Comparison of cyclic nucleotide phosphodiesterase isoenzymes in rat and rabbit ventricular myocardium: positive inotropic and phosphodiesterase inhibitory effects of Org 30029, milrinone and rolipram

Abstract

The species dependent variation in the cardiotonic activity of selective cyclic nucleotide phosphodiesterase (PDE) isoenzyme inhibitors was examined by comparing the inotropic and PDE inhibitory effects of Org 30029 (N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide HCl), 3-isobutyl-1-methyl-xanthine (IBMX), milrinone and rolipram in rat and rabbit ventricular myocardium. The relative activities of PDE isoenzymes in rat and rabbit cardiac ventricle were also examined to assess the role of the different PDE subtypes in modulating contractile force in the two species. In rabbit papillary muscles, IBMX, Org 30029 and milrinone increased contractile force whilst rolipram was inactive. The rank order of potency of the active compounds was Org 30029 greater than IBMX greater than milrinone. Only Org 30029 and IBMX produced significant positive inotropic responses in rat papillary muscles, milrinone and rolipram being inactive. However, large positive inotropic responses were obtained in rat papillary muscles when milrinone and rolipram were tested in combination. In rabbit papillary muscles, the positive inotropic action of milrinone was markedly potentiated by rolipram. Four main types of PDE (I, II, III, IV) isoenzymes were resolved, by DEAE-sepharose or Mono-Q ion-exchange chromatography, from both rat and rabbit cardiac ventricular tissue. In rabbit, Ca2+/calmodulin dependent PDE (PDE I) and cyclic GMP inhibited PDE (PDE III) were the dominant cAMP activities. In contrast, cyclic GMP stimulated PDE (PDE II), PDE III and cGMP insensitive PDE (PDE IV) represented the main cAMP activities in rat cardiac ventricle. The inhibitory effects of Org 30029, IBMX, milrinone and rolipram on PDE isoenzymes from rat and rabbit cardiac ventricle were essentially similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

“…Second, in agreement with a number of previous studies, we identified PDE3 and PDE4 as critical regulators of cAMP signals in cardiac myocytes. This finding is also consistent with the predominant impact of PDE3 and PDE4 activities for the ␤-adrenergic regulation of I Ca,L in rat ventricular myocytes (20) and the positive inotropic effect of PDE3 and PDE4 inhibitors in rats (41,42).…”

Endothelium‐dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors

“…This was also observed in the presence of high concentration of another PDE III inhibitor milrinone (100pM) by Shahid & Nicholson (1990). In rat aorta without functional endothelium, the PDE IV inhibitors (rolipram and denbufylline) were by themselves weak relaxant agents, acting at high concentrations only.…”

Incomplete reversal of β‐adrenoceptor desensitization in human and guinea‐pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors

“…The surprisingly large responses of IBMX may be due to its additional effects, all of which may increase contractility. These include its competitive reversible effect on inhibitory adenosine (Bohm et al, 1988b), its possible activation of the sarcoplasmic reticulum calcium release channels and sensitization of the myofilaments to calcium (Scholz & Meyer, 1986), reduction of the activity of inhibitory guanine nucleotide protein (Gi) function (Parsons et al, 1988) or additional effects on other PDE isoenzymes, see Shahid & Nicholson (1990).…”