Role of COX-2-derived PGE2 on vascular stiffness and function in hypertension.

BACKGROUND AND PURPOSE: Prostanoids derived from COX-2 and EP receptors are involved in vascular remodelling in different cardiovascular pathologies. This study evaluates the contribution of COX-2 and EP1 receptors to vascular remodelling and function in hypertension. EXPERIMENTAL APPROACH: Spontaneously hypertensive rats (SHR) and angiotensin II (AngII)-infused (1.44 mg · kg(-1) · day(-1), 2 weeks) mice were treated with the COX-2 inhibitor celecoxib (25 mg · kg(-1) · day(-1) i.p) or with the EP1 receptor antagonist SC19220 (10 mg · kg(-1) · day(-1) i.p.). COX-2(-/-) mice with or without AngII infusion were also used. KEY RESULTS: Celecoxib and SC19220 treatment did not modify the altered lumen diameter and wall : lumen ratio in mesenteric resistance arteries from SHR-infused and/or AngII-infused animals. However, both treatments and COX-2 deficiency decreased the augmented vascular stiffness in vessels from hypertensive animals. This was accompanied by diminished vascular collagen deposition, normalization of altered elastin structure and decreased connective tissue growth factor and plasminogen activator inhibitor-1 gene expression. COX-2 deficiency and SC19220 treatment diminished the increased vasoconstrictor responses and endothelial dysfunction induced by AngII infusion. Hypertensive animals showed increased mPGES-1 expression and PGE2 production in vascular tissue, normalized by celecoxib. Celecoxib treatment also decreased AngII-induced macrophage infiltration and TNF-α expression. Macrophage conditioned media (MCM) increased COX-2 and collagen type I expression in vascular smooth muscle cells; the latter was reduced by celecoxib treatment. CONCLUSIONS AND IMPLICATIONS: COX-2 and EP1 receptors participate in the increased extracellular matrix deposition and vascular stiffness, the impaired vascular function and inflammation in hypertension. Targeting PGE2 receptors might have benefits in hypertension-associated vascular damage.

Elevation of plasma noradrenaline levels in urethane-anaesthetized rats by activation of central prostanoid EP3 receptors.

1. We studied the effects of intracerebroventricular (i.c.v.) administration of prostaglandin E2 (PGE2) and its receptor subtype ligands on plasma levels of catecholamines in urethane-anaesthetized rats. 2. Administration of PGE2 (0.15, 0.3 and 1.5 nmol per animal, i.c.v.) dose-dependently elevated plasma levels of noradrenaline (NA), while the levels of adrenaline were not affected. 3. Administration of sulprostone (EP3/EP1 agonist) and misoprostol (EP3/EP2 agonist) effectively elevated plasma NA levels in a dose-dependent manner (0.1, 0.3, and 1.0 nmol per animal). Butaprost (EP2 agonist) (0.3, 1.0 and 3.0 nmol per animal) was without effect. 17-Phenyl-omega-trinor PGE2 (EP1/EP3 agonist) effectively elevated plasma NA levels only at its highest dose (1.0 nmol per animal), but this elevation was not attenuated by pretreatment with SC-19220 (selective EP1 antagonist) (20 nmol per animal, i.c.v.). 4. The potency of these test agents in elevating plasma levels of NA was as follows; misoprostol > sulprostone > PGE2 > > 17-phenyl-omega-trinor PGE2 > > > butaprost. These results suggest that activation of central prostanoid EP3-receptors induces central sympathetic outflow in rats.

Comparison of intradermal and subcutaneous hyperalgesic effects of inflammatory mediators in the rat.

In recent studies, the superfusion of the corium side of the skin with inflammatory mediators failed to produce sensitization of nociceptors to mechanical stimuli. We have studied the effects of intradermal (i.d.) and subcutaneous (s.c.) injections of prostaglandin E2 (PGE2) and bradykinin (BK) in a behavioral model of hyperalgesia. PGE2 or BK was injected into the rat hind-paw, and paw-withdrawal thresholds in response to noxious mechanical stimulation before and after the drug were compared. Subcutaneous injection of PGE2 (1-1000 ng), a hyperalgesic inflammatory mediator, did not significantly alter paw-withdrawal thresholds, under the same conditions in which i.d. injections dose-dependently lowered paw-withdrawal thresholds. Similarly, BK (1-1000 ng), another hyperalgesic mediator, given s.c. failed to significantly alter paw-withdrawal thresholds while i.d. injections dose-dependently lowered paw-withdrawal thresholds. The prostaglandin E-type, EP1 receptor antagonist SC19220 (750 ng), given s.c. prior to PGE2 (i.d.) did not significantly change PGE2-induced hyperalgesia. However, SC19220 significantly attenuated PGE2 hyperalgesia when both were injected i.d. Also, s.c. administration of the mu-opioid antagonist, DAMGO, before PGE2 did not inhibit PGE2-induced hyperalgesia as opposed to i.d. injection. These results suggest that the inability of s.c. injection of PGE2 or BK to reach its receptor site on the terminals of primary afferent nociceptors may be responsible for the ineffectiveness of these hyperalgesic mediators to sensitize cutaneous nociceptors to mechanical stimuli in the rat and underscore the importance of the site of application and site of action of hyperalgesic agents in the study of hyperalgesic mechanisms.

Involvement of organum vasculosum of lamina terminalis and preoptic area in interleukin 1 beta-induced ACTH release.

Intravenous administration of recombinant human interleukin 1 beta (IL-1 beta, 1 micrograms/100 g body wt) resulted in a marked elevation of plasma adrenocorticotropic hormone (ACTH) levels, with peak levels at 10 min, in conscious unrestrained rats. One week after the placement of a lesion by radiofrequency or microinjection of kainic acid in the organum vasculosum of lamina terminalis (OVLT) but not in subfornical organ, ACTH response to intravenous IL-1 beta was enhanced, whereas both radiofrequency-induced lesion and kainic acid in the preoptic area (POA) suppressed the response. Indomethacin or a prostaglandin E (PGE) antagonist microinjected into the OVLT or POA suppressed or abolished the response. On the other hand, PGE, but not PGD2, microinjected into the POA increased plasma ACTH levels. These results suggest an important role for the OVLT, which lacks blood-brain barrier, as a possible site of entry of blood-borne IL-1 beta into the brain and for the POA, which may contain the neurons required for the response. Involvement of PGE in the OVLT and POA in the ACTH response to intravenous IL-1 beta is also suggested.