Inositol-1,4,5-trisphosphate and malignant hyperthermia.
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Humans↗
Biomedical subjects
W Schmitz
Publications and source records attributed to W Schmitz.
Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase III inhibitors pimobendan, adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations.
The present study was performed to compare the effects of the new positive inotropic phosphodiesterase III inhibitors pimobendan, adibendan, and saterinone on the isometric force of contraction in electrically driven ventricular trabeculae carneae isolated from explanted failing (end-stage myocardial failure) with those from nonfailing (prospective organ donors) human hearts. In preparations from nonfailing hearts the phosphodiesterase inhibitors, as well as the beta-adrenoceptor agonist isoprenaline, the cardiac glycoside dihydro-ouabain, and calcium, which were studied for comparison, revealed pronounced positive inotropic effects. The maximal effects of pimobendan, adibendan, and saterinone amounted to 56%, 36% and 45%, respectively, of the maximal effect of calcium. In contrast, in preparations from failing hearts the phosphodiesterase III inhibitors failed to significantly increase the force of contraction and the effect of isoprenaline was markedly reduced. The effects of dihydroouabain and calcium were almost unaltered. The diminished effects of isoprenaline were restored by the concomitant application of phosphodiesterase inhibitors. To elucidate the underlying mechanism of the lack of effect of the phosphodiesterase III inhibitors in the failing heart we also investigated the inhibitory effects of these compounds on the activities of the phosphodiesterase isoenzymes I-III separated by DEAE-cellulose chromatography from both kinds of myocardial tissue. Furthermore, the effects of pimobendan and isoprenaline on the content of cyclic adenosine monophosphate (determined by radioimmunoassays) of intact contracting trabeculae were studied. The lack of effect of the phosphodiesterase inhibitors in failing human hearts could not be explained by an altered phosphodiesterase inhibition, since the properties of the phosphodiesterase isoenzymes I-III and also the inhibitory effects of the phosphodiesterase inhibitors on these isoenzymes did not differ between failing and nonfailing human myocardial tissue. Instead, it may be due to a diminished formation of cyclic adenosine monophosphate in failing hearts, presumably caused mainly by a defect in receptor-adenylate cyclase coupling at least in idiopathic dilated cardiomyopathy. Both the basal and the pimobendan-stimulated or isoprenaline-stimulated contents of cyclic adenosine monophosphate of intact contracting trabeculae from failing hearts were decreased compared with the levels in nonfailing hearts. However, under the combined action of isoprenaline and pimobendan the cyclic adenosine monophosphate level reached values as high as with each compound alone in nonfailing preparations, and in addition the positive inotropic effect of isoprenaline was restored. These findings may have important clinical implications. Along with the elevated levels of circulating catecholamines the positive inotropic effects of the phosphodiesterase inhibitors may be maintained in patients with heart failure.(ABSTRACT TRUNCATED AT 400 WORDS)
1-Methyl-3-isobutylxanthine↗
Distinct down-regulation of cardiac beta 1- and beta 2-adrenoceptors in different human heart diseases.
Cardiac beta-adrenoceptor density and beta 1- and beta 2-subtype distribution were examined in human left ventricular myocardium from transplant donors serving as controls and from patients with mitral valve stenosis, aortic valve stenosis, idiopathic dilated cardiomyopathy, and ischaemic cardiomyopathy respectively. The total beta-adrenoceptor density was similar in transplant donors and patients with moderate heart failure (NYHA II-III) due to mitral valve stenosis, but was markedly reduced in all forms of severe heart failure (NYHA III-IV) studied. A reduction of both beta 1- and beta 2-adrenoceptors was found in patients with severe heart failure due to mitral valve stenosis or ischaemic cardiomyopathy. In contrast, a selective down-regulation of beta 1-adrenoceptors with unchanged beta 2-adrenoceptors and hence a relative increase in the latter was observed in idiopathic dilated cardiomyopathy and aortic valve stenosis. It is concluded that the extent of total beta-adrenoceptor down-regulation is related to the degree of heart failure. Selective loss of beta 1-adrenoceptors is not specific for idiopathic dilated cardiomyopathy but also occurs in aortic valve stenosis. Changes in beta 1- and beta 2-subtype distribution are rather related to the aetiology than to the clinical degree of heart failure.
