Noradrenergic Cell Specific Gene Transfer With Neuronal Nitric Oxide Synthase Reduces Cardiac Sympathetic Neurotransmission in Hypertensive Rats

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 50; no. 1; pp. 69 - 74
• Main Authors: Li, Dan, Wang, Lijun, Lee, Chee-Wan, Dawson, Tom A, Paterson, David J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.07.2007; Hagerstown, MD Lippincott
• Subjects: Adenovirus; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cyclic GMP - biosynthesis; Enzyme Inhibitors - pharmacology; Experimental diseases; Gene Transfer Techniques; Heart - innervation; Heart Atria; Hypertension - physiopathology; Male; Medical sciences; Myocardium - metabolism; Neurons - enzymology; Neurons - metabolism; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase Type I - genetics; Nitric Oxide Synthase Type I - metabolism; Nitroprusside - pharmacology; Norepinephrine - antagonists & inhibitors; Norepinephrine - metabolism; Oxadiazoles - pharmacology; Promoter Regions, Genetic; Quinoxalines - pharmacology; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Substrate Specificity; Sympathetic Nervous System - physiopathology; Synaptic Transmission; Oxidative stress; Rat; Phosphorus-oxygen lyases; Cardiovascular disease; Lyases; Guanylate cyclase; Percutaneous route; Autonomic nervous system; Right atrium; Hypertension; gene transfer; Enzyme; Rodentia; cyclic GMP; 3',5'-GMP; Catecholamine; Nitric-oxide synthase; Vertebrata; Mammalia; Treatment; Animal; Nitric oxide; Neurotransmitter; Surgical approach; Norepinephrine; Transduction; Oxidoreductases; Neurotransmission
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.107.088591

Nitric oxide–cGMP pathway can inhibit cardiac norepinephrine (NE) release. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress impairing this pathway. We tested the hypothesis that the gene transfer of neuronal NO synthase (nNOS) could restore sympathetic balance in the spontaneously hypertensive rat (SHR). An adenovirus (5×10 particles) constructed with a noradrenergic neuron-specific promoter (PRS ×8) encoding nNOS (Ad.PRS-nNOS) or enhanced green fluorescence protein (Ad.PRS-eGFP) was targeted to the right atrial wall by percutaneous injection in age-matched male SHRs and Wistar-Kyoto (WKY) rats. Five days after transduction, right atria were removed, and evoked [H] norephinephrine (NE) release, NOS activity, and cGMP were measured. In the Ad.PRS-eGFP treated group, tissue levels of cGMP were significantly lower in the SHR compared with the WKY atria. NE release was also greater in the SHR, and soluble guanylate cyclase inhibition did not alter evoked [H] NE release in the Ad.PRS-eGFP–treated SHR. All atria treated with Ad.PRS-nNOS had enhanced nNOS activity when compared with Ad.PRS-eGFP atria. Ad.PRS-nNOS in WKY rats reduced NE release compared with the Ad.PRS-eGFP group. Guanylate cyclase inhibition enhanced NE release in both Ad.PRS-nNOS– and Ad.PRS-eGFP–treated WKY atria. Ad.PRS-nNOS restored cGMP levels in the SHR to those seen in the WKY atria. In the SHR, Ad.PRS-nNOS also attenuated NE release compared with Ad.PRS-eGFP group. This was reversed by guanylate cyclase inhibition. We conclude that artificial upregulation of sympathetic nNOS via gene transfer with a noradrenergic promoter may provide a novel approach for correcting peripheral sympathetic hyperactivity in hypertension.