanisms mediated by TXA₂ and/or prostaglandin (PG) H₂ is increased. The cancellation of TXA₂- and/or of PGH₂-mediated pressor mechanisms, after treatment with thromboxane synthase inhibitors or TXA₂/PGH₂ receptor blockers, lowers blood pressure in rats with angiotensin-dependent hypertension. Inhibitors of lipoxygenase also lower blood pressure in such animals, in part by decreasing the synthesis of lipoxygenase-derived inhibitors of prostacyclin synthase. Thus, the vasodepressor effect of these agents is accompanied by increased vascular formation of PGI₂ and can be prevented by cyclooxygenase inhibitors. Cyclooxygenase-derived eicosanoids, PGE₂ and PGI₂, also subserve antihypertensive mechanisms in angiotensin-dependent models of hypertension. The level of blood pressure in such models of hypertension reflects, in part, the interplay among prohypertensive and antihypertensive functions subserved by cyclooxygenase- and lipoxygenase-derived eicosanoids.

Key Words: hypertension • angiotensin II • eicosanoids • cyclooxygenase • lipoxygenase

Abbreviations: HETE = hydroxyeicosatetraenoic acid • HPETE = hydroperoxyeicosatextraenoic acid • PG = prostaglandin • TX = thromboxane

	Introduction

Top Abstract Introduction Vascular and Renal Eicosanoids:... Influence of Cyclooxygenase- and... Cyclooxygenase-Derived... Lipoxygenase-Derived Eicosanoids Vascular and Renal Eicosanoids... Contribution of Cyclooxygenase... Summary and Conclusions References

 
Angiotensin II is a primary contributor to blood pressure elevation in some forms of clinical and experimental hypertension. But the level of blood pressure in angiotensin-dependent hypertension also is influenced by several other blood pressure regulatory factors recruited by the activated renin-angiotensin. Angiotensin-responsive factors such as aldosterone, the sympathetic nervous system, endothelin, reactive oxygen species, nitric oxide, kinins, and various eicosanoids support prohypertensive or antihypertensive mechanisms that modulate the expression of angiotensin-dependent hypertension. Eicosanoids participate in the implementation of both prohypertensive and antihypertensive mechanisms.^1,2 This article reviews the evidence linking cyclooxygenase- and lipoxygenase-derived eicosanoids to the mechanisms underlying angiotensin-dependent hypertension.

	Vascular and Renal Eicosanoids: Pathways of Biosynthesis

Top Abstract Introduction Vascular and Renal Eicosanoids:... Influence of Cyclooxygenase- and... Cyclooxygenase-Derived... Lipoxygenase-Derived Eicosanoids Vascular and Renal Eicosanoids... Contribution of Cyclooxygenase... Summary and Conclusions References

 
The formation of eicosanoids is a complex process initiated by the liberation of arachidonic acid from phospholipids by hormone-regulated phospholipases.^3–5 Once free, arachidonic acid is processed by cyclooxygenases, lipoxygenases, or cytochrome P450 oxygenases to many different eicosanoids.

The occurrence of cyclooxygenases, lipoxygenases, and cytochrome P450 oxygenases in vascular and renal tissues is well documented.^3,5–8 Cyclooxygenases catalyze the formation of PGH₂, which subsequently is converted to TXA₂ by thromboxane synthase, to PGI₂ (or prostacyclin) by prostacyclin synthase, or to PGE₂, PGD₂, or PGF₂ by appropriate enzymes.³ Regiospecific lipoxygenases catalyze the formation of 5-, 12-, or 15-HPETEs, which subsequently undergo spontaneous or peroxidase-catalyzed reduction to the corresponding HETEs and in the case of 5-HPETE to leukotrienes.⁹ Cytochrome P450 oxygenases catalyze arachidonic acid epoxidation to epoxyeicosatrienoic acids, and -1 hydroxylation to 20- and 19-HETE, and allylic oxidation to other HETEs.^7,8

	Influence of Cyclooxygenase- and Lipoxygenase-Derived Eicosanoids on Blood Pressure Regulatory Mechanisms

Top Abstract Introduction Vascular and Renal Eicosanoids:... Influence of Cyclooxygenase- and... Cyclooxygenase-Derived... Lipoxygenase-Derived Eicosanoids Vascular and Renal Eicosanoids... Contribution of Cyclooxygenase... Summary and Conclusions References

 
In 1965, Lee et al¹⁰ reported the isolation from rabbit renal medulla of two blood pressure-lowering lipids. The vasodepressor lipids were identified as prostaglandins, and a role for this class of eicosanoids in blood pressure regulation was suggested. The influence of eicosanoids on vascular and renal functions relevant to the regulation of blood pressure is varied and complex. Some eicosanoids subserve antihypertensive mechanisms, while others subserve prohypertensive mechanisms. In several instances, the same eicosanoid may be capable of contributing to mechanisms that influence blood pressure in a reciprocal manner.

