PubMed · 6804355
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J M O'Loughlin. 1982. Penicillin dose correction.. https://pubmed.ncbi.nlm.nih.gov/6804355/
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The underlying mechanisms of myocardial ischemia in microvascular angina may include endothelial dysfunction, abnormal smooth muscle tone, and abnormal autonomic control of coronary microvasculatures. This randomized, double-blind, placebo-controlled, crossover study was conducted to evaluate the effect of nicorandil (a nitrate-potassium channel opener) therapy on exercise-induced myocardial ischemia and cardiac autonomic activity in 13 patients with microvascular angina. After a 2-week placebo run-in period, patients were randomly assigned to the first 2-week treatment with nicorandil 5 mg tid or placebo, then crossed over to the second 2-week treatment after a 2-week washout period. Treadmill exercise tests and 24-hour ambulatory electrocardiogram monitoring were performed at the end of each treatment phase. The results showed that both time to 1-mm ST depression and total exercise duration were significantly prolonged with nicorandil treatment compared with placebo (p = 0.026 and 0.036, respectively). Maximum exercise ST depression also tended to be less with nicorandil treatment than with placebo (p = 0.083). Compared with 10 healthy control subjects, study patients had significantly reduced heart rate variability in both low- and high-frequency bands while receiving placebo. Nicorandil treatment did not change the altered heart rate variability in either time domain or spectral analysis. Systemic hemodynamics were also unchanged with nicorandil treatment. Thus, 2-week oral nicorandil therapy moderately improved exercise-induced myocardial ischemia without modifying the already altered cardiac autonomic activity, suggesting that nicorandil might have a direct vasodilatory effect on coronary microvasculatures in patients with microvascular angina.
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Induction of protein kinase C (PKC) pathway in the vascular tissues by hyperglycemia has been associated with many of the cellular changes observed in the complications of diabetes. Recently, we have reported that the use of a novel, orally effective specific inhibitor of PKC beta isoform (LY333531) normalized many of the early retinal and renal hemodynamics in rat models of diabetes. In the present study, we have characterized a spectrum of biochemical and molecular abnormalities associated with chronic changes induced by glucose or diabetes in the cultured mesangial cells and renal glomeruli that can be prevented by LY333531. Hyperglycemia increased diacylglycerol (DAG) level in cultured mesangial cells exposed to high concentrations of glucose and activated PKC alpha and beta1 isoforms in the renal glomeruli of diabetic rats. The addition of PKC beta selective inhibitor (LY333531) to cultured mesangial cells inhibited activated PKC activities by high glucose without lowering DAG levels and LY333531 given orally in diabetic rats specifically inhibited the activation of PKC beta1 isoform without decreasing PKC alpha isoform activation. Glucose-induced increases in arachidonic acid release, prostaglandin E2 production, and inhibition of Na+-K+ ATPase activities in the cultured mesangial cells were completely prevented by the addition of LY333531. Oral feeding of LY333531 prevented the increased mRNA expression of TGF-beta1 and extracellular matrix components such as fibronectin and alpha1(IV) collagen in the glomeruli of diabetic rats in parallel with inhibition of glomerular PKC activity. These results suggest that the activation of PKC, predominately the beta isoform by hyperglycemia in the mesangial cells and glomeruli can partly contribute to early renal dysfunctions by alteration of prostaglandin production and Na+-K+ ATPase activity as well as the chronic pathological changes by the overexpression of TGF-beta1 and extracellular matrix components genes.