An Exercise Mimetic Approach to Reduce Poststroke Deconditioning and Enhance Stroke Recovery.

Evidence supports early rehabilitation after stroke to limit disability. However, stroke survivors are typically sedentary and experience significant cardiovascular and muscular deconditioning. Despite growing consensus that preclinical and clinical stroke recovery research should be aligned, there have been few attempts to incorporate cardiovascular and skeletal muscle deconditioning into animal models of stroke. Here, we demonstrate in rats that a hindlimb sensorimotor cortex stroke results in both cardiovascular and skeletal muscle deconditioning and impairments in gait akin to those observed in humans. To reduce poststroke behavioral, cardiovascular, and skeletal muscle perturbations, we then used a combinatorial intervention consisting of aerobic and resistance exercise in conjunction with administration of resveratrol (RESV), a drug with exercise mimetic properties. A combination of aerobic and resistance exercise mitigated decreases in cardiovascular fitness and attenuated skeletal muscle abnormalities. RESV, beginning 24 hours poststroke, reduced acute hindlimb impairments, improved recovery in hindlimb function, increased vascular density in the perilesional cortex, and attenuated skeletal muscle fiber changes. Early RESV treatment and aerobic and resistance exercise independently provided poststroke benefits, at a time when individuals are rapidly becoming deconditioned as a result of inactivity. Although no additive effects were observed in these experiments, this approach represents a promising strategy to reduce poststroke behavioral impairments and minimize deconditioning. As such, this treatment regime has potential for enabling patients to engage in more intensive rehabilitation at an earlier time following stroke when mechanisms of neuroplasticity are most prevalent.

WISE 2005: responses of women to sublingual nitroglycerin before and after 56 days of 6° head-down bed rest.

This study tested the hypothesis that cardiovascular effects of sublingual nitroglycerin (NG) would be exaggerated after 56 days of 6° head-down bed rest (HDBR) in women, and that an aerobic and resistive exercise countermeasure (EX, n = 8) would reduce the effect compared with HDBR without exercise (CON, n = 7). Middle cerebral artery maximal blood flow velocity (CBFV), cardiac stroke volume (SV), and superficial femoral artery blood flow (Doppler ultrasound) were recorded at baseline rest and for 5 min following 0.3 mg sublingual NG. Post-HDBR, NG caused greater increases in heart rate (HR) in CON compared with EX (+24.9 ± 7.7 and +18.8 ± 6.6 beats/min, respectively, P < 0.0001). The increase in HR combined with reductions in SV to maintain cardiac output. Systolic, mean, and pulse pressures were reduced 5-10 mmHg by NG, but total peripheral resistance was only slightly reduced at 3 min after NG. Reductions in CBFV of -12.5 ± 3.8 cm/s were seen after NG, but a reduction in the Doppler resistance index suggested dilation of the middle cerebral artery with no differences after HDBR. The femoral artery dilated with NG and blood flow was reduced ∼50% with the appearance of large negative waves suggesting a marked increase in downstream resistance, but there were no effects of HDBR. In general, responses of women to NG were not altered by HDBR; the greater increase in HR in CON but not EX was probably a consequence of cardiovascular deconditioning. These results contrast with the hypothesis and a previous investigation of men after HDBR by revealing no change in cardiovascular responses to exogenous nitric oxide.

Effect of rowing ergometry and oral volume loading on cardiovascular structure and function during bed rest.

This study examined the effectiveness of a short-duration but high-intensity exercise countermeasure in combination with a novel oral volume load in preventing bed rest deconditioning and orthostatic intolerance. Bed rest reduces work capacity and orthostatic tolerance due in part to cardiac atrophy and decreased stroke volume. Twenty seven healthy subjects completed 5 wk of -6 degree head down bed rest. Eighteen were randomized to daily rowing ergometry and biweekly strength training while nine remained sedentary. Measurements included cardiac mass, invasive pressure-volume relations, maximal upright exercise capacity, and orthostatic tolerance. Before post-bed rest orthostatic tolerance and exercise testing, nine exercise subjects were given 2 days of fludrocortisone and increased salt. Sedentary bed rest led to cardiac atrophy (125 ± 23 vs. 115 ± 20 g; P < 0.001); however, exercise preserved cardiac mass (128 ± 38 vs. 137 ± 34 g; P = 0.002). Exercise training preserved left ventricular chamber compliance, whereas sedentary bed rest increased stiffness (180 ± 170%, P = 0.032). Orthostatic tolerance was preserved only when exercise was combined with volume loading (-10 ± 22%, P = 0.169) but not with exercise (-14 ± 43%, P = 0.047) or sedentary bed rest (-24 ± 26%, P = 0.035) alone. Rowing and supplemental strength training prevent cardiovascular deconditioning during prolonged bed rest. When combined with an oral volume load, orthostatic tolerance is also preserved. This combined countermeasure may be an ideal strategy for prolonged spaceflight, or patients with orthostatic intolerance.

