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Hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) plays a role in a number of cell-protective pathways after ischemia. There are clear sex-related differences in the remodeling process, and hearts from males tend to dilate in response to pathological loads and ischemia to a greater degree than do hearts from females. Thus we hypothesized that there would be a sex-related dimorphic response of HIF-1[alpha] to an ischemic event. Male and female rats were euthanized 5 and 24 h after coronary ligation (M-MI and F-MI; MI, myocardial ischemia), and HIF-1[alpha] expression was determined by immunohistochemistry, Western blot, and quantitative RT-PCR. Sham-operated male and female animals served as controls (M-SH and F-SH). In the ischemic area, histochemical analysis at 5 h showed that HIF was expressed in 33% of cell nuclei in M-MI and in 55% in F-MI. At 24 h, HIF expression increased to 49% in M-MI and to 82% in F-MI (P < 0.05 vs. SH and also M-MI vs. F-MI). This difference was not only statistically significant between the two sexes at 24 h but also within each sex at 5 and 24 h after ligation. Western blots confirmed that, at 24 h after ischemia, HIF protein increased significantly in both male and female hearts relative to sham-operated animals but that the increase in females was 60% greater than that seen in males, mRNA expression of HIF was significantly increased at 24 h in F-MI versus M-MI and sham-operated animals. Expression of downstream HIF target genes (heme oxygenase and brain natriuretic peptide) was increased in proportion to the levels of HIF expression. These data suggest a novel cellular mechanism to explain the sex-related dimorphic response to ischemia and also the possibility that exogenous modulation of HIF might represent a new therapeutic approach to preventing left ventricular remodeling. hypoxia-inducible factor-la; gene expression; remodeling doi:10.1152/ajpheart.00580.2005

Triacylglycerol (TAG) storage and turnover rates in the intact, heating rat heart were determined for the first time using dynamic mode [sup.13]C-NMR spectroscopy to elucidate profound differences between hearts from diabetic rats (DR, streptozotocin treatment) and normal rats (NR). The incorporation of [2,4,6,8,10,12,14,16- [sup.13][C.sub.8]]palmitate into the TAG pool was monitored in isolated hearts perfused with physiological (0.5 mM palmitate, 5 mM glucose) and elevated substrate levels (1.2 mM palmitate, 11 mM glucose) characteristic of the diabetic condition. Surprisingly, although the normal hearts were enriched at a near-linear profile for [greater than or equal to]2 h before exponential characterization, exponential enrichment of TAG in diabetic hearts reached steady state after only 45 min. Consequently, TAG turnover rate was determined by fitting an exponential model to enrichment data rather than conventional two-point linear analysis. In the high-substrate group, both turnover rate (DR 820 [+ or -] 330, NR 190 [+ or -] 150 nmol x [min.sup.-1] x [g.sup.-1] dry wt: P < 0.001) and [TAG] content (DR 78 [+ or -] 10, NR 32 [+ or -] 4 [micro]mol/g dry wt: P < 0.001) were greater in the diabetic group. At lower substrate concentrations, turnover was greater in diabetics (DR 530 [+ or -] 300, NR 160 [+ or -] 30; P < 0.05). However, this could not be explained by simple mass action, because [TAG] content was similar between groups [DR 34 [+ or -] 7, NR 39 [+ or -] 9 p, mol/g dry wt; not significant (NS)]. Consistent with exponential enrichment data, [sup.13]C fractional enrichment of TAG was lower in diabetics (low-substrate groups: DR 4 [+ or -] 1%, NR 10 [+ or -] 4%, P < 0.05; high-substrate groups: DR 8 [+ or -] 3%, NR 14 [+ or -] 9%, NS), thereby supporting earlier speculation that TAG is compartmentalized in the diabetic heart. metabolism; nuclear magnetic resonance: palmitate: triglyceride; fatty acids.

Hypoxia-inducible factor-1α (HIF-1α) plays a role in a number of cell-protective pathways after ischemia. There are clear sex-related differences in the remodeling process, and hearts from males tend to dilate in response to pathological loads and ischemia to a greater degree than do hearts from females. Thus we hypothesized that there would be a sex-related dimorphic response of HIF-1α to an ischemic event. Male and female rats were euthanized 5 and 24 h after coronary ligation (M-MI and F-MI; MI, myocardial ischemia), and HIF-1α expression was determined by immunohistochemistry, Western blot, and quantitative RT-PCR. Sham-operated male and female animals served as controls (M-SH and F-SH). In the ischemic area, histochemical analysis at 5 h showed that HIF was expressed in 33% of cell nuclei in M-MI and in 55% in F-MI. At 24 h, HIF expression increased to 49% in M-MI and to 82% in F-MI (P < 0.05 vs. SH and also M-MI vs. F-MI). This difference was not only statistically significant between the two sexes at 24 h but also within each sex at 5 and 24 h after ligation. Western blots confirmed that, at 24 h after ischemia, HIF protein increased significantly in both male and female hearts relative to sham-operated animals but that the increase in females was 60% greater than that seen in males, mRNA expression of HIF was significantly increased at 24 h in F-MI versus M-MI and sham-operated animals. Expression of downstream HIF target genes (heme oxygenase and brain natriuretic peptide) was increased in proportion to the levels of HIF expression. These data suggest a novel cellular mechanism to explain the sex-related dimorphic response to ischemia and also the possibility that exogenous modulation of HIF might represent a new therapeutic approach to preventing left ventricular remodeling. [ABSTRACT FROM AUTHOR]

Background: In this study, we evaluated the effects of tolvaptan (OPC-41061), a novel, oral, nonpeptide vasopressin V2-receptor antagonist in patients with chronic heart failure (CHF)., Methods and Results: This was a double-blind study investigating the effects of three doses of tolvaptan and placebo in patients with CHF. After a run-in period, 254 patients were randomly assigned to placebo (n=63) or tolvaptan [30 mg (n=64), 45 mg (n=64), or 60 mg (n=63)] once daily for 25 days. Patients were not fluid-restricted and were maintained on stable doses of furosemide. At day 1, when compared with baseline, a decrease in body weight of -0.79+/-0.99, -0.96+/-0.93, and -0.84+/-0.02 kg was observed in the 30-, 45-, and 60-mg tolvaptan groups, respectively, and a body weight increase of +0.32+/-0.46 kg in the placebo group (P<0.001 for all treatment groups versus placebo). Although the initial decrease in body weight was maintained during the study, no further reduction was observed beyond the first day. An increase in urine volume was observed with tolvaptan when compared with placebo (3.9+/-0.6, 4.2+/-0.9, 4.6+/-0.4, and 2.3+/-0.2 L/24 hours at day 1 for 30-, 45-, and 60-mg tolvaptan groups, and placebo, respectively; P<0.001). A decrease in edema and a normalization of serum sodium in patients with hyponatremia were observed in the tolvaptan group but not in the placebo group. No significant changes in heart rate, blood pressure, serum potassium, or renal function were observed., Conclusions: In patients with CHF, tolvaptan was well tolerated; it reduced body weight and edema and normalized serum sodium in the hyponatremic patients.