Adult↗
Isoprenaline-induced increase in mRNA levels of inhibitory G-protein alpha-subunits in rat heart.
Long-term beta-adrenergic stimulation has been shown to desensitize the beta-adrenoceptor/adenylyl cyclase signalling pathway at both the receptor and the G-protein level. To further elucidate the cellular mechanism of G-protein regulation we investigated the influence of prolonged infusion of isoprenaline (2.4 mg/kg.d) on myocardial mRNA levels of different G-protein alpha-subunits in rats. For comparison rats were treated with triiodothyronine (T3; 0.5 mg/kg.d) which induces cardiac hypertrophy like isoprenaline but has different effects on the adenylyl cyclase system. Isoprenaline- and T3-treated animals developed an increase in heart/body weight ratio of 41 +/- 3% and 27 +/- 4%, respectively (P less than 0.05). Isoprenaline increased myocardial total RNA concentration by 39 +/- 6% (P less than 0.05). Hybridization with 32P-labeled rat cDNAs demonstrated an expression rank order of Gs alpha-mRNA greater than Gi alpha-2-mRNA greater than Gi alpha-3-mRNA and no detectable expression of Gi alpha-1-mRNA in rat myocardium. mRNA levels of Gs alpha, Gi alpha-2 and Gi alpha-3 were 36.9 +/- 1.28, 10.7 +/- 1.07 and 3.7 +/- 0.19 pg/micrograms total RNA, respectively. Isoprenaline increased Gi alpha-2- and Gi alpha-3-mRNA concentrations per microgram total RNA by 49 +/- 18% and 27 +/- 7%, respectively (P less than 0.05). This effect was abolished by simultaneously administered propranolol (9.9 mg/kg.d), indicating a beta-adrenoceptor-mediated mechanism. In contrast, T3-induced cardiac hypertrophy was not accompanied by changes in Gi alpha-mRNA expression. Gs alpha-mRNA levels were unaffected by either treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Malignant hyperthermia and inositol phosphate metabolism in the heart and skeletal musculature].
There are recent reports that inositol phosphate metabolism is involved in the development of malignant hyperthermia (MH). Consequently, we investigated the basal concentration of inositol phosphate products in skeletal and heart muscles of malignant hyperthermia-susceptible (MHS) and healthy control (MHN) swine. Different inositol phosphates were measured by high pressure liquid chromatography, including inositol trisphosphate, tetrakisphosphate, pentakisphosphate and hexakisphosphate. All inositol phosphate products measured had a higher concentration in MHS than MHN in skeletal (304-1330%) as well as heart muscles (134-440%). An activation of the inositol phosphate metabolism has been shown to mobilise intracellular calcium from the sarcoplasmic reticulum. It is therefore concluded that, firstly, besides involvement of the skeletal muscles a primary myocardial abnormality in MHS is possible; and secondly, the idea that the inositol phosphate metabolism could be involved in the development of MH is additionally supported.
Animals↗
Possible involvement of inositol-lipid metabolism in malignant hyperthermia.
Alpha-adrenoceptor stimulation may induce malignant hyperthermia (MH) in vivo. Consequently, we have investigated the effects of the alpha-adrenoceptor agonist phenylephrine and, for comparison, the effects of the beta-adrenoceptor agonist isoproterenol on inositol-lipid metabolism of malignant hyperthermia susceptible (MHS) and healthy control (MHN) swine. The experiments were performed on electrically stimulated (frequency 0.2 Hz) trabeculae isolated from the right ventricles of the hearts of MHS and MHN animals. After labelling with [3H]inositol for 6 h, different inositol phosphates were measured by high pressure liquid chromatography, including inositol 1-phosphate, inositol 1,4-bisphosphate, inositol 1,3,4-trisphosphate, inositol 1,4,5-trisphosphate (1,4,5-IP3) and inositol 1,3,4,5-tetrakisphosphate. After stimulation with isoproterenol, the inositol phosphate content did not increase or vary between muscle from MHS and MHN animals. In contrast, all inositol phosphates increased after stimulation with phenylephrine in both muscle types, the effects being greater in MHS than in MHN, especially as regards 1,4,5-IP3 content. As 1,4,5-IP3, a presumed second messenger, has been shown to mobilize intracellular calcium, it is concluded that an enhanced alpha-adrenergic response is involved in the development of MH.
