Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elementary Na+ currents were recorded at 19 degrees C in cell attached and inside-out patches from cultured neonatal rat cardiocytes in order to study the effect of cAMP and other 6-aminopurines. The treatment of the cardiocytes with db-cAMP (1 x 10(-3) mol/liter) led to a decline of reconstructed macroscopic peak INa to 62 +/- 7.6% of the initial control value. This reduction in NPo was mostly accompanied by a decrease in burst activity. Open-state kinetics were preserved even in DPI-modified, noninactivating Na+ channels. Since the stimulator of the adenylate cyclase, forskolin (1 x 10(-6) mol/liter), evoked a similar pattern of response, the NPo decrease can be considered as the functional correlate of Na+ channel phosphorylation brought about by cAMP-dependent protein kinase. As found in inside-out patches, cAMP (1 x 10(-3) mol/liter) remained effective under cell-free conditions and reduced reconstructed macroscopic peak INa to about 50% of the initial control value when the absence of Mg-ATP at the cytoplasmic membrane surface prevents phosphorylation reactions. A very similar response developed in the cytoplasmic presence of other 6-aminopurines including ATP (1 x 10(3) mol/liter), adenosine (1 x 10(-4) mol/liter), adenine (1 x 10(-5) mol/liter) and hypoxanthine (1 x 10(-5) mol/liter). This susceptibility to adenine suggests that cardiac Na+ channels in situ could sense intracellular fluctuations of adenine nucleotides, most likely of ATP.
 ...
PMID:Na+ channel blockade by cyclic AMP and other 6-aminopurines in neonatal rat heart. 164 34

In heart failure, an increase in the activity of the sympathetic nervous system takes place to maintain perfusion pressure to vital organs, resulting in increased levels of noradrenaline in the blood of these patients. This permanent stimulation produces a down-regulation of cardiac beta-adrenoceptors. Since noradrenaline acts primarily on the cardiac beta 1-adrenoceptor subtype, beta 1-adrenoceptors decrease in number, whereas the beta 2-adrenoceptor subpopulation remains unchanged in most instances. Consequently, the positive inotropic response to beta-adrenoceptor agonists is diminished. However, there is also a decrease in the positive inotropic effect of beta 2-adrenoceptor agonists, histamine and cAMP-phosphodiesterase inhibitors such as milrinone, whereas the positive inotropic effect of cAMP-independent Na(+)-channel activators such as DPI 206-106 and the effects of cardiac glycosides are not diminished. These observations suggest a more generalised alteration of the cAMP-adenylate cyclase system in the failing heart. Stimulatory guanine nucleotide-binding protein (Gs) couples receptors to adenylate cyclase that stimulate cAMP formation, such as beta-adrenoceptors, histamine receptors and glucagon receptors. In the failing human heart, Gs content has been reported to remain unchanged as compared with that in non-failing myocardium. However, there is a 35%-40% increase in inhibitory guanine nucleotide-binding proteins (Gi), which are involved in the receptor-mediated inhibition of adenylate cyclase. Taken together, two defects of the cAMP-adenylate cyclase system have been identified: an increase in Gi content and a decrease in the number of beta-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Alterations of the cAMP-adenylate cyclase system in the failing human heart. Consequences for the therapy with inotropic drugs]. 197 43

Intracellular Ca2+ release and reuptake are necessary for normal contraction and relaxation of the human heart. Intracellular Ca2+ transients were recorded with aequorin during isometric contraction of myocardium from patients with end-stage heart failure. In contrast to controls, contractions and Ca2+ transients of muscles from failing hearts were markedly prolonged, and the Ca2+ transients exhibited two distinct components. Muscles from the failing hearts showed a diminished capacity to restore a low resting Ca2+ level during diastole. These data obtained in actively contracting human myocardium suggest that intracellular Ca2+ handling is abnormal and might cause both systolic and diastolic dysfunction in heart failure. The inotropic effectiveness of drugs that act to increase intracellular levels of cyclic adenosine monophosphate (AMP), such as beta-adrenergic agonists and phosphodiesterase inhibitors, was markedly reduced in muscles from patients with heart failure. In contrast, the effectiveness of inotropic stimulation with drugs that act by cyclic AMP-independent mechanisms, such as the cardiotonic steroids and DPI 201-106, were preserved. Stimulation of intracellular cyclic AMP production by the adenylate cyclase activator forskolin restored the inotropic response to phosphodiesterase inhibitors. These studies indicate that an abnormality in cyclic AMP production may be a fundamental defect in patients with end-stage heart failure that may markedly diminish the effectiveness of agents that depend on generation of this nucleotide for a positive inotropic effect. Moreover, deficient production of cyclic AMP seems, at least in part, to account for the reversal of the force-frequency relation that characterizes failing myocardium. Of interest, direct measurement of total cellular cyclic AMP content and protein kinase activity did not reveal significant differences between the control and myopathic tissue, suggesting the presence in human ventricular muscle of physiologically distinct compartmentalized pools of cyclic AMP. Finally, changes in the sensitivity of the contractile apparatus to Ca2+ also seem to play an important role in the differential responsiveness to drugs of myopathic versus normal human myocardium.
 ...
PMID:Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure. 215 79

