Estudou-se o efeito do treinamento físico sobre a freqüência cardíaca (FC), a freqüência cardíaca intrínseca (FCI), o efeito vagal (EV), o tônus vagal (TV), o efeito simpático (ES) e o tônus simpático (TS), de ratos idosos em repouso volitivo, na esteira, e durante o exercício de intensidade progressiva (4 estágios de 5 min à 5; 7,5; 10 e 15 m.min-1). Verificaram-se, também, as respostas da FC à doses crescentes de agonistas ?-adrenérgico (isoproterenol) e muscarínico (metacolina). Utilizaram-se 20 ratos Wistar machos, aleatoriamente divididos em dois grupos: Treinado (T, 28+2 meses, 460+36 g), submetido a 10 semanas de treinamento físico de moderada intensidade; e Sedentário-controle (S, 28+2 meses, 461+43 g), apenas manipulado, três a cinco vezes por semana, durante nove semanas, e submetido a cinco minutos de exercício diário, na décima semana, para habituação ao pesquisador e ao ambiente experimental. Utilizaram-se duplos bloqueios farmacológicos (propranolol/atropina e atropina/propranolol) para determinação da FCI, bem como bloqueios farmacológicos autonômicos unilaterais que permitiram a medida do EV, do TV, do ES e do TS. Definições: EV = FC após atropina - FC controle, ES = FC controle - FC após propranolol, TV = FCI - FC após propranolol, TS = FC após atropina - FCI. Registros: batimento-a-batimento, 500Hz (AT/CODAS). Para comparação realizou-se análise de variância de dois caminhos para medidas repetidas, com contraste. Significância estatística, P<0,05. FC e FCI foram menores em T que S, em repouso e nos quatro estágios estudados: FC = 296+6, T vs. 325+16, S; 374+33, T vs. 420+29, S; 380+ 39, T vs. 423+29, S; 407+46, T vs. 434+25, S; 441+48, T vs. 455+30, S; e FCI = 288+28, T vs. 312+18, S; 302+27, T vs. 332+24, S; 301+30, T vs. 339+26, S; 308+30, T vs. 344+30, S; 316+31, T vs. 348+31, S. Não houve diferença na atividade vagal entre T e S, tanto considerando o EV, como o TV, em nenhuma das condições estudadas. A influência simpática para o coração se mostrou semelhante entre T e S, tanto se considerando o ES quanto o TS, em todas as condições estudadas. T e S responderam de forma semelhante aos agonistas muscarínico e adrenérgico. Tanto a FC, quanto a FCI aumentaram do repouso para o exercício, e com o aumento da intensidade do mesmo. A atividade vagal diminuiu do repouso para o exercício, mas apenas em intensidade elevada. A atividade simpática aumentou na passagem do repouso para o exercício, e com o aumento da intensidade do mesmo. Concluiu-se que, em ratos idosos: a) o treinamento físico de moderada intensidade promoveu bradicardia de repouso e atenuação da taquicardia induzida pelo exercício essencialmente à custa de redução da FCI; e b) independentemente da condição de treinamento físico, a estimulação simpática contribuiu para o aumento da FC, em resposta ao exercício, de leve à alta intensidade, enquanto a retirada vagal o fez, apenas em alta intensidade. / We studied the effect of exercise training on heart rate (HR), on intrinsic heart rate (IHR), on vagal effect (VE), on vagal tone (VT), on sympathetic effect (SE) and on sympathetic tone (ST) during both treadmill resting and exercise of progressive intensity (four 5-min stages at 5, 7.5, 10 and 15 m.min-1) in old rats. HR responses to crescent doses of ?-adrenergic (isoproterenol) and muscarinic (metacholine) agonists were also verified. We used 20 male Wistar rats randomly assigned to two groups: trained (T, 28+2 months, 460+36 g) and sedentary control (S, 28+2 months, 461+43 g) rats. T was submitted to a ten-week moderate intensity exercise training program, while S was just handled, three to five times a week, for nine weeks and submitted to five-min bouts of daily exercise during the tenth week for taming and to become accustomed to experimental environment. Double pharmacological blockades (propranolol/ methylatropine and methylatropine/propranolol) were performed in order to determine IHR. Autonomic influences on heart rate were evaluated using also unilateral autonomic pharmacological blockade, which allowed us to measure VE and VT as well as SE and