	Cyclooxygenase-Derived Eicosanoids

Top Abstract Introduction Vascular and Renal Eicosanoids:... Influence of Cyclooxygenase- and... Cyclooxygenase-Derived... Lipoxygenase-Derived Eicosanoids Vascular and Renal Eicosanoids... Contribution of Cyclooxygenase... Summary and Conclusions References

 
Several renal and vascular actions of PGE₂ and PGI₂ are conducive to their involvement in the implementation of antihypertensive mechanisms that counteract pressor systems, which promote systemic and renal vasoconstriction and conservation of salt and water. For example, PGE₂ and PGI₂ dilate resistance vessels, reduce release of norepinephrine from sympathetic nerves, attenuate the vasoconstrictor responsiveness to angiotensin II and other constrictor hormones, and facilitate renal excretion of salt and water.⁵ Conversely, decreased synthesis of PGI₂ and PGE₂, after treatment with inhibitors of cyclooxygenases, results in augmentation of systemic and renal vascular resistance, increased vascular responsiveness to angiotensin II and other constrictor hormones, increased antidiuretic responsiveness to vasopressin, and attenuation of the pressure-natriuresis response.^1,2,5,11 Collectively, these observations support the concept that PGE₂ and PGI₂ serve as a counterregulatory influence to pressor mechanisms mediated by the reninangiotensin system, the sympathetic nervous system, and vasopressin.

A caveat to the conclusion that PGE₂ and PGI₂ subserve antihypertensive mechanisms is that these eicosanoids stimulate renin secretion.¹² Relative to this point, treatment with cyclooxygenase inhibitors reduces plasma renin activity,¹³ and in some hypertensive subjects and animals this effect is accompanied by lowering of blood pressure.^2,14 These observations are consistent with the concept that PGE₂ and PGI₂ support prohypertensive functions by promoting renin secretion.^2,14

Prohypertensive mechanisms also may be subserved by TXA₂ and PGH₂, its immediate precursor.^1,15 These eicosanoids stimulate contraction of vascular smooth muscle via activation of shared receptors.¹⁵ In the kidney, activation of TXA₂/PGH₂ receptors produces renal vasoconstriction and reduces renal blood flow,¹⁵ effects which are in part related to potentiation of tubuloglomerular feedback.¹⁶ Long-term systemic infusion of a synthetic agonist for TXA₂/PGH₂ receptors produces sustained elevation of blood pressure, part of which effect is attributable to activation of central pressor mechanisms.¹⁷ Activation of TXA₂/PGH₂ receptors also elicits vasoconstriction via facilitation of sympathetic activity.¹⁸ Reports that treatment with inhibitors of thromboxane synthase lowers blood pressure in some models of experimental hypertension in rats suggest a contribution of TXA₂ to the implementation of prohypertensive functions.^19,20 Also PGH₂ may subserve pressor mechanisms, as there is evidence that it is a mediator of endothelium-dependent vasoconstrictor responses in arterial vessels of hypertensive animals.²¹

Blood pressure was reported to increase, decrease, or remain unaffected during treatment with inhibitors of cyclooxygenase.² This variability in response is not unexpected since cyclooxygenase-derived eicosanoids subserve both antihypertensive and prohypertensive mechanisms.^1,2,15 In general, treatment with cyclooxygenase inhibitors increases blood pressure more frequently in hypertensive that in normotensive states and the pressor response is usually accompanied by deterioration of renal function.^2,13 On the other hand, reduction of blood pressure after treatment with cyclooxygenase inhibitors was noted in normotensive and hypertensive conditions in which the renin-angiotensin system is overactive.^2,14 The net blood pressure response to inhibition of cyclooxygenase may reflect the sum of alterations in blood pressure regulatory mechanisms resulting from the deficit in cyclooxygenase-dependent antihypertensive and prohypertensive functions.

