Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and beta-adrenergic hyporesponsiveness in heart failure.

Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). beta-Adrenergic hyporesponsiveness and abnormalities in Ca(2+) cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences beta-adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dt(max)), lusitropic (tau), and vascular (elastance; E(a)) responses to beta-adrenergic (beta-AR) stimulation with dobutamine in conscious dogs administered allopurinol (100 mg po daily) or placebo during a 4-wk induction of pacing HF. With HF induction, the decreases in both baseline and dobutamine-stimulated inotropic responses were offset by allopurinol. Additionally, allopurinol converted a vasoconstrictor effect to dobutamine to a vasodilator response and enhanced both lusitropic and preload reducing effects. To assess molecular correlates for this phenotype, we measured myocardial sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA), phospholamban (PLB), phosphorylated PLB (P-PLB), and Na(+)/Ca(2+) transporter (NCX) gene expression and protein. Although SERCA mRNA and protein concentrations did not change with HF, both PLB and NCX were upregulated (P < 0.05). Additionally, P-PLB and protein kinase A activity were greatly reduced. Allopurinol ameliorated all of these molecular alterations and preserved the PLB-to-SERCA ratio. Preventing maladaptive alterations of Ca(2+) cycling proteins represents a novel mechanism for XO inhibition-mediated preservation of cardiac function in HF, raising the possibility that anti-oxidant therapies for HF may ameliorate transcriptional changes associated with adverse cardiac remodeling and beta-adrenergic hyporesponsiveness.

Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure.

We hypothesized that chronic xanthine oxidase inhibition (XOI) would have favorable effects on both ventricular and vascular performance in evolving heart failure (HF), thereby preserving ventricular-vascular coupling. In HF, XOI reduces oxidative stress and improves both vascular and myocardial function. Dogs were randomized to receive either allopurinol (100 mg/day p.o.) or placebo following surgical instrumentation for chronic measurement of left-ventricular pressure and dimension and during induction of HF by rapid pacing. In the placebo group (n = 8), HF was characterized by increased LV end-diastolic pressure (LVEDP, 10.2 +/- 5.5 and 29.8 +/- 3.9 mmHg, before and after HF, respectively, P < 0.05), end-diastolic dimension (LVEDD, from 29.5 +/- 3.2 to 34.3 +/- 3.2 mm, P < 0.001), and afterload (arterial elastance, Ea, from 17.9 +/- 1.2 to 42.6 +/- 7.9 mmHg/mm, P < 0.05), and reduced contractility (End-systolic ventricular elastance, Ees, from 10.8 +/- 1.3 to 5.6 +/- 2.3 mmHg/mm, P < 0.05). Thus, ventricular-vascular coupling (Ees/Ea ratio) fell 57.6+/-9% (0.61 +/- 0.1 to 0.16 +/- 0.1, P < 0.05). Allopurinol (n = 9) profoundly attenuated both the Ea increase (from 22.3 +/- 3 to 25.6 +/- 4.6 mmHg/mm, P = NS) and the fall in Ees (from 11.8+/-1.1 to 11.7+/-1, P = NS), thereby preserving the Ees/Ea ratio (from 0.58 +/- 0.1 to 0.56 +/- 0.1, P < 0.001 vs. placebo). Allopurinol did not affect the increase in preload (LVEDP and LVEDD). XO cardiac mRNA and protein were similarly upregulated approximately fourfold in both groups. Allopurinol ameliorates increases in afterload and reductions in myocardial contractility during evolving HF, thereby preserving ventricular-vascular coupling. These results demonstrate a unique and potent hemodynamic profile of XOI, thereby providing further rationale for developing XOIs as a novel HF therapy.

West Nile virus and high death rate in American crows.

We document effects of West Nile virus (WNV) on American Crows. More than two thirds of our crows died of WNV infection, peaking when the proportion of infected mosquitoes at roosts was greatest. WNV antibody prevalence in crows was low. Local ecologic effects can be dramatic as WNV inhabits new areas.

Antibody prevalence of West Nile virus in birds, Illinois, 2002.

Antibodies to West Nile virus were detected in 94 of 1,784 Illinois birds during 2002. Captive and urban birds had higher seropositivity than did birds from natural areas, and northern and central Illinois birds' seropositivity was greater than that from birds from the southern sites. Adult and hatch-year exposure rates did not differ significantly.

Effect of polar day on plasma profiles of melatonin, testosterone, and estradiol in high-Arctic Lapland Longspurs.

In polar habitats, continuous daylight (polar day) can prevail for many weeks or months around the summer solstice. In the laboratory, continuous light conditions impair or disrupt circadian rhythms in many animals. To determine whether circadian rhythms are disrupted under natural polar day conditions in a species that is only a summer resident in polar regions we analyzed diel rhythms in plasma concentrations of melatonin, testosterone (T), and 17-beta estradiol (E(2)) during the summer solstice in Arctic-breeding Lapland Longspurs (Calcarius lapponicus). We compared these profiles to those of conspecifics housed in outdoor aviaries at a mid-latitude site in Seattle, Washington, during spring, summer, fall, and winter. Under polar day conditions plasma melatonin concentrations of Lapland Longspurs were strongly suppressed, but still showed a significant diel rhythm. Likewise, plasma T in males, and E(2) in females, showed significant diel changes in Arctic birds. Lapland Longspurs housed at mid-latitude in Seattle showed high-amplitude melatonin cycles at all times of the year, and the duration of the nightly melatonin secretion was positively correlated with the duration of the dark phase. We found no diel changes in plasma T in Seattle males in May, but Seattle females showed significant day/night differences in plasma E(2) in May. The data suggest that even under polar day conditions diel rhythms can persist. The maintenance of hormone rhythms could provide a physiological basis to reports of rhythmic behavior in many birds during the Arctic summer.