Effect of phosphodiesterase inhibitors on human arteries in vitro.

In the present study, we investigated if the relaxant effects of phosphodiesterase (PDE) III inhibitors on human vessels could be inhibited by a nitric oxide synthase blocker, L-NAME, or by a blocker of ATP-sensitive potassium channels (KATP), glibenclamide. The experiments were performed using an isometric myograph in isolated human s.c. small arteries obtained from healthy donors. After a priming procedure consisting of exposure to high potassium (120 mmol litre-1) solutions, phenylephrine 10 mumol litre-1 and an equilibrium period of 30 min, the preparations were contracted with a thromboxane A2 mimetic agent, U46619 1 mumol litre-1. Subsequently, cumulative concentration-response curves were constructed for the selective PDE III inhibitors amrinone, milrinone and enoximone, and for theophylline and dipyridamole, with and without the addition of L-NAME 100 mumol litre-1 or glibenclamide 1 mumol litre-1. Addition of L-NAME to the organ bath resulted in significantly higher pEC50 values (-log of the concentration required for 50% relaxation) for milrinone compared with the control: 2.77 (SEM 0.24) mol litre-1 (n = 5) vs 3.49 (0.17) mol litre-1 (n = 7) (P < 0.05). There was no significant difference between any other group. From our data we conclude that the relaxant properties of amrinone, enoximone, theophylline and dipyridamole are not dependent on nitric oxide release or on interaction with KATP channels. However, the effect of milrinone may be partly endothelium-dependent in human vessels in vitro.

Interaction between inhalational anaesthetics and enoximone on isolated heart muscle.

1. The present study describes the effects of halothane or isoflurane on enoximone activity in the isolated left atria of the rat. 2. Concentration-response curves were obtained for the positive inotropic effects of enoximone on electrically stimulated left atria. 3. Enoximone significantly (P < 0.01) increased the contractile force (56% maximum) with all the concentrations tested (10(-9) -10(-3) M). 4. When halothane (1.5% v/v) was present in the organ bath, the maximum effect obtained with enoximone (9%) was significantly lower than that obtained with enoximone alone. 5. Similar results were obtained with enoximone in the presence of halothane plus diltiazem. Isoflurane (1.5% v/v) did not significantly modify the maximum effect obtained with enoximone alone. 6. The administration of diltiazem antagonized the positive inotropic effects of enoximone in the presence of isoflurane or halothane. 7. These results shows that halothane, but not isoflurane, decreased the potency of enoximone on the isolated left atria and suggests that this effect may be mediated by the blocking of the influx of extracellular calcium through voltage-dependent calcium channels inhibited by diltiazem.