A method to assess concomitant cardiac phosphodiesterase inhibition and positive inotropy.
The ability of positive inotropic drugs to inhibit phosphodiesterase was assessed by observance of the potentiation of inotropic responses to the low intrinsic efficacy beta-adrenoceptor partial agonist prenalterol. Previous studies have shown that an increase in tissue stimulus response capability, as is produced for beta-adrenoceptors by blockade of phosphodiesterase, produces an increase in the maximal response to beta-adrenoceptor partial agonists. Using this principle, we tested cardiotonic drugs on normal and prenalterol-pretreated guinea pig left atria and compared the resulting inotropic responses statistically. Prenalterol pretreatment did not potentiate inotropic responses to methoxamine and CaCl2 and blocked (in accordance with beta-adrenoceptor occupation by a low-efficacy partial agonist) responses to norepinephrine (NE), tyramine, and to a certain extent ouabain. This latter finding was attributed to a low-level catecholamine-release by ouabain in this tissue. The inotropic responses to the phosphodiesterase inhibitors isobutylmethylxanthine (IBMX), theophylline, and enprophylline were greatly potentiated. Similarly, the responses to the cardiotonic drugs (known also to be inhibitors of phosphodiesterase) milrinone, amrinone, and fenoximone were potentiated. Positive inotropy to the cardiotonic drug sulmazole was not significantly potentiated by this procedure, indicating that in this tissue sulmazole may produce inotropic responses by other mechanisms as well. In general, this simple assay may be useful to detect blockade of cardiac phosphodiesterase concomitant with positive inotropy. Although a causal relationship between the PDE inhibition and positive inotropy may not be made from these data, knowledge of PDE blockade may still be useful in the assessment of inotropic mechanism and propensity for toxic side effects.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000502:physiology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008954:Models, Biological; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011294:Prenalterol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011943:Receptors, Adrenergic, beta; D000249:Adenosine Monophosphate; D011294:Prenalterol; D015056:1-Methyl-3-isobutylxanthine