No abstract

The transient receptor potential type V1 channel (vanilloid receptor 1, TRPV1) is a Ca 2ϩ -permeable nonspecific cation channel activated by various painful stimuli including ischemia. We hypothesized that TRPV1 is expressed in the arterioles and is involved in the regulation of microvascular tone. We found that TRPV1 stimulation by capsaicin (intra-arterial administration) of the isolated, perfused right hind limb of the rat increased vascular resistance (by 98 Ϯ 21 mm Hg at 10 g) in association with decreased skeletal muscle perfusion and elevation of skin perfusion (detected by dual-channel laser Doppler flowmetry). Denervation of the hind limb did not affect capsaicin-evoked changes in vascular resistance and tissue perfusion in the hind limb but reduced the elevation of perfusion in the skin. In isolated, pressurized skeletal (musculus gracilis) muscle arterioles (diameter, 147 Ϯ 35 m), capsaicin had biphasic effects: at lower concentrations, capsaicin (up to 10 nM) evoked dilations (maximum, 32 Ϯ 13%), whereas higher concentrations (0.1-1 M) elicited substantial constrictions (maximum, 66 Ϯ 7%). Endothelium removal or inhibition of nitric-oxide synthase abolished capsaicin-induced dilations but did not affect arteriolar constriction. Expression of TRPV1 was detected by reverse transcriptase-polymerase chain reaction in the aorta and in cultured rat aortic vascular smooth muscle cells (A7r5). Immunohistochemistry revealed expression primarily in the smooth muscle layers of the gracilis arteriole. These data demonstrate the functional expression of TRPV1 in vascular smooth muscle cells mediating vasoconstriction of the resistance arteries. Because of the dual effects of TRPV1 stimulation on the arteriolar diameter (dilation in skin, constriction in skeletal muscle), we propose that TRPV1 ligands represent drug candidates for tissue-specific modulation of blood distribution.The transient receptor potential type V1 channel (vanilloid receptor-1, TRPV1) is a nonselective cation channel, structurally belonging to the transient receptor potential family of ion channels. TRPV1 is found in sensory C and A-␦ fibers (Caterina et al., 1997) and functions as a ligand-, proton-, and heat-activated molecular integrator of nociceptive stimuli in the periphery (Szallasi and Blumberg, 1999;

BACKGROUND AND PURPOSEOmecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions. EXPERIMENTAL APPROACHES Ca 2+-dependent active force production (Factive), its Ca 2+ sensitivity (pCa50), the kinetic characteristics of Ca 2+-regulated activation and relaxation, and Ca 2+ -independent passive force (Fpassive) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 μM). KEY RESULTSIn permeabilized cardiomyocytes, OM increased the Ca 2+ sensitivity of force production (ΔpCa50: 0.11 or 0.34 at 0.1 or 1 μM respectively). The concentration-response relationship of the Ca 2+ sensitization was bell-shaped, with maximal effects at 0.3-1 μM OM (EC50: 0.08 ± 0.01 μM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased Fpassive in the cardiomyocytes with an apparent EC50 value of 0.26 ± 0.11 μM. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics. CONCLUSIONS AND IMPLICATIONS OM acted as a Ca 2+-sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation-relaxation kinetics and at higher OM concentrations increased Fpassive production. ]; ktr,max, rate constant of force redevelopment at pCa 4.75; LV, left ventricle; MHC, myosin heavy chain; nHill, Hill coefficient; OM, omecamtiv mecarbil; pCa, −log of calcium ion concentration; pCa50, −log of calcium ion concentration at half-maximal isometric force production; Pi, inorganic phosphate; trelax, relaxation time BJP