Hindlimb unloading elicits anhedonia and sympathovagal imbalance.

The hindlimb-unloaded (HU) rat model elicits cardiovascular deconditioning and simulates the physiological adaptations to microgravity or prolonged bed rest in humans. Although psychological deficits have been documented following bed rest and spaceflight in humans, few studies have explored the psychological effects of cardiovascular deconditioning in animal models. Given the bidirectional link established between cardiac autonomic imbalance and psychological depression in both humans and in animal models, we hypothesized that hindlimb unloading would elicit an alteration in sympathovagal tone and behavioral indexes of psychological depression. Male, Sprague-Dawley rats confined to 14 days of HU displayed anhedonia (a core feature of human depression) compared with casted control (CC) animals evidenced by reduced sucrose preference (CC: 81 +/- 2.9% baseline vs. HU: 58 +/- 4.5% baseline) and reduced (rightward shift) operant responding for rewarding electrical brain stimulation (CC: 4.4 +/- 0.3 muA vs. 7.3 +/- 1.0 muA). Cardiac autonomic blockade revealed elevated sympathetic [CC: -54 +/- 14.1 change in (Delta) beats/min vs. HU: -118 +/- 7.6 Delta beats/min] and reduced parasympathetic (CC: 45 +/- 11.8 Delta beats/min vs. HU: 8 +/- 7.3 Delta beats/min) cardiac tone in HU rats. Heart rate variability was reduced (CC: 10 +/- 1.4 ms vs. HU: 7 +/- 0.7 ms), and spectral analysis of blood pressure indicated loss of total, low-, and high-frequency power, consistent with attenuated baroreflex function. These data indicate that cardiovascular deconditioning results in sympathovagal imbalance and behavioral signs consistent with psychological depression. These findings further elucidate the pathophysiological link between cardiovascular diseases and affective disorders.

Consequences of cardiovascular adaptation to spaceflight: implications for the use of pharmacological countermeasures.

There is little evidence obtained from space flight to support the notion that occurrence of cardiac dysrhythmias, impaired cardiac and vascular function, and manifestation of asymptomatic cardiovascular disease represent serious risks during space flight. Therefore, the development of orthostatic hypotension and instability immediately after return from spaceflight probably reflect the most significant operational risks associated with the cardiovascular system of astronauts. Significant reductions in stroke volume and lower reserve for increasing peripheral vascular resistance contribute to ineffective maintenance of systemic arterial blood pressure during standing after spaceflight despite compensatory elevations in heart rate. The primary mechanism underlying reduced stroke volume appears to be a reduction in preload associated with less circulating blood volume while inadequate peripheral vasoconstriction may be caused partly by hyporeactivity of receptors that control arterial smooth muscle function. A focus for development of future countermeasures for hemodynamic responses to central hypovolemia includes the potential application of pharmacological agents that specifically target and restore blood volume (e.g., fludrocortisone, electrolyte-containing beverages) and reserve for vasoconstriction (e.g., midodrine, vasopressin). Based on systematic evaluations, acute physical exercise designed to elicit maximal effort or inspiratory resistance have shown promise as successful countermeasures that provide protection against development of orthostatic hypotension and intolerance without potential risks and side effects associated with specific pharmacological interventions.

Computer systems analysis of the cardiovascular mechanisms of reentry orthostasis in astronauts.

Reentry orthostasis secondary to a prolonged exposure to microgravity is a common problem among astronauts. However, the physiologic mechanisms are poorly understood due to the many control systems involved. In this study an advanced computer model of cardiovascular functioning was employed in a systems analysis approach to clarify the relative importance of some of the adaptive physiologic processes engaged when humans return from space. After simulation of the conditions of zero gravity for one month, the model predicted that the change in capacitance of the lower extremity veins resulting from a loss of external fluid forces in the dehydrated extracellular compartment was the dominant mechanism associated with reentry orthostasis. This condition appears accentuated in women due to their inherent lower center of gravity and proportionately larger mass in the lower extremities.

Salt-loading and simulated microgravity on baroreflex responsiveness in rats.

