cyclic-gmp and olprinone

Olprinone, one of the most frequently used phosphodiesterase-3 inhibitors, exerts its positive inotropic and vasodilation effects by inhibiting the degradation of intracellular cyclic adenosine monophosphate (cAMP). The vasodilation response to olprinone is not uniform among the different vascular beds. This study was designed to compare the vasorelaxation response to olprinone between renal and common carotid arteries, and investigate its underlying mechanisms.. Isometric force measurement, enzyme immunoassay, and western blotting techniques were used to investigate the vasorelaxation action of olprinone in isolated rabbit renal and common carotid arteries.. Olprinone inhibited the contractile response to phenylephrine (PE) both in the renal and carotid arteries in a concentration-dependent manner with IC50 values of 40 +/- 10 and 103 +/- 43 nM, respectively. The IC50 value was lower (P = 0.004) and the maximal inhibition was greater (P = 0.002) in the renal artery compared with the carotid artery. A cell-permeable cAMP analogue, 8-bromo-cAMP, also inhibited the contractile response to PE in the renal and carotid arteries with IC50 values of 581 +/- 150 and 740 +/- 179 microM, respectively; however no differences were observed both in the IC50 value and the maximal inhibition between two arteries. Olprinone (0.1 microM) increased the intracellular cAMP level in the renal arterial smooth muscle cells (ASMCs) but not in the carotid ASMCs. The expression of PDE3A was greater (P = 0.008) in the carotid ASMCs than the renal ASMCs.. The enhanced vasodilator action of olprinone in the renal artery is presumably because of its ability to stimulate the cAMP production, which might be attributable to the heterogeneous expression of PDE3A.

Topics: Animals; Carotid Artery, Common; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Imidazoles; In Vitro Techniques; Isoenzymes; Male; Muscle, Smooth, Vascular; Organ Specificity; Phosphodiesterase 3 Inhibitors; Phosphodiesterase Inhibitors; Pyridones; Rabbits; Random Allocation; Renal Artery; Vasoconstriction; Vasodilation; Vasodilator Agents

Olprinone, an inhibitor of cyclic nucleotide phosphodiesterase III, inhibited an increase in intracellular Ca(2+) concentrations for acutely dissociated rat hippocampal pyramidal neurons induced by extracellular high K(+) (35 mM) depolarization. Olprinone (100 microM) significantly reduced spontaneous glutamate release from rat hippocampal slices. Furthermore, olprinone significantly decreased the rate of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated miniature excitatory postsynaptic currents (AMPA-mEPSCs) monitored from CA1 pyramidal neurons of rat hippocampal slices, and the effect was blocked by KT5823, an inhibitor of protein kinase G (PKG), but not by H-89, an inhibitor of protein kinase A (PKA). In the PKA assay using PC-12 cells, olprinone did not activate PKA. Taken together, the results of the present study show that olprinone attenuates intracellular Ca(2+) rise through voltage-sensitive Ca(2+) channels and inhibits presynaptic glutamate release via a cGMP/PKG pathway.

Topics: Animals; Calcium; Carbazoles; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Excitatory Postsynaptic Potentials; Glutamic Acid; Hippocampus; Imidazoles; In Vitro Techniques; Isoquinolines; Male; Membrane Potentials; Phosphodiesterase 3 Inhibitors; Phosphodiesterase Inhibitors; Potassium; Protein Kinase Inhibitors; Pyramidal Cells; Pyridones; Rats; Rats, Wistar; Receptors, AMPA; Signal Transduction; Sulfonamides