Nicholas G. Jendzjowsky

Short-term exercise training enhances functional sympatholysis through a nitric oxide-dependent mechanism.

Sympathetic nervous system activity causes tonic vasoconstriction in resting and contracting skeletal muscle. Vasoactive molecules released from the active skeletal muscle and/or endothelium have been shown to inhibit sympathetic vasoconstriction, a phenomenon defined as functional sympatholysis. A definitive mechanism responsible for functional sympatholysis has yet to be identified; however, nitric oxide (NO) appears to be involved. It is unknown whether exercise training alters the inhibition of sympathetic vasoconstriction and NO‐mediated sympatholysis in resting and contracting skeletal muscle. The present findings demonstrate that short‐term exercise training augments functional sympatholysis in a training‐intensity‐dependent manner through a NO‐dependent mechanism. These novel findings advance our understanding of the effects of exercise training on the regulation of sympathetic vasoconstriction in resting and contracting skeletal muscle.

Short-term exercise training augments sympathetic vasoconstrictor responsiveness and endothelium-dependent vasodilation in resting skeletal muscle

We tested the hypotheses that 4 wk of exercise training would diminish the magnitude of vasoconstriction in response to sympathetic nerve stimulation and augment endothelium-dependent vasodilation (EDD) in resting skeletal muscle in a training intensity-dependent manner. Sprague-Dawley rats were randomly assigned to sedentary time-control (S), mild- (M; 20 m/min, 5% grade), or heavy-intensity (H; 40 m/min, 5% grade) treadmill exercise groups. Animals trained 5 days/wk for 4 wk with training volume matched between groups. Rats were anesthetized and instrumented for study 24 h after the last training session. Arterial pressure and femoral artery blood flow were measured, and femoral vascular conductance (FVC) was calculated. Lumbar sympathetic chain stimulation was delivered continuously at 2 Hz and in patterns at 20 and 40 Hz. EDD was assessed by the vascular response to intra-arterial bolus injections of ACh. The response (% change FVC) to sympathetic stimulation increased (P < 0.05) in a training intensity-dependent manner at 2 Hz (S: -20.2 ± 9.8%, M: -34.0 ± 6.7%, and H: -44.9 ± 2.0%), 20 Hz (S: -22.0 ± 10.6%, M: -31.2 ± 8.4%, and H: -42.8 ± 5.9%), and 40 Hz (S: H -24.5 ± 8.5%, M: -35.1 ± 8.9%, H: -44.9 ± 6.5%). The magnitude of EDD also increased in a training intensity-dependent manner (P < 0.05). These data demonstrate that short-term exercise training augments the magnitude of vasoconstriction in response to sympathetic stimulation and EDD in resting skeletal muscle in a training intensity-dependent manner.

Role of neuronal nitric oxide in the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle of healthy rats.

Isoform-specific nitric oxide (NO) synthase (NOS) contributions to NO-mediated inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle are incompletely understood. The purpose of the present study was to investigate the role of neuronal NOS (nNOS) in the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle of healthy rats. We hypothesized that acute pharmacological inhibition of nNOS would augment sympathetic vasoconstriction in resting and contracting skeletal muscle, demonstrating that nNOS is primarily responsible for NO-mediated inhibition of sympathetic vasoconstriction. Sprague-Dawley rats (n = 13) were anesthetized and instrumented with an indwelling brachial artery catheter, femoral artery flow probe, and lumbar sympathetic chain stimulating electrodes. Triceps surae muscles were stimulated to contract rhythmically at 60% of maximal contractile force. In series 1 (n = 9), the percent change in femoral vascular conductance (%FVC) in response to sympathetic stimulations delivered at 2 and 5 Hz was determined at rest and during muscle contraction before and after selective nNOS blockade with S-methyl-l-thiocitrulline (SMTC, 0.6 mg/kg iv) and subsequent nonselective NOS blockade with N(ω)-nitro-l-arginine methyl ester (l-NAME, 5 mg/kg iv). In series 2 (n = 4), l-NAME was injected first, and then SMTC was injected to determine if the effect of l-NAME on constrictor responses was influenced by selective nNOS inhibition. Sympathetic stimulation decreased FVC at rest (-25 ± 7 and -44 ± 8%FVC at 2 and 5 Hz, respectively) and during contraction (-7 ± 3 and -19 ± 5%FVC at 2 and 5 Hz, respectively). The decrease in FVC in response to sympathetic stimulation was greater in the presence of SMTC at rest (-32 ± 6 and -49 ± 8%FVC at 2 and 5 Hz, respectively) and during contraction (-21 ± 4 and -28 ± 4%FVC at 2 and 5 Hz, respectively). l-NAME further increased (P < 0.05) the sympathetic vasoconstrictor response at rest (-47 ± 4 and -60 ± 6%FVC at 2 and 5 Hz, respectively) and during muscle contraction (-33 ± 3 and -40 ± 6%FVC at 2 and 5 Hz, respectively). The effect of l-NAME was not altered by the order of nNOS inhibition. These data demonstrate that NO derived from nNOS and endothelial NOS contribute to the inhibition of sympathetic vasoconstriction in resting and contracting skeletal muscle.