	Lipoxygenase-Derived Eicosanoids

Top Abstract Introduction Vascular and Renal Eicosanoids:... Influence of Cyclooxygenase- and... Cyclooxygenase-Derived... Lipoxygenase-Derived Eicosanoids Vascular and Renal Eicosanoids... Contribution of Cyclooxygenase... Summary and Conclusions References

 
Several studies suggest that 12-HETE and other lipoxygenase-derived eicosanoids subserve blood pressure regulatory functions. 12-HETE inhibits renin secretion in slices of rat renal cortex.⁶ Conversely, lipoxygenase inhibitors increase plasma renin activity when administered to rats.⁶ These findings suggest that 12-HETE is an inhibitory regulator of renin secretion,⁶ a role expected to support antipressor functions. However, 12-HETE and other lipoxygenase-derived eicosanoids also display vascular actions that are conducive to their involvement in prohypertensive functions. For example, 12-HPETE and 15-HPETE inhibit prostacyclin synthase,^22,23 an action which may decrease the activity of antihypertensive mechanisms mediated by PGI₂. Also, 12-HETE was shown to facilitate the stimulatory actions of angiotensin II and vasopressin on calcium transients in cultured vascular smooth muscle cells.²⁴ That treatment with lipoxygenase inhibitors attenuates the vasoconstrictor action of angiotensin II^25,26 and decreases blood pressure in spontaneously hypertensive rats^27,28 and rats with renovascular hypertension²⁹ supports the notion that lipoxygenase-derived eicosanoids contribute to the implementation of prohypertensive mechanisms.

	Vascular and Renal Eicosanoids in Angiotensin-Dependent Hypertension

Top Abstract Introduction Vascular and Renal Eicosanoids:... Influence of Cyclooxygenase- and... Cyclooxygenase-Derived... Lipoxygenase-Derived Eicosanoids Vascular and Renal Eicosanoids... Contribution of Cyclooxygenase... Summary and Conclusions References

 
The notion that the renin-angiotensin system influences eicosanoid formation was first advanced by McGiff et al who in 1970 reported release of a prostaglandin-like substance into renal venous blood in response to an infusion of angiotensin II.³⁰ It is now well documented that angiotensin II stimulates synthesis and release of many different eicosanoids from a variety of cells and tissues and that this action is primarily the consequence of phospholipase(s) activation with attendant elevation in the amount of free arachidonic acid available for metabolism by oxygenases.^4,5 The profile of eicosanoids synthesized in response to angiotensin II is cell specific, reflecting the relative expression of the various arachidonic acid- and prostaglandin endoperoxide-metabolizing enzymes. Angiotensin II promotes synthesis of prostaglandins and, to a lesser extent, of TXA₂ in vascular and renal tissues.^2,31 Angiotensin II also stimulates production of lipoxygenase-derived HETEs in arterial vessels and kidney.²⁵

Rats made hypertensive by chronic angiotensin II infusion display increased plasma levels of 6-keto-PGF₁ (a PGI₂ derivative), increased urinary excretion of 6-keto-PGF₁ and TXB₂ (a TXA₂ derivative), and increased release of 6-keto-PGF₁ and TXB₂ from arterial and renal tissues incubated ex vivo.^15,32 The vascular and renal production of 6-keto-PGF₁ and TXB₂ and the urinary excretion of 6-keto-PGF₁ and TXB₂ also are elevated in rats with aortic coarctation-induced hypertension³³ and in rats with two-kidney, one-clip hypertension,³⁴ both models of angiotensin-dependent hypertension. Yet, it is unlikely that these abnormalities in eicosanoid production by vascular and renal tissues are solely a consequence of an overactive renin-angiotensin system, since they are also demonstrable in rats with deoxycorticosterone-salt-induced hypertension,^33,35 a model of angiotensin-independent hypertension. In rats with angiotensin II-induced hypertension, the release of 6-keto-PGF₁, PGE₂, and TXB₂ from rings of descending thoracic aorta incubated ex vivo correlated positively with the level of blood pressure.^1,32 Hence, the possibility arises that the increased production of these eicosanoids by the aorta of hypertensive rats is secondary to the hypertension, perhaps reflecting pressure-induced overexpression of vascular cyclooxygenase as suggested by studies in spontaneously hypertensive rats.³⁶

In the aorta and other arterial vessels, PGH₂ is metabolized primarily by prostacyclin synthase to yield PGI₂. Recent studies demonstrated that aortic rings from rats with aortic coarctation-induced hypertension or with angiotensin-induced hypertension are impaired in their ability to convert exogenous PGH₂ to PGI₂ ex vivo, suggesting a dysfunction in the activity or expression of vascular prostacyclin synthase.^23,37 In the face of such an impairment in vascular prostacyclin synthase, the increased production of PGI₂ (measured as 6-keto-PGF₁) in aortic rings of hypertensive rats may be driven by the enhanced production of PGH₂.²³ As discussed later in this article, the association of increased PGH₂ synthesis and impaired ability to metabolize PGH₂ to PGI₂ in arterial vessels of rats made hypertensive by aortic coarctation or by angiotensin II infusion may be expected to foster the activity of vasoconstrictor mechanisms mediated by PGH₂, while minimizing the activity of vasodilatory mechanisms mediated by PGI₂.

