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Human vascular to cardiac tissue selectivity of L- and T-type calcium channel antagonists
D Sarsero1, T Fujiwara, P Molenaar
1Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
Abstract:
1. Voltage-operated calcium channel (VOCC) antagonists are effective antihypertensive and antianginal agents but they also depress myocardial contractility. 2. We compared four L-type calcium channel antagonists, felodipine, nifedipine, amlodipine and verapamil and a relatively T-type selective calcium channel antagonist, mibefradil, on human and rat isolated tissue assays to determine their functional vascular to cardiac tissue selectivity (V/C) ratio. 3. The V/C ratio was calculated as the ratio of the IC50 value of the antagonist that reduced (by 50%) submaximally contracted (K+ 62 mM) human small arteries from the aortic vasa vasorum (vascular, V) mounted in a myograph and the IC50 value of the antagonist that reduced (-)-isoprenaline (6 nM) submaximally stimulated human right atrial trabeculae muscle (cardiac, C) mounted in organ chambers. 4. The average pIC50 values (-log IC50 M) for the human vascular preparations were felodipine 8.30, nifedipine 7.78, amlodipine 6.64, verapamil 6.26 and mibefradil 6.22. The average pIC50 values for the cardiac muscle were felodipine 7.21, nifedipine 6.95, verapamil 6.91, amlodipine 5.94, and mibefradil 4.61. 5. The V/C ratio calculated as antilog [pIC50V-pIC50C] is thus mibefradil 41, felodipine 12, nifedipine 7, amlodipine 5 and verapamil 0.2. 6. In rat small mesenteric arteries the pIC50 values for the five drugs were similar to the values for human vasa vasorum arteries contracted by K+ 62 mM. However for methoxamine (10 microM) contraction in the rat arteries the pIC50 values were lower for felodipine 7.24 and nifedipine 6.23, but similar for verapamil 6.13, amlodipine 6.28 and mibefradil 5.91. 7. In conclusion. in the human tissue assays, the putative T-channel antagonist mibefradil shows the highest vascular to cardiac selectivity ratio; some 3 fold higher than the dihydropyridine, felodipine, and some 200 fold more vascular selective than the phenylalkylamine, verapamil. This favourable vascular to cardiac selectivity for mibefradil, from a new chemical class of VOCC antagonist, may be explained by its putative T-channel selectivity.
Insights
Mibefradil, a T-type calcium channel blocker, exhibits superior vascular selectivity over cardiac effects compared to L-type blockers like felodipine. This enhanced selectivity suggests potential advantages for cardiovascular treatments.
Area of Science:
- Pharmacology
- Cardiovascular Medicine
- Ion Channel Research
Background:
- Voltage-operated calcium channel (VOCC) antagonists are crucial for treating hypertension and angina.
- However, these drugs can negatively impact myocardial contractility, limiting their therapeutic use.
- Understanding the vascular versus cardiac selectivity of VOCC antagonists is critical for developing safer medications.
Purpose of the Study:
- To compare the vascular to cardiac tissue selectivity (V/C ratio) of five calcium channel antagonists.
- To evaluate L-type calcium channel antagonists (felodipine, nifedipine, amlodipine, verapamil) and a T-type selective antagonist (mibefradil).
- To determine if T-channel selectivity correlates with improved V/C ratio.
Main Methods:
- Human isolated small arteries (vasa vasorum) and atrial trabeculae were used.
- Vascular and cardiac tissues were submaximally contracted and stimulated, respectively.
- IC50 values were determined for each antagonist, and the V/C ratio was calculated (antilog [pIC50V-pIC50C]).
Main Results:
- Mibefradil demonstrated the highest V/C ratio (41) in human tissue assays, indicating superior vascular selectivity.
- Felodipine (12), nifedipine (7), and amlodipine (5) showed moderate V/C ratios, while verapamil had a low ratio (0.2).
- Results in rat mesenteric arteries were generally consistent, with some variations in response to different contractile agents.
Conclusions:
- Mibefradil exhibits significantly higher vascular to cardiac selectivity compared to L-type calcium channel antagonists.
- This selectivity is approximately 3-fold greater than felodipine and 200-fold greater than verapamil.
- The superior selectivity of mibefradil may be attributed to its putative T-channel selectivity, suggesting a novel therapeutic profile.