ENDOTOXIN-EXPOSED ATRIA EXHIBIT-G PROTEIN-BASED DEFICITS IN INOTROPICREGULATION

Background. Diminished response at the myocardial beta1-adrenoceptor i s established in endotoxemia. The myocardial muscarinic-2 acetylcholin e receptor (M2ACHR) has not been investigated in endotoxemia, although it shares a G protein-mediated link to adenyl cyclase (AC) This study aimed to assess the contractile responses elicited at the M2ACH and b eta1 receptors, their respective G proteins, and the AC unit in endoto xemia. Methods. Isometric force and rate of contraction were measured in atria from Sprague-Dawley rats after exposure to 24-hour continuous intravenous infusion of 0.2 mg/kg endotoxin or vehicle. The responses to isoproterenol, acetylcholine, sodium fluoride (NaF), and forskolin were studied. Results. In a comparison of endotoxic versus control at ria, diminished force response at the beta1-adrenoceptor was confirmed (4.98 +/- 1.343 vs 7.26 +/- 1.568 gx10 gx10 is unit of measure used for force!, p = 0.0006, n = 10), and an analogous defect at the M2ACHR was identified (6.66 +/- 0.906 vs 8.16 +/- 1.307 gx 10, p = 0.009, n = 10). NaF was able to directly activate G(s) and G(i) in a dose-depen dent differential manner. Both G(s) (5.40 +/- 0.795 vs 7.81 +/- 1.05 7 gx 10, p = 0.0015, n = 6) and G(i) (2.73 +/- 0.528 vs 3.76 +/- 0.332 gx10, p = 0.003) force responses were diminished in endotoxic atria. S timulus of AC by forskolin yielded similar force increases (3.15 +/- 0 .731 vs 3.21 +/- 0.66 7 gx10, p = 0.89, n = 9). Conclusions. In this m odel only contractile responses were altered by endotoxemia. The use o f NaF revealed dysfunction distal to agonist receptor interaction and with the data from M2ACHR activation confirmed that this defect is not adrenergic specific. The preserved response at AC localized the site of this myocardial receptor dysfunction to the G proteins.