Intrauterine growth restriction-induced deleterious adaptations in endothelial progenitor cells: possible mechanism to impair endothelial function.

Intrauterine growth restriction (IUGR) can induce deleterious changes in the modulatory ability of the vascular endothelium, contributing to an increased risk of developing cardiovascular diseases in the long term. However, the mechanisms involved are not fully understood. Emerging evidence has suggested the potential role of endothelial progenitor cells (EPCs) in vascular health and repair. Therefore, we aimed to evaluate the effects of IUGR on vascular reactivity and EPCs derived from the peripheral blood (PB) and bone marrow (BM) in vitro. Pregnant Wistar rats were fed an ad libitum diet (control group) or 50% of the ad libitum diet (restricted group) throughout gestation. We determined vascular reactivity, nitric oxide (NO) concentration, and endothelial nitric oxide synthase (eNOS) protein expression by evaluating the thoracic aorta of adult male offspring from both groups (aged: 19-20 weeks). Moreover, the amount, functional capacity, and senescence of EPCs were assessed in vitro. Our results indicated that IUGR reduced vasodilation via acetylcholine in aorta rings, decreased NO levels, and increased eNOS phosphorylation at Thr495. The amount of EPCs was similar between both groups; however, IUGR decreased the functional capacity of EPCs from the PB and BM. Furthermore, the senescence process was accelerated in BM-derived EPCs from IUGR rats. In summary, our findings demonstrated the deleterious changes in EPCs from IUGR rats, such as reduced EPC function and accelerated senescence in vitro. These findings may contribute towards elucidating the possible mechanisms involved in endothelial dysfunction induced by fetal programming.

Intrauterine growth restriction increases circulating mitochondrial DNA and Toll-like receptor 9 expression in adult offspring: could aerobic training counteract these adaptations?

It has been demonstrated that intrauterine growth restriction (IUGR) can program increase cardiometabolic risk. There are also evidences of the correlation between IUGR with low-grade inflammation and, thus can contribute to development of several cardiometabolic comorbidities. Therefore, we investigated the influence of IUGR on circulating mitochondrial DNA (mtDNA)/Toll-like receptor 9 (TLR9) and TNF-α expression in adult offspring. Considering that the aerobic training has anti-inflammatory actions, we also investigated whether aerobic training would improve these inflammatory factors. Pregnant Wistar rats received ad libitum or 50% of ad libitum diet throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to control, trained control, restricted and trained restricted. Aerobic training protocol was performed on a treadmill and after that, we evaluated circulating mtDNA, cardiac protein expression of TLR9, plasma and cardiac TNF-α levels, and left ventricle (LV) mass. We found that IUGR promoted an increase in the circulating mtDNA, TLR9 expression and plasma TNF-α levels. Further, our results revealed that aerobic training can restore mtDNA/TLR9 content and plasma levels of TNF-α among restricted rats. The cardiac TNF-α content and LV mass were not influenced either by IUGR or aerobic training. In conclusion, IUGR can program mtDNA/TLR9 content, which may lead to high levels of TNF-α. However, aerobic training was able to normalize these alterations. These findings evidenced that the association of IUGR and aerobic training seems to exert an important interaction effect regarding pro-inflammatory condition and, aerobic training may be used as a strategy to reduce deleterious adaptations in IUGR offspring.

Effect of gender on training-induced vascular remodeling in SHR

There is accumulating evidence that physical inactivity, associated with the modern sedentary lifestyle, is a major determinant of hypertension. It represents the most important modifiable risk factor for cardiovascular diseases, which are the leading cause of morbidity and mortality for both men and women. In addition to involving sympathetic overactivity that alters hemodynamic parameters, hypertension is accompanied by several abnormalities in the skeletal muscle circulation including vessel rarefaction and increased arteriole wall-to-lumen ratio, which contribute to increased total peripheral resistance. Low-intensity aerobic training is a promising tool for the prevention, treatment and control of high blood pressure, but its efficacy may differ between men and women and between male and female animals. This review focuses on peripheral training-induced adaptations that contribute to a blood pressure-lowering effect, with special attention to differential responses in male and female spontaneously hypertensive rats (SHR). Heart, diaphragm and skeletal muscle arterioles (but not kidney arterioles) undergo eutrophic outward remodeling in trained male SHR, which contributed to a reduction of peripheral resistance and to a pressure fall. In contrast, trained female SHR showed no change in arteriole wall-to-lumen ratio and no pressure fall. On the other hand, training-induced adaptive changes in capillaries and venules (increased density) were similar in male and female SHR, supporting a similar hyperemic response to exercise.

Effect of gender on training-induced vascular remodeling in SHR.

There is accumulating evidence that physical inactivity, associated with the modern sedentary lifestyle, is a major determinant of hypertension. It represents the most important modifiable risk factor for cardiovascular diseases, which are the leading cause of morbidity and mortality for both men and women. In addition to involving sympathetic overactivity that alters hemodynamic parameters, hypertension is accompanied by several abnormalities in the skeletal muscle circulation including vessel rarefaction and increased arteriole wall-to-lumen ratio, which contribute to increased total peripheral resistance. Low-intensity aerobic training is a promising tool for the prevention, treatment and control of high blood pressure, but its efficacy may differ between men and women and between male and female animals. This review focuses on peripheral training-induced adaptations that contribute to a blood pressure-lowering effect, with special attention to differential responses in male and female spontaneously hypertensive rats (SHR). Heart, diaphragm and skeletal muscle arterioles (but not kidney arterioles) undergo eutrophic outward remodeling in trained male SHR, which contributed to a reduction of peripheral resistance and to a pressure fall. In contrast, trained female SHR showed no change in arteriole wall-to-lumen ratio and no pressure fall. On the other hand, training-induced adaptive changes in capillaries and venules (increased density) were similar in male and female SHR, supporting a similar hyperemic response to exercise.

Time course of training-induced microcirculatory changes and of vegf expression in skeletal muscles of spontaneously hypertensive female rats.

Exercise-induced vessel changes modulate arterial pressure (AP) in male spontaneously hypertensive rats (SHR). Vascular endothelial growth factor (VEGF) is important for angiogenesis of skeletal muscle. The present study evaluated the time course of VEGF and angiogenesis after short- and long-term exercise training of female SHR and Wistar Kyoto (WKY) rats, 8-9 weeks (200-250 g). Rats were allocated to daily training or remained sedentary for 3 days (N = 23) or 13 weeks (N = 23). After training, the carotid artery was catheterized for AP measurements. Locomotor (tibialis anterior and gracilis) and non-locomotor skeletal muscles (temporalis) were harvested and prepared for histologic and protein expression analyses. Training increased treadmill performance by all groups (SHR = 28%, WKY = 64%, 3 days) and (SHR = 141%, WKY = 122%, 13 weeks). SHR had higher values of AP than WKY (174 +/- 4 vs 111 +/- 2 mmHg) that were not altered by training. Three days of running increased VEGF expression (SHR = 28%, WKY = 36%) simultaneously with an increase in capillary-to-fiber ratio in gracilis muscle (SHR = 19%, WKY = 15%). In contrast, 13 weeks of training increased gracilis capillary-to-fiber ratio (SHR = 18%, WKY = 19%), without simultaneous changes in VEGF expression. Training did not change VEGF expression and capillarity of temporalis muscle. We conclude that training stimulates time- and tissue-dependent VEGF protein expression, independent of pressure levels. VEGF triggers angiogenesis in locomotor skeletal muscle shortly after the exercise starts, but is not involved in the maintenance of capillarity after long-term exercise in female rats.