Angiotensin II was reported to increase the expression of 12-lipoxygenase protein and mRNA in cultured aortic smooth muscle cells.³⁸ Moreover, the production of lipoxygenase-derived HETEs is increased in the thoracic aorta of rats with two-kidney, one-clip hypertension²⁹ or with aortic coarctation-induced hypertension.²³ It is well established that lipoxygenase-derived products such as 12-HPETE and 15-HPETE, the precursors of 12-HETE and 15-HETE, respectively, inhibit prostacyclin synthase.^22,23 Prostacyclin synthase also is inhibited by hydroperoxides derived from linoleic acid, -linoleic acid, and dihomo--linolenic via metabolism by lipoxygenases. Hence, endogenous hydroperoxides arising from arachidonic acid or from other polyunsaturated fatty acids are candidates for mediating the impairment in prostacyclin synthase activity noted in aortic rings of rats made hypertensive by aortic coarctation or by angiotensin II infusion.^22,23,37 This prediction is supported by a report that treatment of aortic rings from hypertensive rats with inhibitors of 12-lipoxygenase, baicalein or cinnamyl-3,4-dihydroxy--cyanocinnamate, corrects the impairment in the conversion of PGH₂ to PGI₂.²³ The notion that lipoxygenase inhibition has a facilitatory influence on PGI₂ production fits well with the observation that the administration of baicalein to rats with angiotensin II-induced hypertension increases both the blood level and urinary excretion of 6-keto-PGF₁, without increasing either the blood concentration or urinary excretion of PGE₂.³⁷

It would appear from the preceding discussion that the development of hypertension in angiotensin-dependent models is accompanied by increased vascular and renal production of PGI₂ and TXA₂, as well as by overexpression of a vascular 12-lipoxygenase with the ability to manufacture fatty acid hydroperoxides that produce partial disruption in the coupling between PGH₂ synthesis by cyclooxygenase and PGH₂ metabolism by prostacyclin synthase. The impact of these abnormalities in eicosanoid metabolism on the mechanisms of angiotensin-dependent hypertension is considered next.

	Contribution of Cyclooxygenase-Derived Eicosanoids to Prohypertensive Mechanisms in Angiotensin-Dependent Hypertension

Top Abstract Introduction Vascular and Renal Eicosanoids:... Influence of Cyclooxygenase- and... Cyclooxygenase-Derived... Lipoxygenase-Derived Eicosanoids Vascular and Renal Eicosanoids... Contribution of Cyclooxygenase... Summary and Conclusions References

 
Blood Pressure Response to Pharmacological Blockade of the Synthesis or Actions of Cyclooxygenase-Derived Eicosanoids
Treatment with the cyclooxygenase inhibitor indomethacin lowers blood pressure and plasma renin activity in rats with aortic coarctation-induced hypertension^14,33 and rats with two-kidney, one-clip hypertension,³⁴ models of angiotensin-dependent hypertension in which the production of TXA₂ and prostaglandins by vascular and/or renal structures is increased. The blood pressure-lowering effect of indomethacin in these animals may be due to reduction in plasma renin activity consequent to diminished renal production of cyclooxygenase-derived eicosanoids, PGE₂ and PGI₂, that promote renin secretion. However, it also may be due to decreased vascular and renal synthesis of TXA₂ and its precursor, PGH₂, which are potent vasoconstrictors in the renal and systemic circulations.^1,15

The involvement of TXA₂ and PGH₂ in the mechanisms underlying angiotensin-dependent hypertension was addressed in several studies by examining the effect of thromboxane synthesis inhibitors and TXA₂/PGH₂ receptor blockers on blood pressure of normotensive rats and rats with angiotensin-independent and angiotensin-dependent hypertension. Neither thromboxane synthesis inhibitors nor TXA₂/PGH₂ receptor blockers changed blood pressure or renal hemodynamics in awake normotensive rats.^20,39 In anesthetized normotensive rats subjected to surgical stress, short-term treatment with a TXA₂/ PGH₂ receptor antagonist did not affect blood pressure but increased renal blood flow.⁴⁰ The renal vasodilatory response to TXA₂/PGH₂ receptor blockade in this experimental setting was positively correlated with the prevailing concentration of angiotensin II in plasma and was not observed in rats pretreated with an inhibitor of converting enzyme or an angiotensin II receptor antagonist.⁴⁰ Pertaining to these findings, it has been reported that acute blockade of TXA₂/PGH₂ receptors attenuates the pressor and renal vasoconstrictor actions of angiotensin II.¹⁵

