cyclic-gmp and flosequinan

1. Flosequinan, milrinone, isoprenaline and forskolin given intravenously at similarly hypotensive doses have been evaluated in separate studies for their effect on ischaemia-induced arrhythmias and on ventricular cyclic nucleotide content following coronary artery ligation in the pentobarbitone anaesthetized rat. 2. Flosequinan did not affect mortality or arrhythmias following coronary artery ligation in either study and no change in ventricular cyclic nucleotide content was observed. 3. Isoprenaline caused a significant increase in mortality (P < 0.05) in both studies whereas milrinone and forskolin caused a significant increase in mortality in only one of the two studies conducted. All three agents caused significant increases in cyclic AMP which were associated with increased incidence of arrhythmias. 4. When compared at similarly hypotensive doses, flosequinan, in contrast to milrinone, isoprenaline and forskolin, did not influence ischaemia-induced arrhythmias or raise ventricular cyclic nucleotide levels in the anesthetized rat.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Anesthesia; Animals; Arrhythmias, Cardiac; Blood Pressure; Colforsin; Coronary Vessels; Cyclic AMP; Cyclic GMP; Enzyme Activation; Isoproterenol; Male; Milrinone; Myocardial Ischemia; Myocardium; Phosphodiesterase Inhibitors; Pyridones; Quinolines; Rats; Rats, Wistar; Vasodilator Agents

In rat aorta endothelin-1 (10(-8) M) induces significant increases in inositol 1,4,5-trisphosphate (IP3) levels after a 30 s exposure. An increase in particulate protein kinase C activity is also observed at 30 s with a second peak of activity occurring after 10 min. Flosequinan, at concentrations of 10(-6) M or greater, inhibits these endothelin-1-induced changes in both IP3 and particulate protein kinase C activity in the absence of changes in either cyclic GMP or cyclic AMP. It is likely therefore that flosequinan inhibits the transduction mechanisms between the endothelin-1 receptor and hydrolysis of phosphatidylinositol 4,5-bisphosphate, possibly at the level of a G-protein. These results provide a mechanism to explain the vasodilator effects of flosequinan observed in vitro.

Topics: Animals; Aorta, Thoracic; Cyclic AMP; Cyclic GMP; Cytosol; Endothelins; In Vitro Techniques; Inosine Triphosphate; Male; Muscle Proteins; Protein Kinase C; Quinolines; Rats; Rats, Wistar; Vasodilator Agents