Preeclampsia pravastatin early VS late treatment: Effects on oxidative stress and vascular reactivity.

Early diagnosis and efficient treatment of preeclampsia remains a medical challenge and etiological factors converge in a deficient placentation that triggers oxidative stress. There is evidence that statins show antioxidant effects that can improve endothelial function without adverse perinatal effects. We aimed to compare early vs. late pravastatin treatment on the oxidative stress and cardiovascular features of an experimental model of preeclampsia. Female Wistar rats were randomly divided into preeclampsia phenotype rats (PEP) developed by sub renal aortic coarctation (SRAC) and healthy pregnant rats (C). Each group received pravastatin (5 mg/Kg) p.o. either for one week before and during the first week or during the last two weeks of gestation. Blood pressure was determined using the plethysmographic method. Phenylephrine (Phe)-induced contractility was evaluated in isolated thoracic and abdominal aortic rings with or without endothelium. Blood samples were obtained to determine anion superoxide concentration as indicator of NADPH activity. Two-way ANOVA and Bonferroni post hoc tests were used to define statistical significance. Early or late pravastatin treatment decreased hypertension of PEP animals but did not change BP of the healthy pregnant group. Thoracic and abdominal aorta from PEP rats showed increased contractility that was reverted by pravastatin early treatment in endothelium intact rings. Pravastatin did not significantly change contractility neither in the thoracic nor in the abdominal aorta segments from healthy pregnant control rats (C), and decrease anion superoxide concentration by NADPH activity. We conclude pravastatin can improve both blood pressure and endothelium-dependent Phe-induced contractility in an experimental model of preeclampsia by reducing oxidative stress.

Divergent impact of gestational diabetes mellitus between the thoracic and abdominal rat aorta: Influence of endothelium and angiotensin II receptors.

Gestational diabetes mellitus (GDM) affects 5-10% of pregnancies and increases the risk of fetal and maternal adverse outcomes. Interestingly, the vascular response to AngII is decreased by pregnancy while the response is increased by diabetes. It remains unclear how GDM affects vascular tone and how angiotensin II receptors contribute to these changes. In this work, we sought to establish the vascular impact of a hypercaloric diet-induced GDM through changes in AT1 and AT2 receptor's expression. Female rats fed for 7 weeks with standard (SD) or hypercaloric (HD) diet were divided at week 4. Half of the rats of each group were mated to become pregnant and those fed with a HD developed GDM. AngII-induced vasoconstriction was measured in thoracic or abdominal aorta rings using a conventional isolated organ bath and AT1 and AT2 receptors were searched by immunohistochemistry. Experiments where conducted on the pregnant standard diet group (PSD) and the pregnant hypercaloric-gestational diabetes mellitus group (PHD-GDM). Vasoconstriction was reduced in the thoracic aorta (P < 0.05 vs PSD) but increased in the abdominal aorta of PHD-GDM rats (P < 0.05 vs PSD). Blockade of AT2 receptors using PD123319 decreased vasoconstriction, particularly in the abdominal aorta of PHD-GDM animals (P < 0.05 vs PSD). PHD-GDM increased AT1 receptors expression (P < 0.05 vs PSD). Also, PHD-GDM reverted physiologic hypoglycemia and hypotension of healthy pregnancy. Findings provide new insight into the hypercaloric diet induced damage on the vasculature during pregnancy.

Evidence of changes in alpha-1/AT1 receptor function generated by diet-induced obesity.

To study whether hypercaloric diet-induced obesity deteriorates vascular contractility of rat aorta through functional changes in α1 adrenergic and/or AT1 Angiotensin II receptors. Angiotensin II- or phenylephrine-induced contraction was tested on isolated aorta rings with and without endothelium from female Wistar rats fed for 7 weeks with hypercaloric diet or standard diet. Vascular expression of Angiotensin II Receptor type 1 (AT1R), Angiotensin II Receptor type 2 (AT2R), Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), inducible Nitric Oxide Synthase (iNOS) and endothelial Nitric Oxide Synthase (eNOS), as well as blood pressure, glucose, insulin and angiotensin II blood levels were measured. Diet-induced obesity did not significantly change agonist-induced contractions (Emax and pD2 hypercaloric diet vs standard diet n.s.d.) of both intact (e+) or endothelium free (e-) vessels but significantly decrease both phenylephrine and angiotensin II contraction (Emax p < 0.01 hypercaloric diet vs standard diet) in the presence of both prazosin and losartan but only in endothelium-intact vessels. Diet-induced obesity did not change angiotensin II AT1, AT2 receptor proteins expression but reduced COX-1 and NOS2 ( p < 0.05 vs standard diet). Seven-week hypercaloric diet-induced obesity produces alterations in vascular adrenergic and angiotensin II receptor dynamics that suggest an endothelium-dependent adrenergic/angiotensin II crosstalk. These changes reflect early-stage vascular responses to obesity.

Experimental gestational diabetes mellitus induces blunted vasoconstriction and functional changes in the rat aorta.

Diabetic conditions increase vascular reactivity to angiotensin II in several studies but there are scarce reports on cardiovascular effects of hypercaloric diet (HD) induced gestational diabetes mellitus (GDM), so the objective of this work was to determine the effects of HD induced GDM on vascular responses. Angiotensin II as well as phenylephrine induced vascular contraction was tested in isolated aorta rings with and without endothelium from rats fed for 7 weeks (4 before and 3 weeks during pregnancy) with standard (SD) or hypercaloric (HD) diet. Also, protein expression of AT1R, AT2R, COX-1, COX-2, NOS-1, and NOS-3 and plasma glucose, insulin, and angiotensin II levels were measured. GDM impaired vasoconstrictor response (P < 0.05 versus SD) in intact (e+) but not in endothelium-free (e-) vessels. Losartan reduced GDM but not SD e- vasoconstriction (P < 0.01 versus SD). AT1R, AT2R, and COX-1 and COX-2 protein expression were significantly increased in GDM vessels (P < 0.05 versus SD). Results suggest an increased participation of endothelium vasodilator mediators, probably prostaglandins, as well as of AT2 vasodilator receptors as a compensatory mechanism for vasoconstrictor changes generated by experimental GDM. Considering the short term of rat pregnancy findings can reflect early stage GDM adaptations.