Relaxant effect of magnesium and zinc on histamine-induced bronchoconstriction in dogs.
OBJECTIVE
Magnesium sulfate (MgSO4) has been reported to produce bronchodilation in asthmatic patients. In vitro studies have suggested that divalent cations inhibit L-type voltage-sensitive calcium ion (Ca2+) channels in cardiac and smooth muscles. In this study, we evaluated the in vitro and in vivo effects of magnesium ion (Mg2+) and zinc ion (Zn2+) on the airway contracted by histamine.


METHODS
A university research laboratory.


METHODS

Tracheal smooth muscle from guinea pigs.
Mongrel dogs.


RESULTS

The tension of isolated guinea pig tracheal strips was measured isometrically with a force displacement transducer. The specimen was contracted with histamine (10 microM). Then, MgSO4 (n = 6), zinc sulfate (ZnSO4, n = 6), or sodium sulfate (Na2SO4, n = 6) was cumulatively added to the organ bath.
The bronchial cross-sectional area of mongrel dogs was measured by a direct visualization method demonstrated previously. The dogs were randomly assigned to three groups: group Mg (n = 7), group Zn (n = 7), and group Na (n = 7). Bronchoconstriction was elicited with histamine (10 microg/kg plus 500 microg/kg/hr iv). Thirty minutes after the start of histamine infusion, 0 (saline), 1, 10, and 100 micromol/kg ZnSO4 or 1, 10, 100, and 1000 micromol/kg MgSO4 or Na2SO4 were administered intravenously in group Zn, Mg, or Na, respectively. The bronchial cross-sectional area was assessed before (basal) and 30 mins after the start of histamine infusion and 5 mins after each dose of ZnSO4, MgSO4, or Na2SO4. Arterial blood was also obtained to measure plasma levels of epinephrine and norepinephrine by gas chromatography-mass spectrometry. All data are expressed as mean +/- SEM. The doses of the divalent cations that reversed histamine-induced contraction by 50% were calculated by GraphPad Prism. MgSO4 and ZnSO4 (9.38+/-0.28 and 1.84+/-0.30 mM, respectively) relaxed histamine-contracted tracheal strip in a concentration-dependent manner, whereas Na2SO4 did not. Similarly, the in vivo study showed that MgSO4 and ZnSO4 dose-dependently reversed histamine-induced bronchoconstriction (potency, ZnSO4 > MgSO4), whereas Na2SO4 did not. In groups Mg and Zn, the plasma catecholamine levels also dose-dependently increased except when 1000 micromol/kg MgSO4 was administered.


CONCLUSIONS
Because the divalent cations tested produced a spasmolytic effect on the contracted airway, infusion of divalent cations might be effective against asthmatic attack. However, high concentrations of these cations produce significant toxicity, so dosage will be an important concern in development of these agents.
Hirota
K
K
Department of Anesthesiology, University of Hirosaki School of Medicine, Japan.
Sato
T
T
Hashimoto
Y
Y
Yoshioka
H
H
Ohtomo
N
N
Ishihara
H
H
Matsuki
A
A
D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D001999:Bronchoscopy; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D002413:Cations, Divalent / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000097:blood; D006168:Guinea Pigs; D006632:Histamine; D007262:Infusions, Intravenous; D008278:Magnesium Sulfate / Q000008:administration & dosage / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects; D009638:Norepinephrine / Q000097:blood; D011897:Random Allocation; D013431:Sulfates / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects; D019287:Zinc Sulfate / Q000008:administration & dosage / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D002413:Cations, Divalent; D013431:Sulfates; C012036:sodium sulfate; D008278:Magnesium Sulfate; D019287:Zinc Sulfate; D006632:Histamine; D009638:Norepinephrine; D004837:Epinephrine