Accumulation of bisphosphonates in human artery and their effects on human and rat arterial function in vitro.

Clodronate, etidronate and pamidronate are bisphosphonates introduced in the treatment of hypercalcaemia and osteoporosis. Interestingly, they also inhibit development of experimental atherosclerosis and affect smooth muscle tone of isolated rat tail artery. We have studied in vitro whether these hydrophilic compounds 1) accumulate in the wall of the human artery, 2) influence human arterial tone, and 3) interfere with the vascular action of L-type Ca2+ antagonists. Human internal mammary artery rings were incubated with 14C-labelled bisphosphonates. After a 2-hr incubation, the ratios of artery-to-incubate concentrations with 4 and 40 mumol/l of clodronate were, respectively, 3.0 +/- 0.5 (mean +/- S.E.M.) and 1.3 +/- 0.2, with 4 and 40 mumol/l of etidronate 7.4 +/- 0.9, and 3.2 +/- 0.4, and with 0.4 and 4 mumol/l of pamidronate 4.7 +/- 0.7 and 3.9 +/- 0.8. Both tested bisphosphonates, clodronate and pamidronate, reduced the arterial contractile force induced by alpha-adrenergic stimulation with noradrenaline and membrane depolarization with high concentration of KCl. Clodronate also decreased the arterial contraction induced by cumulative addition of Ca2+ with KCl as the agonist, and had an additive inhibitory effect on this response with the L-type Ca2(+)-channel blocker nifedipine. The results demonstrate that 1) bisphosphonates accumulate markedly in human artery, 2) clodronate and pamidronate reduce human arterial contactile force to alpha-adrenergic and depolarizing stimuli, and 3) as shown with clodronate, bisphosphonates may exert an additive inhibitory effect on human arterial contractions with an L-type Ca2(+)-channel blocker.