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Sympathetic nervous system (SNS) vasoconstriction is primarily achieved through the binding of norepinephrine (NE) to α-adrenoreceptors. However, NE may also bind to β-adrenoreceptors and cause vasodilation that may oppose/blunt SNS-mediated vasoconstriction. Therefore, this study investigated the hypothesis that β-adrenoreceptor–mediated vasodilation opposes evoked vasoconstriction in resting and contracting skeletal muscle. Male (n = 9) Sprague–Dawley rats were anesthetized and surgically instrumented for stimulation of the lumbar sympathetic chain and measurement of arterial blood pressure and femoral artery blood flow. The percentage change of femoral vascular conductance in response to sympathetic chain stimulation delivered at 2 and 5 Hz was determined at rest and during triceps surae skeletal muscle contraction before (control) and after β-adrenoreceptor blockade (propranolol; 0.075 mg·kg−1, intravenously). β-Adrenoreceptor blockade did not alter (P > 0.05) baseline hemodynamics or the hyperemic response to exercise. At the 2 Hz stimulation frequency, sympathetic vasoconstriction was similar (P > 0.05) in control and β-blockade conditions in resting (control, −34% ± 6%; β-blockade, −33% ± 8%) and contracting (control, −16% ± 6%; β-blockade, −14% ± 7%) muscle. At the 5 Hz stimulation frequency, sympathetic vasoconstrictor responsiveness was reduced (main effect of drug, P < 0.05) following β-blockade (rest: control, −52% ± 7%; β-blockade, −51% ± 9%; contraction: control, −32% ± 11%; β-blockade, −29% ± 13%). Novelty These data indicate that β-adrenoreceptor blockade did not augment sympathetic vasoconstriction at rest or during exercise. The study demonstrates that β-adrenoreceptors do not oppose evoked sympathetic vasoconstriction in resting or contracting skeletal muscle or contribute to functional sympatholysis.

Key points Physical inactivity increases the risk of cardiovascular disease and may alter sympathetic nervous system control of vascular resistance. Hindlimb unweighting (HU), a rodent model of physical inactivity, has been shown to diminish sympathetic vasoconstrictor responsiveness and reduce NO synthase expression in isolated skeletal muscle blood vessels. Our understanding of the effects of HU on sympathetic vascular regulation in vivo is very limited. The present findings demonstrate that HU did not alter sympathetic vasoconstrictor responsiveness and NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. This study suggests that short-term physical inactivity does not alter in vivo sympathetic vascular control in the skeletal muscle vascular bed at rest and during contraction. Abstract We tested the hypothesis that physical inactivity would increase sympathetic vasoconstrictor responsiveness and diminish NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. Sprague–Dawley rats (n = 33) were randomly assigned to sedentary time control (S) or hindlimb unweighted (HU) groups for 21 days. Following the intervention, rats were anaesthetized and instrumented for measurement of arterial blood pressure and femoral artery blood flow and stimulation of the lumbar sympathetic chain. The percentage change of femoral vascular conductance (%FVC) in response to sympathetic chain stimulation delivered at 2 and 5 Hz was determined at rest and during triceps surae muscle contraction before (control) and after NO synthase blockade with l-NAME (5 mg kg i.v.). Sympathetic vasoconstrictor responsiveness was not different (P > 0.05) in S and HU rats at rest (S, 2 Hz, −26 ± 8% and 5 Hz, −46 ± 12%; and HU, 2 Hz, −29 ± 9% and 5 Hz, −51 ± 10%) and during contraction (S, 2 Hz, −10 ± 7% and 5 Hz, −23 ± 11%; and HU, 2 Hz, −9 ± 5% and 5 Hz, −22 ± 7%). Nitric oxide synthase blockade caused a similar increase (P > 0.05) in sympathetic vasoconstrictor responsiveness in HU and S rats at rest (S, 2 Hz, −41 ± 7% and 5 Hz, −58 ± 8%; and HU, 2 Hz, −43 ± 6% and 5 Hz, −63 ± 8%) and during muscle contraction (S, 2 Hz, −15 ± 6% and 5 Hz, −31 ± 11%; and HU, 2 Hz, −12 ± 5% and 5 Hz, −29 ± 8%). Skeletal muscle NO synthase expression and ACh-mediated vasodilatation were also not different between HU and S rats. These data suggest that HU does not alter sympathetic vasoconstrictor responsiveness and NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle.

