Nebulised Magnesium Sulphate In Conscious Guinea-Pigs – Bronchodilator And Bronchoprotective?

Dawn Turner1, William Ford1, Emma Kidd1, Colin Powell2, Kenneth Broadley1. 1Cardiff University, Welsh School of Pharmacy, Cardiff, UK, 2Cardiff University School of medicine, Cardiff, UK

Asthma is a chronic inflammatory disease of the airways affecting more than 5million people in the UK and leads to more than 70,000 hospital admissions each year. Intravenous magnesium sulphate (MgSO4) as an add-on therapy in the emergency department improves lung function and reduces hospital admissions in acute severe asthma (Bloch et al, 1995). However, this route of administration can lead to significant side-effects including vasodilatation and systolic hypotension. Although evidence has been conflicting, nebulised MgSO4 in acute severe asthma has also demonstrated a potent bronchodilator effect without significant side-effects and reduced the risk of admission to hospital (Gallegos-Solórzano et al, 2010). The aims of this study were to examine the effects of nebulised MgSO4 against histamine-induced bronchoconstriction in conscious guinea-pigs and in an animal model of asthma.

Naïve, male, Dunkin-Hartley guinea-pigs (350-400g, N = 6) were challenged with 0.5mM histamine 24hrs pre- and 0.25hrs post-treatment with nebulised MgSO4 (250mmol, 15mins). Whole-body plethysmography was used to measure specific airway conductance (sGaw) 0, 5 and 10min after the histamine challenge. Groups of 6 male, Dunkin-Hartley guinea-pigs (300g) were sensitised to ovalbumin on days 1, 4 and 7, receiving an intra-peritoneal bilateral injection of 1ml of a solution containing ovalbumin (0.3mg) and Al(OH)3 (100mg). On day 19 animals were treated with nebulised MgSO4 (250mMol) or saline for 15mins. 15mins after completion of this exposure, animals were challenged with nebulised ovalbumin (0.03%) for 1hr. sGaw was measured immediately after the ovalbumin challenge, every 15mins for the first hour and then every hour for 12hrs. Airway hyper-responsiveness (AHR) to inhaled histamine (0.3mM) was examined 24hrs before and 24hrs after the ovalbumin challenge. After the final histamine challenge animals were sacrificed and a bronchoalveolar lavage was performed.

MgSO4 (250mmol) increased baseline sGaw values in naïve guinea-pigs by 21.8+12.8% (increasing sGaw from 0.28+0.8 pre-treatment to 0.36+0.8 post-treatment) and inhibited histamine-induced bronchoconstriction by 40.8+5.3%.

Sensitised guinea-pigs challenged with nebulised ovalbumin exhibited an immediate early asthmatic response (EAR) of -64.0+4.3% and a late asthmatic response (LAR) 7hrs later of -25.9+3.7%. The EAR was significantly reduced (-32.3+9.3%) in animals treated with nebulised MgSO4 (Unpaired t-test; p<0.01) but the LAR (-17.9+3.1%) was not different. Total cell counts were not different between the MgSO4 treated animals (9.2+0.13x106) and saline treated 8.35+0.91x106), however; the number of macrophages was significantly lower in MgSO4-treated animals (1.86+0.21x106) compared to saline (2.75+0.62x106); p<0.05, Unpaired t-test.

MgSO4 produced an increase in baseline sGaw values and also protected against histamine-induced bronchoconstriction in conscious guinea-pigs. Bronchoconstriction in response to nebulised ovalbumin in sensitised guinea-pigs was also inhibited by MgSO4. These data suggest that MgSO4 can cause bronchodilatation following different bronchoconstrictor stimuli which may explain its beneficial clinical effects.

Bloch et al, Chest 1995; 107:1576-81

Gallegos-Solórzano et al, Pulm Pharmcol & Therapeutics 2010; 23: 432-437