Short-term exercise training augments α2-adrenoreceptor-mediated sympathetic vasoconstriction in resting and contracting skeletal muscle

•  Postsynaptic α1‐ and α2‐adrenoreceptors produce tonic vasoconstriction in resting and contracting skeletal muscle. •  Muscular contraction attenuates sympathetic vasoconstriction (functional sympatholysis). The blunting of sympathetic vasoconstriction during contraction has been mechanistically linked to a reduction in postsynaptic α1‐ and α2‐adrenoreceptor responsiveness and nitric oxide. •  We recently demonstrated that exercise training augmented sympathetic vasoconstrictor responsiveness and functional sympatholysis. Whether these vascular adaptations were mediated by changes to postsynaptic adrenoreceptors was not investigated. •  The present findings demonstrate that exercise training augmented α2‐adrenoreceptor‐ mediated vasoconstriction in resting and contracting skeletal muscle. •  These data indicate that exercise training alters the relative contributions of α‐adrenoreceptors to sympathetic vasoconstriction in resting and contracting skeletal muscle and that the regulation of sympathetic vasoconstriction becomes more complex following exercise training.

Pulmonary Oxygen Uptake and Heart Rate Kinetics During the Six-Minute Walk Test in Transplant Recipients

Background. The effect of organ transplantation on arterial compliance, pulmonary oxygen uptake (&OV0312;O2p) and heart rate kinetics during the 6-minute walk test (6-MWT) remains unknown. Methods. Twenty-two thoracic (heart and/or lung) organ transplant recipients (TOTR, 51±12 years) and 30 abdominal (kidney, kidney-pancreas, or liver) organ transplant recipients (AOTR, 46±11 years) from the 2006 Canadian Transplant Games, and 37 healthy controls (HC) completed a 6-MWT. &OV0312;O2p, heart rate kinetics, and arterial compliance were determined. Results. The 6-MWT distance and highest &OV0312;O2p were significantly lower in TOTR and AOTR versus HC. The highest 6-MWT heart rate was lower in TOTR (11%) and AOTR (13%) versus HC. &OV0312;O2p kinetics were slower in TOTR (52±11 sec, P≤0.001) and AOTR (45±24 sec, P≤0.001) versus HC (28±9 sec). Heart rate kinetics were slower in TOTR (100±49 sec) versus AOTR (41±21 sec, P≤0.001) and HC (34±21 sec, P≤0.001), but not between AOTR and HC. Small and large artery compliance were 26% (P=0.007) and 19% (P=0.004) lower, respectively, in TOTR versus HC. Large artery compliance was 14% lower in TOTR versus AOTR (P=0.017). 6-MWT distance was significantly related to &OV0312;O2p kinetics (r=−0.35) and the highest 6-MWT &OV0312;O2p (r=0.72). Conclusions. TOTR and AOTR have abnormal &OV0312;O2p kinetics, which is secondary to prolonged heart rate kinetics and impaired vascular function in TOTR, but not AOTR.

Exercise training augments neuronal nitric oxide synthase‐mediated inhibition of sympathetic vasoconstriction in contracting skeletal muscle of rats

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.

A prospective evaluation of non-interval- and interval-based exercise training progressions in rodents

