Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels

Article Abstract:

Since the function of the heart relies on an adequate supply of oxygen, it is appropriate for the blood vessels of the heart to dilate when the oxygen tension in the blood falls. However, the mechanism by which this dilation occurs has been controversial. Now, experiments with isolated guinea pig hearts have demonstrated that this effect is due to the fall in intracellular adenosine triphosphate (ATP) in the smooth muscle cells around the arteries, which in turn results in the opening of ATP-sensitive potassium ion channels in the muscle cells' membranes. This was demonstrated by subjecting them to lower oxygen tension while measuring the pressure required to push the perfusate (in a sense, artificial blood) through the arteries. A drop in the pressure meant that the vessels had dilated and were offering lowered resistance. The same reduction in pressure was measured if the flow of perfusate was temporarily halted, a condition identical to ischemia. These effects occurred within 30 seconds. This effect could be blocked, however, by the application of the drug glibenclamide, which blocks the ATP-sensitive potassium ion channels. The drug cromakalim, which opens the same channels, exerted an effect similar to that observed with hypoxia. Both the dilation due to cromakalim and that due to hypoxia was blocked by glibenclamide. To demonstrate that the effect was directly due to effects on the smooth muscle itself, vasodilation was also demonstrated by treatment with the drug bradykinin. Since bradykinin acts indirectly, by affecting the endothelium, or lining, of the artery rather than by affecting the smooth muscle directly, the drug glibenclamide should have no effect in this case, and that is what is observed. The results suggest that the ATP-sensitive potassium ion channels in the membrane of arterial smooth muscle cells are directly responsible for dilating the artery when the oxygen supply drops. Drugs like cromakalim, pinacidil, and nicorandil, all of which open ATP-sensitive potassium channels, may serve as starting models for the development of drugs which dilate coronary arteries while having minimal effects on regional blood flow. Such drugs may be valuable in the treatment of coronary heart disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

Health aspects, Coronary heart disease, Oxygen, Hypoxia, Anoxia, Coronary arteries

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Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis

Article Abstract:

The complement pathway is a sequence of events in which the complement proteins become activated. Often, their target is a bacteria; the complement system can punch fatal holes through the membrane of the invading bacteria. The complement system is also involved in the acute inflammatory response. Sometimes, this response leads to damage of the body's own tissues, as is the case with several autoimmune diseases. The complement system can also exacerbate damage to tissues in non-immune conditions; notable among these are burns and ischemia, reduction of blood flow such as occurs during a myocardial infarction (MI, heart attack). Since the complement-mediated destruction of heart muscle after an MI is considerable, there is interest in the development of a treatment to mitigate this tissue damage. Investigators have now reported the use of a naturally occurring protein related to the complement system to achieve this goal. Using the techniques of molecular biology, researchers cloned the gene for the type 1 complement receptor. By this means they were able to obtain quantities of soluble complement receptor type 1 (sCR1). This material binds to proteins of the complement pathway; once these proteins have been bound by the sCR1, they are susceptible to inactivation. In order to evaluate whether this substance could actually provide protection against damage to the heart muscle, the investigators used a rat model of myocardial infarction. When blood flow is restored to regions of the heart muscle which have been deprived of blood and therefore oxygen, inflammatory damage is a common result. However, using the sCR1 they had obtained, the myocardial infarction size was reduced by 44 percent. The soluble complement receptor type 1 shows promise for the suppression of tissue damage in cases of myocardial infarction, and a number of autoimmune disorders as well. (Consumer Summary produced by Reliance Medical Information, Inc.)

Heart attack, Inflammation, Complement (Immunology)

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Increased activity of calcium leak channels in myotubes of Duchenne human and mdx mouse origin

Article Abstract:

Dystrophin (a protein) is deficient in people with Duchenne muscular dystrophy (a hereditary, progressive, fatal condition of muscle weakness) and in the mdx mouse (a genetic model of muscular dystrophy) as a result of a defective gene. Because of certain properties of dystrophin and its attachment to the cell membrane, it was hypothesized that dystrophin deficiency could lead to alterations in the muscle cell membrane channels through which calcium normally ''leaks'' (moves passively). The consequence of this would be increased calcium concentrations inside the cell, causing abnormal muscle contraction. After establishing that Duchenne human and mdx mouse cells did, in fact, lack dystrophin, researchers measured leak currents in these and in normal cells. Results showed that leak channels were open approximately the same amount of time in normal and dystrophic cells, but they were closed a shorter amount of time in the dystrophic cells. This resulted in a considerably elevated calculated open probability for channels in the affected muscle cells. Furthermore, the dystrophic cells seemed to suffer from defective regulation of closing times, a finding that was especially striking for the Duchenne cells. The results support the hypothesis that excess calcium enters the muscle cells through defective leak channels in these models of dystrophy, leading to muscle impairment. (Consumer Summary produced by Reliance Medical Information, Inc.)

Models, Calcium channels, Duchenne muscular dystrophy

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