Time course of training-induced microcirculatory changes and of vegf expression in skeletal muscles of spontaneously hypertensive female rats

Exercise-induced vessel changes modulate arterial pressure (AP) in male spontaneously hypertensive rats (SHR). Vascular endothelial growth factor (VEGF) is important for angiogenesis of skeletal muscle. The present study evaluated the time course of VEGF and angiogenesis after short- and long-term exercise training of female SHR and Wistar Kyoto (WKY) rats, 8-9 weeks (200-250 g). Rats were allocated to daily training or remained sedentary for 3 days (N = 23) or 13 weeks (N = 23). After training, the carotid artery was catheterized for AP measurements. Locomotor (tibialis anterior and gracilis) and non-locomotor skeletal muscles (temporalis) were harvested and prepared for histologic and protein expression analyses. Training increased treadmill performance by all groups (SHR = 28 percent, WKY = 64 percent, 3 days) and (SHR = 141 percent, WKY = 122 percent, 13 weeks). SHR had higher values of AP than WKY (174 ± 4 vs 111 ± 2 mmHg) that were not altered by training. Three days of running increased VEGF expression (SHR = 28 percent, WKY = 36 percent) simultaneously with an increase in capillary-to-fiber ratio in gracilis muscle (SHR = 19 percent, WKY = 15 percent). In contrast, 13 weeks of training increased gracilis capillary-to-fiber ratio (SHR = 18 percent, WKY = 19 percent), without simultaneous changes in VEGF expression. Training did not change VEGF expression and capillarity of temporalis muscle. We conclude that training stimulates time- and tissue-dependent VEGF protein expression, independent of pressure levels. VEGF triggers angiogenesis in locomotor skeletal muscle shortly after the exercise starts, but is not involved in the maintenance of capillarity after long-term exercise in female rats.

Chronic AT(1) receptor blockade alters autonomic balance and sympathetic responses in hypertension.

In the coarctation hypertension model, we have shown that chronic treatment with losartan causes both normalization of impaired reflex control of heart rate and partial correction of the depressed aortic nerve activity/pressure relationship, even with the persistence of hypertension. In the present study, we analyzed the effects of angiotensin II blockade on the efferent pathways of coarcted and sham-operated groups treated chronically with vehicle or losartan (10 mg/kg per day PO). Hypertension was induced by subdiaphragmatic aortic coarctation, and the treatments lasted 9 days (4 control and 5 experimental days). On day 5, autoregressive power spectral analysis was performed on heart rate recordings made in conscious rats. Other groups were used for sympathetic splanchnic nerve activity recordings made simultaneously with pressure (anesthetized rats) at basal condition and during loading/unloading of baroreceptors. Losartan treatment induced a significant reduction in basal pressure but did not interfere with the development of hypertension (similar pressure increases of 24% and 28% over control values in losartan and vehicle groups, respectively). In vehicle-treated rats, establishment of hypertension was accompanied by a marked change in power spectral density from high- (1.19+/-0.06 Hz, 33+/-6%) to low-frequency components (0,42+/-0.03 Hz, 54+/-6%), with increased low-frequency-to-high-frequency ratio. When compared with sham-operated vehicle-treated rats, there was also increase in the gain of sympathetic activity/pressure relationship, with displacement of lower plateau toward high levels of sympathetic activity. No changes in the power spectral density and sympathetic activity/pressure relationship were observed when hypertension developed in the presence of chronic angiotensin type 1 (AT(1)) receptor blockade. The data suggest that angiotensin II, activated during the establishment of coarctation hypertension, acts via AT(1) receptors to alter sympathovagal balance, facilitating the sympathetic outflow to heart and peripheral circulation during baroreceptors unloading. Data also indicate that the observed effects are not conditioned by preexisting pressure levels.

Receptor changes in the nucleus tractus solitarii of the rat after exercise training.

