Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002962 (angina)
 21,142 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ATP-sensitive K+ (KATP) channels are therapeutic targets for several diseases, including angina, hypertension, and diabetes. This is because stimulation of KATP channels is thought to produce vasorelaxation and myocardial protection against ischemia, whereas inhibition facilitates insulin secretion. It is well known that native KATP channels are inhibited by ATP and sulfonylurea (SU) compounds and stimulated by nucleotide diphosphates and K+ channel-opening drugs (KCOs). Although these characteristics can be shared with KATP channels in different tissues, differences in properties among pancreatic, cardiac, and vascular smooth muscle (VSM) cells do exist in terms of the actions produced by such regulators. Recent molecular biology and electrophysiological studies have provided useful information toward the better understanding of KATP channels. For example, native KATP channels appear to be a complex of a regulatory protein containing the SU-binding site [sulfonylurea receptor (SUR)] and an inward-rectifying K+ channel (Kir) serving as a pore-forming subunit. Three isoforms of SUR (SUR1, SUR2A, and SUR2B) have been cloned and found to have two nucleotide-binding folds (NBFs). It seems that these NBFs play an essential role in conferring the MgADP and KCO sensitivity to the channel, whereas the Kir channel subunit itself possesses the ATP-sensing mechanism as an intrinsic property. The molecular structure of KATP channels is thought to be a heteromultimeric (tetrameric) assembly of these complexes: Kir6.2 with SUR1 (SUR1/Kir6.2, pancreatic type), Kir6.2 with SUR2A (SUR2A/ Kir6.2, cardiac type), and Kir6.1 with SUR2B (SUR2B/Kir6.1, VSM type) [i.e., (SUR/Kir6.x)4]. It remains to be determined what are the molecular connections between the SUR and Kir subunits that enable this unique complex to work as a functional KATP channel.
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PMID:ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells. 945 9

Low-voltage-activated T-type Ca2+ channels are present in most excitable tissues including the heart (mainly pacemaker cells), smooth muscle, central and peripheral nervous systems, and endocrine tissues, but also in non-excitable cells, such as osteoblasts, fibroblasts, glial cells, etc. Although they comprise a slightly heterogeneous population, these channels share many defining characteristics: small conductance (< 10 pS), similar Ca2+ and Ba2+ permeabilities, slow deactivation, and a voltage-dependent inactivation rate. In addition, activation at low voltages, rapid inactivation, and blockade by Ni2+ are classical properties of T-type Ca2+ channels, which are less specific. T-type Ca2+ channels are weakly blocked by standard Ca2+ antagonists. Pharmacological blockers are scarce and often lack specificity and/or potency. The physiological modulation of T-type Ca2+ currents is complex: they are enhanced by endothelin-1, angiotensin II (AT1-receptor), ATP, and isoproterenol (cAMP-independent), but are reduced by angiotensin II (AT2-receptor), somatostatin and atrial natriuretic peptide. Norepinephrine enhances these currents in some cells but decreases them in others. T-type Ca2+ currents have many known or suggested physiological and pathophysiological roles in growth (protein synthesis, cell differentiation, and proliferation), neuronal firing regulation, some aspects of genetic hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac rhythm (normal and abnormal), and atherosclerosis. Mibefradil is a new Ca2+ antagonist that is effective in hypertension and angina pectoris. Its favorable pharmacological profile and limited side effects appear to be related to selective block of T-type Ca2+ channels: mibefradil reduces vascular resistance and heart rate without negative inotropy or neurohormonal stimulation, and it also has significant antiproliferative actions.
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PMID:T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. 951 67

Chronic administration of cyclosporin A induces nephrotoxicity in humans. This is related to a cyclosporin A-induced constriction of afferent glomerular arterioles and mesangial cells, which leads to a decrease in filtration pressure and creatinine clearance. Afterwards, cellular lesions are observed involving mainly tubular atrophy and interstitial fibrosis, both of which are nonspecific. The initial mechanism of its toxicity is not clearly explained. The current pharmacological approach is symptomatic in order to counteract or minimize the consequences of a prime cause, which still remains to be defined. However, cyclosporin A has a deletereous effect on mitochondrial functions and mainly on ATP synthesis, which occurs when Ca2+ accumulates in matrix mitochondria. The effects of trimetazidine, an antischemic drug used in the treatment of angina pectoris, have been assessed. This drug is effective in experimental models of hypoxia induced by cyclosporin A: it restores ATP synthesis previously decreased by Ca2+ and cyclosporin A, and releases a part of Ca2+ excess accumulated by mitochondria at concentrations reached in humans at usual dosage regimens. At higher concentrations, it reverses the mitochondrial permeability transition previously generated (opened) by Ca2+ and a pro-oxidant such as terbutylperoxide (t-BH). It was also observed that trimetazidine does not modify the immunosuppressive effects of cyclosporin A in various models. These data suggest that nephrotoxicity of cyclosporin A is not irrevocably linked to its immunosuppressive effect but that it may be possible to counteract at least partly its nephrotoxic effects without altering its effectiveness in preventing graft rejection.
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PMID:Potential interest of anti-ischemic agents for limiting cyclosporin A nephrotoxicity. 952 74

1. Ranolazine shifts ATP production away from fatty acid oxidation toward glucose oxidation. 2. Because more oxygen is required to phosphorylate a given amount of ATP during fatty acid oxidation than during carbohydrate oxidation, the ranolazine-induced shift in substrate selection reduces the cell's demand for oxygen without decreasing its ability to do work. The shift also maintains coupling of glycolysis to glucose oxidation during ischemia, thus reducing tissue acidosis. 3. This unique, non-hemodynamic mechanism offers the potential to treat angina without reducing blood pressure, heart rate or myocardial contractility. 4. At least three double-blind, randomized, placebo-controlled clinical trials have yielded data consistent with this hypothesis.
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PMID:Ranolazine: a novel metabolic modulator for the treatment of angina. 955 12

Endothelium represents a large paracrine gland with an enormous reactive surface. By means of its numerous vasodilation and vasospastic factors it manages the basal and working tonus of vessels and thus also the regional flow and the access of target tissues to hormones and metabolic substrates. It manages also the proliferation and migration of myocytes of the vascular wall and thus its adaptation to overload. The dysfunctional states of endothelium are observed in arterial hypertensions, diabetes, dyslipoproteinaemia and they grow with age. They are the first stage of atherothrombogenic processes. They manifest themselves by a decreased vasodilation reserve of the vascular wall to strain, insulin and many other stimuli. On the contrary, quite frequently they paradoxically react to physical strain, acetylcholine, histamine, ATP etc. by vascular spasms which can determine vasospastic and microvascular angina pectoris including spasms and occlusions of e.g. coronary arteries in sites of insignificant stenoses with the origin of infarctions. The damaged endothelium, so to explain, conceives these stimuli in accordance with the encoded programme as a stimulus to the protection from haemorrhage during stress (fight or flight) and develops "suicidal" defensive reaction against them which we are nowadays able to modulate by administration of ACE-inhibitors, beta-blockers, hypolipidaemic drugs, inhibitors of cyclooxygenase-1 (30--100 mg of aspirin), Ca-antagonists and antioxidants including numerous nonpharmacological procedures. We can retard or halt the process of atherothrombogenesis and avoid or lower thus the number of sudden vascular ventricular as well as brain episodes, including the congestive heart failures, limb amputations and ischaemic damage of the brain. (Fig. 4, Ref. 70.).
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PMID:[In Process Citation] 966 42

