Augmented adrenergic vasoconstriction in hypertensive diabetic obese Zucker rats

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 04/2002; 282(3):H816-20. DOI: 10.1152/ajpheart.00695.2001
Source: PubMed


This study examined skeletal muscle microvessel reactivity to constrictor stimuli in obese (OZR) versus lean Zucker rats (LZR). Gracilis arteries from both rat groups were isolated, cannulated with glass micropipettes, and viewed via television microscopy. Changes in vessel diameter were measured with a video micrometer. Arterial constriction to norepinephrine was elevated in OZR versus LZR, although vasoconstrictor reactivity to endothelin and angiotensin II was unaltered. Differences in reactivity between vessels of LZR and OZR were not explained by the loss of either endothelial nitric oxide synthase or beta-adrenergic receptor function. Reactivity of in situ cremasteric arterioles of OZR to norepinephrine was elevated versus LZR. Treatment with prazosin increased the diameter of in vivo gracilis arteries of OZR to levels determined in LZR and also normalized blood pressure in OZR. These results suggest that the constrictor reactivity of skeletal muscle microvessels in OZR is heightened in response to alpha-adrenergic stimuli and that development of diabetes in OZR may be associated with impaired skeletal muscle perfusion and hypertension due to microvessel hyperreactivity in response to sympathetic stimulation.

