Forskolin, cyclic nucleotides and positive inotropism in isolated papillary muscles of the rabbit

Rodger, Ian W.; Shahid, Mohammed

doi:10.1111/j.1476-5381.1984.tb10755.x

Cited by 42 publications

(30 citation statements)

References 9 publications

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“…Litosch et al (1982) reported that 10-6 M forskolin increased cAMP levels 4-fold with little stimulation of lipolysis whereas a similar elevation of cAMP by Isoproterenol was accompanied by maximum activation of lipolysis in rat adenocytes. In the rabbit papillary muscle, forskolin causes much greater increase in cAMP than does isoproterenol at the same level of function (Rodger and Shahid 1984). The data presented in this study are consistent with these reports in other tissues.…”

Section: Discussionsupporting

confidence: 83%

The time course of changes in force and cyclic AMP levels produced by isoproterenol and forskolin in isolated rabbit detrusor muscle.

Morita

Kondo

Dohkita

et al. 1987

Tohoku J. Exp. Med.

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The effects of forskolin and isoproterenol on contractile force and cyclic AMP (cAMP) levels were compared in rabbit detrusor. Both forskolin and isoproterenol produced relaxation of rabbit detrusor and an increase in cAMP levels in the tissue. Although the relaxant response to forskolin was similar to that of isoproterenol, the increase in cAMP levels induced by forskolin was significantly larger than that induced by isoproterenol. These results suggest that there is a discrepancy in the relaxation responses and cAMP levels in response to forskolin and isoproterenol.forskolin ; isoproterenol ; rabbit detrusor ; relaxantion : cAMP levels Forskolin has been reported to produce relaxation in various smooth muscles and to increase cAMP levels (Dubey et al. 1981;Muller and Baer 1983). Isoproterenol also causes smooth muscle relaxation associated with an increase of cAMP (Bar 1974). The purpose of the present study is to compare the changes in cAMP levels with relaxation of rabbit urinary bladder smooth muscle induced by forskolin and isoproterenol. MATERIALS AND METHODSTen male New Zealand white rabbits weighing 2-2.5 kg were stunned and bled. Two muscle strips, 2 mm wide and 10 mm long, were dissected from each urinary bladder dome (detrusor).Measurement of contractile force. Muscle strips were mounted in a 3.0 ml bath containing modified Krebs solution bubbled with 95% 02 and 5% CO2 at 37°C. One end of the strip was attached with a 4-0 silk thread to a hook fixed at the bottom of the bath and the other end was similary attached to a Statham UC-2 force transducer. A baseline force of 1.0 g was applied and maintained during the experiment. The strip was equilibrated for 60 min prior to the administration of the drug. Drugs were added directly to the muscle bath in an amount of 0.1 ml. Effects of drugs were determined by calculating the change in peak contractile force (active force+baseline force).

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Section: Discussionsupporting

confidence: 83%

The time course of changes in force and cyclic AMP levels produced by isoproterenol and forskolin in isolated rabbit detrusor muscle.

Morita

Kondo

Dohkita

et al. 1987

Tohoku J. Exp. Med.

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“…For example, SNP and other NO-releasing agents have been reported to have no e ect on twitch tension in canine and rabbit ventricular tissue (Endoh & Yamashita, 1981;Inui et al, 1982;Rodger & Shahid, 1984), on maximal ventricular pressure or force in rat and guinea pig perfused hearts (Lincoln & Keely, 1980Grocott-Mason et al, 1994), on the force and time course of contraction in rat, guinea pig and human cardiac preparations (Nawrath et al, 1995) and on maximal cell shortening in guinea pig isolated ventricular cells (Stein et al, 1993). On the other hand, negative inotropic e ects of SNP have been reported in the literature (e.g.…”

Section: Discussionmentioning

confidence: 99%

Cyclic GMP‐dependent protein kinase activation in the absence of negative inotropic effects in the rat ventricle

MacDonell

Diamond

1997

British J Pharmacology

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1 It has been suggested that activation of cyclic GMP-dependent protein kinase (PKG) is a necessary step in the chain of events leading to the production of negative inotropy by muscarinic receptor agonists in mammalian ventricles, and that some cyclic GMP-elevating agents, such as sodium nitroprusside (SNP), fail to exert a negative inotropic e ect because they elevate cyclic GMP levels in a pool that does not activate the kinase. This hypothesis was tested in the present study by monitoring the e ects of carbachol, SNP and atrial natriuretic peptide (ANP) on contractility, cyclic GMP content and PKG activity in rat intact ventricular preparations and freshly isolated ventricular cardiomyocytes. 2 The presence of PKG in both the intact vehicle and in isolated ventricular cardiomyocytes was con®rmed by MonoQ anion exchange chromatography and Western blotting. The elution pro®le indicated that the conditions of the PKG assay were selective for measuring PKG activity. 3 Carbachol induced a marked negative inotropic e ect in intact, perfused hearts and ventricular strips in the presence of isoproterenol. The negative inotropic e ect of carbachol was not associated with signi®cant changes in cyclic GMP content or PKG activity in intact ventricular tissue, or in PKG activity in isolated cardiomyocytes. 4 SNP and ANP signi®cantly increased cyclic GMP levels and activated PKG in intact ventricular preparations. Both drugs also activated PKG in isolated cardiomyocytes. However, neither drug had any negative inotropic e ect in isoprenaline-stimulated perfused hearts and ANP did not change the contractility of isoprenaline-stimulated isolated cardiomyocytes. 5 The results of this study demonstrate that the negative inotropic e ects of muscarinic receptor agonists can occur in the absence of signi®cant activation of PKG. Conversely, marked increases in ventricular cyclic GMP content and PKG activity caused by SNP or ANP were not accompanied by a negative inotropic e ect. 6 These results suggest that increases in cyclic GMP levels and activation of PKG do not play important roles in the regulation of rat ventricular contractility by muscarinic receptor agonists.

