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)

This study examines the relaxation produced by the sesquiterpene polygodial and compares its action with those caused by acetylcholine (ACh) and sodium nitroprusside (SNP) in the rabbit corpus cavernosum (RbCC) in vitro. RbCC was set up in a 5-ml bath containing Krebs solution at 37 degrees C, at pH 7.2, and under 2 g of tension. Polygodial, ACh, and SNP elicited graded relaxation in RbCC with mean EC50 values of 46.70 microM, 0.38 microM, and 0.30 microM, respectively. The nitric oxide (NO) synthase inhibitor L-NOARG and the guanylate cyclase inhibitors LY 83583 and ODQ markedly inhibited the relaxation induced by polygodial (% of inhibition of 79, 48, and 51, respectively) and those caused by ACh (% of inhibition of 100, 49, and 32, respectively). Tetraethylammonium (TEA) and glibenclamide inhibited the relaxation induced by polygodial (52% and 43%, respectively), but only TEA caused shift to the right on ACh-mediated relaxation. In contrast, apamin, charybdotoxin, and 4-aminopyridine or the protein kinase A inhibitor KT 5720 all failed to affect either polygodial or ACh-mediated relaxation in these preparations. The authors concluded that polygodial produced graded relaxation in the RbCC in vitro via a mechanism that was partially dependent on the release of NO or a NO-derived substance through an activation of guanylate cyclase but was independent of adenylate cyclase mechanism. In addition, the opening of K+ channels sensitive to TEA and glibenclamide, but not those sensitive to apamin, 4-aminopyridine, or charybdotoxin, also contributed to the relaxant action produced by polygodial in the RbCC.
J Cardiovasc Pharmacol 2003 Feb
PMID:Role of nitric oxide and K+ channels in relaxation induced by polygodial in rabbit corpus cavernosum in vitro. 1254 92

In order to investigate the signal transduction mechanisms of lysophosphatidic acid (LPA)-induced vascular smooth muscle (VSM) DNA synthesis, rat aortic A10 cells were used as an experimental model and [ H]-thymidine incorporation was used as an index of DNA synthesis. LPA caused dose- and time-dependent increase in DNA synthesis in A10 VSM cells. LPA (10 microM) also stimulated the activity of casein kinase II (CKII) in a time-dependent manner. The inhibitors of CKII, daidzein and 5,6-dichlorobenzimidazole riboside, diminished the LPA-induced increase in CKII activity and DNA synthesis. The LPA-stimulated activities of extracellularly regulated kinases (ERK) and p38 kinases as well as the stimulatory effects of LPA on DNA synthesis were blocked by ERK inhibitor, PD98059, and p38 kinase inhibitor, SB203580. The LPA-induced increase in intracellular free Ca and the LPA-induced DNA synthesis were not affected by Ca channel blockers, verapamil and diltiazem, as well as a Ca -dependent protein phosphatase (calcineurin) inhibitor, cyclosporine A. These data suggest that the LPA-induced DNA synthesis in VSM cells may be mediated by a signal transduction mechanism involving CKII, ERK, and p38 K.
J Cardiovasc Pharmacol 2003 Mar
PMID:Mechanisms of lysophosphatidic acid-induced DNA synthesis in vascular smooth muscle cells. 1260 16

