Mechanism of Ca++ antagonist-induced vasodilation. Intracellular actions.

Abstract

We studied the effects of Ca++ antagonists on intact and skinned muscles of rabbit mesenteric artery. Intact muscle contractions were inhibited by 10(-6) M diltiazem, whereas greater levels were required to abolish contractions in skinned muscle fibers. In contrast, nisoldipine had no effect on skinned muscle contractions, although it inhibited, almost completely, the contraction of intact muscle at concentrations below 10(-6) M. In the presence of EGTA, norepinephrine-induced contractions result from a release of Ca++ from an intracellular store. Diltiazem inhibited these contractions at concentrations between 10(-6) and 10(-4) M. Higher doses were required in studies with skinned muscle preparations. Unlike diltiazem, nisoldipine only partially inhibited the Ca++-free norepinephrine-induced contractions in the range of 10(-7) to 10(-5) M. From these results, we assumed that at low concentrations (below 10(-6) M), diltiazem induced relaxation by blocking Ca++ influx, whereas at relatively high concentrations (above 10(-6) M), an inhibition of Ca++ release from an intracellular store also occurred. A similar conclusion was reached regarding the mechanism whereby nisoldipine inhibits force developments.

Effects of diltiazem on calcium concentrations in the cytosol and on force of contractions in porcine coronary arterial strips

“…These observations suggest that the mechanisms by which histamine produces a greater extent of tension development for a given change in [Ca2+] (Shachtele et al, 1989) and that diltiazem did not affect the pCa-tension relationship in skinned muscles (Suzuki et al, 1982). However, other workers have shown that diltiazem, at high concentrations, has direct effects on contractile elements (Bostrom et al, 1981;Johnson et al, 1982) and decreases the effectiveness of Ca2 +-tension relationship (Saida & van Breemen, 1983). Diltiazem (> 10-6M) decreased the resting levels of [Ca2+]i without causing relaxation in the normal PSS.…”

Vasodilatation Produced by Orientin and Its Mechanism Study

“…Furthermore, Orientin inhibited NE, CaCl 2 and KCl-induced vasoconstriction concentration dependently in a non-competitive manner. The fact that it inhibited NE-induced vasoconstriction indicated that Orientin inhibited receptor-operating calcium channels, because NE can open receptor-operating calcium channels 21,22) ; its inhibition of CaCl 2 and KCl-induced vasoconstriction concentration dependently and non-competitively, indicatd that it inhibited voltage-dependent Ca 2ϩ channels, for high K ϩ can excite voltage-dependent Ca 2ϩ channels and increase Ca 2ϩ influx. 23) Thus the results suggest that Orientin blocks both voltage-dependent Ca 2ϩ channels and receptor-operating Ca 2ϩ channels.…”

Calcium channel blockers suppress the contact hypersensitivity reaction (CHR) by inhibiting antigen transport and presentation by epidermal Langerhans cells in mice

“…CCB, such as nifedipine, verapamil, and diltiazem, promote the relaxation of cardiac and smooth muscle cells by inhibiting calcium influx through calcium channels (slow channels) and calcium release from intracellular stores, and are commonly used as therapeutic agents for cardiovascular disorders [35][36][37][38]. In addition to their effects on muscle cells, several in vitro studies have shown that CCB suppress the activation of various participants in immune reactions, such as T cells [16,39], mast cells [40] and macrophages [41,42] via the inhibition of calcium influx, suggesting that CCB can act as an immunosuppressant.…”

“…For example, calcium mobilization and the subsequent activation of PKC were shown to be important events in monocyte and B cell stimulation via ligation of Ia antigens [48,49]. Therefore, it is possible that CCB down-regulate LC migration by inhibiting transient calcium release from intracellular stores, and/or by interfering with a sustained calcium influx through calcium channels, which is required for the activation of PKC [35,36].…”