Intracoronary administration of the alpha 1-receptor agonist, methoxamine, does not reproduce the infarct-limiting effect of ischemic preconditioning in dogs.
BACKGROUND
The cardioprotective effect of ischemic preconditioning has been hypothesized to occur through one or more signalling mechanisms which activate protein kinase C. Stimulation of alpha 1-adrenergic receptors by catecholamines released during the preconditioning episodes of ischemia is one of these putative signalling mechanisms.


METHODS
To determine whether stimulation of alpha 1-adrenergic receptors before an ischemic challenge can mimic preconditioning, anesthetized dogs were treated with 4 intracoronary infusions of methoxamine HCl (10 micrograms/kg/min; n = 8), each 5 min in duration and followed by 5 min of washout. Control dogs (n = 10) were given similar infusions of 0.9% NaCl. A third group of dogs was preconditioned with 4 cycles of 5 min ischemia, each followed by 5 min of reperfusion (n = 8). All dogs then underwent 60 min of ischemia (circumflex coronary occlusion) followed by 3 h of reperfusion. Infarct size (expressed as % of area-at-risk) was measured with TTC macrochemistery and analyzed (using analysis of covariance [ANCOVA]) with respect to coronary collateral blood flow (measured using radioactive microspheres).


RESULTS
Methoxamine markedly increased systemic arterial and left atrial pressures prior to but not during the ischemic challenge. Baseline predictors of infarct size were not different among the groups. Mean infarct size (adjusted from ANCOVA) did not differ between control and methoxamine-treated groups, 28.3 +/- 2.8% vs. 29.7 +/- 3.2%, respectively (P = NS), but was only 12.7 +/- 3.2% in the preconditioned group (P < 0.01 vs. control and methoxamine).


CONCLUSIONS
A series of methoxamine infusions before an ischemic challenge did not affect infarct size. Thus, stimulation of alpha 1-adrenergic receptors alone is insufficient to mimic the cardioprotective effect of ischemic preconditioning in this canine model.
Sebbag
L
L
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Katsuragawa
M
M
Verbinski
S
S
Jennings
R B
RB
Reimer
K A
KA
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D005260:Female; D007261:Infusions, Intra-Arterial; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008729:Methoxamine / Q000008:administration & dosage* / Q000494:pharmacology; D009203:Myocardial Infarction / Q000517:prevention & control*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D013268:Stimulation, Chemical
D000316:Adrenergic alpha-Agonists; D011942:Receptors, Adrenergic, alpha; D008729:Methoxamine