Endothelium represents a large paracrine gland with an enormous reactive surface. By means of its numerous vasodilation and vasospastic factors it manages the basal and working tonus of vessels and thus also the regional flow and the access of target tissues to hormones and metabolic substrates. It manages also the proliferation and migration of myocytes of the vascular wall and thus its adaptation to overload. The dysfunctional states of endothelium are observed in arterial hypertensions, diabetes, dyslipoproteinaemia, and they grow with age. They are the first stage of atherothrombogenic processes. They manifest themselves by a decreased vasodilation reserve of the vascular wall to strain, insulin and many other stimuli. On the contrary, quite frequently they paradoxically react to physical strain, acetylcholine, histamine, ATP etc. by vascular spasms which can determine vasospastic and microvascular angina pectoris including spasms and occlusions of e.g. coronary arteries in sites of insignificant stenoses with the origin of infarctions. The damaged endothelium, so to explain, conceives these stimuli in accordance with the encoded programme as a stimulus to the protection from haemorrhage during stress (fight or flight) and develops "suicidal" defensive reaction against them which we are nowadays able to modulate by administration of ACE-inhibitors, beta-blockers, hypolipidaemic drugs, inhibitors of cyclooxygenase-1 (30-100 mg of aspirin), Ca-antagonists and antioxidants including numerous non-pharmacological procedures. We can retard or halt the process of atherothrombogenesis and avoid or lower thus the number of sudden vascular ventricular as well as brain episodes, including the congestive heart failures, limb amputations and ischaemic damage of the brain. (Fig. 4, Ref. 70.)
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PMID:[Functions and dysfunctions of the vascular endothelium]. 991 50

The vascular effects of JTV-506 ((-)-(3S,4R)-2.2-bis(methoxymethyl)- 4-[(1,6-dihydro-l-methyl-6-oxo-3-pyridazinyl)amino]-3-hydroxychroman+ ++-6- carbonitrile hemihydrate, CAS 170148-29-5), a new potassium channel opener, was evaluated in isolated coronary arteries and anesthetized dogs. JTV-506 (1 nmol/l-3 mumol/l) produced a concentration-dependent relaxation in porcine isolated epicardial large coronary arteries precontracted with KCl (30 mmol/l), phenylephrine (3 mumol/l), histamine (3 mumol/l), serotonin (5-HT; 300 nmol/l), prostaglandin F2 alpha (PGF2 alpha; 10 mumol/l), U-46619 (100 nmol/l), endothelin-1 (ET-1; 30 nmol/l) and Bay K-8644 (100 nmol/l). JTV-506 was 2.5-8.5 and 13.3-81.5 times more potent than levcromakalim (CAS 94535-50-9) and nicorandil (CAS 65141-46-0), respectively, but was less potent than nifedipine (CAS 21829-25-4). JTV-506 and levcromakalim produced almost a complete relaxation in arteries precontracted with various kinds of vasoconstrictor, except for KCl. In contrast, nifedipine produced about 80-90% relaxation in arteries, precontracted with PGF2 alpha, U-46619 and ET-1. Thus, this potassium channel opener can be characterized as an agonist-nonselective vasorelaxant. The relaxing effects of JTV-506 and levcromakalim on coronary arteries precontracted with 30 mmol/l KCl was competitively antagonized by 3 mumol/l glibenclamide, an ATP-sensitive potassium (KATP) channel blocker. In canine isolated epicardial large coronary arteries, 10 mumol/l JTV-506, 10 mumol/l levcromakalim, 100 mumol/l nicorandil and 0.1 mumol/l nifedipine eliminated 10 mmol/l 3,4-diaminopyridine-induced rhythmic contractions. In anesthetized dogs, when administered directly into the coronary artery, JTV-506 induced dose-dependent increases in coronary arterial diameter and coronary blood flow. These results suggest that JTV-506 elicits coronary vasorelaxation through activation of the KATP channel. It is expected that JTV-506 might be useful in the treatment of coronary vasospasm in angina pectoris.
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PMID:Effects of the new potassium channel opener JTV-506 on coronary vessels in vitro and in vivo. 1021 62

Sensory neurons that innervate the heart sense ischemia and mediate angina. To use patch-clamp methods to study ion channels on these cells, we fluorescently labeled cardiac sensory neurons (CSNs) in rats so that they could later be identified in dissociated primary culture of either nodose or dorsal root ganglia (DRG). Currents evoked by a variety of different agonists imply the importance of lowered pH (</=7.0) in signaling ischemia. Acidic pH evoked extremely large depolarizing current in almost all cardiac afferent neurons from the DRG (CDRGNs). In contrast, only about half of the unlabeled DRG neurons responded to acid, and their current amplitudes were much less than that in CDRGNs. In all respects tested--kinetics, selectivity, and pharmacology--the acid-evoked current was similar to that of previously described native and cloned acid-sensing ion channels. Cardiac afferents from the nodose ganglia differed from CDRGNs in having smaller acid-evoked currents but clearly larger currents evoked by ATP. Serotonin, acetylcholine, bradykinin, and adenosine elicited currents in fewer CSNs than did ATP or lowered pH, and the currents were relatively small. Capsaicin, an activator of small nociceptive sensory neurons that innervate skin, evoked only small and rare currents in CDRGNs. The extremely large amplitude and prevalent expression of acid-evoked current in CSNs imply a critical role for acidity in sensation associated with myocardial ischemia.
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PMID:Acid-evoked currents in cardiac sensory neurons: A possible mediator of myocardial ischemic sensation. 1022 39

