Adriana Susana Donoso

Central natriuretic peptides regulation of peripheral atrial natriuretic factor release

Atrial natriuretic factor (ANF) and C-type natriuretic peptide (CNP) receptors have been described in encephalic areas and nuclei related to the regulation of cardiovascular as well as sodium and water homeostasis. Stimulation of the anterior ventral third ventricular region of the brain modifies plasma ANF concentration, suggesting the participation of the central nervous system in the regulation of circulating ANF. The aim of this work was to study the effect of centrally applied ANF or CNP on plasma ANF. Normal and blood volume expanded rats (0.8 ml isotonic saline/100 g body weight) were intra cerebralventricularly injected with 1, 10 or 100 ng/microl/min ANF. Blood volume expanded animals were also centrally injected with the same doses of CNP. Blood samples were collected at 5 and 15 min. after intracerebralventricular administration of either ANF or CNP. Centrally applied ANF did not affect circulating ANF in normal blood volume rats. In blood volume expanded animals both ANF (1, 10 or 100 ng/microl/min) and CNP (1 ng/microl/min) decreased plasma ANF concentration after 15 min. Moreover, CNP (10 and 100 ng/microl/min) lowered circulating ANF levels not only at 15 min but also at 5 min. Neither ANF nor CNP elicited any change in mean arterial pressure and heart rate in normal and blood volume expanded rats. These results suggest the existence of a central regulation exerted by natriuretic peptides on circulating ANF levels. Furthermore, this is the first study reporting an effect on plasma ANF induced by centrally applied CNP.

A high-fat plus fructose diet produces a vascular prostanoid alterations in the rat.

In the rat, a high-fat (HF) plus fructose (F) diet produces cardiovascular and metabolic alterations that resemble human metabolic syndrome. Prostanoids (PR), cyclo-oxygenase-derived arachidonic acid metabolites, have vasoactive properties and mediate inflammation. The aim of this study was to analyse the effect of a HF+F diet on blood pressure (BP), metabolic parameters and mesenteric vascular bed PR production in male Sprague-Dawley rats. Four groups were studied over 9 weeks (n = 6 each): control (C), standard diet (SD) and tap water to drink; F+SD and 10% w/v F solution to drink; HF 50% (w/w) bovine fat added to SD and tap water; and HFF, both treatments. PR were determined by HPLC. Blood pressure was elevated in all experimental groups. Triglyceridaemia, insulinaemia and HOMA-IR were increased in the F and HF groups. HF+F animals showed elevated glycaemia, insulinaemia, HOMA-IR and triglyceridaemia. F decreased the vasodilator prostanoids PGI2 and PGE2 in the mesenteric vascular bed. Body weight was not significantly altered. In HFF, production of PGE2 , PGF2 alpha and TXB2 was elevated. The increased BP in HF and HFF could be partly attributed to the imbalance in vascular PR production towards vasoconstrictors. On the other hand, this dietary modification could induce inflammation, which would explain the elevation of PGE2 . In the F group, hypertension could be related to decreased vasodilator PRs. The simultaneous administration of HF and F in the rat produces deleterious effects greater than observed when treatments are applied separately.

Metformin reduces vascular production of vasoconstrictor prostanoids in fructose overloaded rats

Metformin is a hypoglycaemic drug currently used to increase insulin sensitivity in the treatment of type 2 diabetes and metabolic syndrome. Its main mechanism of action is through activation of AMP-activated protein kinase, an enzyme that regulates cellular and whole organ metabolism. The fructose-overloaded rat is an experimental model with features that resemble human metabolic syndrome. We have previously reported alterations in vascular prostanoids (PR) in this model. The aim of this study was to analyse the effects of metformin treatment on blood pressure, metabolic parameters and PR production in aorta and mesenteric vascular bed (MVB) from fructose-overloaded animals. Four groups of male Sprague-Dawley rats were used: control, fructose overloaded (10% w/v fructose), metformin treated (50 mg kg(-1) day(-1) ) and fructose-overloaded treated with metformin. Rats with fructose overload had significantly elevated systolic blood pressure, glycaemia, triglyceridaemia, cholesterolaemia and insulinaemia compared with controls. Except for insulinaemia, metformin limited all these increases in fructose-overloaded animals. Fructose overload reduced prostacyclin levels in aorta and MVB, but prostaglandin E(2) levels were only reduced in MVB. Metformin treatment reduced the levels of the vasoconstrictor prostaglandins, PGF(2) α and thromboxane, in both vascular preparations from fructose-overloaded rats. PGF(2) α levels were significantly reduced by metformin in controls. In conclusion, one of the mechanisms by which metformin reduced blood pressure in this model is by decreasing vasoconstrictor prostaglandin production.

