Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of the renin-angiotensin system on the control of cell communication was investigated in isolated ventricular cell pairs of adult rats. It was found that angiotensin II (1 microgram/ml) reduced the junctional conductance (gj) by about 55% within 20 s. This effect of angiotensin II was suppressed by DuP 753--an angiotensin receptor blocking agent. Enalapril (1 microgram/ml)--an angiotensin converting enzyme inhibitor--caused an increase in junctional conductance (106%) within 2 min. The effect of enalapril on gj was not related to activation of beta-adrenergic receptors or cAMP-dependent protein kinase. The effect of angiotensin II on gj was suppressed by staurosporine--a potent inhibitor of protein kinase C. This finding indicates that the peptide is changing gj through activation of protein kinase C. The increase in cell coupling caused by enalapril raises the possibility that the antiarrhythmic action of enalapril as well its effect in congestive heart failure are related to an increase in electrical synchronization of cardiac myocytes.
J Cardiovasc Pharmacol 1992 Oct
PMID:The role of the renin-angiotensin system in the control of cell communication in the heart: effects of enalapril and angiotensin II. 128 Jul 22

Cyclic guanosine monophosphate (cGMP)-dependent protein kinase has been cloned from bovine trachea. The isozymes I alpha and I beta, which differ only in their amino-terminal domains were expressed transiently in COS-7 cells. Both isozymes were activated by cGMP and cyclic adenosine monophosphate (cAMP). However, approximately 10-fold higher concentrations of cyclic nucleotides were needed to activate the I beta enzyme than the I alpha enzyme. The KA values for cAMP were 9.1 and greater than 20 microM for the I alpha and I beta isozymes, respectively. It is therefore unlikely that an unmodified I beta enzyme that occurs in high concentrations in vascular smooth muscle can be activated in vivo by cAMP.
J Cardiovasc Pharmacol 1992
PMID:Cyclic GMP-dependent protein kinase and smooth muscle relaxation. 138 Jun 14

Heart rate and force can be increased by noradrenaline and adrenaline through an interaction with both beta 1-adrenoceptors (beta 1AR) and beta 2-adrenoceptors (beta 2 AR). Several ionic currents (I) can flow upon beta AR activation: ICa (through either beta 1AR or beta 2AR), INa, IK, and ICl. Calcium currents (ICa) can be increased directly by the alpha s unit of a GTP binding protein, Gs, or by coupling of Gs to adenylyl cyclase with subsequent formation of cyclic AMP, release of the catalytic unit of cyclic AMP-dependent protein kinase, and phosphorylation of calcium channels and other proteins. Chronic exposure (days or months), but not acute exposure (hours), to a catecholamine downregulates human heart beta 1AR. Acute desensitization partially uncouples human heart beta AR from the adenylyl cyclase. Both acute and chronic desensitization reduce positive inotropic responses to catecholamines. In human heart, catecholamine-induced activation of one beta 2AR causes the production of at least four times more cyclic AMP than activation of one beta 1AR. Chronic treatment of patients with beta 1AR-selective blockers paradoxically induces selective inotropic beta 2AR hyperresponsiveness, presumably by increasing coupling of beta 2AR to Gs. Several partial agonists with high affinity for heart beta 1AR and beta 2AR cause stimulant effects that are resistant to blockade of beta 1AR and beta 2AR. Such nonconventional partial agonists could perhaps interact with beta AR that resemble beta 3 adrenoceptors.
Cardiovasc Drugs Ther 1991 Jun
PMID:Some aspects of heart beta adrenoceptor function. 165 75

We have examined the effects of xamoterol, a partial beta 1-adrenoceptor agonist, on cardiac beta-adrenoceptors using isolated myocytes and cell-free preparations. Xamoterol was considerably less effective than isoproterenol in stimulating adenylate cyclase activity but the difference was narrowed by 1 microM forskolin, presumably by inducing more efficient coupling to the catalytic subunit of the enzyme. Xamoterol mediated a time- and concentration-dependent loss of beta-adrenoceptors from the cell surface of cardiac myocytes through a process of internalization sensitive to the cytoskeleton inhibitors, colchicine and cytochalasine. In cell-free preparations, loss of membrane-bound beta-adrenoceptors induced by xamoterol, but not that induced by 1 microM isoproterenol, was prevented by the inhibitor of protein kinase A. In contrast, 100 nM heparin (an inhibitor of beta-receptor kinase) prevented the isoproterenol-but not the xamoterol-mediated decline of beta-receptors. In addition, 1 microM xamoterol attenuated the isoproterenol-mediated internalization of beta-adrenoceptors in cardiac myocytes over a wide range of isoproterenol concentrations. This attenuation required activation of protein kinase A. These results suggest that the influence of xamoterol on the cycling of cardiac beta-adrenoceptors involves different pathways than those utilized by isoproterenol.
J Cardiovasc Pharmacol 1990 Dec
PMID:Effects of xamoterol on the reversible cycling of cardiac beta-adrenoceptors. 170 88