Animals↗
Beta-adrenoceptor stimulation-induced increase in cardiac Gi-protein expression and in carbachol sensitivity.
Increased plasma concentrations of catecholamines are assumed to be responsible for the decreased sensitivity to catecholamines of the failing heart. We investigated in rat heart the influence of a 4-day infusion of isoprenaline (Iso; 2.4 mg.kg-1.d-1), propranolol (Prop; 9.9 mg.kg-1.d-1), Iso + Prop or 0.9% NaCl as control (Ctr) on myocardial Gi-mRNA and Gi-protein levels and on the negative inotropic effect of carbachol in papillary muscles. In Iso-treated rats, hybridization experiments with 32P-cDNAs revealed a 49 +/- 18% (n = 7-8) and 27 +/- 7% (n = 8) increase in Gi alpha-2- and Gi alpha-3-mRNA respectively, and pertussis toxin-catalyzed ADP-ribosylation revealed a 22 +/- 7% (n = 8) increase in Gi-protein as compared to Ctr. These alterations were accompanied by an increased potency of carbachol (mean EC50: 0.04 microM vs. 0.28 microM) in the presence of Iso in isolated electrically driven (1 Hz) papillary muscles. Prop had no effect on Gi-protein expression but antagonized all Iso-induced effects. In conclusion, beta-adrenergic stimulation leads to an increased expression of Gi and to an enhanced negative inotropic potency of muscarinic agonists. An enhanced muscarinic receptor coupling via Gi might play a pathophysiological role in heart diseases with increased plasma catecholamine levels.
Animals↗
The role of alpha 1-adrenergic and muscarinic receptors in cardiac function.
The positive inotropic effect of an alpha 1-adrenoceptor agonist, such as phenylephrine, is accompanied by an increase in the presumed second messenger, inositol 1,4,5-trisphosphate (1,4,5-IP3) and inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4), which may release calcium from the sarcoplasmic reticulum (SR) and/or facilitate calcium entry from the extracellular space. In addition, phenylephrine sensitizes the contractile proteins for calcium. Alpha 1-adrenergic positive inotropic effects are enhanced in heart muscle preparations from cardiomyopathic hamsters and are reduced in heart muscle preparations from human failing myocardium. How the negative inotropic effects of M-cholinoceptor agonists work in the presence of cAMP-increasing agents in ventricular heart muscle preparations is discussed. It involves cAMP-reduction, an increase in cGMP and activation of phosphatase activity. In a rat model, chronic beta-adrenergic stimulation leads to increased sensitivity of rat ventricular tissue for the negative inotropic effect of the M-cholinoceptor agonist, carbachol. This might be due to facilitated signal transduction via increased Gi proteins. In human ventricular tissue from hearts with end-stage heart failure, due to idiopathic dilated cardiomyopathy (IDC), an increased Gi protein has also been found. However, the negative inotropic effects of carbachol were unchanged. The data indicate that changes in alpha-adrenergic and M-cholinergic responses in the heart may depend on underlying causes that induce changes.
Animals↗
Effects of isomazole on force of contraction and phosphodiesterase isoenzymes I-IV in nonfailing and failing human hearts.
