Effect of the calcium antagonist, diltiazem, on beta-agonist-induced reduction of beta-adrenergic responsiveness in the guinea pig lung.
This study was designed to clarify the mechanism of tolerance that occurs during prolonged administration of a beta-agonist in relation to membrane phospholipid degradation and to elucidate the effect of diltiazem, a calcium antagonist. Guinea pigs were divided into 3 groups: (1) control--physiological saline (0.5 ml) was injected once a day for 7 successive days: (2) metaproterenol (Mp)--Mp was injected intraperitoneally (10 mg/kg/day) for 7 successive days: (3) Mp + diltiazem--diltiazem was injected intraperitoneally (20 mg/kg/day) 30 min before Mp injection for 7 successive days. The number of beta-adrenoceptors and the 10(5)M (-)-isoproterenol-stimulated adenylate cyclase activity were significantly decreased in the metaproterenol group. Diltiazem reduced these decreases. Phospholipase activity was increased and phosphatidylcholine and phosphatidylethanolamine levels were decreased in the metaproterenol group. Diltiazem also reduced these changes. These results suggest that the degradation of membrane phospholipids by phospholipase may be involved in a decrease in beta-adrenergic response caused by successive administration of metaproterenol. Diltiazem protects membrane phospholipids from phospholipase attack, which in turn maintains beta-adrenergic responsiveness.
Taki
F
F
Department of Internal Medicine, Faculty of Medicine, University of Nagoya, Japan.
Hayashi
K
K
Sugiyama
S
S
Satake
T
T
Ozawa
T
T
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D004110:Diltiazem / Q000494:pharmacology*; D006168:Guinea Pigs; D008168:Lung / Q000032:analysis / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D009921:Metaproterenol / Q000494:pharmacology*; D010740:Phospholipases / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D008563:Membrane Lipids; D010743:Phospholipids; D011943:Receptors, Adrenergic, beta; D009921:Metaproterenol; D010740:Phospholipases; D000262:Adenylyl Cyclases; D004110:Diltiazem