Sex differences in the neurovascular control of blood pressure and vascular resistance have been reported. However, the mechanisms underlying the modulatory influence of sex have not been fully elucidated. Nitric oxide (NO) has been shown to inhibit sympathetic vasoconstriction in resting and contracting skeletal muscle, and estrogen modulates NO synthase (NOS) expression and NO bioavailability. Therefore NO-mediated inhibition of sympathetic vasoconstriction may be enhanced in females. Thus the purpose of the present study was to investigate the hypothesis that sympathetic vasoconstrictor responsiveness would be blunted and NO-mediated inhibition of sympathetic vasoconstriction would be enhanced in females compared with males. Male (M; n = 8) and female (F; n = 10) Sprague-Dawley rats were anesthetized and surgically instrumented for measurement of arterial blood pressure and femoral artery blood flow and stimulation of the lumbar sympathetic chain. The percentage change of femoral vascular conductance in response to sympathetic chain stimulation delivered at 2 and 5 Hz was determined at rest and during triceps surae muscle contraction before (control) and after NOS blockade [ Nω-nitro-l-arginine methyl ester (l-NAME), 10 mg/kg iv]. At rest, sympathetic vasoconstrictor responsiveness was augmented ( P < 0.05) in female compared with male rats at 2 Hz [F: −33 ± 8% (SD); M: −26 ± 6%] but was not different at 5 Hz (F: −55 ± 7%; M: −47 ± 7%). During muscle contraction, evoked vasoconstriction was similar ( P > 0.05) in females and males at 2 Hz (F: −12 ± 5%; M: −13 ± 5%) but was blunted ( P < 0.05) in females compared with males at 5 Hz (F: −24 ± 5%; M: −34 ± 8%). l-NAME increased ( P < 0.05) sympathetic vasoconstrictor responsiveness in both groups at rest and during contraction. Contraction-mediated inhibition of vasoconstriction (sympatholysis) was enhanced ( P < 0.05) in females compared with males; however, sympatholysis was not different ( P > 0.05) between males and females in the presence of NOS blockade, indicating that NO-mediated sympatholysis was augmented in female rats. These data suggest that sex modulates sympathetic vascular control in resting and contracting skeletal muscle and that a portion of the enhanced sympatholysis in female rats was NO dependent. NEW & NOTEWORTHY Sex differences in the neurovascular regulation of blood pressure and vascular resistance have been documented. However, our understanding of the underlying mechanisms that mediate these differences is incomplete. The present study demonstrates that female rats have an enhanced capacity to inhibit sympathetic vasoconstriction during exercise (sympatholysis) and that NO mediates a portion of the enhanced sympatholysis.