The phosphodiesterase (PDE) inhibitor isomazole increased the force of contraction to 278.3 +/- 89.1% (n = 7) of the predrug value in ventricular trabeculae carneae isolated from nonfailing human hearts. This effect can be attributed mainly to a PDE III or a combined PDE III/IV inhibition since at the concentration of the maximal positive inotropic effect of isomazole, PDE III and PDE IV were completely inhibited. In explanted failing human hearts (end-stage myocardial failure, NYHA IV), isomazole increased the force of contraction only marginally to 110.1 +/- 10.7% of the predrug value. The lack of a distinct positive inotropic efficacy of isomazole in failing human hearts could not be explained by an impairment of PDE inhibition since the properties of the PDE I-IV isoenzymes separated by DEAE-Sepharose chromatography and the inhibitory effects of isomazole did not differ in both preparations. The positive inotropic effect of the beta-adrenoceptor agonist isoprenaline was also reduced in failing hearts. However, in the presence of isomazole, the diminished positive inotropic effect of isoprenaline was restored to values obtained with isoprenaline alone in nonfailing hearts. Thus, the decreased effect of inotropic drugs like isoprenaline or isomazole in preparations from failing human heart might be explained mainly by a diminished cAMP formation due to a defect in receptor-adenylate cyclase coupling.
Adult↗
Effects of caffeine, halothane, succinylcholine, phenylephrine and isoproterenol on myocardial force of contraction of malignant hyperthermia susceptible swine.
The effects of caffeine, halothane, succinylcholine, phenylephrine and isoproterenol on force of contraction were studied in electrically driven (0.2 Hz) trabeculae isolated from the right ventricles of the hearts of malignant hyperthermia susceptible (MHS) and healthy control (nMHS) swine. Caffeine (0.1-10 mmol/l) had positive inotropic effects, amounting to 275 +/- 35% of control in nMHS and 268 +/- 34% in MHS (n = 16). Halothane (0.25-4 vol%) decreased the force of contraction maximally to 52 +/- 4% in nMHS and 51 +/- 5% of control in MHS (n = 16). Propranolol did not change these effects. Succinylcholine (0.1-10000 mumol/l) had a small positive inotropic effect in both groups, which was blocked by propranolol. Phenylephrine (0.1-300 mumol/l) increased the force of contraction maximally to 188 +/- 24% of control in nMHS and to 193 +/- 23% in MHS (n = 16). The inotropic effect was blocked by prazosin but not by succinylcholine (1 mmol/l). Isoproterenol (0.01-10 mumol/l) had a positive inotropic effect of maximally 275 +/- 21% of control in nMHS and 396 +/- 31% in MHS (n = 17) (P less than 0.05). Succinylcholine potentiated this effect, and propranolol shifted the concentration-response curves to the right. We conclude that caffeine, halothane, succinylcholine and phenylephrine have similar inotropic effects in the hearts of nMHS and MHS, whereas isoproterenol has a significantly greater effect in MHS than in nMHS.
Animals↗
Evidence for isoproterenol-induced phosphorylation of phosphatase inhibitor-1 in the intact heart.
The positive inotropic effect of the beta-adrenoceptor agonist isoproterenol is accompanied by inhibition of phosphatase type 1 activity in myocardium. Indirect assays suggest that this effect is due to activation of protein phosphatase inhibitor-1, which inhibits phosphatase activity only when phosphorylated. To test this hypothesis directly, electrically stimulated (3 Hz) guinea pig ventricular preparations were perfused according to the Langendorff method with physiological buffers with or without 5 mCi 32P/heart, and then various concentrations of isoproterenol were applied. Contractility was recorded. Hearts were freeze-clamped and cAMP and inhibitor-1 activities were measured. In 32P-labeled hearts a protein at about 26 kd on autoradiograms of 12% sodium dodecyl sulfate gels was detected. Isoproterenol (1 microM) increased rate of tension development to 238% of the predrug value, cAMP concentrations 1.5-fold, and inhibitor-1 activity threefold. Concomitantly, there was an increase in a 32P-labeled band at about 26 kd from 380 to 540 pmol 32P/mg protein. This protein at about 26 kd, after transfer to nitrocellulose, was recognized by an antiserum prepared against rabbit skeletal muscle inhibitor-1. More radioactive protein of about 26 kd could be immunoprecipitated by the antiserum from isoproterenol-treated than from untreated hearts. It is concluded that a protein, probably identical to phosphatase inhibitor-1, is phosphorylated in vivo in the heart in the presence of isoproterenol. Phosphorylation of inhibitor-1 with consequent modification of type 1 phosphatase activity may contribute to the effects of isoproterenol in the heart.
