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Differential effects of calcium channel antagonists in rat normal and skinned fundus
V Villagrasa1, J L Ortiz, B Sarriá
1Departament de Farmacología, Universitat de València, Spain.
Abstract:
CaCl2 (0.1-25 mM, in K(+)-depolarized tissues), KCl (10-112 mM) and acetylcholine (1 nM-1 mM) produced concentration-dependent contractions of rat isolated fundus. Nifedipine (0.01-500 mcM), diltiazem (0.01-100 mcM) and flunarizine (10-500 mcM) each produced a concentration-related inhibition of the log concentration-effect curve for CaCl2. The rank order of potencies of these antagonists, measured as the IC50 against Ca2+ (25 mM)-induced contraction of depolarized fundus, was nifedipine (1.9 mcM) = diltiazem (2.5 mcM) >> flunarizine (660 mcM). Diltiazem depressed KCl-induced contraction with an effectiveness and potency similar to that displayed against CaCl2 but nifedipine and flunarizine were less effective against contractions to KCl compared to CaCl2. Flunarizine (500 mc), but not the other antagonists tested, depressed Ca2+ (20 mc)-evoked contraction of skinned rat fundus preparations. It is concluded that distinct differences exist between the Ca2+ channel antagonists examined. The action of nifedipine and diltiazem is restricted to the plasmalemma, whereas flunarizine also acts on the intracellular contractile apparatus.
Insights
Calcium channel blockers like nifedipine and diltiazem inhibit contractions in rat fundus tissue by acting on the cell membrane. Flunarizine, however, also affects intracellular mechanisms, indicating distinct actions among these calcium channel antagonists.
Area of Science:
- Pharmacology
- Physiology
- Gastroenterology
Background:
- Rat fundus smooth muscle exhibits concentration-dependent contractions.
- Calcium ions play a crucial role in smooth muscle contraction.
- Various agents, including calcium chloride, potassium chloride, and acetylcholine, can induce fundus contractions.
Purpose of the Study:
- To investigate the effects of different calcium channel antagonists on rat fundus contractions.
- To compare the potencies and mechanisms of action of nifedipine, diltiazem, and flunarizine.
- To determine if these antagonists act solely on the plasma membrane or also on intracellular targets.
Main Methods:
- Isolated rat fundus preparations were used.
- Contractions were induced by calcium chloride (CaCl2), potassium chloride (KCl), and acetylcholine.
- Concentration-response curves for contractile agents were generated in the presence of varying concentrations of nifedipine, diltiazem, and flunarizine.
- Experiments were conducted on both intact and skinned fundus preparations to differentiate between membrane-bound and intracellular actions.
Main Results:
- Nifedipine and diltiazem demonstrated potent inhibition of CaCl2-induced contractions, with similar efficacy.
- Flunarizine was significantly less potent in inhibiting CaCl2-induced contractions compared to nifedipine and diltiazem.
- Diltiazem effectively inhibited KCl-induced contractions, while nifedipine and flunarizine showed reduced efficacy against KCl-induced contractions.
- Flunarizine, unlike nifedipine and diltiazem, inhibited Ca2+-evoked contractions in skinned fundus preparations, suggesting intracellular targets.
Conclusions:
- Nifedipine and diltiazem primarily act on plasmalemmal calcium channels.
- Flunarizine exhibits a dual mechanism, affecting both plasmalemmal and intracellular calcium-dependent processes.
- Distinct differences exist in the sites of action among the tested calcium channel antagonists, impacting their therapeutic profiles.