Browsing by Author "Giachini, Fernanda Regina Casagrande"

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    Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension.
    (2008) Carneiro, Fernando Silva; Nunes, Kenia Pedrosa; Giachini, Fernanda Regina Casagrande; Lima, Victor Vitorino; Carneiro, Zidonia N.; Nogueira, Edson F.; Leite, Romulo; Ergul, Adviye; Rainey, William E.; Webb, Robert Clinton; Tostes, Rita de Cassia Aleixo
    Introduction. The cavernosal tissue is highly responsive to endothelin-1 (ET-1), and penile smooth muscle cells not only respond to but also synthesize ET-1. Aim. Considering that ET-1 is directly involved in end-organ damage in salt-sensitive forms of hypertension, we hypothesized that activation of the ET-1/ETA receptor pathway contributes to erectile dysfunction (ED) associated with mineralocorticoid hypertension. Methods. Wistar rats were uninephrectomized and submitted to deoxycorticosterone acetate (DOCA)-salt treatment for 5 weeks. Control (Uni [uninephrectomized control]) animals were uninephrectomized and given tap water. Uni and DOCA-salt rats were simultaneously treated with vehicle or atrasentan (ETA receptor antagonist, 5 mg/ Kg/day). Cavernosal reactivity to ET-1, phenylephrine (PE), ETB receptor agonist (IRL-1620) and electric field stimulation (EFS) were evaluated in vitro. Expression of ROCKa, ROCKb, myosin phosphatase target subunit 1 (MYPT-1), and extracellular signal-regulated kinase 1/2 (ERK 1/2) were evaluated by western blot analysis. ET-1 and ETA receptor mRNA expression was evaluated by real-time reverse-transcriptase polymerase chain reaction. Voltage-dependent increase in intracavernosal pressure/mean arterial pressure (ICP/MAP) was used to evaluate erectile function in vivo. Main Outcome Measure. ETA receptor blockade prevents DOCA-salt-associated ED. Results. Cavernosal strips from DOCA-salt rats displayed augmented preproET-1 expression, increased contractile responses to ET-1 and decreased relaxation to IRL-1620. Contractile responses induced by EFS and PE were enhanced in cavernosal tissues from DOCA-salt hypertensive rats. These functional changes were associated with increased activation of the RhoA/Rho-kinase and ERK 1/2 pathways. Treatment of rats with atrasentan completely prevented changes in cavernosal reactivity in DOCA-salt rats and restored the decreased ICP/MAP, completely preventing ED in DOCA-salt rats. Conclusion. Activation of the ET-1/ETA pathway contributes to mineralocorticoid hypertension-associated ED. ETA receptor blockade may represent an alternative therapeutic approach for ED associated with salt-sensitive hypertension and in pathological conditions where increased levels of ET-1 are present.
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    Adenosine actions are preserved in corpus cavernosum from obese and type II diabetic db/db mouse.
    (2008) Carneiro, Fernando Silva; Giachini, Fernanda Regina Casagrande; Lima, Victor Vitorino; Neotzold, Zidonia Nunes; Leite, Romulo; Inscho, Edward W.; Passaglia, Rita de Cassia Aleixo Tostes; Webb, Robert Clinton
    Introduction—Erectile dysfunction (ED) in diabetes is associated with autonomic neuropathy and endothelial dysfunction. Whereas the nonadrenergic-noncholinergic (NANC)/neurogenic nitric oxide pathway has received great attention in diabetes-associated ED, few studies have addressed sympathetic overactivity. Aim—To test the hypothesis that adenosine-induced inhibition of adrenergic-mediated contractile responses in mouse corpus cavernosum is impaired in the presence of diabetes. Methods—The db/db (obesity and type II diabetes caused by a leptin receptor mutation) mouse strain was used as a model of obesity and type II diabetes, and standard procedures were performed to evaluate functional cavernosal responses. Main Outcome Measures—Increased cavernosal responses to sympathetic stimulation in db/ db mice are not associated with impaired prejunctional actions of adenosine. Results—Electrical field stimulation (EFS)-, but not phenylephrine (PE)-, induced contractions are enhanced in cavernosal strips from db/db mice in comparison with those from lean littermates. Direct effects of adenosine, 2-chloro-adenosine, A1 receptor agonist C-8031 (N6 cyclopentyladenosine), and sodium nitroprusside are similar between the strips from lean and db/ db mice, whereas relaxant responses to acetylcholine and NANC stimulation are significantly impaired in the cavernosal strips from db/db mice. 5′-Iodotubercidin (adenosine kinase inhibitor) and dipyridamole (inhibitor of adenosine transport), as well as the A1 agonist C-8031, significantly and similarly inhibit contractions induced by stimulation of adrenergic nerves in the cavernosal strips from lean and db/db mice. Conclusions—Results from this study suggest that corpora cavernosa from obese and diabetic db/db mice display altered neural-mediated responses that would favor penile detumescence, i.e., increased contractile response to adrenergic nerve stimulation and decreased relaxant responses upon activation of NANC nerves. However, increased cavernosal responses to adrenergic nerve stimulation are not due to impaired negative modulation of sympathetic neurotransmission by adenosine in this diabetic model.
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    Anti-Platelet therapy with clopidogrel prevents endothelial dysfunction and vascular remodeling in aortas from hypertensive rats.
