β2-adrenergic stimulation attenuates left ventricular remodeling, decreases apoptosis, and improves calcium homeostasis in a rodent model of ischemic cardiomyopathy

The benefit of the β2-adrenergic agonist, clenbuterol, in left ventricular assist device patients with dilated cardiomyopathy has been reported, but its effect on ischemic heart failure (HF) is unknown. We investigated whether clenbuterol improves left ventricular remodeling, myocardial apoptosis and has synergy with a β1 antagonist, metoprolol, in a model of ischemic HF. Rats were randomized to: 1) HF only; 2) HF + clenbuterol; 3) HF + metoprolol; 4) HF + clenbuterol + metoprolol; and 5) rats with sham surgery. HF was induced by left anterior descending artery (LAD) artery ligation and confirmed by decreased left ventricular fractional shortening, decreased maximum left ventricular dP/dt (dP/dtmax), and elevated left ventricular end-diastolic pressure (LVEDP) compared with sham rats (p < 0.01). After 9 weeks of oral therapy, echocardiographic, hemodynamic, and ex vivo end-diastolic pressure-volume relationship (EDPVR) measurements were obtained. Immunohistochemistry was performed for myocardial apoptosis and DNA damage markers. Levels of calcium-handling proteins were assessed by Western blot analysis. Clenbuterol-treated HF rats had increased weight gain and heart weights versus HF rats (p < 0.05). EDPVR curves revealed a leftward shift in clenbuterol rats versus metoprolol and HF rats (p < 0.05). The metoprololtreated group had a lower LVEDP and higher dP/dtmax versus the HF group (p < 0.05). Clenbuterol and metoprolol groups had decreased myocardial apoptosis and DNA damage markers and increased DNA repair markers versus HF rats (all p < 0.01). Protein levels of the ryanodine receptor and sarcoplasmic reticulum calcium-ATPase were improved in clenbuterol-, metoprolol-, and clenbuterol+metoprolol-treated groups versus HF rats. However, as a combination therapy, there were no synergistic effects of clenbuterol+metoprolol treatment. We conclude that clenbuterol ameliorates EDPVR, apoptosis, and calcium homeostasis but does not have synergy with metoprolol in our model of ischemic HF. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.link_to_subscribed_fulltex

Neonatal Hyperbilirubinemia in infants with <it>G6PD c.563C > T</it><it>Variant</it>

<p>Abstract</p> <p>Background</p> <p>There is a strong correlation between glucose-6-phosphate dehydrogenase (G6PD) deficiency and neonatal hyperbilirubinemia with a rare but potential threat of devastating acute bilirubin encephalopathy. G6PD deficiency was observed in 4–14% of hospitalized icteric neonates in Pakistan. <it>G6PD c.563C > T</it> is the most frequently reported variant in this population. The present study was aimed at evaluating the time to onset of hyperbilirubinemia and the postnatal bilirubin trajectory in infants having <it>G6PD c.563C > T.</it></p> <p>Methods</p> <p>This was a case–control study conducted at The Aga Khan University, Pakistan during the year 2008. We studied 216 icteric male neonates who were re-admitted for phototherapy during the study period. No selection was exercised. Medical records showed that 32 were G6PD deficient while 184 were G6PD normal. Each infant was studied for birth weight, gestational age, age at the time of presentation, presence of cephalhematoma, sepsis and neurological signs, peak bilirubin level, age at peak bilirubin level, days of hospitalization, whether phototherapy or exchange blood transfusion was initiated, and the outcome. During hospital stay, each baby was tested for complete blood count, reticulocyte count, ABO and Rh blood type, direct antiglobulin test and quantitative G6PD estimation [by kinetic determination of G6PDH]. <it>G6PDgenotype</it> was analyzed in 32 deficient infants through PCR-RFLP analysis and gene sequencing.</p> <p>Results</p> <p><it>G6PD variants c.563C > T</it> and <it>c.131 C > G</it> were observed in 21 (65%) and three (9%) of the 32 G6PD deficient infants, respectively. DNA of eight (25%) newborns remained uncharacterized. In contrast to G6PD normal neonates, infants with <it>c.563C > T</it> variant had significantly lower enzyme activity (mean ± 1SD; 0.3 ± 0.2 U/gHb vs. 14.0 ± 4.5 U/gHb, <it>p</it> < 0.001) experienced higher peak levels of total serum bilirubin (mean ± 1SD; 16.8 ± 5.4 mg/dl vs. 13.8 ± 4.6 mg/dl, <it>p =</it> 0.008) which peaked earlier after birth (mean ± 1SD 2.9 ± 1.6 vs. 4.3 ± 2.3 days, <it>p =</it> 0.007). No statistically significant difference was observed in mean weight, age at presentation, hemoglobin, reticulocyte count, TSH level, hospital stay or in the frequency of initiation of phototherapy or blood exchange between the two groups.</p> <p>Conclusions</p> <p>We concluded that infants with <it>G6PD c.563C > T</it> variant developed jaundice earlier than infants with normal G6PD enzyme levels. Compared to G6PD normal infants, <it>G6PD c.563C > T</it> carrying infants had significantly low G6PD activity.</p