PURPOSE: The aim of the present study was to evaluate neurotransmitter receptor changes in the nucleus tractus solitarii (NTS) of the rat after exercise training. METHODS: Twelve Wistar Kyoto rats were used. Six rats were submitted to a progressive training program in which they ran on a treadmill 5 d x wk(-1) for 13 wk (trained). The other rats were kept as controls (sedentary). After this period, the rats were killed and the brains processed for quantitative receptor autoradiography. Coronal brain sections were obtained using a cryostat and were incubated with a specific buffer solution containing [(3)H]vasopressin or (3)Hp-aminoclonidine. RESULTS: In the NTS of the trained rats, a decrease in the values of binding parameters (IC(50) and K(D)) of vasopressin receptors was observed, indicating an increase in the affinity of vasopressin receptors. On the other hand, a decreased affinity was observed for alpha(2)-adrenoceptors in the NTS of the trained rats in comparison with the sedentary animals. CONCLUSION: Exercise training leads to changes in vasopressin and alpha(2)-adrenoceptors, which may explain several physiological alterations occurring during physical activity.

Oxytocin in the NTS. A new modulator of cardiovascular control during exercise.

The role of brain stem oxytocinergic projections in the modulation of heart rate control during exercise is discussed on the basis of both changes in endogenous peptide content and heart rate changes observed during exercise. Running on a treadmill caused an increase in oxytocin content in dorsal/ventral brain stem areas and spinal cord, specifically in trained rats. Trained rats pretreated with a specific oxytocin receptor antagonist into the dorsal brain stem area (corresponding to the nucleus tractus solitarii and dorsal motor nucleus of the vagus, or NTS/DMV) showed a significant potentiation of exercise tachycardia with no change in the blood pressure response. The same treatment in sedentary rats was without effect. On the other hand, administration of exogenous oxytocin into this area caused significant blunting of exercise tachycardia in both groups, with no change in the pressure response. It is proposed that long-descending oxytocinergic pathways from the hypothalamus to the NTS/DMV area serve as a link between the two main neural controllers of the circulation--that is, the central command and feedback control mechanisms driven by the peripheral receptor signals. Our results strongly suggest that oxytocinergic input to NTS/DMV, by restraining the tachycardic response of trained individuals, contributes to the smaller response observed after training, without compromising cardiac output adjustment and the circulatory demand during exercise.

Exercise training causes skeletal muscle venular growth and alters hemodynamic responses in spontaneously hypertensive rats.

OBJECTIVE: To investigate whether training changes skeletal muscle venular profile and hemodynamic responses to exercise we studied spontanesouly hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats submitted to training programme (T = 50-60% of VO2max). DESIGN: Training (T) was performed on a treadmill over a period of 13 weeks. Age-matched control groups were kept sedentary (S). T and S rats were chronically instrumented for hindlimb flow (HLF) and arterial pressure (AP) measurements at rest, during dynamic exercise and recovery in two different situations: control and after extensive intravenous blockade (hexamethonium + losartan + Nomega-nitro-L-arginine methyl ester + hydralazine). For morphometric analysis, skeletal muscle samples (gracilis) were obtained after transcardiac perfusion with fixative. RESULTS: T caused a significant reduction of resting mean arterial pressure (MAP) (-11%) only in the SHR group without changing basal HLF. In the sedentary SHR (SHRs), basal relative hindlimb resistance was increased by 45%, but was significantly reduced after T (P < 0.05). During dynamic exercise, MAP increased similarly (10-20 mmHg) in all groups. HLF increases were similar for the four groups up to 0.8 km/h; at higher workloads, HLF was higher in trained SHR (SHRT) versus trained WKY (WKYT) (3.9- versus 2.9-fold increase over basal HLF, respectively). After blockade (and pressure correction with IV phenylephrine infusion), steady-state exercise was performed with similar hindlimb vasodilation in all groups and was accompanied by MAP reduction (-17 +/- 8 mmHg) only in SHRT group. Skeletal muscle venular profile (density, diameter and lumen cross-sectional area) was similar in WKY(T), WKY(S) and SHR(S), but significantly increased in SHR(T). In this group the two-fold increase in venule density was correlated with both the reduction in baseline MAP and the increase in HLF during dynamic exercise. CONCLUSIONS: The results suggest that increased venule density is a specific adaptation of SHR skeletal muscle to training. Venular growth may contribute to both the pressure-lowering effect and the large HLF at high exercise intensities observed in the trained SHR.

