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Influence of drugs that block calcium channels on the microbicidal function of human neutrophils
Abstract:
The central role of calcium ions in cell physiology prompted us to examine the hypothesis that pharmacological concentrations of calcium channel-blocking drugs might affect human neutrophil (PMN) functions. The capacity of PMNs suspended in verapamil hydrochloride for killing Pseudomonas aeruginosa during two hour incubations was significantly impaired (P less than .05). Several observations suggested that this drug effect was the result of altered calcium metabolism: exposure to verapamil decreased the uptake of 45Ca++ by PMNs subsequently exposed to the calcium ionophore A23187; verapamil did not impair PMN function in the absence of extracellular calcium; and the addition of A23187 concomitantly with (but not following) verapamil prevented PMN dysfunction. In addition, nifedipine, a structurally dissimilar calcium channel-blocking drug, also impaired the bactericidal activity of PMNs against Pseudomonas aeruginosa (P less than .02). Further studies revealed that treatment with verapamil did not affect PMN phagocytosis, but significantly impaired the PMN respiratory burst (as shown by superoxide anion generation assay; P less than .05). We conclude that PMNs exposed to pharmacological concentrations of calcium channel-blocking drugs exhibit a reduced capacity to kill bacteria.
Insights
Pharmacological concentrations of calcium channel blockers impair human neutrophil (PMN) killing of Pseudomonas aeruginosa. This effect is linked to altered calcium metabolism and reduced respiratory burst activity in PMNs.
Area of Science:
- Immunology
- Pharmacology
- Cell Biology
Background:
- Calcium ions are crucial for cell physiology.
- Calcium channel-blocking drugs are widely used.
- The effect of these drugs on neutrophil function is not fully understood.
Purpose of the Study:
- To investigate the impact of calcium channel-blocking drugs on human neutrophil functions.
- To determine if these drugs affect the ability of neutrophils to kill bacteria.
- To elucidate the mechanisms underlying any observed effects.
Main Methods:
- Human neutrophils (PMNs) were incubated with verapamil hydrochloride or nifedipine.
- Bacterial killing assays using Pseudomonas aeruginosa were performed.
- Calcium uptake, phagocytosis, and respiratory burst activity (superoxide anion generation) were measured.
Main Results:
- Verapamil hydrochloride significantly impaired the killing capacity of PMNs against Pseudomonas aeruginosa.
- This impairment was linked to altered calcium metabolism, with decreased 45Ca++ uptake and dependence on extracellular calcium.
- Nifedipine also impaired PMN bactericidal activity.
- Neutrophil phagocytosis was unaffected, but the respiratory burst was significantly impaired.
Conclusions:
- Pharmacological concentrations of calcium channel-blocking drugs reduce the bactericidal capacity of human neutrophils.
- The mechanism involves interference with calcium metabolism and impairment of the respiratory burst.
- These findings have implications for understanding drug interactions and host defense mechanisms.