Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.17 (adenosine deaminase)
 5,206 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conventional inhibitors of cyclic AMP-dependent protein kinase lack membrane-permeability or selectivity, or both. The Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate, Rp-cAMPS, is a novel membrane-permeable antagonist of cyclic AMP. We have assessed the ability of this compound to distinguish between cyclic AMP-dependent and cyclic AMP-independent contractile responses elicited in ventricular cardiomyocytes isolated from the hearts of adult rats. Cardiomyocytes were stimulated to contract at 0.5 Hz in the presence of calcium ion (2 mM) and adenosine deaminase (5 units/ml). Contractile shortening was expressed as maximum shortening relative to prestimulus cell length (delta L%). In the presence of a maximally-effective concentration of isoprenaline (100 nM), which acts by a cyclic AMP-dependent mechanism, Rp-cAMPS inhibited the contractile response in a concentration-dependent and time-dependent manner. Following preincubation for 30 min with Rp-cAMPS (100 microM), the contractile response to isoprenaline (100 nM) was 14% of that elicited in the absence of this inhibitor. An incubation time of 30 min was chosen for all subsequent studies. Rp-cAMPS (< or = 200 microM) inhibited the contractile response to isoprenaline (100 nM) significantly and in a concentration-dependent manner, but failed to inhibit the contractile responses elicited by phenylephrine (2 microM) and calcium ion (7 mM) which act by cyclic AMP-independent mechanisms. In the presence of Rp-cAMPs (200 microM), the contractile response to isoprenaline (100 nM) was 24% of that in the absence of inhibitor. Rp-cAMPS was used subsequently to investigate the contractile-coupling mechanisms associated with some novel inotropic agents. Rp-cAMPS (< or = 200 microM) also inhibited the contractile responses to secretin (20 nM) and VIP (20 nM) significantly. In the presence of Rp-cAMPS (200 microM), the contractile response elicited by secretin (20 nM) was 19% of that in the absence of inhibitor, while that elicited by VIP (20 nM) was abolished completely. Rp-cAMPS (< or = 200 microM) failed to inhibit the contractile response elicited by CGRP (1 nM). In summary, Rp-cAMPS is a membrane-permeable, selective antagonist of cyclic AMP in ventricular cardiomyocytes and can be used, in conjunction with the bioassay of the intracellular accumulation of cyclic AMP, to distinguish between cyclic AMP-dependent and cyclic AMP-independent contractile coupling mechanisms in these cells.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Use of the cyclic AMP antagonist, Rp-cAMPS, to distinguish between cyclic AMP-dependent and cyclic AMP-independent contractile responses in rat ventricular cardiomyocytes. 789 68

Non-adrenergic, non-cholinergic (NANC) nerve stimulation results in excitation (e.j.p., rebound depolarization, contractions) or inhibition (i.j.p., afterhyperpolarization, relaxations) of the gut. NANC neuronal mechanisms participate in the maintenance of the basal tone and spontaneous activity of the gut. There are however species differences, i.e. both NANC excitation and inhibition are present in the guinea pig and only NANC inhibition in the rat intestine. Substance P-like neuropeptide/s are suggested to be mediators released from excitatory NANC and sensory nerves. The latter are activated by histamine and degenerated by capsaicin. There is evidence in favor of a nitric oxide-like substance rather than ATP, dopamine, GABA and neuropeptides (e.g. VIP, PHI/PHM) as the inhibitory NANC mediator in the gut. TTX, high Mg(2+)-low Ca2+ media, 3,4-diaminopyridine, dipyridamol and adenosine deaminase modulate NANC excitation and inhibition. The NANC excitation is more sensitive than the NANC inhibition to the action of catecholamines, reserpine, 6-hydroxydopamine, chymotrypsin, prednisolon, bacitracin, opioids, free oxygen species and low concentration of local anesthetics.
 ...
PMID:NANC transmission in intestines and its pharmacological modulation. 839 Nov 98

The effects of group 2- versus group 3-selective metabotropic glutamate (mGlu) receptor agonists were examined against forskolin (10 microM)-, vasoactive intestinal peptide (VIP; 1 microM)- and 5'-N-ethylcarboxamidoadenosine (NECA; 10 microM)-stimulated cAMP accumulations in adult rat hippocampal slices (in the presence of adenosine deaminase). Group 2 mGlu receptor-selective ((1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid (1S,3R-ACPD) and (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCG I)) and group 3 mGlu receptor-selective (L-2-amino-4-phosphonobutyric acid (L-AP4) and L-serine-O-phosphate) agonists greatly inhibited forskolin-stimulated cAMP formation ( > 80% at maximally effective concentrations). In contrast, stimulation of cAMP by VIP or NECA was inhibited by group 3, but not by group 2, mGlu receptor agonists. In fact, group 2 mGlu receptor agonists greatly potentiated cAMP accumulation evoked by NECA. Both the inhibitory effects of 1S,3R-ACPD on forskolin-stimulated cAMP and the potentiating effects on NECA-stimulated cAMP accumulation were reversed by the competitive group 1/2 mGlu receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG). However, (+)-MCPG had no effects on L-AP4 inhibition of cAMP. Thus, the effects of group 2 versus group 3 mGlu receptor agonists on cAMP coupling can be pharmacologically as well as functionally differentiated in the rat hippocampus.
 ...
PMID:Differentiation of group 2 and group 3 metabotropic glutamate receptor cAMP responses in the rat hippocampus. 866 60

Adenosine can regulate synaptic transmission through modulation of the action of other neurotransmitters. The influence of adenosine on VIP enhancement of synaptic transmission in hippocampal slices was investigated. Facilitation of fEPSP slope by 1 nM VIP (23.3+/-1.3%) was turned into an inhibition (-12.1+/-3.4%) when extracellular endogenous adenosine was removed using adenosine deaminase (ADA, 1U/ml). Blockade of adenosine A(1) receptors with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10 nM) or of A(2A) receptors with ZM241385 (20 nM) attenuated the effect of VIP. When both DPCPX and ZM241385 were present the effect of VIP was abolished. In the presence of ADA, selective A(1) receptor activation with N(6)-cyclopentyladenosine (CPA, 15 nM) or A(2A) receptor-activation with CGS21680 (10 nM) partially readmitted the excitatory effect of VIP on fEPSPs. In contrast, facilitation of PS amplitude by 1 nM VIP (19.1+/-1.2%) was attenuated in the presence of ADA or DPCPX but was not changed by ZM241385. CPA, in the presence of ADA, fully restored the effect of VIP on PS amplitude. In conclusion, VIP facilitation of synaptic transmission to hippocampal pyramidal cell dendrites is dependent on both A(1) and A(2A) receptor activation by endogenous adenosine. VIP effects on PS amplitude are only dependent on A(1) adenosine receptor activation. This differential sensitivity to adenosine modulation might be due to the different VIP circuits contributing to VIP effects on pyramidal cell dendrites and pyramidal cell bodies.
 ...
PMID:Tonic adenosine A1 and A2A receptor activation is required for the excitatory action of VIP on synaptic transmission in the CA1 area of the hippocampus. 1703 44