Exercise training normalizes wall-to-lumen ratio of the gracilis muscle arterioles and reduces pressure in spontaneously hypertensive rats.

OBJECTIVE: To investigate mechanisms underlying the training-induced blood pressure-lowering effect we analyzed the hemodynamic responses and morphometric changes of the skeletal muscle microcirculation of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats during an exercise training program. DESIGN TRAINING: (50-60% VO2 max) was performed on a treadmill for 13 weeks and control groups were kept sedentary over the same period of time. Trained and sedentary rats were chronically instrumented for hindlimb flow and arterial pressure (AP) recordings under conscious unrestrained conditions. Gracilis and myocardial muscle samples were obtained for morphometric analysis after transcardiac perfusion of fixative. RESULTS: SHR, when compared to WKY presented an elevated blood pressure, an increased relative hindlimb vascular resistance, capillary rarefaction in both gracilis and myocardium and an increased wall-to-lumen ratio of gracilis arterioles. Training increased significantly both capillary density and capillary/fiber ratio in the gracilis and myocardium of WKY and SHR groups, causing a complete reversal of capillary rarefaction in trained SHR. In SHR, training also reduced resting blood pressure and caused normalization of both relative hindlimb vascular resistance and gracilis arterioles wall-to-lumen ratio. Regression analysis revealed strong positive correlation between hindlimb vascular resistance and mean AP (MAP) and between arterioles wall-to-lumen ratio and MAP. CONCLUSIONS: The results suggest that low-intensity training can significantly reduce pressure in SHR while normalizing both the arteriole morphology and the resistance of the skeletal muscle microcirculation.

Central oxytocin modulates exercise-induced tachycardia.

We have shown that vasopressinergic projections to dorsal brain stem are activated during exercise and facilitate exercise tachycardia in both trained (T) and sedentary (S) rats (Dufloth DL, Morris M, and Michelini LC. Am J Physiol Regulatory Integrative Comp Physiol 273: R1271-R1282, 1997). In the present study, we investigated whether oxytocinergic projections to the nucleus of the solitary tract (NTS)-dorsal motor nucleus of the vagus (DMV) complex (NTS/DMV) are involved in the differential heart rate (HR) response to exercise in T and S rats. Arterial pressure (AP) and HR responses to dynamic exercise (0.4-1.4 km/h) were compared in S and T pretreated with vehicle (saline), oxytocin (OT; 20 pmol/200 nl) or OT-receptor antagonist (OT(ant); 20 pmol/200 nl) into the NTS/DMV. OT content in specific brain regions and plasma were measured in separate S and T groups at rest and immediately after exercise. Exercise increased OT content in dorsal (4.5-fold) and ventral brain stem (2.7-fold) and spinal cord (3.4-fold) only in T rats. No significant changes were observed in neurosecretory regions or medial eminence and posterior pituitary, but plasma levels of T rats were reduced immediately after exercise. Blockade of NTS/DMV OT receptors did not change basal mean AP (MAP) and HR or the MAP response to exercise. However, OT(ant) potentiated exercise-induced tachycardia (average increase of 26%) only in the T group. Pretreatment with exogenous OT in the NTS/DMV blunted the tachycardic response both in S and T rats without changing the MAP response. Administration of OT-receptor antagonist or OT into the fourth cerebral ventricle had no effect on the cardiovascular response to dynamic exercise. Taken together, the results suggest that oxytocinergic projections to the NTS/DMV are stimulated when T rats exercise and that OT released at this level acts on OT receptors to restrain exercise-induced tachycardia.

Endogenous vasopressin modulates the cardiovascular responses to exercise.

