Nitric oxide protects cardiac sarcolemmal membrane enzyme function and ion active transport against ischemia-induced inactivation.
Nitric oxide (NO.) generated from nitric oxide synthase (NOS) isoforms bound to cellular membranes may serve to modulate oxidative stresses in cardiac muscle and thereby regulate the function of key membrane-associated enzymes. Ischemia is known to inhibit the function of sarcolemmal enzymes, including the (Na+ + K+)-ATPase, but it is unknown whether concomitant injury to sarcolemma (SL)-associated NOS isoforms may contribute to this process by reducing the availability of locally generated NO. Here we report that nNOS, as well as eNOS (SL NOSs), are tightly associated with cardiac SL membranes in several different species. In isolated perfused rat hearts, global ischemia caused a time-dependent irreversible injury to cardiac SL NOSs and a disruption of SL NO. generation. Pretreatment with low concentrations of the NO. donor 1-hydroxy-2-oxo-3-(N-3-methyl-aminopropyl)-3-methyl-1-triazene (NOC-7) markedly protected both SL NOS and (Na+ + K+)-ATPase functions against ischemia-induced inactivation. Moreover, ischemia impaired SL Na+/K+ binding, and NOC-7 significantly prevented ischemic injury to the ion binding sites on (Na+ + K+)-ATPase. These novel findings indicate that NO. can protect cardiac SL NOSs and (Na+ + K+)-ATPase against ischemia-induced inactivation and suggest that locally generated NO. may serve to regulate SL Na+/K+ ion active transport in the heart.
Xu
Kai Y
KY
Department of Medicine, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21224, USA. kxu002@umaryland.edu
Kuppusamy
Shanmuga P
SP
Wang
Jing Q
JQ
Li
Haiquan
H
Cui
Hongmei
H
Dawson
Ted M
TM
Huang
Paul L
PL
Burnett
Arthur L
AL
Kuppusamy
Periannan
P
Becker
Lewis C
LC
D000818:Animals; D001693:Biological Transport, Active; D004789:Enzyme Activation; D005260:Female; D066298:In Vitro Techniques; D017136:Ion Transport; D007511:Ischemia / Q000201:enzymology* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000648:ultrastructure*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D020011:Protective Agents / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000201:enzymology* / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D020011:Protective Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496316:Nos3 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase