The role of external Ca²⁺ in the action of Ca²⁺-channel agonists and antagonists on isolated human thoracic arteries.

In systemic atherosclerosis develops the abnormal vascular tone which is associated with elevated calcium influx into smooth muscle cells and their calcification that may be proportional to the extent and severity of atherosclerotic disease. The goal of the present study was to investigate the responses of isolated human arterial samples to Ca²⁺-channel agonists and antagonists by varying the external Ca²⁺ concentration. Two dihydropyridine type calcium-channel blockers, amlodipine and cerebrocrast, were used in this study. The benzodiazepine-type calcium-channel blocker diltiazem, the benzimidazole derivative 1-acetyl-5,6-dimethoxy-2-methylthiobenzimidazole and 3,4'-bipyridine derivative milrinone were also used. Experiments were carried out on isolated human thoracic artery samples obtained from 74 patients, aged 38-88 years, during conventional myocardial revascularisation operations. The contraction of artery samples was recorded using an iFOT10 force transducer. Cumulative concentration-contraction curves of the tested agents (10⁻⁷ to 10⁻⁴ M) were established by varying the external Ca²⁺ concentration from 0.9 mM to 2.7 mM. Cerebrocrast, regardless of the Ca²⁺ concentration significantly increased arterial contraction, particularly at the lower Ca²⁺ (≈77%). Diltiazem, the benzimidazole derivative and milrinone caused the artery samples to relax at 10⁻⁴ M concentrations by 55%, 55% and 44%, respectively, when the external Ca²⁺ corresponded to the physiological standard. Shifting to lower or higher Ca²⁺ concentrations significantly altered the response of vessel samples by increasing their contraction. In conclusion, the present study shows that the response of isolated human thoracic artery samples to both the slow calcium channel suppressant diltiazem and to agonists of that channel (milrinone and the benzimidazole derivative) is regulated by the amount of calcium present in the physiological solution. Treatment with a slow calcium channel inhibitor, the 1,4-dihydropyridine derivative cerebrocrast, resulted in a response that was independent of the external Ca²⁺ concentration.