In anesthetized rats with deoxycorticosterone-salt-induced hypertension, a classical model of angiotensin-independent hypertension, neither blood pressure nor renal hemodynamics were changed by short-term treatment with a thromboxane synthase inhibitor or a TXA₂/PGH₂ receptor antagonist.³⁵ Blockade of TXA₂/PGH₂ receptors also was without effect on the blood pressure of awake rats with deoxycorticosterone-salt-induced hypertension, of stroke-prone spontaneously hypertensive rats, and of rats in the late phase of aortic coarctation-induced hypertension, when plasma renin activity has declined to near normal levels.³³ In contrast, in anesthetized rats with two-kidney, one-clip hypertension, short-term treatment with either a thromboxane synthesis inhibitor or a TXA₂/PGH₂ receptor antagonist decreased blood pressure while increasing glomerular filtration rate in the kidney contralateral to the clip.¹⁹ In awake rats with two-kidney, one-clip hypertension, the administration of a TXA₂/PGH₂ receptor antagonist, for 6 weeks⁴¹ or for 3 days,⁴² also decreased blood pressure.

In the angiotensin-dependent phase of aortic coarctation-induced hypertension in rats, 7 to 14 days after aortic coarctation, a model of severe and rapidly developing hypertension, short-term administration of a TXA₂/PGH₂ receptor blocker elicited a prompt and sustained reduction of blood pressure, which was positively correlated with the prevailing plasma renin activity.³³ In marked contrast, short-term treatment with an inhibitor of thromboxane synthase did not lower blood pressure in this model of hypertension.³³ Similar observations were made in another model of severe hypertension produced in saline-drinking rats by long-term infusion of angiotensin II (125 ng/min IP).⁴³ In the established phase of angiotensin II-salt-induced hypertension, on the 12th day of angiotensin II infusion, the administration of a TXA₂/PGH₂ receptor antagonist reduced blood pressure rapidly⁴³ and produced renal vasodilation not attributable to autoregulation,³⁹ whereas the administration of an inhibitor of thromboxane synthase was without effect.^39,43 Collectively, these findings suggest that a cyclooxygenase product other than TXA₂, most likely PGH₂, participates in the implementation of pressor mechanisms in these most severe models of hypertension.

In additional experiments, designed to investigate the effect of thromboxane synthase inhibition and TXA₂/PGH₂ receptor blockade on the development of angiotensin II-salt-induced hypertension, treatment with the appropriate pharmacological agents was initiated concurrently with the onset of angiotensin II infusion and was continued for 12 days.⁴⁴ The results clearly showed that the TXA₂/PGH₂ receptor antagonist attenuated the development of severe angiotensin II-salt-induced hypertension, whereas an inhibitor of thromboxane synthase did not, even though the pharmacological intervention was effective in decreasing several indices of TXA₂ production.⁴⁴ However, a recent study in a milder model of angiotensin II-induced hypertension (angiotensin II infusion at 20 ng kg^-1 min^-1 IV in water-drinking rats receiving a converting enzyme inhibitor), showed that the development of hypertension was attenuated by long-term administration of a thromboxane synthase inhibitor.²⁰

From the preceding discussion it is apparent that the status of the renin-angiotensin system is a major determinant of the blood pressure response to treatment with agents that inhibit thromboxane synthase or block TXA₂/PGH₂ receptors. These agents had little or no effect on the blood pressure of animals, either normotensive or hypertensive, in which plasma renin activity is normal or subnormal. In contrast, inhibitors of thromboxane synthase and/or blockers of TXA₂/PGH₂ receptors reduced the blood pressure of rats with two-kidney, one-clip hypertension, aortic coarctation-induced hypertension of 7 to 14 days duration, or angiotensin II-induced hypertension, all models of hypertension in which plasma renin activity and/or circulating angiotensin II levels are increased. These observations imply that sustained activation of the renin-angiotensin system creates conditions conducive to the recruitment of prohypertensive mechanisms mediated by cyclooxygenase-derived eicosanoids.