The role of brain-stem vasopressinergic projections in the genesis of reflex bradycardia and in the modulation of heart rate control during exercise is discussed on the basis of both changes in endogenous peptide content and heart rate changes observed during exercise. Dynamic running caused an increase in vasopressin content specifically in dorsal and ventral brain-stem areas. Rats pretreated with vasopressin or the V1 receptor antagonist into the nucleus tractus solitarii (NTS) showed a significant potentiation or a marked blunting of the exercise tachycardia, respectively, without any change in the blood pressure response. It is proposed that long-descending vasopressinergic pathways from the hypothalamus to the NTS serves as one link between the two main neural controllers of the circulation, that is, the central command and feedback control mechanisms driven by the peripheral receptors signals. Therefore vasopressinergic input contributes to the adjustment of heart rate response (and cardiac output) to the circulatory demand during exercise.

Endogenous vasopressin and the central control of heart rate during dynamic exercise

The present article contains a brief review on the role of vasopressinergic projections to the nucleus tractus solitarii in the genesis of reflex bradycardia and in the modulation of heart rate control during exercise. The effects of vasopressin on exercise tachycardia are discussed on the basis of both the endogenous peptide content changes and the heart rate response changes observed during running in sedentary and trained rats. Dynamic exercise caused a specific vasopressin content increase in dorsal and ventral brainstem areas. In accordance, rats pretreated with the peptide or the V1 blocker into the nucleus tractus solitarii showed a significant potentiation or a marked blunting of the exercise tachycardia, respectively, without any change in the pressure response to exercise. It is proposed that the long-descending vasopressinergic pathway to the nucleus tractus solitarii serves as one link between the two main neural controllers of circulation, i.e., the central command and feedback control mechanisms driven by the peripheral receptors. Therefore, vasopressinergic input could contribute to the adjustment of heart rate response (and cardiac output) to the circulatory demand during exercise.

Chronic AT1 receptor blockade alters aortic nerve activity in hypertension.

In the chronic phase of coarctation hypertension (CH) we have shown both reduction in baroreceptor sensitivity (Hypertension. 1992;19[suppl II]:II-198-II-201.) and normalization of the depressed baroreceptor reflex control of heart rate, even with the persistence of hypertension in losartan-treated animals (Am J Physiol. 1995;269:H812-H818). In the present study we analyzed the effects of angiotensin II blockade on afferent aortic nerve activity of CH and sham-operated groups treated chronically with vehicle or losartan (10 mg/kg per day p.o.). CH was induced by subdiaphragmatic aortic coarctation, and the treatments lasted 8 days (4 control and 4 experimental days). Aortic pressure (conscious rats) and aortic nerve activity simultaneous to pressure (anesthetized rats) were recorded on the fourth day of the experimental period. Losartan-treated rats showed reduced tail pressure (104+/-3 versus 117+/-3 mm Hg in the vehicle group). In both groups, aortic coarctation caused a significant increase in pressure (25% and 28%, respectively) and a depression of the aortic nerve activity/pressure relationship when compared with sham-operated coarcted animals. In the physiological range of pressure changes, the depression was significantly smaller after losartan treatment (3.30+/-0.33 versus 2.18+/-0.37%/mm Hg in the losartan- and vehicle-treated CH groups, respectively, versus 5.05+/-0.33%/mm Hg in the sham-operated vehicle-treated group). Angiotensin type 1 (AT1) receptor blockade was also accompanied by reduced variability of the afferent discharge. The data suggested that apart from its pressure effect, angiotensin II acts at AT1 receptors to decrease the sensitivity of aortic afferents during physiological (+/-10 mm Hg) increases and decreases in pressure. Thus, angiotensin II may contribute to reductions of baroreceptor gain in chronic hypertension.

Role of endogenous nitric oxide in the nucleus tratus solitarii on baroreflex control of heart rate in spontaneously hypertensive rats.