ST. Definitions: VE = HR after atropine - control HR, SE = control HR - HR after propranolol, VT = IHR - HR after propranolol, ST = HR after atropine - IHR. HR was recorded on a beat-to-beat basis with a 500 Hz acquisition frequency (AT/CODAS). For statistical analysis we used two-way ANOVA for repeated measurements with contrast, considering a P<0.05 as statistically significant. T rats had lower HR as well as IHR than their sedentary counterparts both at rest and during all progressive exercise stages: HR = 296+6,T vs. 325+16,S; 374+33,T vs. 420+29,S; 380+39,T vs. 423+29,S; 407+46,T vs. 434+25,S; 441+48,T vs. 455+30,S, respectively; and IHR = 288+28,T vs. 312+18,S; 302+27,T vs. 332+24,S; 301+30,T vs. 339+26,S; 308+30,T vs. 344+30,S; 316+31,T vs. 348+31,S, respectively. Vagal activity was not significantly different between groups, either considering VE or VT. Sympathetic influence was also similar between S and T considering both SE and ST in all of the studied conditions. T and S responded similarly to both muscarinic and ?-adrenergic agonists. Both HR and IHR increased from rest to exercise and with increasing exercise intensity. Vagal activity decreased from rest to exercise but only in high intensity exercise. Sympathetic activity increased from rest to exercise and also with increasing exercise intensity. We concluded that in old rats: a) exercise training of moderate intensity led to resting bradycardia and attenuation of exercise tachycardia essentially due to the decrease in IHR; and b) independently from exercise training status, sympathetic stimulation contributed to HR increase from light to high intensity exercise while vagal withdrawal became important only at high intensity exercise

Indiana University-Purdue University Indianapolis (IUPUI) / Autonomic innervation of the heart begins in utero and continues during the neonatal phase of life. A balance between the sympathetic and parasympathetic arms of the autonomic nervous system is required to regulate heart rate as well as the force of each contraction. Our lab studies the development of sympathetic innervation of the early postnatal heart in a conditional knockout (cKO) of Src homology protein tyrosine phosphatase 2 (Shp2). Shp2 is a ubiquitously expressed non-receptor phosphatase involved in a variety of cellular functions including survival, proliferation, and differentiation. We targeted Shp2 in post-migratory neural crest (NC) lineages using our novel Periostin-Cre. This resulted in a fully penetrant mouse model of diminished cardiac sympathetic innervation and concomitant bradycardia that progressively worsen. Shp2 is thought to mediate its basic cellular functions through a plethora of signaling cascades including extracellular signal-regulated kinases (ERK) 1 and 2. We hypothesize that abrogation of downstream ERK1/2 signaling in NC lineages is primarily responsible for the failed sympathetic innervation phenotype observed in our mouse model. Shp2 cKOs are indistinguishable from control littermates at birth and exhibit no gross structural cardiac anomalies; however, in vivo electrocardiogram (ECG) characterization revealed sinus bradycardia that develops as the Shp2 cKO ages. Significantly, 100% of Shp2 cKOs die within 3 weeks after birth. Characterization of the expression pattern of the sympathetic nerve marker tyrosine hydroxylase (TH) revealed a loss of functional sympathetic ganglionic neurons and reduction of cardiac sympathetic axon density in Shp2 cKOs. Shp2 cKOs exhibit lineage-specific suppression of activated pERK1/2 signaling, but not of other downstream targets of Shp2 such as pAKT (phosphorylated-Protein kinase B). Interestingly, restoration of pERK signaling via lineage-specific expression of constitutively active MEK1 (Mitogen-activated protein kinase kinase1) rescued TH-positive cardiac innervation as well as heart rate. These data suggest that the diminished sympathetic cardiac innervation and the resulting ECG abnormalities are a result of decreased pERK signaling in post-migratory NC lineages.

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