Urinary excretion of cross-linked N-telopeptide of type I collagen (NTX) has been reported to be a specific indicator of bone resorption. We studied the utility of a new immunoassay for NTX as an indicator of changes in bone resorption caused by treatment with pamidronate (APD) followed by T3. Twenty-two male subjects received either placebo (Group 1) or APD on study days 1-2 (Group 2). One week later all subjects received T3 100 micrograms/day (days 8-15). Urinary NTX, pyridinoline (PYD), hydroxyproline (HYP), and creatinine (cr) were measured on 2-hour fasting urine samples at baseline (day 1), after APD/placebo (day 8), after T3 (day 16), and at days 30 and 58. NTX/cr excretion fell 85% after treatment with APD (P < 0.001 versus baseline), but not after placebo. The fall in mean urinary NTX after receiving APD was greater than the fall in PYD (25%) or HYP (31%) (P < 0.001 NTX versus PYD and HYP). After treatment with APD, NTX excretion remained suppressed below baseline until day 58, whereas PYD and HYP excretion returned to baseline by study day 16. Persistence of APD's effect on bone until day 58 was suggested by the fact that serum calcium and parathyroid hormone levels had not returned to baseline by day 58. On day 16, after all subjects were treated with T3, urinary NTX/cr rose significantly (P < 0.01) in Group 1 (-bisphosphonate) but not in Group 2 (+bisphosphonate).(ABSTRACT TRUNCATED AT 250 WORDS)
Intestinal ischemia is characterized by rapid early inhibition of absorptive function and the appearance of net secretion, although why active secretion persists in the setting of a mucosal energy deficit is unknown. The cryptlike epithelial line T84, a well-characterized model of intestinal Cl -secretion, develops a prominent increase in short-circuit current (I,, indicative of active Cl-transport) in response to "hypoxia" induced by metabolic inhibitors. The increased L is associated with the initial decrease in monolayer ATP content. The LC is transient and disappears with progressive energy depletion, although graded degrees of ATP depletion induce a more sustained L response. Chromatographic analysis and secretory bioassays show that the IS response to metabolic inhibitors is related to the endogenous release of adenosine into the extracellular space in quantities sufficient to interact locally with stimulatory adenosine receptors. Unlike its classical role as a metabolic feedback inhibitor, adenosine appears to function as an autocrine "feedforward" activator of active intestinal Cl -secretion. These studies suggest a novel role for adenosine in the conversion of the gut from an absorptive to a secretory organ during ischemic stress, thus contributing to the initial diarrheal manifestations of intestinal ischemia. (J. Clin. Invest. 1995. 96:117-125.)
The purpose of the present study was to examine the role of adenosine triphosphate-sensitive potassium channels in mediating the coronary hyperemic response after crystalloid cardioplegia. Thirteen pigs were placed on normothermic cardiopulmonary bypass support. Hearts were arrested with cold (4 degrees C) crystalloid ([K+] 25 mmol/L) cardioplegic solution for 60 minutes. In seven of these pigs, hearts were then reperfused for 60 minutes with warm blood, and the animal was separated from cardiopulmonary bypass. The in vivo responses to the intracoronary administration of the K+ adenosine triphosphate channel blocker glibenclamide (50 gm/kg per minute) or the K+ adenosine triphosphate channel opener pinacidil (2 gm/kg per minute) were evaluated before cardiopulmonary bypass (baseline) and after 2 minutes and 60 minutes of reperfusion in the cardioplegia-reperfusion group. Under baseline conditions, glibenclamide and pinacidil induced a respective decrease and increase in coronary blood flow and an increase and a decrease in coronary vascular resistance. Coronary responses to glibenclamide and pinacidil were markedly enhanced after 2 minutes or 60 minutes of postcardioplegia reperfusion. In vitro responses of coronary arterioles (90 to 180 microns) were examined in a pressurized, no-flow state with video microscopy. The contractile response of coronary arterioles to glibenclamide and the relaxation response to pinacidil were significantly enhanced 2 minutes or 60 minutes after reperfusion (all p < 0.05 versus control). The response to pinacidil was markedly inhibited by glibenclamide, which confirms these antagonistic effects on K+ adenosine triphosphate channels. Decreased tissue concentrations of adenosine triphosphate in the coronary arterial smooth muscle and myocardium were observed after cardioplegia and persisted for up to 60 minutes of reperfusion (both p < 0.05 versus control). These results suggest that coronary hyperemia associated with postischemic cardioplegia is mediated in part by activation of K+ adenosine triphosphate channels in the coronary microcirculation.
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