Cytosolic inorganic phosphate (P(i)) is important for glucose metabolism. It plays a role in homeostatic regulation of glucose by insulin and glucagon. Recently, we isolated two cDNA clones for rat Na+/P(i) cotransporter-1 (rNaPi-1) and demonstrated that they are expressed primarily in the rat liver and kidney. We now report that the expression of rNaPi-1 in these tissues is regulated by fasting and streptozotocin-induced diabetes. Using rat hepatocytes in primary culture, we also demonstrate that glucose and insulin upregulate rNaPi-1 expression, whereas glucagon and elevated intracellular adenosine 3',5'-cyclic monophosphate levels downregulate its expression. Because 2-deoxyglucose exhibits no effect on rNaPi-1 gene expression, we suggest that some metabolite accumulated during glucose metabolism may be responsible for the effects of glucose and insulin on rNaPi-1 gene expression. Our data also reveal that other known Na+/P(i) cotransporter genes, NaPi-2 and Ram-1 (a receptor for amphotropic murine retrovirus), are not regulated by insulin and glucose. It is therefore proposed that various subtypes of Na+/P(i) cotransporters are differentially regulated and that each subtype may be involved in a specific cellular function, rNaPi-1 may be responsible for Pi uptake by liver and kidney for glucose metabolism, whereas NaPi-2 may play a key role in P(i) reabsorption in the kidney.
Isolated heart-lung preparations from hypertensive inbred Dahl salt-hypertension sensitive (S) and normotensive inbred Dahl salt-hypertension resistant (R) rats were perfused using 15% washed rat red blood cells in Krebs-Ringer bicarbonate buffer. Atrial pressures were increased by increasing venous return (preload) or by increasing the arterial resistance (afterload). Increases in preload at a constant afterload produced increases in the right and left atrial pressures equivalent between S and R strains. Atrial natriuretic factor (ANF) release was linearly related to right atrial pressure (RAP) or left atrial pressure (LAP) in either strain, but S released more ANF at each level of preload, and the slope of the line relating ANF release to RAP was significantly greater in S than R. When the heart-lung preparations were subjected to changes in afterload at a constant preload, LAP was significantly increased in R but not in S rats, and concomitantly ANF increased in R but not in S. In the afterload experiments, as in the preload studies, S released more ANF than R for comparable LAP. It is concluded that 1) at any atrial pressure, hearts of hypertensive S rats release more ANF than hearts of normotensive R rats, 2) this strain difference is probably a consequence of hypertension, and 3) the observed relationships between ANF release and atrial pressures support the contention that atrial distention stimulates the release of ANF.
The primary objective of this study was to test the hypothesis that an increase in the alpha1-adrenoceptor tone would potentiate the myocardial biphasic contractile response to inorganic phosphate [Pi, the substrate of Na/Pi-cotransporter (NP)]. A second aim was to determine whether activation of alpha1-adrenoceptor is necessary for the NP-mediated increase in myocardial contractility (+dP/dt). Earlier study from this laboratory showed that high concentration of Pi (10 mM) produces a biphasic contractile response: initial increase in +dP/dt was followed by decline. In another study, Pi (3.5 mM) potentiated phenylephrine (PHE)-induced increase in +dP/dt. The alpha1-adrenoceptor was not blocked in these studies, and it can still be activated by the electrical stimulation of the sympathetic nerve terminals to the heart. Additionally, alpha1-adrenoceptor-activated increases in the activity of NP have been reported in numerous studies in noncardiac tissues and cell lines; therefore it is not clear whether Pi-induced increase in +dP/dt occurs only in the presence of alpha1-adrenoceptor activation. This study was performed by using isolated perfused rat heart in the condition of controlled extracellular calcium activity (0.72 mM); fixed preload (15 mm Hg); and constant heart rate (280 beats/min) and coronary flow (8 ml/min). The electronically differentiated value of the left ventricular pressure (LVP) signal was used as an index of myocardial contractility. The data show that activation of the alpha1-adrenoceptor is not necessary for the Pi-induced increase in +dP/dt (i.e., NP-mediated increase in +dP/dt has both the alpha1-adrenoceptor-dependent and alpha1-adrenoceptor-independent components. The interaction between alpha1-adrenoceptor agonist (PHE) and Pi (10 mM) did not produce a biphasic myocardial contractile response in the presence of propranolol. Because our earlier data on myocardial biphasic contractile response to 10 mM Pi was obtained when neither the beta- nor the alpha-adrenoceptor was blocked, we carried out more studies to see whether beta-adrenoceptor plays a role in this Pi-induced biphasic response. When both the alpha- and beta-adrenoceptors were activated with norepinephrine (NE), myocardial depression by high Pi concentration was markedly potentiated. This myocardial depression did not occur in the presence of phosphonoformate, a selective inhibitor of NP. It also did not occur when alpha1-adrenoceptor was blocked. Our data suggest that alpha1- and beta-adrenoceptors do not interact with the cardiac NP to potentiate the Pi-induced biphasic contractile response, but they interact in a manner that potentiates Pi-induced myocardial depression.
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