Animals↗
[Mechanism of the positive inotropic effect of phosphodiesterase inhibitors].
Many of newly developed positive inotropic agents are phosphodiesterase inhibitors (PDEI). These are (in contrast to the classical, unselective PDEIs) in most cases selective inhibitors of PDE III which is inhibitable by cGMP. The most important action of PDEIs is a receptor-independent increase in intracellular cAMP, resulting from an inhibition of the degradation of cAMP. An increase in intracellular cAMP levels can also be produced by stimulation of adenylate cyclase, which leads to an increase in cAMP formation. Therefore, the effects of beta-adrenoceptor agonists (e. g., isoprenaline) and PDEIs are rather similar. The main effect of cAMP is to increase the slow Ca inward current during the action potential. This leads to an increase in Ca release from intracellular Ca stores, to an increase in the Ca concentration in the vicinity of the contractile proteins and, hence, to a positive inotropic effect. In addition, PDEIs also produce vasodilatation, which might be of even greater importance than the cardiostimulatory effects of these drugs ("inodilators"). However, two potential disadvantages of PDEIs must also be mentioned: 1) increase in beat frequency and tachyarrhythmias that also result from an increase in intracellular cAMP concentration and 2) decrease in effectiveness or tolerance, which might be due to an increase in inhibitory G proteins.
Cardiotonic Agents↗
Effects of the triazolopyrimidine trapidil on force of contraction, beating frequency and phosphodiesterase I--IV activity in guinea-pig hearts.
The effects of the triazolopyrimidine trapidil (5-methyl-7-diethylamino-s-triazolo [1,5-alpha]pyrimidine, CAS 15421-84-8) on force of contraction, beating frequency and phosphodiesterase (PDE) activity were investigated in isolated preparations from guinea-pig hearts. The effects of 3-isobutyl-1-methylxanthine (IBMX), theophylline and milrinone were studied for comparison. Trapidil exerted a concentration-dependent (1000-3000 mumol(s)/l) positive inotropic effect (EC50 562.4 mumol(s)/l) in guinea-pig papillary muscles. The positive inotropic effect was accompanied by a shortening of the duration of contraction as described for IBMX, or isoprenaline. The efficacy of trapidil was lower than that of IBMX or milrinone. Both agents maximally enhanced force of contraction to a 3fold (milrinone) or even 6fold greater amount (IBMX). The potency of trapidil was almost in the same order of magnitude as that of milrinone. The positive inotropic effect of trapidil is at least partially due to a cyclic adenosine monophosphate (cAMP)-dependent mechanism because carbachol antagonized the increase in force of contraction. Trapidil concentration-dependently but nonselectively inhibited the activities of cAMP PDE isoenzymes I-IV as did theophylline or IBMX. Based on IC50 values (275 mumol(s)/l on the average) trapidil had a potency similar to that of theophylline while IBMX was about one order of magnitude more potent. Regarding the inhibition of PDE III, IBMX was 49fold and milrinone 114fold more potent than trapidil. Trapidil revealed only a marginal positive chronotropic effect. The frequency of spontaneously beating right auricles was increased by 13% at most. Trapidil did not produce any tachyarrhythmias or contractures. It is concluded that the positive inotropic effect of trapidil is mainly due to PDE inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
1-Methyl-3-isobutylxanthine↗
Effects of carbachol and (-)-N6-phenylisopropyladenosine on myocardial inositol phosphate content and force of contraction.