OBJECTIVE: Toinvestigate the modulatory effect of endogenous nitric oxide (NO) in the nucleus tractus solitarii (NTS) on the baroreceptor reflex control of heart rate in conscious spontaneously hypertensive (SHR) and normotensive (WKY) rats. DESIGN AND METHODS: Male age- and weight-matched SHR and WKY chronically instrumented with cannulas in the NTS, artery and vein were used. Basal pressure (AP), heart rate (HR) and reflex HR responses during loading/unloading of baroreceptors (phenylephrine/sodium nitroprusside, iv) were recorded during vehicle (3 nl/min) NG-monomethyl-L-arginine (L-NMMA) and L-arginine (L-Arg) infusions into the NTS. Constitutive NO synthase (NOS) activity was inferred by 3H-citrulline formation in the dorsal brain stem of other SHR and WKY groups. RESULTS: In SHR a small dose of L-NMMA (30 ng/kg/min) restricted to the NTS did not change AP and HR (185+/-4 mmHg, 373+/-12 beats/min, respectively), but decreased the HR range (57+/-7 beats/min, a 34% reduction, P< 0.05) without changing further the impaired gain of baroreceptor reflex control of HR. In the WKY group similar results (significant 32% reduction in HR range, gain unchanged) were only attained with a dose 10 times higher (L-NMMA(NTS) = 300 ng/kg/min), no effect being observed with the small dose (HR range = 163+/-12 beats/min). In SHR, L-Arg(NTS) (900 ng/kg/min) did not improve baroreflex control of HR, but restored the depression of HR range when given after L-NMMA(NTS). Basal NOS activity in the dorsal brain stem was reduced in SHR (P < 0.05) when compared to WKY group. CONCLUSIONS: NO modulates, at the NTS level, the baroreceptor reflex control of HR in both SHR and WKY not by altering the gain, but by increasing HR range during afferent stimulation. In SHR the depressed NO modulation is in accordance with the smaller NOS activity in the dorsal brain stem.

Endogenous vasopressin and the central control of heart rate during dynamic exercise.

The present article contains a brief review on the role of vasopressinergic projections to the nucleus tractus solitarii in the genesis of reflex bradycardia and in the modulation of heart rate control during exercise. The effects of vasopressin on exercise tachycardia are discussed on the basis of both the endogenous peptide content changes and the heart rate response changes observed during running in sedentary and trained rats. Dynamic exercise caused a specific vasopressin content increase in dorsal and ventral brainstem areas. In accordance, rats pretreated with the peptide or the V1 blocker into the nucleus tractus solitarii showed a significant potentiation or a marked blunting of the exercise tachycardia, respectively, without any change in the pressure response to exercise. It is proposed that the long-descending vasopressinergic pathway to the nucleus tractus solitarii serves as one link between the two main neural controllers of circulation, i.e., the central command and feedback control mechanisms driven by the peripheral receptors. Therefore, vasopressinergic input could contribute to the adjustment of heart rate response (and cardiac output) to the circulatory demand during exercise.

Modulation of exercise tachycardia by vasopressin in the nucleus tractus solitarii.

Our objective was to study the role of vasopressinergic synapses at the nucleus tractus solitarii (NTS) in the modulation of exercise-induced tachycardia. We evaluated the effect of NTS administration of vasopressin (AVP) or vasopressin antagonist (AVP(ant)) on heart rate (HR) and mean arterial pressure (MAP) responses during dynamic exercise in male rats with chronic arterial and NTS cannulas. Sedentary (S) and trained (T) animals were tested at three or four exercise levels (from 0.4 up to 1.4 km/h) after NTS injection of AVP or AVP(ant) 20-30 min before treadmill exercise. Plasma and regional brain levels of AVP were measured in separate groups of S and T rats at rest and immediately after acute exercise. When administered into the NTS, exogenous AVP (20 pmol) caused a small but significant decrease in baseline HR and potentiated the tachycardiac response to mild to moderate exercise intensities (on average, increases of 35-46 beats/min over control tachycardic response). The potentiation of exercise tachycardia by AVP was long lasting and more pronounced in T than in S rats. Even 2 days after NTS AVP injection, there was evidence for an alteration in the HR response to exercise. Mediation by V1 receptors was supported by the blunted tachycardiac response to exercise after administration of a V1 antagonist d(CH2)5Tyr MeAVP into the NTS in both T and S rats (average reductions of 23-34 and 13-19 beats/min below control tachycardia, respectively). No changes were observed in baseline MAP or the exercise-induced pressor responses. There were specific changes in brain stem AVP levels that were related to the exercise treatment. T rats showed a marked increase in dorsal and ventral brain stem AVP content after acute exercise. There were no changes in hypothalamus, median eminence, posterior pituitary, or plasma AVP. These data indicate that vasopressinergic synapses and V1 receptors in the NTS are involved in the potentiation of tachycardic response to exercise. The vasopressinergic mechanism operates in both S and T rats, but training alters the sensitization of V1 receptors by AVP.

