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.

Molecular heterogeneity of circulating prolactin in chronic uremic men and renal transplant recipients.

Serum PRL levels and its molecular heterogeneity were analyzed, basally and after 500 micrograms TRH given acutely, in four groups of men: normal (C, n = 12), chronic renal failure (CRF, n = 11), hemodialysis (HD, n = 12), and transplant recipients (T, n = 11). The mean basal PRL level was higher in group CRF than in group C and even higher in group HD. The basal hyperprolactinemia was due to increased concentrations of little PRL. The absolute levels of total and little PRL 20 min after TRH were comparable in the four groups. The disappearance index (DI = PRL20-PRL120/PRL20) for total and little PRL was lower in CRF than in C and even lower in HD. A positive correlation was found between the DIs of total and little PRL and creatinine clearance in group CRF. Group T had basal and 20 min serum PRL levels and a pattern of molecular distribution similar to those of group C but total and little PRL DI was lower. These results demonstrate that uremic hyperprolactinemia is due to increases in little PRL without major changes in big and big-big forms of PRL. The reduction of glomerular filtration rate seems to be one of the most important mechanisms responsible for little PRL accumulation.

Prolactin plasma levels and its size heterogeneity in acutely uremic rats.

The size distribution pattern of circulating rPRL was studied in intact control (C) rats and in three uremic models, namely urine autoinfusion (UA), bilateral ureteral ligation (BUL), and bilateral nephrectomy (BNx). Plasmas were chromatographed by gel filtration in Sephadex G-100. Rat PRL was measured by RIA. The rPRL levels as well as the size distribution pattern of UA were similar to that of C. BUL and BNx showed a similar degree of hyperprolactinemia which corresponded to an increase in little rPRL. The results suggest that acute uremic hyperprolactinemia seems to be the result of accumulation of little rPRL. Acute uremia by itself does not increase rPRL plasma levels nor does it seem to affect the size distribution pattern of circulating rPRL.

A radioimmunoassay method for measurement of urinary kinins.

A sensitive and specific radioimmunoassay for measuring urinary kinins was developed. Antibodies against bradykinin were induced in rabbits by injecting bradykinin coupled to bovine albumin. One of the antisera generated was used at a final dilution of 1:18,000 to obtain a 30% total binding of bradykinin-(8-tyrosine)-[125I]-triacetate. Synthetic bradykinin (5-1,000 pg) was used as standard in the curves. The sensitivity of the assay was 5 pg. The recovery of bradykinin added to urinary samples was 86.85 +/- 6%. The intraassay and interassay coefficients of variation were 3.3% (n = 12) and 4.4% (n = 5), respectively. The antiserum showed no cross-reactivity with oxytocin or low molecular weight kininogen and cross-reacted with kallidin (lys-bradykinin), met-kallidin, and angiotensin I, but cross-reaction with angiotensin I (2.5%) was low enough to be disregarded. The mean urinary levels of total kinins in 12 normal subjects were 23.2 +/- (SEM) 2.2 micrograms/day.