Sodium molybdate prevents hypertension and vascular prostanoid imbalance in fructose-overloaded rats

(1) Fructose (F) overload produces elevated blood pressure (BP), hyperglycaemia, hypertriglyceridemia and insulin resistance, resembling human metabolic syndrome. Previously, we found altered vascular prostanoid (PR) production in this model. (2) Sodium molybdate (Mo), as well as sodium tungstate, causes insulin-like effects and normalizes plasma glucose levels in streptozotocin-treated diabetic rats. We studied the effects of Mo on BP, metabolic parameters and release of PR from the mesenteric vascular bed (MVB) in F-overloaded rats. (3) Four groups of male Sprague-Dawley rats were analysed: Control, tap water to drink; F, F solution 10% W/V to drink; CMo, Mo 100 mg kg day(-1) and FMo, both treatments. After 9 weeks, the animals were killed and MVBs removed and the released PRs measured. (4) F increased BP, glycemia, triglyceridemia and insulinemia. Mo treatment prevented the increases in BP and glycemia, but did not modify triglyceridemia or insulinemia. In addition, Mo decreased BP in controls. (5) Prostaglandins (PG) F2 alpha and E2, PG 6-ketoF1 alpha and thromboxane (TX) B2 , as well as inactive metabolites of prostacyclin (PGI2 ) and TXA2 were detected. F decreased the production of vasodilator PRs PGI2 and PGE2 in MVB. Mo prevented these alterations and increased PGE2 in controls. Vasoconstrict or PRs PGF2 alpha and TXA2 release was not modified. (6) Mo treatment, beyond its known lowering effect on glycemia, prevents the reduction in the vascular release of vasodilator PR observed in this model. This could be one of the mechanisms by which Mo avoids the increase in BP caused by F overload in the rat.

[PP.12.03] EFFECTS OF LOSARTAN ON PROSTANOIDS RELEASE IN TWO MODELS OF METABOLIC ALTERATION IN THE RAT

Objective: Fructose-overload and high-fat diet in rats are experimental models that resemble human metabolic syndrome. This multifactorial alteration is associated to hypertension. The systemic renin-angiotensin system plays an important role in the regulation of vascular tone. Prostanoids (PR) are endogenous substances derived from arachidonic acid via the cyclooxygenases with vasoactive effects. The aim of this study was to analyze the effects of losartan (L, angiotensin 1 receptor antagonist) on prostanoids (PR) release by the mesenteric vascular bed (MVB) in both models of dietary alteration. Design and method: Six groups (n = 6) of male Sprague-Dawley rats were studied during 9 weeks: Control (C), standard diet (SD) and tap water to drink; fructose-overloaded (F), SD and fructose solution (10% W/V) to drink; HF diet (HF), 50% (w/w) bovine fat added to SD and tap water; C + L (CL), SD + 30 mg/Kg/day L in the drinking water; F + L (FL) 30 mg/Kg/day L in the fructose solution; and HF + L (HFL) 30 mg/Kg/day L in the drinking water. MVBs were removed and incubated and the released PRs measured by HPLC. Results: F and HF increased systolic blood pressure (SBP, mmHg, 133 ± 3, 145 ± 5 vs. C: 116 ± 2, p < 0.01 and p < 0.001). In the FL and HFL groups, L decreased SBP (102 ± 5 vs. F, 111 ± 3 vs. HF, p < 0.001 and p < 0.01). F diminished prostaglandin (PG) 6-ketoF1alpha, stable metabolite of the vasodilator prostacyclin (PGI2), (ng PR/mg tissue, 58 ± 11 vs. C: 98 ± 8, p < 0.05); and PGE2 (ng/mg, 35 ± 7 vs. C: 87 ± 6, p < 0.01). HF diet increased thromboxane (TX) B2, stable metabolite of the vasoconstrictor TXA2, (ng PR/mg tissue, 111 ± 5 vs. C: 64 ± 7, p < 0.001); and PGF2alpha (150 ± 10 vs. C: 83 ± 8, p < 0.01). In the FL group, L increased PG6-ketoF1alpha (117 ± 10 vs. F, p < 0.05) and PGE2 (104 ± 11 vs. F, p < 0.01). In the HFL group, L decreased TXB2 (66 ± 7 vs. HF, p < 0.01); and PGF2alpha (90 ± 7 vs. HF, p < 0.05). Conclusions: In conclusion, one of the possible mechanisms by which L reduced blood pressure in these models could be an improvement of endothelial function through a regulation of PR release which produced a decrease in vasoconstriction.