Increased Efferent Cardiac Sympathetic Nerve Activity and Defective Intrinsic Heart Rate Regulation in Type 2 Diabetes

Abstract

Elevated sympathetic nerve activity (SNA) coupled with dysregulated b-adrenoceptor (b-AR) signaling is postulated as a major driving force for cardiac dysfunction in patients with type 2 diabetes; however, cardiac SNA has never been assessed directly in diabetes. Our aim was to measure the sympathetic input to and the b-AR responsiveness of the heart in the type 2 diabetic heart. In vivo recording of SNA of the left efferent cardiac sympathetic branch of the stellate ganglion in Zucker diabetic fatty rats revealed an elevated resting cardiac SNA and doubled firing rate compared with nondiabetic rats. Ex vivo, in isolated denervated hearts, the intrinsic heart rate was markedly reduced. Contractile and relaxation responses to b-AR stimulation with dobutamine were compromised in externally paced diabetic hearts, but not in diabetic hearts allowed to regulate their own heart rate. Protein levels of left ventricular b 1 -AR and G s (guanine nucleotide binding protein stimulatory) were reduced, whereas left ventricular and right atrial b 2 -AR and G i (guanine nucleotide binding protein inhibitory regulatory) levels were increased. The elevated resting cardiac SNA in type 2 diabetes, combined with the reduced cardiac b-AR responsiveness, suggests that the maintenance of normal cardiovascular function requires elevated cardiac sympathetic input to compensate for changes in the intrinsic properties of the diabetic heart.

Differential Modulation of Cardiac Sympathetic Neural Control and β-Adrenoceptor–G Protein Signaling Cascade in Rats With Type 1 and Type 2 Diabetes

“…Whether the downregulation of cardiac b 1 -adrenoceptor expression in ZDF rats occurred through transcriptional or posttranscriptional mechanisms remains an open question. Thaung et al (15) also found a decrease in G sa protein and an increase in G ia protein in ZDF rat hearts. This is in striking contrast to the results obtained in STZ rat models of type 1 diabetes (13,14).…”

“…The study by Thaung et al (15) shows no difference in in vivo resting heart rate between ZDF rats and their nondiabetic littermates despite the observation that the intrinsic heart rate was markedly lowered in ex vivo perfused hearts from ZDF rats, suggesting that the resting heart rate in ZDF rats under in vivo conditions could be redressed by elevated cardiac sympathetic nerve activity. Clinically, resting tachycardia can be observed in patients with diabetes with vagal impairment, occurring earlier in the course of cardiovascular autonomic neuropathy than sympathetic nerve function (2).…”

“…The new study by Thaung et al (15) demonstrates that the expression level of b 1 -adrenoceptors was downregulated in ZDF rat hearts, whereas that of b 2 -adrenoceptors was upregulated. Cardiac gene expression level of b 1 -adrenoceptors has been reported to be unaltered in type 2 diabetic obese db/db mice (17).…”

“…In this issue of Diabetes, Thaung et al (15), using direct in vivo recording of the left efferent cardiac sympathetic nerve, underscore that cardiac sympathetic nerve activity can be highly elevated rather than decreased in Zucker type 2 diabetic fatty (ZDF) rats compared with their nondiabetic littermates. They assume that elevated cardiac sympathetic input may be a compensatory response to the diabetes-associated hypofunction in the heart to ensure the maintenance of normal hemodynamic status.…”

Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK

“…These conditions featuring long‐term changes in cardiac metabolism are characterized by changes in the autonomic control of cardiovascular function (Lambert, Straznicky, Lambert, Dixon, & Schlaich, ). Higher levels of muscle (Agapitov, Correia, Sinkey, & Haynes, ; Huggett et al., ) and cardiac (Thaung, Baldi et al., ) sympathetic nerve activity indicate a systemic sympathetic overdrive, but importantly, increased sympathetic input directly to the heart. Consequently, several studies have demonstrated decreased β‐adrenoceptor (β‐AR) expression in, and reduced β‐AR responsiveness of, the heart in obesity (Bass & Ritter, ; Bunag, Tomita, & Krizsan, ; Chatelain et al., ; Jiang et al., ; Sherwood, Hill, Blumenthal, Johnson, & Hinderliter, ; Strassheim, Houslay, & Milligan, ), with similar reports in diabetes (Cook, Bussey, Mellor, Cragg, & Lamberts, ; Dincer et al., ; Dincer, Onay, Ari, Ozcelikay, & Altan, ; Lamberts et al., ; Thaung, Baldi et al., ).…”