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(Circulation Research. 2003;93:364.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Type 5 Adenylyl Cyclase Disruption Alters Not Only Sympathetic But Also Parasympathetic and Calcium-Mediated Cardiac Regulation

Satoshi Okumura, Jun-ichi Kawabe, Atsuko Yatani, Gen Takagi, Ming-Chih Lee, Chull Hong, Jing Liu, Ikuyo Takagi, Junichi Sadoshima, Dorothy E. Vatner, Stephen F. Vatner, Yoshihiro Ishikawa

From the Cardiovascular Research Institute, Department of Cell Biology & Molecular Medicine and Department of Medicine, University of Medicine and Dentistry of New Jersey–New Jersey Medical School, Newark, NJ.

Correspondence to Stephen F. Vatner, MD, and Yoshihiro Ishikawa, MD, PhD, Department of Cell Biology & Molecular Medicine, MSB G-609, UMDNJ–New Jersey Medical School, Newark, NJ 07101-1709. E-mail vatnersf{at}umdnj.edu and ishikayo@umdnj.edu

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.

Key Words: ß-adrenergic receptors • muscarinic receptors • calcium channels • knockout • adenylyl cyclase isoforms

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