Mechanisms of agonist-induced smooth muscle cell contraction. Smooth muscle contraction is triggered by an elevation in intracellular calcium (↑[Ca2+]i) which catalyses the interaction between the cellular actin and myosin filaments. Under resting conditions an intracellular environment with a high potassium concentration and a low calcium concentration exists with potassium ions moving along their concentration gradient to the extracellular media via calcium, voltage and ATP-sensitive potassium channels (KCa, KV and KATP) in the membrane, generating a resting membrane potential of −60 mV. (A) Addition of mM concentrations of extracellular KCl disrupts the potassium concentration gradient, preventing the intracellular to extracellular movement of potassium ions, which are instead retained intracellularly. Depolarization of the membrane potential ensues, activating voltage-operated calcium channels (VOCCs) and triggering extracellular calcium influx (Nelson & Quayle, 1995). BAY K8644 acts as a direct activator of VOCCs (Schramm et al., 1983). (B) Noradrenaline (NA) elicits smooth muscle contraction via alpha-1 adrenoceptor stimulation, which results in a G-protein coupled activation of phospholipase C (PLC) with subsequent generation of inositol triphosphate (IP3) and diacyl glycerol (DAG) from the membrane phospholipid phosphatidyl inositol biphosphate (PIP2). IP3 acts at its receptor (IP3R) located on the intracellular membrane of the sarcoplasmic and endoplasmic reticulum, triggering calcium release from these stores whereas DAG activates VOCCs through modulation of chloride channels (Criddle et al., 1996). In contrast, prostaglandin F2α (PGF2α) acts at prostanoid receptors gated directly to receptor-operated calcium channels (ROOCs) (Tosun et al., 1997). NA is also reported to activate ROCCs in smooth muscle (Tanaka et al., 2000), the proportion of the response attributed to this additional pathway varying between vascular beds. (C) Caffeine and carbachol trigger smooth muscle contraction through stimulation of calcium release from discrete intracellular stores. Carbachol activates the intracellular IP3 receptors whilst caffeine activates intracellular ryanadine receptors (RyrR) (Xu et al., 1994). (D) Thapsigargin (Thap) triggers contraction via its inhibitory action on the calcium pumps of the sarcoplasmic and endoplasmic reticulum (SERCA). Under normal conditions a cycling of calcium occurs between these intracellular stores and the cytoplasm, calcium being released from the endoplasmic reticulum and then actively pumped back into these stores via the SERCA. In the presence of thapsigargin the SERCA are irreversibly inhibited but the passive calcium release from intracellular stores is unaffected. Consequently an emptying of the intracellular calcium stores ensues, resulting in the activation of store operated calcium channels (SOCCs) and extracellular calcium entry (Treiman et al., 1998).