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)

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

Certain angina and coronary artery disease forms do not respond to Ca2+ channel blockers, and a role for vasoactive eicosanoids such as PGF2alpha in Ca2+ antagonist-insensitive coronary vasospasm is suggested; however, the signaling mechanisms are unclear. We investigated whether PGF2alpha-induced coronary smooth muscle contraction is Ca2+ antagonist insensitive and involves activation of a PKC-dependent pathway. We measured contraction in single porcine coronary artery smooth muscle cells and intracellular free Ca2+ concentration ([Ca2+]i) in fura 2-loaded cells and examined cytosolic and particulate fractions for PKC activity and reactivity with isoform-specific PKC antibodies. In Hanks' solution (1 mM Ca2+), PGF2alpha (10-5 M) caused transient [Ca2+]i increase followed by maintained [Ca2+]i increase and 34% cell contraction. Ca2+ channel blockers verapamil and diltiazem (10-6 M) abolished maintained PGF2alpha-induced [Ca2+]i increase but only partially inhibited PGF2alpha-induced cell contraction to 17%. Verapamil-insensitive PGF2alpha contraction was inhibited by PKC inhibitors GF-109203X, calphostin C, and epsilon-PKC V1-2. PGF2alpha caused Ca2+-dependent alpha-PKC and Ca2+-independent epsilon-PKC translocation from cytosolic to particulate fractions that was inhibited by calphostin C. Verapamil abolished PGF2alpha-induced alpha-but not epsilon-PKC translocation. PMA (10-6 M), a direct activator of PKC, caused 21% contraction with no significant [Ca2+]i increase and epsilon-PKC translocation that were inhibited by calphostin C but not verapamil. Membrane depolarization by 51 mM KCl, which stimulates Ca2+ influx, caused 36% cell contraction and [Ca2+]i increase that were inhibited by verapamil but not GF-109203X or calphostin C and did not cause alpha- or epsilon-PKC translocation. Thus a significant component of PGF2alpha-induced contraction of coronary smooth muscle is Ca2+ antagonist insensitive, involves Ca2+-independent epsilon-PKC activation and translocation, and may represent a signaling mechanism of Ca2+ antagonist-resistant coronary vasospasm.
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PMID:Ca2+ antagonist-insensitive coronary smooth muscle contraction involves activation of epsilon-protein kinase C-dependent pathway. 1460 78