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العنوان
Nicotine Interaction with Sex-Related Hemodynamic and Inflammatory Influences of Endotoxemia in Rats /
المؤلف
ElLakany, Mohammed Abd alla.
هيئة الاعداد
باحث / محمد عبدالله محمد اللقا
مشرف / محمود محمد محمود الماس
مشرف / حنان سمير الجويلي
مشرف / محمد امين فوده
الموضوع
Nicotine - .Interaction Pharmacology. Toxicology.
تاريخ النشر
2019.
عدد الصفحات
132 p. :
اللغة
الإنجليزية
الدرجة
ماجستير
التخصص
العلوم الصيدلية
تاريخ الإجازة
1/1/2019
مكان الإجازة
جامعة الاسكندريه - كلية الصيدلة - (علم الأدوية و السموم)
الفهرس
Only 14 pages are availabe for public view

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from 163

Abstract

Sepsis is a clinical condition accompanied by a gender-specific generalized inflammatory response to infection with possibly lethal complications. The female gender is better positioned to combat septic insults.
Pharmacologic, biochemical, and protein expression studies were employed in the current investigation to evaluate gender and hormonal modulation of cardiovascular, autonomic and inflammatory responses to LPS.
The dose-related effects of nicotine on endotoxic responses in female rats and underlying mechanisms have been also investigated. Experiments were performed in conscious freely moving male and female (sham and OVX) rats pre-instrumented with intravascular (femoral) cannulas.
A summary of novel findings and conclusions of the study is outlined below. 1.Cardiovascular, inflammatory and autonomic features of endotoxemia were evident in male rats such as significant elevations in serum TNFα, falls in MAP, tachycardia, and cardiac autonomic dysfunction.
The latter was evidenced by the reductions in total power of spectral analysis of HRV and LF/HF ratio of spectral HRV indices, signifying predominance of the cardiac parasympathetic control. None of these effects was observed in age-matched female rats.
2.Intact and functional ERβ and progesterone receptors play integral roles in offsetting inflammatory and cardiovascular derangements caused by endotoxemia in female rats.
This viewpoint receives support from the following findings obtained from receptor antagonist studies: (i) pretreatment of female rats with fulvestrant (nonselective ER blocker), PHTPP (ERβ blocker), mifepristone (progesterone receptor blocker), formestane (aromatase inhibitor), but not MPP (ERα blocker), uncovered inflammatory and cardiovascular responses to LPS that mimicked those observed in endotoxic male rats, and (ii) TNFα inhibition by PTX eliminated the falls in BP and cardiac autonomic dysregulation caused by LPS in fulvestrant-treated female rats.
3.In male rats, androgen receptor blockade by flutamide variably modulated hemodynamic and cardiac autonomic responses elicited by endotoxemia. Flutamide accentuated the hypotensive response to endotoxemia, but completely abolished the associated cardiac parasympathetic dominance and rises in serum TNFα.
4.The effects of ovarian hormone depletion (bilateral OVX) and repletion on endotoxic manifestations were evaluated.
While having no effect in sham rats, LPS treatment of OVX rats caused robust elevations in ventricular and aortic expressions of NFκB and iNOS, hypotension, and cardiac autonomic and baroreflex dysfunctions, suggesting key roles for endogenous gonadal hormones in guarding against the endotoxic offense.
Supplementation of OVX rats with E2 caused more obvious counteraction of inflammatory and cardiovascular influences of endotoxemia than MPA. Moreover, PPT (ERα agonist) was more effective
Summary and Conclusions 98 than DPN (ERβ agonist) in ameliorating the inflammatory and cardiovascular insults induced by endotoxemia in OVX rats.
5.LPS produced a 3-fold increase in HSP70 expression in ventricular and aortic tissues of sham, but not OVX, rats.
The elevated tissue HSP70 may have served as an adaptive mechanism that diminished the inflammatory response and cardiovascular damage induced by endotoxemia in sham rats.
A defensive role for HSP70 is further validated by the observations that similar increases in ventricular and aortic HSP70 expressions were noted upon supplementation of endotoxic OVX rats with estrogenic drugs (E2, PPT, and DPN).
6.While the individual treatment of female rats with LPS or nicotine elicited no cardiovascular changes, rats treated simultaneously with the two drugs exhibited significant reductions in BP and increases in cardiac sympathetic dominance. Mechanistic studies implicate estrogen withdrawal and iNOS-derived NO in cardiovascular complications induced by the combined LPS/nicotine regimen in female rats.
7.Clinically, the current study provides insights on the possibility of exploiting female gonadal hormones or selective ER agonists as therapeutic modalities against endotoxic manifestations of hypotension and cardiac autonomic dysfunction.