Related Experiment Videos
Effect of calcium antagonist darodipine on the isolated human heart
Insights
Darodipine effectively blocks calcium channels in human coronary arteries but not in heart muscle, demonstrating significant tissue selectivity. This calcium antagonist impacts both potential-dependent and receptor-operated channels in coronary arteries.
Area of Science:
- Cardiovascular Pharmacology
- Clinical Pharmacology
- Calcium Channel Blockers
Background:
- Dihydropyridine calcium antagonists are crucial in cardiovascular medicine.
- Understanding their tissue-specific effects is vital for therapeutic development.
- Darodipine is a novel, light-stable dihydropyridine with potential clinical applications.
Purpose of the Study:
- To investigate the efficacy and selectivity of darodipine in human cardiovascular tissues.
- To compare darodipine's mechanism of action in human coronary arteries versus ventricular myocardium.
- To elucidate darodipine's effects on different types of calcium channels in human cardiac tissues.
Main Methods:
- Utilized isolated human epicardial coronary arteries and right ventricular trabecula from cardiac transplant explants.
- Assessed the effects of darodipine on calcium-induced and carbachol-induced contractions (PD'2).
- Quantified 45Ca2+ uptake in response to potassium and histamine in the presence of darodipine.
Main Results:
- Darodipine demonstrated potent calcium antagonism in human coronary arteries (PD'2 for calcium 9.7, carbachol 9.5).
- Darodipine showed minimal effect in human ventricular myocardium (PD'2 for calcium 6.5), indicating high tissue selectivity.
- In human coronary arteries, darodipine inhibited 45Ca2+ uptake and contraction mediated by both potential-dependent and receptor-operated channels.
Conclusions:
- Darodipine is a potent and highly selective calcium antagonist for human epicardial coronary arteries, with limited activity in ventricular myocardium.
- Unlike findings in animal models (e.g., rabbit aorta), darodipine modulates both L-type and receptor-operated calcium channels in human coronary arteries.
- These findings highlight darodipine's specific therapeutic potential in treating conditions involving coronary artery vasospasm.
Abstract:
Darodipine is a new light stable dihydropyridine calcium antagonist. In isolated large conductance vessels from experimental animals, darodipine blocks the potential-dependent but not the receptor-operated calcium channel. We studied the effects of darodipine in isolated human epicardial coronary arteries and in isolated right ventricular trabecula obtained from the explanted hearts of patients undergoing cardiac transplantation. In the coronary artery, the PD'2 for calcium was 9.7 and for carbachol was 9.5. In the cardiac muscle, the PD'2 for calcium was 6.5. Using 45Ca2+, darodipine blocked uptake in presence of potassium and histamine. We conclude that darodipine is (1) a potent calcium antagonist in the isolated human coronary artery, but not in ventricular myocardium, thus showing very pronounced target tissue selectivity, and (2) in contrast to findings obtained in rabbit aorta, it inhibits contraction and 45Ca2+ uptake mediated by both the potential-dependent and receptor-operated channels in the human epicardial coronary artery.