Key points Sympathetic nervous system activity causes tonic vasoconstriction in resting and contracting skeletal muscle. Nitric oxide (NO) has been shown to inhibit sympathetic vasoconstriction. NO derived from both the neuronal and endothelial isoforms of NO synthase (NOS) has been shown to contribute to the inhibition of sympathetic vasoconstriction. Our laboratory recently demonstrated that exercise training augmented NO-dependent inhibition of sympathetic vasoconstriction. However, the NOS isoform responsible for the increase in NO-mediated inhibition of sympathetic vasoconstriction following exercise training has not been established. The present findings demonstrate that exercise training improves neuronal NOS-mediated inhibition of sympathetic vasoconstriction in contracting skeletal muscle. Abstract We tested the hypothesis that exercise training would increase neuronal nitric oxide synthase (nNOS)-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. Sprague–Dawley rats (n = 18) were randomized to sedentary or exercise-trained (40 m min−1, 5° grade; 5 days week−1 for 4 weeks) groups. Following completion of sedentary behaviour or exercise training, rats were anaesthetized and instrumented with a brachial artery catheter, femoral artery flow probe and stimulating electrodes on the lumbar sympathetic chain. The percentage change of femoral vascular conductance (%FVC) in response to sympathetic chain stimulations delivered at 2 and 5 Hz was determined at rest and during triceps surae muscle contraction before (control) and after selective nNOS blockade with S-methyl-l-thiocitrulline (SMTC, 0.6 mg kg−1, i.v.) and subsequent non-selective NOS blockade with l-NAME (5 mg kg−1, i.v.; SMTC + l-NAME). At rest, sympathetic vasoconstrictor responsiveness was greater (P 0.05) between exercise trained (2 Hz: −11 ± 4%FVC; 5 Hz: −21 ± 5%FVC) and sedentary rats (2 Hz: −7 ± 6%FVC; 5 Hz: −18 ± 10%FVC) in control conditions. SMTC augmented (P 0.05) in exercise-trained and sedentary rats. These data demonstrate that exercise training augmented nNOS-mediated inhibition of sympathetic vasoconstriction in contracting muscle.

Sympathetic vasoconstriction in the skeletal muscle vascular bed is essential for the regulation of vascular resistance and therefore control of blood pressure and muscle blood flow at rest and during exercise. In this article, we address the hypothesis that aerobic exercise training alters sympathe

We tested the hypothesis that exercise training would increase neuronal nitric oxide synthase (nNOS)-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle. Sprague-Dawley rats (n = 18) were randomized to sedentary or exercise-trained (40 m min(-1), 5° grade; 5 days week(-1) for 4 weeks) groups. Following completion of sedentary behaviour or exercise training, rats were anaesthetized and instrumented with a brachial artery catheter, femoral artery flow probe and stimulating electrodes on the lumbar sympathetic chain. The percentage change of femoral vascular conductance (%FVC) in response to sympathetic chain stimulations delivered at 2 and 5 Hz was determined at rest and during triceps surae muscle contraction before (control) and after selective nNOS blockade with S-methyl-l-thiocitrulline (SMTC, 0.6 mg kg(-1), i.v.) and subsequent non-selective NOS blockade with l-NAME (5 mg kg(-1), i.v.; SMTC + l-NAME). At rest, sympathetic vasoconstrictor responsiveness was greater (P 0.05) in exercise-trained compared to sedentary rats in control, SMTC and SMTC + l-NAME conditions. During contraction, the constrictor response was not different (P 0.05) between exercise trained (2 Hz: -11 ± 4%FVC; 5 Hz: -21 ± 5%FVC) and sedentary rats (2 Hz: -7 ± 6%FVC; 5 Hz: -18 ± 10%FVC) in control conditions. SMTC augmented (P 0.05) sympathetic vasoconstriction in sedentary and exercise-trained rats; however, sympathetic vasoconstrictor responsiveness was greater (P 0.05) in exercise-trained (2 Hz: -27 ± 5%FVC; 5 Hz: -39 ± 5%FVC) compared to sedentary (2 Hz: -17 ± 6%FVC; 5 Hz: -27 ± 8%FVC) rats during selective nNOS inhibition. SMTC + l-NAME further augmented (P 0.05) sympathetic vasoconstrictor responsiveness by a similar magnitude (P 0.05) in exercise-trained and sedentary rats. These data demonstrate that exercise training augmented nNOS-mediated inhibition of sympathetic vasoconstriction in contracting muscle.

We hypothesized that hindlimb unloading (HU) would increase sympathetic vasoconstrictor responsiveness and diminish nitric oxide (NO) mediated inhibition of sympathetic vasoconstriction in resting ...

