| To investigate the precise way in which adrenergic blockade is cardioprotective and the way in which chronic adrenergic stimulation becomes toxic to the heart we developed mouse models of adrenergic overload heart dysfunction and used them to test the hypothesis that phasic dampening of adrenergic stimulation during the rest phase of the daily cycle would protect the heart. The first model involved chronically increasing adrenergic stimulation by the genetic ablation of the alpha2 A and alpha2C adrenergic receptors (presynaptic receptors which shut off norepinephrine release). The second model involved using implanted osmotic mini-pumps to continuously infuse Wt mice with the adrenergic agonist isoproterenol (0.51mul/hr; 150mug/kg/day) for 14 days. Phasic drug treatments were undertaken using a combination of metoprolol tartrate (30mg/kg) with the A1 adenosine receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) (50mug/kg) or saline SC. Drug effect was phasic, i.e. limited to a window of 3 hours or less during the rest segment of the mouse daily cycle.; The alpha2 A/C AR DKO mice varied widely in cardiac phenotype. A group from the Brazilian DKO strain showed a mean fractional shortening of 40.02% +/- 1.5 n=16 at the outset. After two months (from 5 to 7 months of age) fractional shortening deteriorated to 25.19% +/-2.4 n=8) in the untreated group. In contrast, the group receiving drug treatment showed significantly better LV fractional shortening (34.03% +/-3.2 n=8) than the saline-treated controls at the end of the study (p= 0.0002). Isoproterenol-infused Wt mice had baseline LV ejection fraction of 80.93%+/-1.512 n=12 and after 14 days saline treated mice showed LVEFs of 67.65%+/-3.0 n=6 while drug-treated mice showed 81.38%+/-2.0 n=6 (p=0.04).; In conclusion we found that the effectiveness of phasic treatment with drugs which reduce adrenergic stimulation is dependent on the degree to which pre-treatment levels of adrenergic stimulation have impaired cardiac performance, and also that infusion of adrenergic agonist by mini-pump is more reliable than genetic ablation of alpha2A and alpha2C adrenergic receptors in creating such dysfunction.; Finally, we present evidence that, in the case of cardiac dysfunction caused by adrenergic overstimulation, phasic treatment to reduce adrenergic stimulation during rest can improve heart function. |