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    • "This adaptation is important to match oxygen delivery with metabolic demand of the exercising muscle. In contrast, α-adrenergic-mediated vasoconstriction is greater during simulated exercise in the obese Zucker rat (a rodent model of MetSyn) when compared with control animals (Stepp & Frisbee, 2002; Frisbee, 2003, 2004, 2006). Such impairments in neurovascular control may adversely affect oxygen and glucose delivery, waste removal and blood pressure regulation, all of which may be especially detrimental in a clinical population at high risk of developing cardiovascular disease. "
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    ABSTRACT: Background. Alpha-adrenergic-mediated vasoconstriction is greater during simulated exercise in animal models of metabolic syndrome (MetSyn) when compared with control animals. In attempt to translate such findings to humans, we hypothesized adults with MetSyn (n = 14, 35±3 years) would exhibit greater α-adrenergic responsiveness during exercise when compared with age-matched healthy controls (n = 16, 31±3 years). Methods. We measured muscle sympathetic nerve activity (MSNA, microneurography) and forearm blood flow (FBF, Doppler ultrasound) during dynamic forearm exercise (15% of maximal voluntary contraction). Alpha-adrenergic agonists (phenylephrine and clonidine) and antagonist (phentolamine) were infused intra-arterially to assess α-adrenergic receptor responsiveness and restraint, respectively. Results. Resting MSNA was ∼35% higher in MetSyn adults (p<0.05) but did not change in either group with dynamic exercise. Clonidine-mediated vasoconstriction was greater in MetSyn adults (p<0.01). Group differences in vascular responses to phenylephrine and phentolamine were not detected (p>0.05). Interestingly, exercise-mediated vasodilation was greater in MetSyn (p<0.05). Conclusion. Adults with MetSyn exhibit greater resting MSNA and clonidine-mediated vasoconstriction, yet preserved functional sympatholysis and higher exercise blood flow during low-intensity handgrip exercise when compared with age-matched healthy controls. These results suggest adults with MetSyn exhibit compensatory vascular control mechanisms capable of preserving blood flow responses to exercise in the face of augmented sympathetic adrenergic activity.This article is protected by copyright. All rights reserved
    Experimental physiology 03/2014; 99(9). DOI:10.1113/expphysiol.2014.078048 · 2.67 Impact Factor
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    • "However, this adaptation appears to be lost in MetSyn. Animal models of MetSyn exhibit increased sympathetic activity in addition to increased basal α-adrenergic tone and responsiveness when compared with healthy control animals (Stepp & Frisbee, 2002; Naik et al. 2008). This altered relationship may have important clinical implications for the progression of MetSyn toward cardiovascular disease and diabetes; however, an understanding of neurovascular control and its functional significance in human MetSyn is unknown. "
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    ABSTRACT: Young healthy adults exhibit an inverse linear relationship between muscle sympathetic nerve activity (MSNA) and α-adrenergic responsiveness. This balance may be reversed in metabolic syndrome (MetSyn) given animal models exhibit increased sympathetic activity and α-mediated vasoconstriction. We hypothesized humans with MetSyn would demonstrate increased α-adrenergic vasoconstriction and the inverse relationship between MSNA and adrenergic responsiveness would be lost. We measured MSNA (microneurography of the peroneal nerve) and forearm blood flow (FBF, Doppler ultrasound) in 16 healthy control subjects (31±3 years) and 14 adults with MetSyn (35±3 years; p>0.05) during local administration of α-adrenergic agonists (phenylephrine, PE α1; clonidine, CL α2). MSNA was greater in MetSyn subjects when compared with healthy controls (p<0.05). A group difference in vasoconstriction to PE was not detected (p=0.08). The level of α1-mediated vasoconstriction was inversely related to MSNA in control subjects (r=0.5, p=0.04); this balance between MSNA and α1-responsiveness was lost in adults with MetSyn. MetSyn subjects exhibited greater vasoconstriction to CL infusion when compared with healthy controls (p<0.01). A relationship between MSNA and α2-mediated vasoconstriction was not detected in either group. In summary, altered neurovascular control in human MetSyn is receptor-specific. The observed uncoupling between MSNA and α1-adrenergic responsiveness and increased α2 -vasoconstriction may lead to reduced FBF, altered flow distribution, and/or severe hypertension with the progression toward diabetes and cardiovascular disease.
    The Journal of Physiology 10/2012; 590(23). DOI:10.1113/jphysiol.2012.239780 · 5.04 Impact Factor
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    • "Alterations in purinergic sympathetic neurotransmission have been described in spontaneously hypertensive and deoxycorticosterone acetate (DOCA)-salt hypertensive rats (Vidal et al. 1986; Brock & Van Helden, 1995; Demel & Galligan, 2008) yet despite established links between obesity and hypertension, no studies have examined the effects of diet-induced obesity on sympathetic nerve-mediated control of vascular tone at physiologically relevant pressures, nor the contribution of adrenergic versus purinergic mechanisms. While the effects of exogenous application of noradrenaline were reported to be enhanced in the skeletal and renal circulations of a genetic animal model of obesity (Hayashi et al. 2002; Stepp & Frisbee, 2002), these data may not tell us about the actions of neurally released sympathetic neurotransmitters, since studies in the heart and intestine have shown that global application of neurotransmitter activates intracellular pathways which are different to those initiated by neurally released neurotransmitter (Hirst et al. 1996). Thus, the present study has utilised a more physiologically relevant approach, involving neural stimulation of pressurised small mesenteric resistance arteries taken from control and long-term diet-induced obese rats, to probe the effects of obesity on sympathetic nerve-mediated vasomotor function. "
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    ABSTRACT: Non-technical summary The maintenance of healthy blood pressure is influenced by the activity of the sympathetic perivascular nerves which surround small arteries and arterioles. Increases in sympathetic neurovascular control may play a role in the genesis and progression of cardiovascular disease during obesity. Our data show that sympathetic nerve-mediated vasoconstriction is augmented during diet-induced obesity and that ATP and purinergic mechanisms play a significant role. Changes occur due to an increase in sympathetic nerve density and release of ATP, with a potential contribution from a decreased sensitivity to sensory vasodilatory neurotransmitters. Improving control of sympathetic function through the identification of potential therapeutic targets is likely to lead to increased cardiovascular health benefits for overweight and obese individuals. Abstract While a close correlation exists in obese humans between sympathetic, adrenergic hyperactivity and structural and functional organ damage, a role for the co-transmitter, ATP, in vascular function remains unexplored. We therefore studied sympathetic nerve-mediated responses of pressurised small mesenteric arteries from control and obese rats. Diet-induced obesity significantly increased the amplitude of vasoconstriction to transmural nerve stimulation (1–10 Hz; P < 0.05). At 1 and 5 Hz, both adrenergic and purinergic responses were significantly augmented, while only the purinergic component was increased at 10 Hz (P < 0.05). Nerve stimulation at 1 Hz evoked contractions and underlying excitatory junction potentials (EJPs), which were both significantly increased in amplitude during obesity (P < 0.05) and abolished by αβ-methylene ATP (1 μm; desensitises purinergic receptors). The rise time and rate of decay of these EJPs were significant decreased (P < 0.05), without change in resting membrane potential. Amplitude and frequency of spontaneous EJPs and the density of perivascular sympathetic nerves were also significantly increased (P < 0.05). Inhibition of sensory neurotransmitter release (capsaicin; 10 μm) significantly increased the amplitude of nerve-mediated contraction (P < 0.05), with a greater effect in control than obese animals, although the density of sensory nerves was unaffected by obesity. We demonstrate that sympathetic nerve-mediated vasoconstriction is enhanced by diet-induced obesity due to upregulation of purinergic, in addition to adrenergic, neurotransmission. Changes result from increased perivascular sympathetic innervation and release of ATP. We conclude that augmented sympathetic control of vasoconstriction induced by obesity could contribute directly to hypertension and global organ damage. A decrease in sensitivity to sensory vasodilatory neurotransmitters may also affect these processes.
    The Journal of Physiology 05/2011; 589(Pt 13):3289-307. DOI:10.1113/jphysiol.2011.207944 · 5.04 Impact Factor
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