This review deals with the principal mechanisms which are known to play a role in positive inotropism: 1) The myoplasmic Ca2+ concentration may be increased by increases in cyclic AMP. Beside receptor-mediated stimulation (isoprenaline) or direct stimulation (forskolin) of the adenylate cyclase, the cyclic AMP may be increased by phosphodiesterase inhibition; 2) Cyclic AMP-independent activation of Ca2+ channels can be brought about by alpha-adrenergic agents (phenylephrine) or so-called calcium agonists; 3) Only a small increase in myoplasmic Na+ concentration can greatly enhance the force of contraction by an increase in the intracellular Ca2+ concentration. This is possible by inhibition of the Na+/K+-ATPase (glycosides) or by prolongation of the open state of Na+ channels (DPI 201-106); 4) A direct inhibition of the Na+/Ca2+ exchange has been discussed for amiloride; 5) A prolongation of the action potential induced by K+ channel-inhibiting agents such as 4-amino-pyridine may increase the myoplasmic Ca2+ concentration by a prolongation of the slow Ca2+ inward current; 6) An increased Ca2+ sensitivity of the contractile proteins has been demonstrated for a number of compounds in vitro; the contribution of such an effect to the overall positive inotropism is unknown because a calcium sensitizer without any effects on calcium or sodium movements is not yet available.
 ...
PMID:Mechanisms of positive inotropic effects. 255 73

The positive inotropic activity of the novel cardiotonic DPI 201-106 was investigated in rat and guinea pig isolated hearts. For comparative purposes, the adenylate cyclase stimulant forskolin and the sodium channel agonist veratridine were also evaluated in both species. DPI 201-106 and veratridine produced greater inotropic effects in rat hearts than in guinea pig hearts, whereas forskolin produced comparable effects. In both species the inotropic response to DPI 201-106 and veratridine, but not forskolin, was reversed by the sodium channel antagonist tetrodotoxin. These results confirm that the positive inotropic effect of DPI 201-106 is due to stimulation of the sodium channel and demonstrate for the first time that species differences exist in the inotropic response to this novel cardiotonic drug.
 ...
PMID:Species differences in the positive inotropic response to DPI 201-106, a novel cardiotonic agent. 256 Jun 76

A number of new positive inotropic agents with diverse mechanisms of action have been discovered over the past 20 years. Most of these cardiotonic drugs exhibit characteristic electrophysiologic profiles. This prompted us to propose a classification scheme based on electrophysiologic principles, modifying the categories recently suggested by another author. Class I actions designate positive inotropic mechanisms that enhance the transmembrane calcium current by various means, such as beta-receptor stimulation (dobutamine, class I/A), phosphodiesterase inhibition (milrinone, class I/B), direct stimulation of adenylate cyclase (forskolin, class I/C), or direct modulation of calcium channel gating (BAY K 8644, class I/D). Class II action includes mechanisms that lead to elevation of intracellular sodium activity either by inhibiting the Na,K pump (digitalis, class II/A) or by increasing transmembrane sodium influx (DPI 201-106, class II/B). Class III action involves a mechanism by which sensitivity of the myofilaments to calcium increases (EMD 53998, levosimendan). This mechanism is not associated with apparent electrophysiologic manifestations. Positive inotropism due to lengthening of the cardiac repolarization (almokalant) is considered as class IV action. The possible clinical implications of the various positive inotropic mechanisms are also discussed.
 ...
PMID:Classification of positive inotropic actions based on electrophysiologic characteristics: where should calcium sensitizers be placed? 890 29

The type III-secreted proteins NopE1 and NopE2 of Bradyrhizobium japonicum contain a repeated domain of unknown function (DUF1521), which is present in a few uncharacterized proteins. A nopE1/nopE2 double mutant strain exhibited higher nodulation efficiency on Vigna radiata KPS2 than the wild type or single nopE1 or nopE2 mutants. This indicates that both proteins are effectors that functionally overlap. To test translocation into the plant cell compartment during symbiosis, NopE1 and NopE2 were fused with adenylate cyclase (cya) as reporter. A fusion with the full-length proteins or N-terminal peptides resulted in increased cAMP levels in nodules, indicating translocation. Purified NopE1 exhibited self-cleavage in the presence of Ca(2+). Two identical cleavage sites (GD'PHVD) were identified inside the DUF1521 domains. The C-terminal cleavage site was analyzed by alanine scanning. Protein variants in which aspartate or proline next to the cleavage sites was substituted displayed no cleavage. A noncleavable protein was obtained by exchange of the aspartate residues preceding both cleavage sites. Complementation analysis with the noncleavable NopE1 variant did not restore wild-type phenotype on Vigna radiata KPS2, indicating a physiological role of NopE1 cleavage in effector function.
 ...
PMID:The type III-secreted protein NopE1 affects symbiosis and exhibits a calcium-dependent autocleavage activity. 1995 45