Exercise training (ET) increases sympathetic vasoconstrictor responsiveness and enhances contraction‐mediated inhibition of sympathetic vasoconstriction (i.e., sympatholysis) through a nitric oxide (NO)‐dependent mechanism. Changes in α2‐adrenoreceptor vasoconstriction mediate a portion of these training adaptations, however the contribution of other postsynaptic receptors remains to be determined. Therefore, the purpose of this study was to investigate the effect of ET on α1‐adrenoreceptor‐mediated vasoconstriction in resting and contracting muscle. It was hypothesized that α1‐adrenoreceptor‐mediated sympatholysis would be enhanced following ET. Male Sprague Dawley rats were randomized to sedentary (S; n = 12) or heavy‐intensity treadmill ET (n = 11) groups. Subsequently, rats were anesthetized and instrumented for lumbar sympathetic chain stimulation and measurement of femoral vascular conductance (FVC) at rest and during muscle contraction. The percentage change in FVC in response to sympathetic stimulation was measured in control, α1‐adrenoreceptor blockade (Prazosin; 20 μg, IV), and combined α1 and NO synthase (NOS) blockade (l‐NAME; 5 mg·kg−1 IV) conditions. Sympathetic vasoconstrictor responsiveness was increased (P 0.05) stimulation frequencies at rest (S: 2 Hz: −25 ± 4%; 5 Hz: −45 ± 5 %; ET: 2 Hz: −35 ± 7%, 5 Hz: −52 ± 7%), whereas sympathetic vasoconstrictor responsiveness was not different (P > 0.05) between groups during contraction (S: 2 Hz: −11 ± 8%; 5 Hz: −26 ± 11%; ET: 2 Hz: −10 ± 7%, 5 Hz: −27 ± 12%). Prazosin blunted (P 0.05) during contraction. ET enhanced (P 0.05) sympatholysis in S or ET rats. In conclusion, ET augmented α1‐adrenoreceptor‐mediated vasoconstriction in resting skeletal muscle and enhanced α1‐adrenoreceptor‐mediated sympatholysis. Furthermore, these data suggest that NO is not required to inhibit α2‐adrenoreceptor‐ and nonadrenoreceptor‐mediated vasoconstriction during exercise.

Tetrahydrobiopterin (BH4) is an essential cofactor for the production of nitric oxide (NO) and supplementation with BH4 improves NO‐dependent vasodilation. NO also reduces sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle. Thus, we hypothesized that supplementation with BH4 would blunt sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle. Sprague‐Dawley rats (n = 15, 399 ± 57 g) were anesthetized and instrumented with an indwelling brachial artery catheter, femoral artery flow probe, and a stimulating electrode on the lumbar sympathetic chain. Triceps surae muscles were stimulated to contract rhythmically at 30% and 60% of maximal contractile force (MCF). The percentage change of femoral vascular conductance (%FVC) in response to sympathetic stimulations delivered at 2 and 5 Hz was determined at rest and during muscle contraction in control and acute BH4 supplementation (20 mg·kg−1 + 10 mg·kg−1·h−1, IA) conditions. BH4 reduced (P < 0.05) the vasoconstrictor response to sympathetic stimulation (i.e., decrease in FVC) at rest (Control: 2 Hz: −28 ± 5%FVC; 5 Hz: −45 ± 5%; BH4: 2 Hz: −17 ± 4%FVC; 5 Hz: −34 ± 7%FVC) and during muscular contraction at 30% MCF (Control: 2 Hz: −14 ± 6%FVC; 5 Hz: −28 ± 11%; BH4: 2 Hz: −6 ± 6%FVC; 5 Hz: −16 ± 10%) and 60% MCF (Control: 2 Hz: −7 ± 3%FVC; 5 Hz: −16 ± 6%FVC; BH4: 2 Hz: −2 ± 3%FVC; 5 Hz: −11 ± 6%FVC). These data are consistent with our hypothesis that acute BH4 supplementation decreases sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle., Tetrahydrobiopterin (BH4) is an essential cofactor for the production of nitric oxide (NO) and NO reduces sympathetic vasoconstrictor responsiveness in the skeletal muscle vascular bed. Thus, we hypothesized that supplementation with BH4 would blunt sympathetic vasoconstrictor responsiveness. The data demonstrate that acute BH4 supplementation decreases sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle.