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[3H]-nitrendipine binding in normal and cardiomyopathic hamster hearts: modulation by temperature, verapamil and
1Department of Pharmacology, University of Alberta, Edmonton, Canada.
Insights
High affinity dihydropyridine binding sites in cardiomyopathic hamster hearts show no defects. Kinetic studies confirm normal calcium channel function, ruling out calcium overload as a cause of cardiomyopathy.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Pharmacology
Background:
- Cardiomyopathy is characterized by muscle necrosis, potentially linked to calcium overload.
- Dihydropyridine binding sites are crucial components of voltage-gated calcium channels.
Purpose of the Study:
- To investigate potential defects in dihydropyridine binding sites within the calcium channel of cardiomyopathic hamster hearts.
- To determine if abnormalities in these sites contribute to calcium overload and subsequent muscle necrosis.
Main Methods:
- Kinetic studies of [3H]-nitrendipine binding to ventricular homogenates from normal and cardiomyopathic hamsters.
- Analysis of temperature dependence (Q10) and allosteric interactions with verapamil and diltiazem.
Main Results:
- The rate of [3H]-nitrendipine dissociation was highly temperature-dependent in normal hearts (Q10 = 4.40) and unaffected by cardiomyopathy.
- The rate of association was weakly temperature-dependent (Q10 = 1.25) and also unaffected by the disease.
- Allosteric interactions with verapamil and diltiazem were identical in both normal and cardiomyopathic hearts.
Conclusions:
- There are no detectable abnormalities in the dihydropyridine, verapamil, or diltiazem binding sites of the calcium channel in cardiomyopathic hamster hearts.
- The normal kinetic properties and temperature sensitivity suggest the calcium channel is not the primary defect leading to cardiomyopathy in this model.
Abstract:
The characteristics of high affinity dihydropyridine binding sites were compared in normal and cardiomyopathic hamster hearts to probe for possible defects in the calcium channel which could lead to calcium overload and, in turn, to the muscle necrosis characteristic of cardiomyopathy. Kinetic studies of the temperature dependence of [3H]-nitrendipine binding to ventricular homogenates from 60-day-old normal and cardiomyopathic hamsters showed that, in normal hamsters, the rate of dissociation (0.049 +/- 0.006/min at 25 degrees C) was highly temperature-dependent (Q10 = 4.40 +/- 0.69) and that neither the rate nor the temperature dependence was influenced by disease. The rate of association (1.12 +/- 0.11/min/nM at 25 degrees C) was weakly temperature-dependent (Q10 = 1.25 +/- 0.04) and similarly unaffected by disease. The rate of dissociation of [3H]-nitrendipine was increased by verapamil and decreased by diltiazem with little effect on the association rate. Allosteric interactions of diltiazem and verapamil with the dihydropyridine receptor were identical in normal and cardiomyopathic hearts and, together with the normal temperature sensitivity, show that there is no abnormality at the related binding sites for nitrendipine, verapamil and diltiazem in the calcium channel of the cardiomyopathic heart.