Adenosine (ADO) is a potent cerebral vasodilator and has been proposed as a metabolic regulator of cerebral blood flow. However, the signal transduction pathway by which ADO causes vasodilation in cerebral microvessels is currently unknown. The current study was designed to investigate the role of cyclic nucleotides and cyclic nucleotide-dependent protein kinases in ADO-induced dilation of resistance-sized rat cerebral arterioles that develop spontaneous tone. Arterioles were cannulated and perfused intraluminally at constant flow (2 microl/min) and pressure (60 mm Hg). ADO (29.7 +/- 2.0%; 1 microM), CGS-21680 (16 +/- 4%, 1 microM), 8-bromo-cyclic guanosine monophosphate (8 Br-cGMP; 29.9 +/- 3.9%; 100 microM), sodium nitroprusside (SNP; 30.6 +/- 3.3%, 1 microM), cyclic guanine monophosphate-dependent protein kinase activator (Sp-8-pCPT-cGMPS, 25.9 +/- 4.2%; 10 microM), forskolin (30.5 +/- 5.9%; 0.1 microM), and pH 6.8 all produced large dilations. The selective cGMP-dependent protein kinase inhibitor, Rp-8-pCPT-cGMPS (10 microM), had no effect on resting diameter or reactivity to acidic pH, but significantly ( < 0.05) attenuated arteriolar dilations to ADO (59%, n = 8), CGS-21680 (60%, n = 4), SNP (62%, n = 3), 8 Br-cGMP (88%, n = 3), and Sp-8-pCPT-cGMPS (98%, n = 3). H8, the less-selective cyclic nucleotide-dependent protein kinase inhibitor, had similar effects as Rp-8-pCPT-cGMPS. Additionally, the inhibitor of the soluble guanylate cyclase, 1H-[1,24]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), blocked the response to SNP (70% inhibition) and significantly inhibited the ADO response (43% inhibition). In contrast, inhibition of the cyclic ADO monophosphate (cAMP)-dependent protein kinase Rp-8-CPT-cAMPS had no effect on the ADO, SNP, or pH responses, but significantly blocked forskolin-induced vasodilation (53%). It is concluded that ADO-induced vasodilation in cerebral microvessels, at least in part, involves cGMP and cGMP-dependent protein kinase, but not cAMP or cAMP-dependent kinase. Our data therefore provides a new insight into mechanisms by which ADO invokes vasodilation in cerebral microvascular arterioles.
J Cardiovasc Pharmacol 2003 Mar
PMID:cGMP-dependent and not cAMP-dependent kinase is required for adenosine-induced dilation of intracerebral arterioles. 1260 23

Numerous attempts have been made to develop strategies for regulating the intracellular cyclic AMP signal pharmacologically, with an intention to establish either new medical therapeutic methods or experimental tools. In the past decades, many pharmacological reagents have been identified that regulate this pathway at the level of the receptor. G protein, adenylyl cyclase, cyclic AMP, protein kinase A and phosphodiesterase. Since the cloning of adenylyl cyclase isoforms during the 1990s, investigators including ourselves have tried to find reagents that regulate the activity of this enzyme directly in an isoform-dependent manner. The ultimate goal of developing such reagents would be to regulate the cyclic AMP signal in an organ-dependent manner. Ourselves and other workers have reported that such reagents may vary from a simple cation to kinases. In a more recent study, using the results from crystallographic studies and computer-assisted drug design programs, we have identified subtype-selective regulators of adenylyl cyclase. Such regulators are mostly based upon forskolin, a diterpene compound obtained from Coleus forskolii, that acts directly on adenylyl cyclase to increase the intracellular levels of cyclic AMP. Similarly, novel reagents have been identified that inhibit a specific adenylyl cyclase isoform (e.g. type 5 adenylyl cyclase). Such reagents would potentially provide a new therapeutic strategy to treat hypertension, for example, as well as methods to selectively stimulate or inhibit this adenylyl cyclase isoform, which may be reminiscent of overexpression or knocking out of the cardiac adenylyl cyclase isoform by the use of a pharmacological method.
J Cardiovasc Pharmacol 2003 Jan
PMID:Isoform-targeted regulation of cardiac adenylyl cyclase. 1268 88

To clarify the regulating mechanism of vascular calcification, the investigators observed the effects of three vasoactive peptides, adrenomedullin (ADM), C-type natriuretic peptide (CNP), and parathyroid hormone-related peptide (PTHrP) on calcification in rat vascular smooth muscle cells (VSMCs). Beta-glycerophosphate stimulated growth and calcification in VSMCs. Adrenomedullin and CNP lowered beta-glycerophosphate-induced increase in VSMC growth. All three vasoactive peptides attenuated the increases of 45Ca accumulation, calcium content, and alkaline phosphatase activity in calcified VSMCs. As for comparing the inhibitory effects, the strongest was PTHrP. Both ADM and PTHrP increased cyclic adenosine monophosphate (cAMP) content in calcified VSMCs, but CNP upregulated cyclic guanosine monophosphate (cGMP) content. The PKA inhibitor PKAI completely reversed the inhibition of ADM on cell growth and all inhibitory effects of PTHrP on the parameters of calcification. The PKG inhibitor H8, however, strongly antagonized all the inhibitory effects of CNP on calcification. These data suggested that beta-glycerophosphate-induced calcification in VSMCs was inhibited by ADM, CNP, and PTHrP. Adrenomedullin and PTHrP inhibited VSMC calcification partially through the cAMP/PKA pathway, whereas CNP inhibited VSMC calcification through the cGMP/PKG pathway. This study could be of help in understanding the pathogenesis of vascular calcification, and providing new target for clinical treatment of cardiovascular diseases associated with vascular calcification.
J Cardiovasc Pharmacol 2003 Jul
PMID:Effects of adrenomedullin, C-type natriuretic peptide, and parathyroid hormone-related peptide on calcification in cultured rat vascular smooth muscle cells. 1282 32