The effect of enalapril and angiotensin II on junctional conductance (gj) of isolated rat heart cell pairs was investigated. It was found that enalapril (1 micrograms/ml) increases gj by 106 +/- 3.1% (SEM) (n = 20) within 4 min. The effect of enalapril on gj was not suppressed by propranolol (10(-6) M) or by a cAMP-dependent protein kinase inhibitor. Angiotensin II (1 micrograms/ml) reduced gj by 55%. These observations might indicate that an intrinsic renin-angiotensin system in heart is involved in the control of gj in cardiac muscle.
J Cardiovasc Pharmacol 1991 Oct
PMID:Enalapril, an inhibitor of angiotensin converting enzyme, increases the junctional conductance in isolated heart cell pairs. 172 43

Relaxation of rat aorta segments with sodium nitroprusside and endothelium-dependent vasodilators, such as acetylcholine, histamine, A23187, ATP, thrombin, and trypsin, is associated with cyclic-GMP (cGMP) accumulation in a concentration- and time-dependent fashion. With rat aorta segments, these agents also increase cyclic GMP-dependent protein-kinase activity and alter the incorporation of 32P into numerous smooth-muscle proteins. Identical patterns of protein phosphorylation were observed with both classes of relaxants on two-dimensional gel electrophoresis and autoradiography. The effects of nitroprusside were observed with or without the endothelium present. In contrast, the effects of the endothelium-dependent agents on all of these parameters (cGMP, cGMP-dependent protein kinase and protein phosphorylation) required the integrity of the endothelium. Various inhibitors of phospholipase and lypoxygenase prevented the effects of the endothelium-dependent agents, suggesting that a metabolite of arachidonic acid is the endothelium-relaxant factor and responsible for guanylate-cyclase activation. A smooth-muscle protein with decreased 32P incorporation after treatment with either class of relaxants has been identified as myosin light chain. A model is presented suggesting that the effects of endothelium-dependent vasodilators and directly acting nitrovasodilators converge at the level of guanylate-cyclase activation and cGMP accumulation, which explains the common biochemical and physiological effects on smooth muscle of these two classes of vasodilators.
J Cardiovasc Pharmacol 1985
PMID:Role of cyclic-GMP in relaxations of vascular smooth muscle. 240 83

The validity of the hypothesis that cyclic AMP (cAMP) is the 2nd messenger for cell activation was reexamined. Some enzymological aspects of adenyl cyclase (AC) should cause concern: the lack of data on the stoichiometry of cAMP formation in mammalian systems and the unusual enzymatic properties, as well as lack of end-product inhibition and linearity. Furthermore, adenyl cyclase assays may lack precision and accuracy; this may depend on the organ studied. There are also problems of artefactual formation of cAMP during the work-up of cAMP extracts. Thus CrP, Pi, or ATP might influence this process and the actual measurement of cAMP, but solid data are apparently not available. Although a hormone-sensitive AC system has now been reconstituted from pure beta-adrenergic receptor, guanine nucleotide regulatory protein (Ns), and from bovine brain, the sensitivity to isoprenaline was very low and many questions remain--questions about the role of ions and Ns, in particular. The assumption that cAMP is the sole 2nd messenger is questioned since other nucleotides (AMP, ADP) and adenosine may change even more during hormone stimulation, and these compounds can also modulate protein kinase at concentrations often observed in vivo. Doubt over cAMP's role also stems from the observation that basal cAMP levels are sufficiently high to stimulate maximally protein kinase. Discrepancies between cAMP formation and lipolysis during isoprenaline or forskolin stimulation have been observed, and could indicate either compartmentalization of cAMP or alternatively disprove the cAMP hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1985
PMID:Is there a role for cAMP and adenyl cyclase? 241 Jul 32

