Intrapulmonary arteries respond to serotonin and adenosine triphosphate in broiler chickens susceptible to idiopathic pulmonary arterial hypertension.

This study examined factors contributing to increased vascular resistance and plexiform lesion formation in broiler chickens susceptible to idiopathic pulmonary arterial hypertension (IPAH). A diet supplemented with excess tryptophan (high-Trp diet), the precursor for serotonin, was used to accelerate the development of IPAH. Broilers fed the high-Trp diet had higher pulmonary arterial pressures than broilers fed the control diet, and plexiform lesion incidences tended to be higher (P = 0.11) in the high-Trp group than in the control group at 30 d of age. The intrapulmonary arteries were assessed for vasoconstriction in response to serotonin and adenosine triphosphate (ATP) and for activities of key metabolic enzymes for serotonin and ATP. The pulmonary artery (defined as the first major branch of the pulmonary artery inside the lung) and the primary pulmonary arterial rami (defined as the second major branch of the pulmonary artery inside the lung) both exhibited vasoconstriction in response to serotonin and ATP. This is the first study to demonstrate purinergic-mediated vasoconstriction in intrapulmonary arteries from broilers. Arteriole responsiveness did not differ between broilers fed the control diet or the high-Trp diet. Therefore, the high-Trp diet enhanced the development of IPAH but did not affect the artery's sensitivity to serotonin or ATP. Monoamine oxidase activity, responsible for the breakdown of serotonin, was severely impaired in pulmonary arteries from broilers in the high-Trp group. Accordingly, serotonin may persist longer and elicit an amplified response in broilers fed the high-Trp diet.

The effect of aging on adrenergic and nonadrenergic receptor expression and responsiveness in canine skeletal muscle.

We tested the hypothesis that adrenergic and nonadrenergic receptor responsiveness and protein expression would be altered with advancing age. Young (n = 6; 22 ± 1 mo; mean ± SE) and old (n = 6; 118 ± 9 mo) beagles were instrumented with flow probes and an indwelling catheter for continuous measurement of external iliac blood flow and arterial blood pressure. Vascular conductance (VC) was calculated as hindlimb blood flow/mean arterial pressure. Selective agonists for α-1, α-2, neuropeptide-Y (NPY), and purinergic (P2X) receptors were infused at rest and during treadmill running at moderate (2.5 mph) and heavy (4 mph with 2.5% grade) exercise intensities. Feed arteries were dissected from gracilis muscles, and α-1D, α-1B, α-2A, P2X-4, P2X-1, and NPY-Y1 receptor protein expression was determined. Phenylephrine produced similar decreases (P > 0.05) in VC in young and old beagles at rest (young: -62 ± 5%; old: -59 ± 5%) and during moderate (young: -67 ± 5%; old: -62 ± 4%) and heavy (young: -54 ± 4%; old: -49 ± 3%) exercise. Clonidine caused similar (P > 0.05) decreases in VC in old compared with young dogs at rest (young: -59 ± 8%; old: -70 ± 6%) and during moderate (young: -52 ± 6%; old: -47 ± 5%)- and heavy (young: -42 ± 5%; old: -43 ± 5%)-intensity exercise. NPY infusion resulted in a similar decline in VC in young and old beagles at rest (young: -40 ± 7%; old: -39 ± 9%) and during moderate (young: -47 ± 6%; old: -40 ± 6%)- and heavy (young: -40 ± 3%; old: -38 ± 4%)-intensity exercise. α-ß-Methylene-ATP also produced similar decreases in VC in young and old beagles at rest (young: -36 ± 6%; old: -40 ± 8%) and during exercise at moderate (young: -42 ± 5%; old: -40 ± 9%) and heavy (young: -47 ± 5%; old: -42 ± 8%) intensities. α-1B receptor protein expression was elevated (P < 0.05) in old compared with young dogs, whereas there were no age-related differences in α-1D or α-2A receptor expression and nonadrenergic P2X-4, P2X-1, and NPY-Y1 receptor expression. The present findings indicate that postsynaptic adrenergic and nonadrenergic receptor responsiveness was not altered by advancing age. Moreover, the expression of adrenergic and nonadrenergic receptors in skeletal-muscle feed arteries was largely unaffected by aging.

Is tonic sympathetic vasoconstriction increased in the skeletal muscle vasculature of aged canines?