Non-interval and interval training progressions were used to determine (i) the mean rate at which treadmill speed could be incremented daily using a non-interval training progression to train rats to run continuously at different intensities and (ii) the number of training days required for rats to run continuously at different exercise intensities with non-interval- and interval-based training progressions to establish methods of progressive overload for rodent exercise training studies. Rats were randomly assigned to mild-intensity (n = 5, 20 m·min(-1), 5% grade), moderate-intensity (n = 5, 30 m·min(-1), 5% grade), and heavy-intensity non-interval groups (n = 5, 40 m·min(-1), 5% grade) or a heavy-intensity interval (n = 5, 40 m·min(-1), 5% grade) group and ran 5 days·week(-1) for 6 weeks. Non-interval training involved a daily increase of treadmill speed, whereas interval training involved a daily increase of interval time, until the animal could run continuously at a prescribed intensity. In mild-, moderate-, and heavy-intensity non-interval-trained rats, treadmill speed was increased by 0.6 ± 0.7 m·min(-1)·day(-1), 0.6 ± 0.2 m·min(-1)·day(-1), and 0.8 ± 0.1 m·min(-1)·day(-1), respectively. Target training intensity and duration were obtained following 0.4 ± 0.5 days, 17 ± 3 days, and 23 ± 3 training days (p < 0.05) in mild-, moderate-, and heavy-intensity groups, respectively. In contrast, interval-trained rodents required 11 ± 1 training days. These data demonstrate that rodents will tolerate an increase in treadmill speed of ∼0.7 ± 0.1 m·min(-1)·day(-1) and that this progression enables rats to run continuously at moderate and heavy intensities with 3-4 weeks of progressive overload. Interval training significantly reduces the number of training days required to attain a target intensity.

Acute superoxide scavenging reduces sympathetic vasoconstrictor responsiveness in short-term exercise-trained rats

We hypothesized that acute superoxide (O2(-)) scavenging would attenuate sympathetic vasoconstrictor responsiveness by augmenting nitric oxide (NO)-mediated inhibition of sympathetic vasoconstriction in exercise-trained rats. Sprague-Dawley rats were randomly assigned to sedentary time control (S; n = 7) or mild- (M: 20 m/min, 5° grade; n = 7) or heavy-intensity (H: 40 m/min, 5° grade; n = 7) exercise training (ET) groups and trained 5 days/wk for 4 wk with matched training volume. Following ET, rats were anesthetized and instrumented for lumbar sympathetic chain stimulation and measurement of femoral vascular conductance. In resting skeletal muscle, the percentage change of femoral vascular conductance in response to continuous (2 Hz) and patterned (20 and 40 Hz) sympathetic stimulation was determined during control conditions, O2(-) scavenging (TIRON, 1 g·kg(-1)·h(-1) iv) and combined O2(-) scavenging + nitric oxide synthase blockade (N(ω)-nitro-l-arginine methyl ester, 5 mg/kg iv). ET augmented the vasoconstrictor response to sympathetic stimulation in a training intensity-dependent manner (P < 0.05) (S: 2 Hz: -26 ± 7.1%; 20 Hz: -26.9 ± 7.3%; 40 Hz: -27.7 ± 7.0%; M: 2 Hz: -37.4 ± 8.3%; 20 Hz: -35.9 ± 7.4%; 40 Hz: -38.2 ± 9.4%; H: 2 Hz: -46.9 ± 7.8%; 20 Hz: -48.5 ± 7.2%; 40 Hz: -51.2 ± 7.3%). O2(-) scavenging did not alter (P > 0.05) the vasoconstrictor response in S rats (S: 2 Hz: -23.9 ± 7.6%; 20 Hz: -26.1 ± 9.1%; 40 Hz: -27.5 ± 7.2%), whereas the response in ET rats was diminished (M: 2 Hz: -26.3 ± 5.1%; 20 Hz: -28.7 ± 5.3%; 40 Hz: -28.5 ± 5.6%; H: 2 Hz: -35.5 ± 10.3%; 20 Hz: -38.6 ± 6.8%; 40 Hz: -43.9 ± 5.9%, P < 0.05). TIRON + N(ω)-nitro-l-arginine methyl ester increased vasoconstrictor responsiveness (P < 0.05) in ET rats (M: 2 Hz: -47.7 ± 9.8%; 20 Hz: -41.2 ± 7.2%; 40 Hz: -50.5 ± 7.9%; H: 2 Hz: -55.8 ± 7.6%; 20 Hz: -55.7 ± 7.8%; 40 Hz: -58.7 ± 6.2%), whereas, in S rats, the response was unchanged (2 Hz: -29.4 ± 8.7%; 20 Hz: -30.0 ± 7.4%; 40 Hz: -35.2 ± 10.3%; P > 0.05). These data indicate that the augmented sympathetic vasoconstrictor responsiveness in ET rats was related to increased oxidative stress and altered nitric oxide-mediated inhibition of vasoconstriction.

Acute tetrahydrobiopterin supplementation attenuates sympathetic vasoconstrictor responsiveness in resting and contracting skeletal muscle of healthy rats

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.

Hindlimb unweighting does not alter vasoconstrictor responsiveness and nitric oxide‐mediated inhibition of sympathetic vasoconstriction

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.