In hypertensive cardiac hypertrophy, inotropic responsiveness of alpha and beta adrenergic stimuli is reduced. We have previously shown that hearts from two-kidney, one-clip renal hypertensive rats (RHR) have increased beta-adrenergic receptor density and a defect in the guanine nucleotide regulatory protein, leading to decreased adenylate cyclase activity. In spontaneously hypertensive rats (SHR), beta-receptor density was decreased with no change in adenylate cyclase. In these present experiments, we have shown that the alpha 1-adrenergic receptor changes are in the opposite direction, decreasing in RHR and increasing in SHR. All these changes are reversible within 4 weeks following removal of the clipped kidney in RHR, at which time blood pressure and heart weight have also returned towards normal. Further studies on the excitation-contraction pathway have indicated that c-AMP-stimulated protein kinase is decreased in SHR with no changes seen in RHR. Subcutaneous infusion of epinephrine leads to some increase of cardiac mass associated with decreased beta-adrenergic receptors element and decreased adenylate cyclase activity. However, following angiotensin II infusion, even though hypertrophy is more pronounced, no changes in receptors or cyclase are detected. We conclude that different models of hypertensive cardiac hypertrophy associated with different biochemical defects in the adrenergic excitation response pathway, and that if some of these changes become irreversible, further cardiac deterioration and even heart failure may ensue.
J Cardiovasc Pharmacol 1985
PMID:Excitation-contraction coupling in hypertrophied myocardium. 241 74

The Ca2+-dependent regulation of contractile protein interactions in cardiac and vascular smooth muscle involves structurally related but distinct Ca2+ binding proteins. In vascular smooth muscle, Ca2+ binds to calmodulin, and Ca2+-calmodulin activates myosin light chain (MLC) kinase with ultimate stimulation of MLC phosphorylation and actin-myosin interactions. The largest class of inhibitors of vascular contractile protein interactions are the calmodulin antagonists which include certain Ca2+ entry blockers. Pharmacologically, some of these agents can be distinguished from pure Ca2+ entry blockers by being more effective vs. vasoconstrictor agents in vitro, less cardiac depressant, and more effective as platelet aggregation inhibitors. An even greater distinction from Ca2+ entry blockers is evident with another series of agents, isoquinolinesulfonamides, which directly inhibit protein kinase activity. Cardiac muscle myofibrillar regulation involves Ca2+ binding to troponin C (TnC). Some cardiotonics, such as Vardax and APP 201-533, increase the Ca2+ sensitivity of cardiac myofibrillar ATPase activity with a concomitant increase in Ca2+ binding to TnC. Several calmodulin antagonists, Ca2+ blockers, and structurally related agents differentially affect cardiac myofibrillar ATPase activity. Potency and efficacy of some of these stimulating agents is markedly greater than Vardax or APP 201-533. Mechanistically, all agents do not affect cardiac MLC phosphorylation, but directly enhance the Ca2+ sensitivity of ATPase activity. However, differential effects on basal and maximum ATPase activity by some agents suggest more complex or additional effects which are related to the type of agent as well as the species (dog vs. hamster). A major subcellular defect in congestive heart failure in various small animal models is a depressed maximum ATPase activity. Thus, a desired goal would be a pharmacological modulator which increases maximum ATPase activity, not necessarily Ca2+ sensitivity. In sum, it is possible to identify agents, Ca2+ binding protein modulators, which directly inhibit vascular smooth muscle and stimulate cardiac muscle contractile protein interactions. The potential advantages/disadvantages of this approach for vasodilator/cardiotonic drug development will have to await future development of novel compounds targeted specifically for these cellular regulatory processes.
J Cardiovasc Pharmacol 1986
PMID:Pharmacological modulation of cardiac and vascular contractile protein function. 243 41

Activation of the cardiac beta-adrenergic receptor stimulates cAMP levels and activates cAMP-dependent protein kinase. The kinase phosphorylates the calcium channel and enhances thereby the availability and the number of channels that are opened during depolarization. The increased calcium influx leads then to a positive inotropic response. The calcium channel can be identified in vitro by organic calcium channel blockers, which bind stereoselectively to a high affinity, low capacity site localized in sarcolemma and junctional sarcoplasmic reticulum. This binding site has been purified from skeletal muscle microsomes. The purified receptor contains three peptides of Mr 165, 55, and 32 kDa in stoichiometric amounts. The high affinity binding sites for dihydropyridines and phenylalkylamines are localized on the 165 kDa peptide. This peptide is phosphorylated up to 2 mol/mol by cAMP-dependent protein kinase. Reconstitution of the purified receptor yields a calcium channel that has many properties of the cardiac L-type calcium channel. It is suggested that these properties are confined to a 165 kDa peptide in skeletal muscle and to a 183 kDa peptide in cardiac muscle.
J Cardiovasc Pharmacol 1988
PMID:The biochemical properties of L-type calcium channels. 246 31


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