Four corticotropin-releasing factor (CRF)-related peptides have been found in mammals and are known as CRF, urocortin, urocortin II, and urocortin III (also known as stresscopin). The three urocortins have considerably higher affinities for CRF receptor type 2 (CRF R2) than CRF, and urocortin II and urocortin III are highly selective for CRF R2. In the present study, the authors examined the hypothesis that urocortin II or urocortin III, in addition to urocortin, produces vasodilation as a candidate for natural ligands of CRF R2beta in rat thoracic aorta. Involvement of protein kinases on urocortin-induced vasodilation was also explored. The vasodilative effects of urocortin II and urocortin III were more potent than that of CRF, but less potent than that of urocortin. Urocortin II-induced vasodilation was significantly attenuated by a CRF R2-selective antagonist, antisauvagine-30. Both SQ22536, an adenylate cyclase inhibitor, and Rp-8-Br-cAMPS, a protein kinase A (PKA) inhibitor, were found to attenuate the urocortin II-induced vasodilation. SB203580, a p38 mitogen-activated protein (MAP) kinase inhibitor, also inhibited the effects of urocortin and urocortin II on vasodilation. Thus, urocortins contribute to vasodilation via p38 MAP kinase as well as PKA pathways.
J Cardiovasc Pharmacol 2003 Oct
PMID:Vasodilative effects of urocortin II via protein kinase A and a mitogen-activated protein kinase in rat thoracic aorta. 1450 43

NF-kappaB is a pleiotropic transcription factor implicated in the regulation of diverse biological phenomena, including apoptosis, cell survival, cell growth, cell division, innate immunity, cellular differentiation, and the cellular responses to stress, hypoxia, stretch and ischemia. In the heart, NF-kappaB has been shown to be activated in atherosclerosis, myocarditis, in association with angina, during transplant rejection, after ischemia/reperfusion, in congestive heart failure, dilated cardiomyopathy, after ischemic and pharmacological preconditioning, heat shock, burn trauma, and in hypertrophy of isolated cardiomyocytes. Regulation of NF-kappaB is complicated; in addition to being activated by canonical cytokine-mediated pathways, NF-kappaB is activated by many of the signal transduction cascades associated with the development of cardiac hypertrophy and response to oxidative stress. Many of these signaling cascades activate NF-kappaB by activating the IkappaB kinase (IKK) complex a major component of the canonical pathway. These signaling interactions occur largely via signaling crosstalk involving the mitogen-activated protein kinase/extracellular signalregulated kinase kinases (MEKKs) that are components of mitogen activated protein kinase (MAPK) signaling pathways. Additionally, there are other signaling factors that act more directly to activate NF-kappaB via IkappaB or by direct phosphorylation of NF-kappaB subunits. Finally, there are combinatorial interactions at the level of the promoter between NF-kappaB, its coactivators, and other transcription factors, several of which are activated by MAPK and cytokine signaling pathways. Thus, in addition to being a major mediator of cytokine effects in the heart, NF-kappaB is positioned as a signaling integrator. As such, NF-kappaB functions as a key regulator of cardiac gene expression programs downstream of multiple signal transduction cascades in a variety of physiological and pathophysiological states. We show that genetic blockade of NF-kappaB reduces infarct size in the murine heart after ischemia/reperfusion (I/R), implicating NF-kappaB as a major determinant of cell death after I/R. These results support the concept that NF-kappaB may be an important therapeutic target for specific cardiovascular diseases.
Cardiovasc Toxicol 2003
PMID:NF-kappaB as an integrator of diverse signaling pathways: the heart of myocardial signaling? 1455 89

n-3 polyunsaturated fatty acids (PUFAs) can prevent life-threatening arrhythmias but the mechanisms responsible have not been established. There is strong evidence that part of the antiarrhythmic action of PUFAs is mediated through inhibition of the Ca(2+)-release mechanism of the sarcoplasmic reticulum (SR). It has also been shown that PUFAs activate protein kinase A (PKA) and produce effects in the cardiac cell similar to beta-adrenergic stimulation. We have investigated whether the inhibitory effect of PUFAs on the Ca(2+)-release mechanism is caused by direct inhibition of the SR Ca(2+)-release channel/ryanodine receptor (RyR) or requires activation of PKA. Experiments in intact cells under voltage-clamp show that the n-3 PUFA eicosapentaenoic acid (EPA) is able to reduce the frequency of spontaneous waves of Ca(2+)-release while increasing SR Ca(2+) content even when PKA activity is inhibited with H-89. This suggests that the EPA-induced inhibition of SR Ca(2+)-release is not dependent on activation of PKA. Consistent with this, single-channel studies demonstrate that EPA (10-100 microM), but not saturated fatty acids, reduce the open probability (Po) of the cardiac RyR incorporated into phospholipid bilayers. EPA also inhibited the binding of [3H]ryanodine to isolated heavy SR. Our results indicate that direct inhibition of RyR channel gating by PUFAs play an important role in the overall antiarrhythmic properties of these compounds.
Cardiovasc Res 2003 Nov 01
PMID:Effects of eicosapentaenoic acid on cardiac SR Ca(2+)-release and ryanodine receptor function. 1461 63

Under basal conditions there is no observable nitric oxide synthase (NOS) activity in vascular smooth muscle (VSM). Pretreatment of endothelium-denuded aortic rings from Sprague-Dawley rats with 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), (0.1 micromol/L) significantly attenuated phenylephrine (PE)-induced contractile responses in a dose-dependent manner. In the presence of 10 micromol/L Nomega-nitro-L-arginine (L-NNA) or 0.1 mmol/L aminoguanidine (AG), the inhibition of contractions at 10 nmol/L PE by H-7 was blocked by 88% or 52%, respectively. The blockade by antagonists was completely reversed by l-arginine but not by d-arginine, and alone they did not significantly alter PE-induced contraction of endothelium-denuded aorta. Methylene blue (MB, 50 micromol/L) also inhibited the action of H-7. The inhibitory effect of H-7 occurred after 5 minutes and was reversible. PE-induced contraction was also inhibited by the selective protein kinase C inhibitors calphostin C (10 micromol/L), and bisindolylmaleimide IV (Bis-IV, 10 micromol/L), but not by the selective protein kinase A inhibitor H-89 (0.1 micromol/L). These results indicate protein kinase C inhibits NOS activity in VSM under basal conditions. Incubation of tissues with either H-7 or calphostin C stimulates NO production, and immunocytochemical studies reveal the presence of NOS in VSM under basal conditions.
J Cardiovasc Pharmacol 2004 Feb
PMID:Protein kinase C masks nitric oxide synthase activity in vascular smooth muscle under basal conditions. 1471 18

There has been much evidence showing that the central sympathetic nervous system may be involved in the control of blood pressure. In the present study, we investigated the role of the presynaptic alpha2-adrenergic receptors and the cyclic adenosine monophosphate-dependent protein kinase (protein kinase A) in the regulation of norepinephrine release in the central nervous system in hypertension. The alpha2-adrenergic receptor agonists UK 14, 304 and clonidine inhibited the stimulation-evoked [3H]norepinephrine release in a dose-dependent manner in the medulla oblongata of Sprague-Dawley rats. Pretreatment of pertussis toxin (a potent inhibitor of the Gi-protein) attenuated the suppression of NE release by UK 14, 304. The protein kinase A inhibitor H-8 also reduced the stimulation-evoked [3H]norepinephrine release in rat medulla oblongata. In spontaneously hypertensive rats, the inhibitory effect of UK 14, 304 on the stimulation-evoked norepinephrine release was significantly less than in age-matched normotensive Wistar-Kyoto rats. By contrast, the protein kinase A inhibitor H-8 reduced the stimulation-evoked norepinephrine release to a greater extent in hypertension than in normotensive controls. The results of the present study showed that the alteration in the presynaptic alpha2-receptor-protein kinase A system might actively participate in the regulation of norepinephrine release in the central nervous system in hypertension.
J Cardiovasc Pharmacol 2003 Dec
PMID:Role of alpha2-adrenergic receptors and cyclic adenosine monophosphate-dependent protein kinase in the regulation of norepinephrine release in the central nervous system of spontaneously hypertensive rats. 1487 Oct 35


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