    (2014) Giachini, Fernanda Regina Casagrande; Leite, Romulo; Osmond, David A.; Lima, Victor Vitorino; Inscho, Edward W.; Webb, Robert Clinton; Tostes, Rita de Cassia Aleixo
    The aim was to investigate the beneficial effects of clopidogrel in thoracic aorta function and structure and to characterize if P2Y12 receptors contribute to these effects. Male Sprague Dawley rats were infused with angiotensin II [(Ang II) 60 ng.min21, 14 days] or saline (control rats) and were simultaneously treated with clopidogrel (10 mg.kg21.day21) or vehicle. After 14 days, systolic blood pressure (mmHg) was similar in Ang II-hypertensive rats treated with clopidogrel or vehicle (19969 vs. 190611, respectively). Systolic blood pressure in control rats was not altered by clopidogrel treatment (12861 vs. vehicle, 13462). Endothelium-dependent relaxation induced by 2-MeS-ADP was decreased in aortas from vehicle-treated Ang II-hypertensive rats, compared to vehicle-treated control rats. This response was elicited via activation of P2Y1 and P2Y12 receptors. In the presence of L-NAME and indomethacin, 2-MeS-ADP induced contraction and this response was augmented in vehicle-treated Ang II-hypertensive rats, compared to vehicle-treated control rats. The contraction to 2-MeS-ADP was evoked by P2Y13 and P2Y12 receptor activation. Clopidogrel-treatment did not normalize relaxation or contractile responses induced by 2-MeS-ADP in aortas from Ang II-hypertensive rats. P2Y1 and P2Y12 protein expression was increased, whereas P2Y13 receptor expression was reduced in aorta from vehicle-treated Ang II-hypertensive rats. Endothelium-dependent relaxation upon acetylcholine-stimulation was reduced in vehicle-treated Ang II-hypertensive rats, and clopidogrel treatment was effective in improving endothelial function. Clopidogrel also prevented vascular remodeling, evidenced by augmented media thickness in aortas from Ang II-hypertensive rats. Clopidogrel has beneficial effects on the aortic endothelium of Ang II-hypertensive rats, but its effects do not seem to be directly related to the presence of P2Y12 receptors in this vessel.
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    Cigarette smoking and erectile dysfunction : focus on NO bioavailability and ROS generation.
    (2008) Tostes, Rita de Cassia Aleixo; Carneiro, Fernando Silva; Lee, Anthony; Giachini, Fernanda Regina Casagrande; Leite, Romulo; Osawa, Yoichi; Webb, Robert Clinton
    Introduction—Thirty million men in the United States suffer from erectile dysfunction (ED) and this number is expected to double by 2025. Considered a major public health problem, which seriously affects the quality of life of patients and their partners, ED becomes increasingly prevalent with age and chronic smoking is a major risk factor in the development of ED. Aim—To review available evidence concerning the effects of cigarette smoking on vascular changes associated with decreased nitric oxide (NO) bioavailability and increased reactive oxygen species (ROS) generation.Methods—We examined epidemiological and clinical data linking cigarette smoking and ED, and the effects of smoking on vascular NO bioavailability and ROS generation. Main Outcome Measures—There are strong parallels between smoking and ED and considerable evidence supporting the concept that smoking-related ED is associated with reduced bioavailability of NO because of increased ROS. Results—Cigarette smoking-induced ED in human and animal models is associated with impaired arterial flow to the penis or acute vasospasm of the penile arteries. Long-term smoking produces detrimental effects on the vascular endothelium and peripheral nerves and also causes ultrastructural damage to the corporal tissue, all considered to play a role in chronic smokinginduced ED. Clinical and basic science studies provide strong indirect evidence that smoking may affect penile erection by the impairment of endothelium-dependent smooth muscle relaxation or more specifically by affecting NO production via increased ROS generation. Whether nicotine or other products of cigarette smoke mediate all effects related to vascular damage is still unknown. Conclusions—Smoking prevention represents an important approach for reducing the risk of ED. The characterization of the components of cigarette smoke leading to ED and the mechanisms by which these components alter signaling pathways activated in erectile responses are necessary for a complete comprehension of cigarette smoking-associated ED.
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    DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosum.
    (2008) Carneiro, Fernando Silva; Giachini, Fernanda Regina Casagrande; Lima, Victor Vitorino; Carneiro, Zidonia N.; Nunes, Kenia Pedrosa; Ergul, Adviye; Leite, Romulo; Tostes, Rita de Cassia Aleixo; Webb, Robert Clinton
    The penis is kept in the flaccid state mainly via a tonic activity of norepinephrine and endothelins (ETs). ET-1 is important in salt-sensitive forms of hypertension. We hypothesized that cavernosal responses to ET-1 are enhanced in deoxycorticosterone acetate (DOCA)-salt mice and that blockade of ETA receptors prevents abnormal responses of the corpus cavernosum in DOCA-salt hypertension. Male C57BL/6 mice were unilaterally nephrectomized and treated for 5 weeks with both DOCA and water containing 1% NaCl and 0.2% KCl. Control mice were uninephrectomized and received tap water with no added salt. Animals received either the ETA antagonist atrasentan (5 mg·day−1·kg−1 body weight) or vehicle. DOCA-salt mice displayed increased systolic blood pressure (SBP), and treatment with atrasentan decreased SBP in DOCA-salt mice. Contractile responses in cavernosal strips from DOCA-salt mice were enhanced by ET-1, phenylephrine, and electrical field stimulation (EFS) of adrenergic nerves, whereas relaxations were not altered by IRL-1620 (an ETB agonist), acetylcholine, sodium nitroprusside, and EFS of nonadrenergic noncholinergic nerves. PD59089 (an ERK1/2 inhibitor), but not Y-27632 (a Rho-kinase inhibitor), abolished enhanced contractions to ET-1 in cavernosum from DOCA-salt mice. Treatment of DOCA-salt mice with atrasentan did not normalize cavernosal responses. In summary, DOCA-salt treatment in mice enhances cavernosal reactivity to contractile, but not to relaxant, stimuli, via ET-1/ETA receptor-independent mechanisms.