1 results for Diong, Crystal Theerin, Undergraduate, 2014

  • Sympathetic hyperexcitation in obesity may be protective against pulmonary hypertension

    Diong, Crystal Theerin (2014)

    Undergraduate thesis
    University of Otago

    Pulmonary hypertension (PH) is a disease characterised by an elevation of mean pulmonary arterial pressure due to excessive vasoconstriction and pulmonary arterial remodelling. Despite the many negative health implications of obesity, epidemiological evidence suggests the presence of an ‘obesity paradox’ in PH, whereby obesity is associated with a lower mortality rate in patients with PH. The physiological mechanism underpinning this paradox is currently unknown. However, it is well established that pulmonary sympathetic nerve activity (pSNA) is an important modulator of pulmonary arterial pressure due to β-adrenergic mediated vasodilation of pulmonary vessels. Sympathetic hyperexcitation, or increased SNA in obesity has been shown to occur in some organ systems but has yet to be investigated in the lungs. Thus, this study aimed explore whether pSNA is increased in obesity and PH and if so, whether pSNA plays a greater role in vasodilating pulmonary vasculature in obesity with or without PH. Experiments were performed on four groups of anaesthetised male Zucker rats: lean control rats (lean-C), lean rats with PH (lean-PH), obese control rats (obese-C), and obese rats with PH (obese-PH). In vivo electrophysiology experiments directly recorded activity from the pulmonary sympathetic nerve in order to establish any differences in pSNA in obesity and PH. The pSNA in obese-C animals (2.4 ± 0.4 µV.s, mean ± SEM, n = 7) was significantly elevated compared to lean-C animals (0.5 ± 0.1 µV.s, P < 0.001, n = 7) while the pSNA in the obese-PH group (7.1 ± 2.5 µV.s, n = 4), was also significantly greater compared to their lean counterparts (lean-PH, 2.0 ± 2.5 µV.s, P < 0.01, n = 4). The development of PH was also associated with a 3-fold increase in pSNA in obese rats (P < 0.05). To determine the effect of differing pSNA on vessel diameter, synchrotron radiation microangiography was performed. This technique facilitated the visualisation of dynamic changes in vessel internal diameter during acute hypoxic pulmonary vasoconstriction (HPV, 8% O2 for 5 minutes), before β-adrenoceptor (β-AR) blockade, after β1-AR blockade (atenolol, 3 mg/kg) and after combined β1- and β2-AR blockade (propranolol, 2 mg/kg). Before β-AR blockade, the magnitudes of HPV were similar between all experimental groups. After β1-AR blockade, a greater magnitude of vasoconstriction was observed in the obese-C animals compared to lean-C. Upon combined β1- and β2-AR blockade, the magnitudes of HPV in obese animals both with and without PH (obese-PH, 33 ± 4% and obese-C, 24 ± 4%) were significantly exacerbated compared to their lean counterparts (lean-PH, 16 ± 3% and lean-C, 12 ± 3%, P < 0.05). These differences were primarily observed in resistance arterioles (< 300 µm), critical in modulating pulmonary arterial pressure. This study shows for the first time, differential sympathetic regulation of pulmonary vascular tone in obesity and PH. Sympathetic hyperexcitation in obese rats, both with and without PH plays a larger role in ‘protecting’ the pulmonary vasculature against constriction during HPV compared to lean counterparts, suggesting sympathetic hyperexcitation in obesity may be a potential mechanism underlying the obesity paradox in PH.

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