Augmented adrenergic vasoconstriction in hypertensive diabetic obese Zucker rats
ABSTRACT 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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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; DOI:10.1113/jphysiol.2012.239780 · 4.54 Impact Factor
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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 · 4.54 Impact Factor
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ABSTRACT: The metabolic syndrome is associated with elevated peripheral vascular disease risk, characterized by mismatched blood flow delivery/distribution and local metabolism. The obese Zucker rat (OZR) model of the metabolic syndrome exhibits myriad vascular impairments, although their integrated impact on functional hyperaemia remains unclear. In this study, arterial pressor responses and skeletal muscle perfusion were assessed in lean Zucker rats (LZRs) and OZRs during adrenergic stimulation (phenylephrine), challenge with thromboxane (U46619) and endothelium-dependent dilatation (methacholine). The OZRs were hypertensive compared with the LZRs, but this was abolished by adrenoreceptor blockade (phentolamine); pressor responses to U46619 were similar between strains and were abolished by blockade with the prostaglandin H(2)/thromboxane A(2) receptor antagonist, SQ-29548. Depressor reactivity to methacholine was impaired in OZRs, but was improved by antioxidant treatment (TEMPOL). Across levels of metabolic demand, blood flow to in situ gastrocnemius muscle was restrained by adrenergic constriction in OZRs, although this diminished with increased demand. Oxygen extraction, reduced in OZRs compared with LZRs across levels of metabolic demand, was improved by TEMPOL or SQ-29548; treatment with phentolamine did not impact extraction, and neither TEMPOL nor SQ-29548 improved muscle blood flow in OZRs. While oxygen uptake and muscle performance were consistently reduced in OZRs versus LZRs, treatment with all three agents improved outcomes, while treatment with individual agents was less effective. These results suggest that contributions of vascular dysfunction to perfusion, oxygen uptake and muscle performance are spatially distinct, with adrenergic constriction impacting proximal resistance and endothelial dysfunction impacting distal microvessel-tissue exchange. Further, these data suggest that increasing skeletal muscle blood flow in OZRs is not sufficient to improve performance, unless distal perfusion inhomogeneities are rectified.Experimental physiology 03/2011; 96(3):369-83. DOI:10.1113/expphysiol.2010.055418 · 2.87 Impact Factor