Cardiovascular adaptations observed during exposure to microgravity results in impairment of baroreflex activity partially as a result of fluid and electrolyte shifts. The head-down tilt rat model mimics some of the physiological observations that have been made in astronauts. We examined the effects of salt-loading on baroreflex activity after 7 day simulated microgravity (30 degrees tail-suspension) and the subsequent 6 hr post-suspension in Sprague-Dawley (SD) rats, using low salt (0.3% NaCl) and high salt (8% NaCl) diets. In suspended animals on a low salt diet, the baroreflex response curve was shifted to the left, while the heart rate (HR) range and MAP50 values were reduced compared to their parallel tethered, non-suspended controls. For non-suspended animals, salt-loading shifted the curve to the right with a reduced HR range. In salt-loaded, suspended animals, the curve and its parameters resemble those of non-suspended animals on a low salt diet. In summary, these data have demonstrated that a short-term (seven days) simulated weightlessness may elicit cardiovascular deconditioning in rats after release from the simulation manifested as an altered responsiveness in baroreceptor-heart rate reflex and a lowered blood pressure while the rats are tethered and horizontal. Our results also suggest the counteracting effect of salt loading on cardiovascular deconditioning.

Biochemical characteristics of beta-adrenoceptors in rats after an 18-day spaceflight (LMS-STS78).

BACKGROUND: To ascertain whether there was autonomic adaptation with the development of adrenoceptor hypersensitivity under microgravity, the biochemical properties of the beta-adrenoceptors were determined using (125I)iodocyanopindolol (ICYP) binding in rats flown for 18 d onboard the space shuttle. METHODS: This study was performed on heart and kidneys of 3 groups of 12 animals: the flight and 2 ground control (vivarium and AEM) groups. To distinguish the possible role of the corticosteroids, half of each animal group was bilaterally adrenalectomized (ADX rats) with an aldosterone and corticosterone supplementation while the other half was SHAM operated. RESULTS: The Scatchard analysis of the ICYP-binding in both organs revealed no significant alterations in the dissociation constant (Kd) and in the maximal binding capacity (Bmax) between SHAM flight and control groups. The Kd of the beta-adrenoceptors in the cardiac atria of the SHAM flight rats (74 +/- 5 pm) was significantly higher (p < 0.05) than in those of the ADX flight rats (60 +/- 3 pm) while the Bmax was nonsignificantly higher (1925 +/- 370 in SHAM flight rats vs. 1482 +/- 283 fmol x mg(-1) protein in ADX flight rats). No significant change was determined for the Bmax and Kd values in the kidneys of the ADX and SHAM flight rats. CONCLUSIONS: This work performed on animals did not show any obvious effect of microgravity on the beta-adrenergic function in the heart and kidneys. Inflight rodent sacrifice protocols should definitely ensure assessment of the influence of microgravity on the animals.

Influence of simulated microgravity on cardiovascular and hemodynamic parameters in Dahl salt-sensitive rats.

Prolonged exposure to microgravity, in humans, induces cardiovascular deconditioning and impairment of baroreflex activity partially as a result of fluid and electrolyte shifts. Animal models of simulated microgravity have been developed to mimic the above responses. We examined the effects of both 24 hr whole body suspension and 7 day tail-suspension and the subsequent 6 hr post-suspension in salt-loaded (2 wks on 8% NaCl diet) Dahl salt-sensitive rats. In both models, mean arterial pressure (MAP) and heart rate (HR) were unchanged during the suspension period. Upon release from suspension, there was no difference in the MAP or HR responses. Blood flows measured in the lower abdominal aorta and renal artery were not different between suspended and control animals. In both models, there was a similar body weight reduction in all groups. MAP responses to both phenylephrine (PHE) and sodium nitroprusside (SNP) were not affected by simulated microgravity. The HR response to SNP in suspended animals was greater than that of control animals; whereas, PHE-induced responses were not different. These data support the notion that simulated microgravity did not alter the MAP responses to SNP and PHE, however, HR responses were enhanced by SNP in the salt-loaded Dahl rats. In addition, salt-sensitivity/salt-loading prevents the reduction in MAP observed post-suspension in normotensive rats.

Effect of acute saline infusion on the cardiovascular deconditioning after 20-days head-down tilt bedrest.

Recent study showed that dehydration induced by prolonged exercise significantly impaired orthostatic tolerance with tachycardia and hypotension, and subsequent rehydration restored it. As physiological changes during exposure to actual or simulated microgravity can be viewed as dehydration process, we hypothesized that rehydration after prolonged bedrest may be a promising candidate to countermeasure not only fluid volume loss but also autonomic nervous deconditioning. Therefore, the purpose of present study was to determine the effect of acute rehydration by saline infusion on orthostatic cardiovascular deconditioning after bedrest.

Countermeasures against cardiovascular deconditioning.

NASA: In this paper, results from four countermeasure procedures that have been tested in groundbased studies and/or during spaceflight will be reviewed and discussed in an effort to examine their effectiveness and physiological basis. The integration of these results provide practical implications for the present use and future development of countermeasures against postflight orthostatic instability.^ieng