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The molecular basis for the use of calcium antagonists in ischaemic heart disease
1Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.
Insights
Calcium antagonists, by limiting calcium ion entry, protect the heart during ischaemia. Prophylactic use of these drugs, like verapamil, reduces cellular damage and preserves energy during cardiac events.
Area of Science:
- Cardiovascular Pharmacology
- Cellular Physiology
- Ischaemic Heart Disease Management
Background:
- Calcium antagonists are vital for managing ischaemic heart disease, offering prophylactic benefits.
- These drugs limit calcium ion (Ca++) influx via voltage-sensitive channels, contributing to energy conservation.
- Long-term use provides additional advantages, including slowing atherogenic lesion development and counteracting endothelin-1 effects.
Purpose of the Study:
- To investigate the protective effects of calcium antagonists on myocardial calcium homeostasis during ischaemia.
- To evaluate the impact of verapamil pretreatment on cytosolic Ca++ levels and energy depletion in an ischaemic rat heart model.
Main Methods:
- Utilized an isolated, perfused rat heart model subjected to global ischaemia.
- Administered verapamil as a pretreatment to assess its effects on cytosolic Ca++ during ischaemia and reperfusion.
- Measured adenosine triphosphate (ATP) levels to assess energy status post-ischaemia.
Main Results:
- Verapamil pretreatment significantly inhibited the rise in cytosolic Ca++ during 20-minute global ischaemia.
- This stereospecific effect correlated with reduced total tissue Ca++ during reperfusion.
- Amelioration of ischaemia-induced adenosine triphosphate depletion was observed.
Conclusions:
- Prophylactic calcium antagonists effectively attenuate the increase in myocardial cytosolic Ca++ during short ischaemic episodes.
- The observed effects are linked to reduced cellular Ca++ overload and preserved energy stores.
- Targeting the early rise in cytosolic Ca++ represents a key strategy for anti-ischaemic drug therapy.
Abstract:
Calcium antagonists are useful for the management of patients with ischaemic heart disease, particularly when used prophylactically. At the cellular level, these drugs act primarily by limiting calcium ion (Ca++) entry through the voltage-sensitive Ca(++)-selective channels, an effect that contributes markedly to their 'energy sparing' properties. However, the long term use of these drugs has additional advantages, particularly with respect to their ability to slow Ca(++)-dependent processes involved in the formation of atherogenic lesions, partially antagonise the effects of the raised levels of circulating endothelin-1 encountered during ischaemia-induced heart failure and hypertension, and trap and immobilise oxyradicals. Prolonged episodes of ischaemia result in an irreversible loss of homeostasis with respect to Ca++. However, the increase in myocardial cytosolic Ca++ caused by relatively short periods of ischaemia is small, reversible, and markedly attenuated by the prophylactic use of calcium antagonists. In the isolated, perfused rat heart, verapamil pretreatment produces statistically significant inhibition of the increase in cytosolic Ca++ during 20-minute global ischaemia. This stereospecific effect is associated with a decrease in the rise in total tissue Ca++ during reperfusion and amelioration of the adenosine triphosphate depletion caused by ischaemia. In general, discussion relating to the molecular basis of the use of calcium antagonists in the management of patients with ischaemic heart disease needs to take into account the duration of the ischaemic event, the workload on the myocardium, the need for prophylactic therapy, and the presence of exacerbating factors such as atherosclerosis and tobacco smoking. The early rise in cytosolic Ca++, the source of which remains uncertain, appears to be an important focus for anti-ischaemic drug therapy.