Pre-eclampsia (PE)-induced fetal programming predisposes offspring to health hazards in adult life. Here, we tested the hypothesis that pre-eclamptic fetal programming elicits sexually dimorphic inflammatory and cardiovascular complications to endotoxemia in adult rat offspring. PE was induced by oral administration of L-NAME (50 mg/kg per day for seven consecutive days) starting from day 14 of conception. Cardiovascular studies were performed in conscious adult male and female offspring preinstrumented with femoral indwelling catheters. Compared with non-PE male counterparts, intravenous administration of lipopolysaccharide (LPS, 5 mg/kg) to PE male offspring caused significantly greater 1) falls in blood pressure, 2) increases in heart rate, 3) rises in arterial dP/dtmax, a correlate of left ventricular contractility, and 4) decreases in time-and frequency-domain indices of heart rate variability (HRV). By contrast, the hypotensive and tachycardic actions of LPS in female offspring were independent of the pre-eclamptic state and no clear changes in HRV or dP/dtmax were noted. Measurement of arterial baroreflex activity by vasoactive method revealed no sex specificity in baroreflex dysfunction induced by LPS. Immunohistochemical studies showed increased protein expression of toll-like receptor 4 in heart as well as in brainstem neuronal pools of the nucleus of solitary tract and rostral ventrolateral medulla in endotoxic PE male, but not female, offspring. Enhanced myocardial, but not neuronal, expression of monocyte chemoattractant protein-1 was also demonstrated in LPS-treated male offspring. Together, pre-eclamptic fetal programming aggravates endotoxic manifestations of hypotension and autonomic dysfunction in male offspring via exacerbating myocardial and neuromedullary inflammatory pathways. SIGNIFICANCE STATEMENTCurrent molecular and neuroanatomical evidence highlights a key role for pre-eclamptic fetal programming in offspring predisposition to health hazards induced by endotoxemia in adult life. Pre-eclampsia accentuates endotoxic manifestations of hypotension, tachycardia, and cardiac autonomic dysfunction in male offspring via exacerbating myocardial and central inflammatory pathways. The absence of such detrimental effects in female littermates suggests sexual dimorphism in the interaction of pre-eclamptic fetal programming with endotoxemia.

The nicotinic/cholinergic antiinflammatory pathway plays integral roles in physiological and pathological regulation of inflammation. In this study, we tested the hypotheses that (i) nicotine guards against hemodynamic and renal vasoconstrictor dysfunction induced by endotoxemia in rats, and (ii) the α7‐nAChRs/heme oxygnase (HO) pathway constitutes a go‐between for the LPS‐nicotine interaction. Hemodynamic or renovascular functions were assessed 6 hr after i.p. administration of lipopolysaccharide (LPS, 5 mg/kg) with or without nicotine. LPS caused significant falls in systolic blood pressure (SBP) and reductions in cumulative renal vasoconstrictions induced by bolus injections of phenylephrine (PE, 0.002 – 4.42 nmol) or vasopressin (VP, 0.00092 – 0.27 nmol) into isolated perfused kidneys. LPS hypotension was demonstrated in both male and female rats, whereas the attenuation of renal vasoconstrictions was seen in male rats only. The reduced PE or VP responsiveness was reversed in preparations pretreated with nicotine (0.5, 1 and 2 mg/kg) in a dose‐dependent manner. This favorable action of nicotine disappeared after blockade of α7‐nAChRs (methyllycaconitine citrate, 2 mg/kg) or inhibition of HO‐1 (zinc protoporphyrin, 10 mg/kg). Moreover, the LPS attenuation of renal vasoconstrictions was improved upon concurrent treatment with pentoxfylline (TNFα inhibitor, 3 mg/kg), hemin (HO‐1 inducer, 10 mg/kg), tricarbonyldichlororuthenium (II) dimer (carbon monoxide‐releasing molecule, 10 mg/kg), in contrast to no effect for bilirubin (5 mg/kg). These data establish the first evidence that implicate the α7‐nAChRs/HO‐1/CO in the nicotine counteraction of renal vasoconstrictor hyporeactivity in endotoxemia. Support or Funding Information Supported by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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