That inhibitors of thromboxane synthase lower blood pressure in rats with two-kidney, one-clip hypertension¹⁹ and attenuate the development of hypertension in rats with mild angiotensin II-induced hypertension²⁰ suggest that TXA₂ is a contributory factor to the mechanisms underlying the elevation of blood pressure in these models of angiotensin-dependent hypertension. A similar role for TXA₂ is not apparent in rats with aortic coarctation-induced hypertension³³ or with angiotensin II-salt-induced hypertension,^43,44 because in these models of severe, rapidly developing hypertension, the administration of a thromboxane synthase inhibitor did not affect blood pressure. However, blockers of TXA₂/PGH₂ receptors did decrease blood pressure when administered to rats with aortic coarctation-induced hypertension³³ or with angiotensin II-salt-induced hypertension,^43,44 suggesting that a pressor mechanism relying on TXA₂/PGH₂ receptor activation by PGH₂ or another eicosanoid is operational and contributes to the mechanisms of hypertension in these animal models.

In settings in which TXA₂/PGH₂ receptor blockers lower blood pressure but thromboxane synthase inhibitors do not, the expected functional consequence of diminished TXA₂ may be obscured by an attendant increase in PGH₂, the precursor of TXA₂ and prostaglandins and a potent vasoconstrictor. But it is also possible that in such settings the vasodepressor effect of treatment with TXA₂/PGH₂ receptor antagonists relates to blockade of the pressor actions of a TXA₂/PGH₂ receptor agonist other than TXA₂. Relevant to this point, conditions favoring elevation of vascular PGH₂ levels, viz, increased cyclooxygenase activity and a partial impairment in ability to metabolize PGH₂ to PGI₂, have been reported in rats made severely hypertensive by aortic coarctation or angiotensin II infusion.^23,37 Hence, in these models of hypertension, PGH₂ rather than TXA₂ may be responsible for the implementation of pressor mechanisms dependent on TXA₂/PGH₂ receptor activation.

PGH₂ and the Expression of Basal and Agonist-Induced Vascular Tone
The endothelium plays a prominent role in the regulation of vascular tone by manufacturing substances that promote contraction or relaxation of vascular smooth muscle.²¹ Removal of the endothelium decreases the constrictor response of some vascular preparations to several substances including acetylcholine, calcium ionophore A23187, norepinephrine, angiotensin II, and arachidonic acid.^21,31,45 Vasoconstrictor events that are endothelium-dependent may be mediated by one or more endothelium-derived constrictor factors including endothelin, reactive oxygen species, and metabolites of arachidonic acid.^21,46

A role of cyclooxygenase-derived eicosanoids in the implementation of endothelium-dependent vasoconstrictor responses is suggested by reports that inhibitors of cyclooxygenase attenuate many such responses.^21,32,45 The identity of the cyclooxygenase-derived eicosanoid mediating constrictor responses varies with animals species and vascular preparations. For example, inhibitors of thromboxane synthase reduce constrictor responses to arachidonic acid, norepinephrine, and calcium ionophore A23187 in canine basilar arteries,²¹ suggesting mediation of such responses by TXA₂. On the other hand, in some rat models of hypertension, the constrictor effect of acetylcholine⁴⁷ and of arachidonic acid²³ in rings of thoracic aorta is reduced by blockers of TXA₂/PGH₂ receptors but not by thromboxane synthase inhibitors, suggesting that the constrictor responses are mediated by PGH₂ rather than by TXA₂. Recent studies have documented endothelium-dependent formation and release of PGH₂ in rabbit and rat aorta.^36,46

There is now evidence that PGH₂ contributes significantly to the constrictor effect of acetylcholine, oxygen free radicals, arachidonic acid, and serotonin in the thoracic aorta of spontaneously hypertensive rats^21,36,47,48 and to the constrictor effect of arachidonic acid, calcium ionophore A23187, and angiotensin II in the thoracic aorta of rats with aortic coarctation-induced hypertension, 7 to 14 days after coarctation.^23,31,45 Importantly, PGH₂-mediated responses to these agonists are minimal in the aorta of normotensive rats.^23,31,48 Accordingly, PGH₂-mediated responses to constrictor agonists are preferentially expressed in hypertensive rats.

Rings of descending thoracic aorta taken from rats with aortic coarctation-induced hypertension, 7 to 14 days after coarctation, display a high level of calcium-dependent basal tone, which is not demonstrable in aortic rings of normotensive rats.⁴⁹ Both an inhibitor of cyclooxygenase and a blocker of TXA₂/PGH₂ receptors, but not an inhibitor of thromboxane synthase, decrease the calcium-dependent basal tone displayed by aortic rings of rats with aortic coarctation-induced hypertension.⁴⁹ Hence, it would appear that the high level of active basal tone found in aortic rings of these rats is, in part, the functional manifestation of a mechanism of vascular contraction mediated by PGH₂, which is overexpressed in this model of angiotensin-dependent hypertension.

In spontaneously hypertensive rats, the increased expression of PGH₂-mediated constrictor responses to acetylcholine was attributed to overexpression of cyclooxygenase-1 and to hypersensitivity to PGH₂.³⁶ In rats with aortic coarctation-induced hypertension, the increased expression of PGH₂-mediated mechanism of vascular contraction was attributed to the combination of increased PGH₂ formation and impaired ability to metabolize PGH₂ to PGI₂ due to partial inhibition of vascular prostacyclin synthase by lipoxygenase-derived fatty acid hydroperoxides.²³ That pretreatment of aortic rings from hypertensive rats with lipoxygenase inhibitors restores to normal the ability of the rings to metabolize PGH₂ to PGI₂, while greatly attenuating the intensity of PGH₂-mediated constrictor response to arachidonic acid, suggests a critical role for lipoxygenase products in creating conditions that favor expression of vasoconstrictor mechanisms mediated by PGH₂.²³

Contribution of Lipoxygenase-Derived Eicosanoids to Prohypertensive Mechanisms in Angiotensin-Dependent Hypertension
Several studies have implicated lipoxygenase-derived eicosanoids in the mechanisms of hypertension in rats with two-kidney, one-clip hypertension,²⁹ spontaneously hypertensive rats,^27,28 and rats made hypertensive by infusion of angiotensin II.³⁷ The production of lipoxygenase-derived HETEs is elevated in arterial structures of two-kidney, one-clip hypertensive rats²⁹ and in platelets of spontaneously hypertensive rats.²⁸ The urinary excretion of 12-HETE is increased in rats with angiotensin II-induced hypertension.³⁷ Prolonged treatment with lipoxygenase inhibitors attenuates the development of hypertension in two-kidney, one-clip hypertensive rats²⁹ and in spontaneously hypertensive rats.²⁷ Short-term administration of lipoxygenase inhibitors brings about blood pressure lowering in two-kidney, one-clip hypertensive rats,²⁹ spontaneously hypertensive rats,²⁸ and rats with angiotensin II-induced hypertension.³⁷ In contrast, inhibitors of lipoxygenase did not affect the blood pressure of rats with deoxycorticosterone-salt-induced hypertension,²⁹ a model of hypertension in which the activity of the renin-angiotensin system is markedly depressed. It would appear, then, that the effectiveness of lipoxygenase inhibitors to lower blood pressure is closely linked to the prevailing activity of the renin-angiotensin system.

According to published studies, the pressor and renal vasoconstrictor actions of angiotensin II are attenuated by inhibitors of lipoxygenase,^25,26 suggesting contribution of lipoxygenase-derived products to the vascular actions of the peptide. Hence, the acute blood pressure-lowering effect of lipoxygenase inhibitors in hypertensive rats may be a functional manifestation of diminished production of lipoxygenase products capable of facilitating or mediating the vasoconstrictor action of angiotensin II. But the acute vasodepressor effect of lipoxygenase inhibitors also may be linked to elimination of the inhibitory influence of 12-HPETE and other lipoxygenase-derived fatty acid hydroperoxides on prostacyclin synthase.^22,23 Such an action would be expected to reduce the expression of vasoconstrictor mechanisms mediated by PGH₂, while increasing that of vasodilatory mechanisms mediated by PGI₂.

A recent study in rats made hypertensive by infusion of angiotensin II examined the contribution of PGI₂ to the antihypertensive effect of baicalein, an inhibitor of 12-lipoxygenase.³⁷ In hypertensive but not in normotensive rats, baicalein lowered blood pressure, associated with significant elevations in the rate of conversion of exogenous PGH₂ to PGI₂ by aortic segments, the blood concentration of 6-keto-PGF₁, and the renal excretion of 6-keto-PGF₁. Importantly, the antihypertensive effect of baicalein in rats with angiotensin II-induced hypertension was prevented by treatment with an inhibitor of cyclooxygenase, indomethacin, and was partially reversed by the administration of 5,6-dihydro-PGI₂ antibodies, which bind PGI₂ and block its vasodepressor action. Hence, in this model of hypertension, the acute antihypertensive response to lipoxygenase inhibition with baicalein is linked to amplification in the activity of a vasodepressor mechanism mediated by PGI₂, consequent to removal of the inhibitory influence of lipoxygenase-derived eicosanoids on prostacyclin synthase.

It would appear from the preceding discussion that lipoxygenase-derived eicosanoids contribute importantly to the mechanisms of angiotensin-dependent hypertension. The ability to inhibit prostacyclin synthase seems to be important to the implementation of prohypertensive mechanism by products of lipoxygenase activity. Indeed, inhibition of vascular prostacyclin synthase not only decreases the activity of vasodilatory mechanisms mediated by PGI₂ but also amplifies the expression of vasoconstrictor mechanisms mediated by PGH₂. Other prohypertensive actions of lipoxygenase-derived eicosanoids, ie, facilitatory action on peptide hormone-induced calcium signals, also may contribute to increase blood pressure in angiotensin-dependent hypertension.

Contribution of Eicosanoids to Antihypertensive Mechanisms in Angiotensin-Dependent Hypertension
The contribution of cyclooxygenase-derived eicosanoids to antihypertensive mechanisms in angiotensin-dependent and angiotensin-independent forms of hypertension has been reviewed previously.^1,2,5 Investigative efforts in this area have been suboptimal because the pharmacological tools that are available for disrupting the formation of PGE₂ and PGI₂, ie, the inhibitors of cyclooxygenase, also disrupt the formation of PGH₂ and TXA₂, the constrictor products of arachidonic acid metabolism by cyclooxygenase. Problems related to the interpretation of data on blood pressure responses to treatment with inhibitors of cyclooxygenase are particularly apparent in models of angiotensin-dependent hypertension, featuring increased vascular and renal formation of cyclooxygenase products linked both to prohypertensive and antihypertensive mechanisms. For example, short-term treatment with an inhibitor of cyclooxygenase did not change the blood pressure of rats with angiotensin II-salt-induced hypertension,¹ and tended to decrease the blood pressure of rats with aortic coarctation-induced hypertension³³ or with two-kidney, one-clip hypertension,³⁴ failing to reveal any contribution of antihypertensive mechanisms involving cyclooxygenase products to setting the level of blood pressure. In marked contrast, short-term treatment with a cyclooxygenase inhibitor increased the blood pressure of rats with angiotensin II-salt-induced hypertension that had been pretreated with a blocker of TXA₂/PGH₂ receptors.¹ Likewise, an inhibitor of cyclooxygenase also increased the blood pressure of rats with aortic coarctation-induced hypertension pretreated with a TXA₂/PGH₂ receptor blocker.³³ In these models of angiotensin-dependent hypertension, the increase in blood pressure accompanying cyclooxygenase inhibition under conditions of TXA₂/PGH₂ receptor blockade results from the elimination of antihypertensive mechanisms subserved by cyclooxygenase-derived eicosanoids. These antihypertensive mechanisms are operational and serve as a counterregulatory influence to the pressor mechanisms underlying the development of angiotensin-dependent hypertension.

	Summary and Conclusions

Top Abstract Introduction Vascular and Renal Eicosanoids:... Influence of Cyclooxygenase- and... Cyclooxygenase-Derived... Lipoxygenase-Derived Eicosanoids Vascular and Renal Eicosanoids... Contribution of Cyclooxygenase... Summary and Conclusions References

 
Many eicosanoids produced in vascular and renal structures are endowed with the ability to influence vascular and renal mechanisms of blood pressure regulation. The development of angiotensin-dependent hypertension in rats is accompanied by increased vascular production of TXA₂ and of lipooxygenase-derived products with the ability to inhibit prostacyclin synthase. As a result of these abnormalities, the activity of pressor mechanisms mediated by TXA₂ and/or PGH₂ is increased. The cancellation of TXA₂- and/or of PGH₂-mediated pressor mechanisms, after treatment with thromboxane synthase inhibitors or TXA₂/PGH₂ receptor blockers, lowers blood pressure in rats with angiotensin-dependent hypertension. Inhibitors of lipoxygenase also lower blood pressure in such animals, in part, by decreasing the synthesis of lipooxygenase-derived inhibitors of prostacyclin synthase. Thus, the vasodepressor effect of lipooxygenase inhibitors is accompanied by increased vascular formation of PGI₂ and can be prevented by cyclooxygenase inhibitors. Cyclooxygenase-derived eicosanoids, PGE₂ and PGI₂, also subserve antihypertensive mechanisms in angiotensin-dependent models of hypertension. The level of blood pressure in such models of hypertension reflects, in part, the interplay among prohypertensive and antihypertensive functions subserved by cyclooxygenase- and lipoxygenase-derived eicosanoids.

	Acknowledgments

 
This work was supported by Grants HL18579 and HL34300 from the National Institutes of Health. The author thanks Chiara Kimmel-Preuss, Jennifer Brown, and Gail D. Price for secretarial assistance.

Received September 16, 1997; first decision September 30, 1997; accepted October 21, 1997.

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