Validation of transit-time flowmetry for chronic measurements of regional blood flow in resting and exercising rats.

The objective of the present study was to validate the transit-time technique for long-term measurements of iliac and renal blood flow in rats. Flow measured with ultrasonic probes was confirmed ex vivo using excised arteries perfused at varying flow rates. An implanted 1-mm probe reproduced with accuracy different patterns of flow relative to pressure in freely moving rats and accurately quantitated the resting iliac flow value (on average 10.43 +/- 0.99 ml/min or 2.78 +/- 0.3 ml min-1 100 g body weight-1). The measurements were stable over an experimental period of one week but were affected by probe size (resting flows were underestimated by 57% with a 2-mm probe when compared with a 1-mm probe) and by anesthesia (in the same rats, iliac flow was reduced by 50-60% when compared to the conscious state). Instantaneous changes of iliac and renal flow during exercise and recovery were accurately measured by the transit-time technique. Iliac flow increased instantaneously at the beginning of mild exercise (from 12.03 +/- 1.06 to 25.55 +/- 3.89 ml/min at 15 s) and showed a smaller increase when exercise intensity increased further, reaching a plateau of 38.43 +/- 1.92 ml/min at the 4th min of moderate exercise intensity. In contrast, exercise-induced reduction of renal flow was smaller and slower, with 18% and 25% decreases at mild and moderate exercise intensities. Our data indicate that transit-time flowmetry is a reliable method for long-term and continuous measurements of regional blood flow at rest and can be used to quantitate the dynamic flow changes that characterize exercise and recovery.

In vivo adaptive responses of the aorta to hypertension and aging.

To investigate the dynamic behavior of the aorta of freely moving rats during the maintenance of hypertension, a longitudinal study was performed in renal hypertensive (Goldblatt 1 kidney, 1 clip) rats aged 3, 6, and 9 mo in which hypertension was maintained for 1, 3, and 6 mo, respectively. The pulsatile caliber of the thoracic aorta was measured (electrolytic strain gauge chronically implanted) simultaneously with aortic pressure under basal conditions and during transient changes of blood pressure. Aortic thickness was determined postmortem by morphometry. Establishment of hypertension (179 +/- 5 mmHg) by increasing the stress developed by the aorta caused increases in the resting values of caliber (20%), thickness (21%), and strain (95%); the maintenance of hypertension for a 6-mo period caused a further increase in thickness (58% vs. age-matched normotensive aortas) but not in aortic caliber and strain, the subsequent alterations of which were due only to growth/aging. Although different calibers, thicknesses, and dynamic strains were presented, the stress-strain relationship during transient blood pressure changes was similar for all hypertensive and normotensive groups with the exception of renal hypertensive rats aged 6 mo, which presented a steeper relationship (a large transitory increase in aortic distensibility was observed at that age). Dynamic adaptive responses of the aorta to hypertension compensate for geometric changes in such a way as to maintain a near-constant distensibility. It was concluded that, in contrast to the extrathoracic vessels, the adaptive responses of the aorta to hypertension were directed to maintain its compliance without changing the distensibility and stress-strain relationship, contributing to partially counterbalance the increased pressure and the decreased compliance of the more peripheral components of the arterial tree.