Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A possible involvement of cyclic nucleotides (cAMP and cGMP) in the regulation of cardiac contractility and glycolysis during hypoxia was examined in spontaneously beating rat atria. A reduction of the high oxygen saturation (HiOxSa) of the incubation medium from 95-100% to half produced a rapid decline of the amplitude. The deterioration of 50% was seen after 30 sec. of hypoxia. The decline was partly antagonized by noradrenaline (NA, 1 X 10(-6) M) or hypercalcaemia (5.7 X 10(-3) M instead of 1.9 X 10(-3) M). The cAMP level remained unchanged during the first 12 min. of hypoxia, but the cGMP content increased gradually and reached a significantly increased level in 4-8 min. Paradoxically, the production of lactate decreased, after 30 sec. of hypoxia, but accelerated then 2-4 min. after the onset of hypoxia. The depletion of creatine phosphate and ATP stores was initiated after 2 min. of hypoxia. The arterial content of the active forms of phosphofructokinase and lactate dehydrogenase gradually rose during hypoxia. Sodium nitroprusside (SNP, 1 X 10(-4) M) and NA produced increases in cGMP and cAMP levels, respectively, both in HiOxSa and hypoxia. SNP induced a slight and NA a marked increase in the amplitude in HiOxSa. Verapamil (1 X 10(-6) M) decreased the contractility, but did not affect the levels of cAMP and cGMP. Both SNP and verapamil decreased the lactate production, but they could not resist the NA-induced increase in the atrial lactate level. Hypercalcaemia increased the amplitude but slightly reduced the lactate production in HiOxSa. 45Ca-uptake was reduced to about 35 per cent of control as measured between 5 and 10 min. of hypoxia. It is concluded that the lack of oxygen could have direct and parallel effects on the sarcolemma and on the mitochondria. The former could result in the deterioration of contractility and the latter in the termination of aerobic energy production. Cyclic nucleotides are not involved in either of these phenomena. However, at the low rate of anaerobic glycolysis, e.g. in HiOxSa or at the very early stage of hypoxia, cGMP could inhibit and cAMP accelerate the lactate production.
 ...
PMID:On the role of cyclic nucleotides in the regulation of cardiac contractility and glycolysis during hypoxia. 627 32

It has been suggested that cyclic nucleotides (cAMP and cGMP) participate in the regulation of cardiac contractility and glycolysis. In the present study, this possible involvement was examined in spontaneously beating rat atria during hypoxia (50% oxygen saturation). Thirty seconds after reduction of high oxygen saturation (HiOxSa) in the incubation medium, the contraction amplitude declined to 50% of the initial level. The decline was partly antagonized by norepinephrine (NE) or hypercalcemia. The cAMP level remained unchanged during hypoxia, but the cGMP content gradually increased. Paradoxically, the production of lactate decreased after 30 sec of hypoxia but had increased by 2 min, when depletion of creatine phosphate and ATP stores was also initiated. Sodium nitroprusside (nitroprusside) and NE elevated the cGMP and cAMP, respectively, in both HiOxSa and hypoxia. Nitroprusside and NE also showed a positive inotropic effect in HiOxSa. Verapamil decreased contractility without changing the levels of cAMP or cGMP. In HiOxSa, both nitroprusside and verapamil decreased lactate production but were not able to resist the increase in atrial lactate level brought about by NE. In hypercalcemia the amplitude increased, but lactate production was slightly reduced in HiOxSa. Between 5 and 10 min of hypoxia, 45Ca uptake was reduced to about one-third of that in the control. It is suggested that lack of oxygen has direct and parallel effects on the sarcolemma and the mitochondria. The former induces deterioration of contractility, the latter termination of aerobic energy production. Cyclic nucleotides are not involved in either of these phenomena. However, at a low rate of anaerobic glycolysis, e.g., in HiOxSa or at the very early stage of hypoxia, cGMP could inhibit and cAMP accelerate lactate production.
 ...
PMID:Regulation of cardiac contractility and glycolysis by cyclic nucleotides during hypoxia. 685 62

Tissue macrophages from patients with granuloma-forming disease, most notably sarcoidosis, express a 25-hydroxyvitamin D-1-hydroxylase which can produce in vivo sufficient quantities of the active vitamin D metabolite 1,25-dihydroxyvitamin D to cause hypercalcemia. In contrast to the NADPH-dependent cytochrome P450-linked mixed function oxidase which is normally only expressed in significant quantity in proximal renal tubular cells and regulated in an endocrine fashion, the mitochondrial-based 1-hydroxylase in the macrophage [1] is stimulated in a paracrine mode by cytokines (i.e., IFN-gamma) and lipopolysaccharide (LPS) [2] requires an extracellular source of L-arginine for full basal expression and [3] can be regulated in an intracrine fashion by nitric oxide (NO). In these experiments we employed inducible nitric oxide synthase (iNOS)-free, intact mitochondria preparations from the avain macrophage-like cell line HD-11, which constitutively express the 1-hydroxylase, and nonenzymatically-generated NO to investigate NO-mediated autoregulation of the macrophage 1-hydroxylase. Sodium nitroprusside (SNP)- or S-nitroso-N-acetyl-penicillamine (SNAP)-induced up-regulation of the 1-hydroxylase required the presence of either NADPH or NADP in the reaction mixture, while NO-induced inhibition of mitochondrial 1,25-(OH)2D3 synthesis was NO-dependent and NADP/NADPH-independent. These data suggest NO has bifunctional effects on the macrophage 1-hydroxylase. At relatively high concentrations NO competes with O2 for enzyme binding, inhibiting hormone synthesis. At lower production levels, NO serves as a source of reducing equivalents for the enzyme by providing for the reduction of NADP to NADPH.
 ...
PMID:Autoregulation of 1,25-dihydroxyvitamin D synthesis in macrophage mitochondria by nitric oxide. 882 16