Milrinone inhibits sympathetic-mediated tachycardia by a postjunctional action independent of cyclic AMP.
In pithed rats with stimulated sympathetic outflow, the phosphodiesterase inhibitor milrinone (0.3 mg/kg, i.v.) decreased the peak tachycardiac response produced by both sympathetic nerve stimulation (15 s at 0.5-3 Hz) and norepinephrine administration (0.3-5 micrograms/kg, i.v.). However, another phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX, 0.5 mg/kg, i.v.) had no effect on the peak tachycardic response to sympathetic stimulation. Similarly, in isolated rat atria, milrinone (9 mumol/L) inhibited the tachycardia produced by norepinephrine, whereas IBMX (1 mumol/L) had no effect. The inhibitory effect of milrinone on sympathetic responses was not due to changes in norepinephrine release since milrinone (9 mumol/L) increased norepinephrine release in isolated rat atria incubated with [3H]norepinephrine. When the duration of the tachycardia (rather than the peak tachycardic response) produced by sympathetic nerve stimulation was measured, it was found to be prolonged by both milrinone and IBMX, suggesting that in this case cyclic AMP was involved. Furthermore, in contrast to its inhibitory effects on norepinephrine-induced tachycardia in rat atria, milrinone enhanced the tachycardia produced by the adenylate cyclase activator forskolin. These results suggest that milrinone has complex actions on sympathetic control of heart rate and that beta-adrenoceptor tachycardia occurs by mechanisms dependent on and independent of cyclic AMP.
Minatoguchi
S
S
Department of Pharmacology, University of Melbourne, Victoria, Australia.
Majewski
H
H
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D003655:Decerebrate State; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
D002316:Cardiotonic Agents; D011728:Pyridones; D009599:Nitroprusside; D005576:Colforsin; D000242:Cyclic AMP; D020105:Milrinone; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine