Actions of the phosphodiesterase inhibitor zardaverine on guinea-pig ventricular muscle

Abstract

The positive inotropic action of the phosphodiesterase inhibitor zardaverine was investigated in guinea-pig heart muscle. In right papillary muscles, 1-30 microM zardaverine reversibly increased the force of contraction in a concentration-dependent manner. This effect was accompanied by a shortening of contraction and relaxation times. Resting membrane potential was unchanged, whereas action potential amplitude was significantly increased and duration was reduced. In papillary muscles partially depolarised with 22 mM K+, zardaverine (10 and 30 microM) restored slow action potentials, which were not influenced by cimetidine, propranolol or prazosin but were blocked by the calcium channel blocker (+)-nitrendipine or the muscarinic agonist carbachol. cAMP-specific phosphodiesterase III, isolated from guinea-pig ventricular muscle was inhibited by zardaverine as was cAMP-specific phosphodiesterase IV, isolated from dog trachea (IC50s: 0.5 and 0.8 microM, respectively). The results suggest that the observed positive inotropic and electrophysiological effects result from an inhibition of cellular phosphodiesterase.

Inhibition of eosinophil cyclic nucleotide PDE activity and opsonised zymosan‐stimulated respiratory burst by ‘type IV’‐selective PDE inhibitors

“…type TI in rat liver plasma membranes (Pyne et al, 1986) and cardiac ventricle (Timouyasse et al, 1989); type III in rat adipocytes (Degerman et al, 1987) and in canine and Rhesus monkey cardiac ventricle (Weishaar et al, 1987); type IV in rat liver plasma membranes (Pyne et al, 1987) (0.16,uM) is approximately 10 to 20 fold lower than that reported for type IV PDE of human monocytes (2.7 pM) and canine trachea (1.5 pM) (Brothers et al, 1982;Elliott & Leonard, 1989;Galvan & Schudt, 1990), but only 4.5 fold lower than its IC50 for PDE IV from human neutrophils (Nielson et al, 1990). This discrepancy appears to suggest that multiple rolipram-sensitive isoenzymes exist and that an enzyme with greater sensitivity to rolipram predominates in neutrophils and eosinophils.…”

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

“…Therefore, it is unlikely that the lack of efficiency of the PDE inhibitors in the myocytes isolated from noradrenaline-treated guinea-pig hearts was due to an impairment in the contractile apparatus, or due to an enhanced breakdown of cyclic AMP. The concentration of IBMX giving half maximal inhibition of cardiac PDE is reported as 10 LM (Galvan & Schudt, 1990) in guinea-pig myocardium. It has been shown that prenalterol-treated (Bobik & Little, 1984) and noradrenaline-treated (Reithmann & Werdan, 1988) chick embryo cells have depressed levels of cyclic AMP under P-adrenoceptor stimulation.…”

Paradoxical facilitation of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by isoprenaline

“…3.2%(9)** +29.1+ 6.6%(10)* Isoprenaline (10 gM) + 0.98+ 6.4%(9) + 5.94+ 5.7% (8) Data represent the mean + s.e.mean of n independent determinations shown in parentheses. *P<0.05; **P<0.01; significant facilitation in [3H]ACh output Zardaverine (10 gM for 15 min), a mixed inhibitor of the PDE3 and PDE4 isoenzyme families which selectively hydrolyse cyclic AMP (Galvan & Schudt, 1990), had no significant effect on EFS-evoked ACh release (Figure 8). Moreover, zardaverine (10 gM) did not potentiate the facilitatory effect of isoprenaline (0.1, 1 and 10 uM) or the inhibitory action of PGE2 (0.1 nm to 1 gM) on cholinergic neurotransmission at any concentration studied (Table 1; Figure 8).…”

“…To gain further information on the biochemical mechanism(s) by which isoprenaline enhanced cholinergic neurotransmission in guinea-pig trachea, the effect of a number of cyclic AMP-elevating drugs was evaluated on the release of Zardaverine (10 gM for 15 min), a mixed inhibitor of the PDE3 and PDE4 isoenzyme families which selectively hydrolyse cyclic AMP (Galvan & Schudt, 1990), had no significant effect on EFS-evoked ACh release (Figure 8). Moreover, zardaverine (10 gM) did not potentiate the facilitatory effect of isoprenaline (0.1, 1 and 10 uM) or the inhibitory action of PGE2 (0.1 nm to 1 gM) on cholinergic neurotransmission at any concentration studied (Table 1; Figure 8).…”