Physiological and biochemical evidence for coordinate increases in muscarinic receptors and Gi during pacing-induced heart failure.
BACKGROUND
It is not clear whether the increase in the myocardial guanylyl nucleotide inhibitory protein (Gi), frequently observed in heart failure, is associated with any functional effects.


RESULTS
Eight sham-operated dogs and 10 dogs were studied with pacing-induced heart failure (240 bpm for 4 to 7 weeks), characterized by reduced (P<.05) left ventricular dP/dt (from 2926+/-99 to 1303+/-126 mm Hg/s). The muscarinic agonist acetylcholine (10 micrograms/kg IV) in the presence of ganglionic blockade reduced left ventricular dP/dt more (P<.05) in heart failure (-23+/-2%) than before heart failure (-8+/-2%), despite lesser reductions in arterial pressure. Gi alpha2 was increased by 55% in heart failure. Dose-response curves for carbachol (10-8 to 10-3 mol/L) inhibition of isoproterenol-stimulated adenylyl cyclase demonstrated significantly greater (P<.05) inhibition in heart failure compared with sham-operated dogs. These changes were associated with a coordinate increase in muscarinic receptor density, determined by antagonist binding with 3H-quinuclidinyl benzilate, in heart failure (153+/-6.2 fmol/mg protein) compared with sham-operated dogs (124+/-7.4 fmol/mg protein). Agonist binding with carbachol also revealed an increase in total muscarinic receptors in heart failure without a change in fraction of high- and low-affinity receptors.


CONCLUSIONS
These data, in the aggregate, provide physiological and biochemical evidence to support the concept that the coordinate increases in muscarinic receptor number and Gi levels in heart failure are coupled to increased inhibition of adenylyl cyclase activity and an increased inhibition of myocardial contractility.
Vatner
D E
DE
New England Regional Primate Research Center, Southborough, Massachusetts 01772-9102, USA.
Sato
N
N
Galper
J B
JB
Vatner
S F
SF
D000109:Acetylcholine / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002303:Cardiac Output, Low / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D018721:Muscarinic Agonists / Q000378:metabolism / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*
D000067956:Adenylyl Cyclase Inhibitors; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D002217:Carbachol; D019204:GTP-Binding Proteins; D000109:Acetylcholine