1. The effects of carbachol and the A1-adenosine receptor agonist (-)-N6-phenylisopropyladenosine (PIA) on force of contraction and inositol lipid metabolism were studied in electrically driven left auricles and papillary muscles isolated from guinea-pig hearts. Both carbachol and PIA (0.01-10 microM) had concentration-dependent negative inotropic effects in auricles. In papillary muscles PIA had no inotropic effect. Carbachol also had no inotropic effect at low concentrations (0.01-1 microM) but at 10-100 microM it exerted a slight positive inotropic effect. 2. In auricles and papillary muscles both carbachol and PIA concentration-dependently increased inositol trisphosphate (IP3; significant at 1 microM). Accordingly phosphatidylinositol bisphosphate (PIP2), the precursor of IP3, was reduced. All effects of carbachol and PIA were antagonized by atropine (10 microM) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 20 microM) respectively, indicating receptor-mediated effects. 3. In auricles the negative inotropic effects of carbachol and PIA preceded the increase in IP3. 4. In papillary muscles the increase in IP3 preceded the slight positive inotropic effect of carbachol, indicating that the M-cholinoceptor-mediated increase in IP3 and force of contraction may be related. However, PIA showed a comparable increase in IP3 but no inotropic effect, indicating a dissociation between those parameters. 5. In conclusion, in previous studies a close relation between increases in IP3 and force of contraction has been shown after alpha 1-adrenoceptor stimulation. The present study with carbachol supports this view. However, the present data for PIA could not show such a close relationship, questioning the role of IP3 as an endogenous regulator of force of contraction.
Animals↗
Evidence for the existence of inositol tetrakisphosphate in mammalian heart. Effect of alpha 1-adrenoceptor stimulation.
The time course of the effects of phenylephrine (10 mumol/l) on force of contraction and on inositol phosphates in electrically driven left auricles from rat hearts labeled with [3H]inositol was studied. All experiments were performed in the presence of propranolol (1 mumol/l) and LiCl (10 mmol/l). Products measured after separation with high-performance liquid chromatography were inositol 1-phosphate (1-IP1), inositol 1,4-bisphosphate (1,4-IP2), inositol 1,3,4-trisphosphate (1,3,4,-IP3), inositol 1,4,5-trisphosphate (1,4,5-IP3), and inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4). All inositol phosphates increased after stimulation with phenylephrine. 1,4,5-IP3 was the first compound to rise maximally within 30 seconds; this rise was followed by an increase in 1,3,4,5-IP4 and 1,4-IP2 beginning within 2 minutes. The increase in 1,3,4-IP3 and 1-IP1 was slower and did not reach steady state within 15 minutes. The positive inotropic effect of phenylephrine was maximal after 5 minutes. It is concluded that the increase in the presumed second messengers 1,4,5-IP3 and 1,3,4,5-IP4 coincides with the positive inotropic effect after alpha 1-adrenoceptor stimulation. Since the increase in 1,4,5-IP3 precedes the increase in force of contraction, 1,4,5-IP3 may initiate the positive inotropic effect of alpha 1-adrenoceptor agonists and 1,3,4,5-IP4 maintains the increase in force of contraction.
Animals↗
Differential antagonism by 1,3-dipropylxanthine-8-cyclopentylxanthine and 9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4-triazolo(1,5-c)quinazolin-5-im ine of the effects of adenosine derivatives in the presence of isoprenaline on contractile response and cyclic AMP content in cardiomyocytes. Evidence for the coexistence of A1- and A2-adenosine receptors on cardiomyocytes.
The antagonism by the A1-adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and the A2-adenosine receptor antagonist [9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4-triazolo (1,5-c)quinazolin-5-imine] (CGS 15943A) of the effects of the A1-adenosine receptor agonist (-)-N6-phenylisopropyladenosine (R-PIA) and the A2-adenosine receptor agonist 5'-N-ethyl-carboxamideadenosine (NECA) in the presence of isoprenaline on contractile response and cyclic AMP (cAMP) content in cardiomyocytes from guinea pig cardiac ventricles were studied. In electrically driven (1 Hz) guinea pig ventricular cardiomyocytes R-PIA concentration-dependently (0.0001-100 microM) reduced the stimulatory effects of isoprenaline (0.01 microM) on contractile response and on cAMP content. The A1-adenosine receptor antagonist DPCPX (0.3 microM) antagonized the effects of R-PIA on contractile reponse and on cAMP content, whereas the A2-adenosine receptor antagonist CGS 15943A (0.01 microM) was ineffective. NECA (0.0001-100 microM) reduced the effects of isoprenaline (0.01 microM) on contractile response to about the same extent as R-PIA. However, NECA did not change cAMP content. DPCPX (0.3 microM) antagonized the effects of NECA on contractile response and evoked a cAMP-increasing effect of NECA, which was 38% of the isoprenaline value at most. In contrast, CGS 15943A did not affect the reduction of contractile response induced by NECA, whereas CGS 15943A revealed a cAMP-decreasing effect of NECA (0.1-10 microM). This study provides functional evidence that both, cAMP-decreasing A1- and cAMP-increasing A2-adenosine receptors are present on ventricular cardiomyocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine↗
Positive inotropic effect of carbachol and inositol phosphate levels in mammalian atria after pretreatment with pertussis toxin.
The m-cholinoceptor agonist carbachol elicits a negative inotropic effect in mammalian atria. Pretreatment with pertussis toxin converts the negative to a positive inotropic effect. In this study we investigated the time course of the effects of carbachol on force of contraction and phosphoinositide products in electrically driven left auricles from guinea pig hearts after pretreatment with pertussis toxin (180 micrograms/kg i.v.; 24 hr). Inositol phosphates and phosphatidylinositols were labeled with [3H]inositol and separated with high-performance liquid chromatography and thin-layer chromatography, respectively. All experiments were performed in the presence of LiCl (10 mmol/l). The positive inotropic effect of carbachol (10 mumol/l) began within 2 min and was maximal within 15 min. Inositol 1,4,5-trisphosphate rose within 1 min followed by an increase in inositol 1,3,4,5-tetrakisphosphate, inositol 1,3,4-trisphosphate, inositol 1,4-bisphosphate and inositol 1-phosphate beginning within 2 min. It is concluded that the carbachol-induced positive inotropic effect is associated with an increase in the presumed second messengers inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. Since the increase in inositol 1,4,5-trisphosphate precedes the increase in force of contraction, it may initiate the positive inotropic effect. The increase in inositol 1,3,4,5-tetrakisphosphate may be involved in maintaining the positive inotropic effect of carbachol.
Animals↗
Effects of adenosine analogues on force and cAMP in the heart. Influence of adenosine deaminase.
The effects of the adenosine receptor agonists (-)-N6-phenylisopropyladenosine (PIA) and 5'-N-ethylcarboxamideadenosine (NECA) on the force of contraction, adenylate cyclase activity and cAMP content in the presence of isoprenaline (Iso) were studied in ventricular preparations of the guinea-pig heart. Only in the presence of adenosine deaminase (ADA) and 50 mM sodium chloride, i.e. under 'optimal' conditions, did PIA and NECA reduce the Iso-stimulated adenylate cyclase activity in broken cell preparations, with a maximal effect of about 25%. In electrically driven (1 Hz) papillary muscles from guinea-pigs, both compounds concentration dependently reduced the Iso-stimulated force of contraction maximally by about 50% in the presence of ADA (1 microgram/ml). cAMP was measured in the same preparations. Low concentrations (0.1-1 microM) of PIA reduced the cyclic AMP content while higher concentrations increased the cyclic AMP content. The negative inotropic effect of NECA was accompanied by a concentration-dependent increase in the cyclic AMP content. We conclude that the negative inotropic effect of PIA in the presence of Iso is only in part due to a decrease in the cyclic AMP content resulting from inhibition of adenylate cyclase activity. Such an effect was only detected in the presence of ADA so that endogenous adenosine can obviously mask small effects of PIA on adenylate cyclase activity or the cyclic AMP content. In addition, the negative inotropic effect of NECA in the presence of isoprenaline was not accompanied by a reduction but an increase in the cyclic AMP content.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine↗