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“…Basal levels of cyclic AMP are low in isolated heart muscle cells (Endoh et al, 1980;Nicholson et al, 1991;Kelso et al, 1992). Hence forskolin, which acts directly on the catalytic subunit of adenylate cyclase to activate the enzyme (Lindner & Metzger, 1983;Rodger & Shahid, 1984;Bristow e\t al., 1984;Evans, 1986) was a useful tool with which to ma ify the effects of the selective PDE inhibitors investigated. The efficacy of forskolin in increasing levels of cyclic AMP was lower in isolated cardiomyocytes thah in the intact myocardium (Rodger & Shahid, 1984;Buschmans et al, 1985) possibly due to the absence of other cell types.…”

Section: Effects Of Pde Inhibitors On Contractile Activitymentioning

confidence: 99%

“…Hence forskolin, which acts directly on the catalytic subunit of adenylate cyclase to activate the enzyme (Lindner & Metzger, 1983;Rodger & Shahid, 1984;Bristow e\t al., 1984;Evans, 1986) was a useful tool with which to ma ify the effects of the selective PDE inhibitors investigated. The efficacy of forskolin in increasing levels of cyclic AMP was lower in isolated cardiomyocytes thah in the intact myocardium (Rodger & Shahid, 1984;Buschmans et al, 1985) possibly due to the absence of other cell types. Levels of cyclic AMP, in the presence of either Ro 20-1724 or IBMX, are similar to those reported by Millar et al (1988) in isolated ventricular cardiomyocytes.…”

Section: Effects Of Pde Inhibitors On Contractile Activitymentioning

confidence: 99%

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Kelso

McDermott

Silke

1993

British J Pharmacology

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1 The contractile effects of the novel cardiotonic agent HN-10200 (2-[3-methoxy-5-methylsulphinyl-2-thienyl]-lH-imidazo-[4,5-c]-pyridine hydrochloride), were examined and comparisons made with the responses obtained to a structurally similar compound, sulmazole, and to a number of other compounds which are known to inhibit phosphodiesterase (PDE) isoenzymes with differing selectivities; namely, enoximone (PDE III inhibitor), Ro 20-1724 (PDE IV inhibitor) and 3-isobutyl-1-methylxanthine (nonselective PDE inhibitor). 2 Contractile function, as measured by mechanical shortening, and biochemical systems involving cyclic AMP were investigated in ventricular cardiomyocytes isolated from adult Sprague-Dawley rats (200-250 g). 3 HN-10200 exerted a concentration-dependent (10-8 M-10-4 M) positive contractile effect, which was independent of a-or 0-adrenoceptor, or histamine receptor stimulation. 4 The efficacies of the contractile responses to the PDE inhibitors were of the order: HN-10200> IBMX> sulmazole> enoximone and maximum stimulations, which were obtained at concentrations of 10-4M, were 54 ± 4%, 41 ± 7%, 38 ± 7% and 26 ± 5% (mean ± s.e.) greater than basal levels, respectively (n = 6); the basal value of contractile amplitude (dL), in the absence of PDE inhibitors was 7.39 ± 0.18% (mean ± s.e.). Ro 20-1724 did not have any effect on contractile activity. 5 Due to low basal levels of cyclic nucleotides in isolated cells, accumulation of cyclic AMP due to the presence of the PDE inhibitors was detected only when the levels of cyclic nucleotide were enhanced with forskolin (10 fM). 6 The PDE inhibitors increased levels of cyclic AMP only at concentrations> 10-' M. HN-10200 and sulmazole had similar concentration-dependent profiles for the accumulation of cyclic AMP; their potencies were lower than that of IBMX (concentrations of forskolin required to increase cyclic AMP by 4 pmol mg-' protein, in the presence of maximum concentrations of the PDE inhibitors, were 13 ± 3 11M, 14 ± 3 JAM and 3 ± 0.6 JAM [mean ± s.e.], respectively). 7 These results indicate that a similar mechanism, probably through a weak inhibition of the cyclic AMP-specific PDE isoenzymes, is responsible for the increase in levels of cyclic AMP by HN-10200 and sulmazole. However, cyclic AMP is only partially responsible for the positive contractile effect of HN-10200 and, similarly, sulmazole and IBMX. The lack of apparent increase in levels of cyclic AMP by enoximone, highlights its degree of selectivity for the PDE III isoenzyme, such that the PDE IV isoform is still present in sufficient quantity to degrade cyclic AMP within the cell. On the other hand, the potent action of Ro 20-1724 on accumulation of cyclic AMP, in addition to the lack of effect on contractile function, is in agreement with the selectivity of this compound for the PDE IV isoenzyme and compartmentalization of cyclic AMP in rat isolated ventricular cardiomyocytes.

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Forskolin, cyclic nucleotides and positive inotropism in isolated papillary muscles of the rabbit

Cited by 42 publications

References 9 publications

The time course of changes in force and cyclic AMP levels produced by isoproterenol and forskolin in isolated rabbit detrusor muscle.

The time course of changes in force and cyclic AMP levels produced by isoproterenol and forskolin in isolated rabbit detrusor muscle.

Cyclic GMP‐dependent protein kinase activation in the absence of negative inotropic effects in the rat ventricle

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

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