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.

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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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