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, th ey also inhibit development of experimental atherosclerosis and affect smooth muscle tone of isolated rat tail artery. We have studied in vi tro whether these hydrophilic compounds 1) accumulate in the wall of t he human artery 2) influence human arterial tone, and 3) interfere wit h the vascular action of L-type Ca2+ antagonists. Human internal mamma ry artery rings were incubated with C-14-labelled bisphosphonates. Aft er a 2-hr incubation, the ratios of artery-to-incubate concentrations with 4 and 40 mu mol/l of clodronate were, respectively, 3.0+/-0.5 (me an+/-S.E.M.) and 1.3+/-0.2 with 4 and 40 mu mol/l of etidronate 7.4+/- 0.9 and 3.2+/-0.4, and with 0.4 and 4 mu mol/l of pamidronate 4.7+/-0. 7 and 3.9+/-0.8. Both tested bisphosphonates, clodronate and pamidrona te! reduced the arterial contractile force induced by cc-adrenergic st imulation with noradrenaline and membrane depolarization with high con centration of KCI. Clodronate also decreased the arterial contraction induced by cumulative addition of Ca2+ with KCI as the agonist, and ha d an additive inhibitory effect on this response with the L-type Ca2+- channel blocker nifedipine. The results demostrate that 1) bisphosphon ates accumulate markedly in human artery, 2) clodronate and pamidronat e reduce human arterial contactile force to alpha-adrenergic and depol arizing stimuli, and 3) as shown with clodronate. bispbosphonates may exert an additive inhibitory effect on human arterial contractions wit h an L-type Ca2+-channel blocker.