Type 5 adenylyl cyclase disruption alters not only sympathetic but also parasympathetic and calcium-mediated cardiac regulation.
In a genetically engineered mouse line with disruption of type 5 adenylyl cyclase (AC5-/-), a major cardiac isoform, there was no compensatory increase in other isoforms of AC in the heart. Both basal and isoproterenol (ISO)-stimulated AC activities were decreased by 30% to 40% in cardiac membranes. The reduced AC activity did not affect cardiac function (left ventricular ejection fraction [LVEF]) at baseline. However, increases in LVEF after ISO were significantly attenuated in AC5-/- (P<0.05, n=11). Paradoxically, conscious AC5-/- mice had a higher heart rate compared with wild-type (WT) mice (613+/-8 versus 523+/-11 bpm, P<0.01, n=14 to 15). Muscarinic agonists decreased AC activity, LVEF, and heart rate more in WT than in AC5-/-. In addition, baroreflex-mediated, ie, neuronally regulated, bradycardia after phenylephrine was also attenuated in AC5-/-. The carbachol-activated outward potassium current (at -40 mV) normalized to cell capacitance in AC5-/- (2.6+/-0.4 pA/pF, n=16) was similar to WT (2.9+/-0.3 pA/pF, n=27), but calcium (Ca2+)-mediated inhibition of AC activity and Ca2+ channel function were diminished in AC5-/-. Thus, AC5-/- attenuates sympathetic responsiveness and also impairs parasympathetic and Ca2+-mediated regulation of the heart, indicating that those actions are not only regulated at the level of the receptor and G-protein but also at the level of type 5 AC.
Okumura
Satoshi
S
Cardiovascular Research Institute, Department of Cell Biology & Molecular Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07101-1709, USA.
Kawabe
Jun-ichi
J
Yatani
Atsuko
A
Takagi
Gen
G
Lee
Ming-Chih
MC
Hong
Chull
C
Liu
Jing
J
Takagi
Ikuyo
I
Sadoshima
Junichi
J
Vatner
Dorothy E
DE
Vatner
Stephen F
SF
Ishikawa
Yoshihiro
Y
D000109:Acetylcholine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001667:Binding, Competitive; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004562:Electrocardiography; D005260:Female; D005838:Genotype; D006321:Heart / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D006339:Heart Rate / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002316:Cardiotonic Agents; D007527:Isoenzymes; D018727:Muscarinic Antagonists; D015221:Potassium Channels; D011943:Receptors, Adrenergic, beta; D014665:Vasodilator Agents; D001285:Atropine; D014700:Verapamil; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D000109:Acetylcholine; D002118:Calcium