The phenomenon of ischaemic preconditioning, highlights a new and endogenous route to myocardial protection, which we believe could be exploited in our search for new therapeutic ways to protect the infarcting myocardium. Ischaemic preconditioning has been shown to be associated with both an early, or acute phase of protection lasting approximately 1-2 hours, as well as a delayed phase or "second window of protection" seen at least 24 hours following the initial sublethal ischaemic insult, and lasting up to 72 hours. We believe that both responses are triggered by similar receptor mediated events in addition to using the similar signalling pathways involving kinase cascades. However it is thought that the ultimate target or end-effector through which the protection is manifest may be different for the early vs. late effects. Some evidence exists that the end-effector involved in early preconditioning may be via the ATP-sensitive potassium channel (K(ATP)). With respect to the second window of protection, the cellular mechanisms underlying this are not fully understood at present, however we believe that they may be dependent upon a similar signalling transduction pathway with upregulation of cytoprotective proteins such as the heat stress proteins, and/or anti-oxidant proteins. Evidence demonstrating that preconditioning can occur in the human myocardium is also accumulating. In this respect cultured human ventricular myocytes as well as human atrial muscle have been shown to be preconditioned with brief episodes of simulated ischemia. These human preparations also respond to the known triggers and possible end-effectors of preconditioning, (e.g. adenosine receptor stimulation and K(ATP) channel opening) as well as being able to elicit their responses through the PKC signalling pathway. Further support for this phenomenon, in man, comes from PTCA studies demonstrating that this invasive procedure can put patients into a "preconditioned state"; this effect being associated with reduced ischaemic symptoms as well as the involvement of the adenosine receptor and K(ATP) channel. Of further interest is the observation that patients with a previous history of angina, prior to a MI, sustain smaller infarcts and have an improved survival. However the most direct evidence that preconditioning occurs in man comes from studies in patients undergoing coronary artery bypass surgery. The above evidence that preconditioning can occur in man makes it now possible to begin to design clinical studies investigating cardioprotective properties of drugs that can specifically mimic this phenomenon.
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PMID:Myocardial adaptation to ischaemia--the preconditioning phenomenon. 1032 17

Ischemic preconditioning, a powerful form of endogenous protection against myocardial infarction, has been demonstrated in several animal species and, recently, in isolated human cardiomyocytes. For both logistic and ethical reasons, no clinical study can meet the strict conditions of experimental studies on preconditioning with infarct size as the end-point. Nevertheless, the demonstration of adaptation to ischemia observed during in vitro studies on human atrial trabeculae, in patients in the setting of coronary bypass surgery, and in the setting of coronary angioplasty in the absence of collateral vessel recruitment strongly suggests that ischemic preconditioning occurs in humans. This notion is further supported by the observation that in these human models, the adaptation to ischemia is influenced by drugs acting on K(ATP) channels and on purinergic and alpha-adrenergic receptors, similar to what is observed in accepted experimental models of ischemic preconditioning. This important form of myocardial endogenous protection may also play a role in the warm-up phenomenon and in mediating the beneficial effects of preinfarction angina. The demonstration of ischemic preconditioning in humans and the identification of some of its mediators suggests that in patients at high risk for myocardial infarction, drugs known to block this endogenous form of protection should be used with caution, whereas drugs known to elicit preconditioning might have a relevant therapeutic role.
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PMID:Ischemic preconditioning in humans: models, mediators, and clinical relevance. 1043 Jul 72


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