calcimycin and ozagrel

We examined whether Ca(2+) mobilizers induce endothelium-dependent contraction and relaxation (EDC and EDR) in isolated rabbit intrapulmonary arteries. Ionomycin (10(-7) M) and A-23187 (10(-7) M), both Ca(2+) ionophores, and thapsigargin (10(-6) M), an endoplasmic reticulum Ca(2+)-ATPase inhibitor, caused a contraction in the non-contracted preparations, and a transient relaxation followed by a transient contraction and sustained relaxation in the precontracted preparations. Endothelium-removal abolished the contraction and transient relaxation (EDC and EDR) but not sustained relaxation (endothelium-independent relaxation, EIR). In the noncontracted preparations, ionomycin-induced EDC was significantly attenuated by quinacrine (10(-5) M), manoalide (10(-6) M), both phospholipase A(2) inhibitors, indomethacin (10(-5) M) and aspirin (10(-4) M), both COX inhibitors, and ozagrel (10(-5) M), a TXA(2) synthetase inhibitor. In the precontracted arteries, EDR was markedly reduced by L-NAME (10(-4) M), a NOS inhibitor, and methylene blue (10(-6) M), a guanylate cyclase inhibitor, and was enhanced by indomethacin, aspirin and ozagrel, probably due to inhibition of EDC. ZM230487, a 5-lipoxygenase inhibitor, had no effect on EDR. EIR was not affected by L-NAME, indomethacin or ZM230487. Arachidonic acid (10(-6) M) evoked EDC sensitive to indomethacin and ozagrel. L-Arginine (10(-3) M) caused EDR sensitive to L-NAME in the ionomycin-stimulated preparations. In conclusion, Ca(2+) mobilizers cause EDC and EDR via production of TXA(2) and NO, respectively.

Topics: Animals; Aspirin; Calcimycin; Calcium; Endothelium, Vascular; Enzyme Inhibitors; Indomethacin; Ionomycin; Ionophores; Male; Methacrylates; Methylene Blue; Muscle Relaxation; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Pulmonary Artery; Quinacrine; Rabbits; Terpenes; Thapsigargin

In most isolated canine basilar arteries tested, Ca++ ionophore A-23187 induced a small relaxation followed by a transient contraction. Both contraction and relaxation were abolished by removal of endothelium. The endothelium-dependent contraction induced by A-23187 was attenuated by a phospholipase A2 inhibitor (quinacrine), cyclooxygenase inhibitors (aspirin and indomethacin), a thromboxane A2 (TXA2) synthetase inhibitor (OKY-046) and a TXA2 antagonist (ONO-3708). The A-23187-induced contraction was abolished by lowering the Ca++ concentration of medium to 10%, whereas the contraction induced by 9,11-epithio-11,12-methano-TXA2 (STA2) was attenuated slightly by lowering [Ca++]. The A-23187-induced contraction was reduced markedly by nifedipine (10(-9) to 10(-7) M), but the STA2-induced contraction was only attenuated slightly by nifedipine. Bay K 8644 did not affect the A-23187- and STA2-induced contractions. The present experiments demonstrate that A-23187 induced an endothelium-dependent contraction in canine basilar artery, and suggest that Ca++ might play a key role in production of an endothelium-derived contracting factor (probably TXA2).

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Aspirin; Basilar Artery; Calcimycin; Dogs; Endothelium, Vascular; Female; Male; Methacrylates; Nifedipine; Quinacrine; Thromboxane A2; Vasoconstriction

The effect of the thromboxane (TX) A2 synthetase inhibitor, OKY-046, on human leukocyte histamine release and bronchial hypersensitivity in asthmatic subjects was evaluated. It was found that OKY-046 inhibited IgE- and Ca2+ ionophore A23187-mediated leukocyte histamine release in a dose-dependent fashion (IC50: 1.0 and 3.0 X 10(-3) M, respectively) and that OKY-046 could diminish bronchial hypersensitivity, determined by leukotriene D4 inhalation, following a 2-week oral medication. These data suggest that the TXA2 synthetase inhibitor can produce favorable effects upon the course of immediate-type hypersensitivity reactions.

Topics: Acrylates; Asthma; Bronchial Provocation Tests; Calcimycin; Drug Evaluation; Female; Histamine Release; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Leukocytes; Male; Methacrylates; SRS-A; Thromboxane-A Synthase

To determine whether thromboxane A2 may be involved in ozone (O3)-induced airway hyperresponsiveness, we studied the effect of a thromboxane synthase inhibitor (OKY-046, 100 micrograms X kg-1 X min-1 iv) in five dogs exposed to O3. Airway responsiveness was assessed by determining the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance by 5 cmH2O X l-1 X s. O3 (3 ppm) increased airway responsiveness as demonstrated by a decrease in acetylcholine provocative concentration from 2.42 (geometric SEM = 1.64) to 0.14 mg/ml (geometric SEM = 1.30). OKY-046 significantly inhibited this effect without altering pre-O3 responsiveness or the O3-induced increase in neutrophils and airway epithelial cells in bronchoalveolar lavage fluid. To further examine the role of thromboxane A2, we studied the effect of a thromboxane A2 mimetic, U-46619, on airway responsiveness in five additional dogs. U-46619 in subthreshold doses (i.e., insufficient to increase base-line pulmonary resistance) caused a fourfold increase in airway responsiveness to acetylcholine. Subthreshold doses of histamine had no effect. These results suggest that thromboxane A2 may be an important mediator of O3-induced airway hyperresponsiveness.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Airway Resistance; Animals; Calcimycin; Dogs; Methacrylates; Neutrophils; Ozone; Prostaglandin Endoperoxides, Synthetic; Prostaglandin-Endoperoxide Synthases; Respiratory System; Thromboxanes