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)

Short periods of ischemia render the myocardium more resistant to a subsequent prolonged coronary occlusion resulting in a reduction of infarct size. This cardioprotective mechanism has been called ischemic preconditioning. Acute myocardial ischemia results in a rapid decline of high energy phosphates. After short periods of ischemia the high energy phosphate levels are better preserved and the increase of lactate is slower during the prolonged subsequent ischemia in the preconditioned group compared to control. The duration of ischemia needed for induction of the protective effect is 2.5 min in dogs and 20 min in our swine model. In porcine myocardium the protection is lost about 1 h after induction and a renewal is not possible at that time, but is 24 h later. For rabbits or dogs, but not in pigs, a late protection 24 h after induction or preconditioning has been shown ("second window of protection"). Adenosine or adenosine A1 receptor agonists, muscarinic M2 receptor agonists, alpha 1-receptor agonists and bradykinin B2 receptor agonists as well as opening of the K+ATP-channel substitute for ischemia in the induction of protection. Activation of protein kinase C results in protection in rats and rabbits, but not in dogs or pigs. Inhibition of protein kinase C translocation or kinase activity results in a loss of the protection induced by preceding ischemia. After blockade of the K+ATP-channel the protection induced by adenosine A1 receptor activation is lost. Therefore opening of the K+ATP-channel is a prerequisite for induction of the protective effect. Inhibition of the inhibitory G-protein by pertussis toxin has been shown to result in a loss of protection, therefore the Gi-protein seems to be involved in the evolution of protection. In humans during coronary angioplasty anginal pain and lactate production during a second balloon occlusion is diminished without any change in the regional myocardial perfusion. This adaptation is inhibited by blockade of the K+ATP-channel or of the adenosine A1 receptor. Intermittent cross-clamping before a longer occlusion during open-heart surgery results in a better preservation of high energy phosphates compared to controls without preceding short ischemia. These observations support the hypothesis that ischemic preconditioning also occurs in humans. Angina pectoris preceding the myocardial infarction may have preconditioned the human heart against the subsequent myocardial infarction, but studies concerning the influence of angina pectoris on short-term outcome after thrombolysis are conflicting. In the future, ischemic preconditioning or preconditioning with drugs may prolong the duration of ischemia tolerated without necrosis and improve the prognosis of patients by reducing the infarct size.
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PMID:-Myocardial protection by preconditioning. Experimental and clinical significance-. 865 Sep 86

Abstract: Pacemaking is a basic physiological process, and the cellular mechanisms involved in this function have always attracted the keen attention of investigators. The "funny" (I(f)) current, originally described in sinoatrial node myocytes as an inward current activated on hyperpolarization to the diastolic range of voltages, has properties suitable for generating repetitive activity and for modulating spontaneous rate. The degree of activation of the funny current determines, at the end of an action potential, the steepness of phase 4 depolarization; hence, the frequency of action potential firing. Because I(f) is controlled by intracellular cAMP and is thus activated and inhibited by beta-adrenergic and muscarinic M2 receptor stimulation, respectively, it represents a basic physiological mechanism mediating autonomic regulation of heart rate. Given the complexity of the cellular processes involved in rhythmic activity, an exact quantification of the extent to which I(f) and other mechanisms contribute to pacemaking is still a debated issue; nonetheless, a wealth of information collected since the current was first described more than 30 years ago clearly agrees to identify I(f) as a major player in both generation of spontaneous activity and rate control. I(f)- dependent pacemaking has recently advanced from a basic, physiologically relevant concept, as originally described, to a practical concept that has several potentially useful clinical applications and can be valuable in therapeutically relevant conditions. Typically, given their exclusive role in pacemaking, f-channels are ideal targets of drugs aiming to pharmacological control of cardiac rate. Molecules able to bind specifically to and block f-channels can thus be used as pharmacological tools for heart rate reduction with little or no adverse cardiovascular side effects. Indeed a selective f-channel inhibitor, ivabradine, is today commercially available as a tool in the treatment of stable chronic angina. Also, several loss-of-function mutations of HCN4 (hyperpolarization-activated, cyclic-nucleotide gated 4), the major constitutive subunit of f-channels in pacemaker cells, are known today to cause rhythm disturbances, such as for example inherited sinus bradycardia. Finally, gene- or cell-based methods for in situ delivery of f-channels to silent or defective cardiac muscle represent novel approaches for the development of biological pacemakers eventually able to replace electronic devices.
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PMID:The role of the funny current in pacemaker activity. 2016 41