Remodeling of the Cardiac Pacemaker L-Type Calcium Current and Its β-Adrenergic Responsiveness in Hypertension After Neuronal NO Synthase Gene Transfer

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 48; no. 3; pp. 443 - 452
• Main Authors: Heaton, Daniel A, Lei, Ming, Li, Dan, Golding, Simon, Dawson, Tom A, Mohan, Ravi M, Paterson, David J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.09.2006; Hagerstown, MD Lippincott
• Subjects: Adenovirus; Adrenergic alpha-Agonists - pharmacology; Animals; Antihypertensive agents; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Calcium Channels, L-Type - drug effects; Calcium Channels, L-Type - metabolism; Cardiology. Vascular system; Cardiovascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cyclic AMP - biosynthesis; Cyclic GMP - biosynthesis; Gene Transfer Techniques; Heart Atria; Heart Rate - drug effects; Hypertension - genetics; Hypertension - physiopathology; Male; Medical sciences; Myocardium - metabolism; Nitric Oxide Synthase Type I - genetics; Nitric Oxide Synthase Type I - metabolism; Norepinephrine - pharmacology; Nucleotides, Cyclic - metabolism; Pharmacology. Drug treatments; Phenotype; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, beta - metabolism; Signal Transduction; Sinoatrial Node - metabolism; Sinoatrial Node - physiopathology; Hypertension; Calcium; Rat; Enzyme; Rodentia; sinoatrial node; Cardiovascular disease; 3',5'-GMP; Catecholamine; Inorganic element; Nitric-oxide synthase; β-Adrenergic receptor; Vertebrata; Phenotype; Mammalia; Pacemaker; Animal; Neurotransmitter; Norepinephrine; Oxidoreductases; nitric oxide synthase; Right atrium
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/01.HYP.0000233383.04280.3c

Hypertension is associated with abnormal neurohumoral activation. We tested the hypothesis that β-adrenergic hyperresponsiveness in the sinoatrial node (SAN) of the spontaneously hypertensive rat occurs at the level of the L-type calcium current because of altered cyclic nucleotide-dependent signaling. Furthermore, we hypothesized that NO, a modulator of cGMP and cAMP, would normalize the β-adrenergic phenotype in the hypertensive rat. Chronotropic responsiveness to norepinephrine (NE), together with production of cAMP and cGMP, was assessed in isolated atrial preparations from age-matched hypertensive and normotensive rats. Right atrial/SAN pacemaking tissue was injected with adenovirus encoding enhanced green fluorescent protein (control vector) or neuronal NO synthase (nNOS). In addition, L-type calcium current was measured in cells isolated from the SAN of transfected animals. Basal levels of cGMP were lower in hypertensive rat atria. These atria were hyperresponsive to NE at all of the concentrations tested, with elevated production of cAMP. This was accompanied by increased basal and norepinephrine-stimulated L-type calcium current. Using enhanced green fluorescent protein, we observed transgene expression within both tissue sections and isolated pacemaking cells. Adenoviral nNOS increased right atrial nNOS protein expression and cGMP content. NE-stimulated cAMP concentration and L-type calcium current were also attenuated by adenoviral nNOS, along with the chronotropic responsiveness to NE in hypertensive rat atria. Decreased calcium current after cardiac nNOS gene transfer contributes to the normalization of β-adrenergic hyperresponsiveness in the SAN from hypertensive rats by modulating cyclic nucleotide signaling.