Endotoxin-exposed atria exhibit G protein-based deficits in inotropic regulation.
BACKGROUND
Diminished response at the myocardial beta 1-adrenoceptor is established in endotoxemia. The myocardial muscarinic-2 acetylcholine 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 beta 1 receptors, their respective G proteins, and the AC unit in endotoxemia.


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 atria, diminished force response at the beta 1-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 gx10, p = 0.009, n = 10). NaF was able to directly activate Gs and G(i) in a dose-dependent differential manner. Both Gs (5.40 +/- 0.795 vs 7.81 +/- 1.057 gx10, 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. Stimulus of AC by forskolin yielded similar force increases (3.15 +/- 0.731 vs 3.21 +/- 0.667 gx10, p = 0.89, n = 9).


CONCLUSIONS
In this model only contractile responses were altered by endotoxemia. The use of 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.
Campbell
K L
KL
New England Deaconess Hospital, Boston, MA 02215.
Forse
R A
RA
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016275:Atrial Function / Q000187:drug effects*; D005576:Colforsin / Q000494:pharmacology; D004731:Endotoxins / Q000633:toxicity*; D019204:GTP-Binding Proteins / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012969:Sodium Fluoride / Q000494:pharmacology
D004731:Endotoxins; D005576:Colforsin; D012969:Sodium Fluoride; D019204:GTP-Binding Proteins; D007545:Isoproterenol; D000109:Acetylcholine