We tested the hypothesis that tonic adrenergic and nonadrenergic receptor-mediated sympathetic vasoconstriction would increase at rest and during exercise with advancing age. Young (n = 6; 22 ± 1 mo; means ± SE) and old (n = 6; 118 ± 9 mo) beagles were studied. Selective antagonists for alpha-1, alpha-2, neuropeptide Y (NPY), and purinergic (P(2x)) receptors were infused at rest and during treadmill running at 2.5 mph and 4 mph with 2.5% grade. Prazosin produced similar increases in vascular conductance in young and old beagles at rest (Young: 158 ± 34%; Old: 98 ± 19%) and during exercise at 2.5 mph (Young: 80 ± 10%; Old: 58 ± 12%) and 4 mph and 2.5% grade (Young: 57 ± 5%; Old: 26 ± 4%). Rauwolscine caused similar (P > 0.05) increases in vascular conductance in old compared with young dogs at rest (Young: 119 ± 25%; Old: 64 ± 22%) and at 2.5 mph (Young: 86 ± 13%; Old: 60 ± 7%) and 4 mph with 2.5% grade (Young: 61 ± 5%; Old: 43 ± 7%). N2-(diphenylacetyl)-N-[4-hydroxyphenyl)methyl]-d-arginine amide (BIBP) caused a smaller increase (P < 0.05) in vascular conductance in old compared with young dogs at rest (Young: 179 ± 44%; Old: 91 ± 22%), whereas similar increases (P > 0.05) of experimental limb vascular conductance in young and old dogs occurred following BIBP during exercise at 2.5 mph (Young: 56 ± 16%; Old: 50 ± 12%) and 4 mph and 2.5% grade (Young: 45 ± 10%; Old: 25 ± 7%). Pyridoxal-phosphate-6-azophenyl-2'-4'-disulfonic acid infusion produced a larger increase in vascular conductance in old compared with young beagles at rest (Young: 88 ± 14%; Old: 191 ± 58%), whereas similar increases were observed at 2.5 mph (Young: 47 ± 18%; Old: 31 ± 11%) and 4 mph with 2.5% grade (Young: 26 ± 13%; Old: -18 ± 8%). At rest, NPY receptor-mediated restraint of skeletal muscle blood flow was reduced with advancing age, whereas P(2x) receptor-mediated restraint of skeletal muscle blood flow was increased. During exercise, the magnitude of adrenergic and nonadrenergic sympathetic vasoconstriction was not different between young and old dogs. Overall, these data demonstrate that adrenergic receptor-mediated vasoconstriction was not elevated at rest, but nonadrenergic sympathetic vasoconstriction was altered under basal conditions in aged beagles.

Cardiac myosin phenotype remodeling following chronic spinal transection.

Spinal transection results in profound neural and functional changes of the heart. However, phenotypic alterations in cardiac myosin heavy chains (MyHC) as a result of spinal transection have not been explored. Hearts were removed from 180 day old rats who had their spinal cords transected between T6 and T9 (ST; n = 10) and intact controls (IN; n = 9). Myosin was isolated from the left and right ventricles and separated into its respective heavy chain components (designated as alpha and beta) by SDS-PAGE. The resulting gels were scanned with a laser scanning densitometer to obtain relative concentrations of these two heavy chains. The left ventricles of the ST rats had a significantly higher (p < 0.05) alpha to beta ratio (10.89) than the intact controls (4.20), while the right ventricle of the ST rats had a significantly lower (p < 0.05) alpha to beta ratio (7.49) relative to intact controls (13.62). The left and right ventricular weight to body weight ratios were not different in ST compared to IN. Additionally, there were significant within group differences (p < 0.05) between the alpha and beta MyHC ratios for the left and right ventricles. These data suggest that 1) spinal transection causes remodeling of the right and left ventricles and 2) the two ventricles do not remodel as a unit.

Vagal modulation of the heart and central hemodynamics during handgrip exercise.

Blood pressure and continuous electrocardiogram recordings were obtained from 12 participants during spontaneous breathing (SB1), dynamic handgrip exercise at 20% (HG(20)) of maximal voluntary contraction (MVC), and spontaneous breathing (SB2) and dynamic handgrip exercise at 60% (HG(60)) of MVC. Repeated-measures ANOVAs were used to examine the effects of the exercise conditions on mean arterial pressure (MAP), on mean standard deviation (SDNN), and on the coefficient of variation of R-R intervals. The mean R-R interval responded to exercise in an intensity-dependent manner. SDNN decreased with exercise but was not intensity dependent. Coefficient of variation decreased during HG(20), and MAP increased following HG(60). These data are consistent with the notion that changes in cardiovascular function with low-intensity exercise are primarily mediated by parasympathetic withdrawal, and as exercise intensity increases, additional cardiovascular reactivity is mediated by increased sympathetic outflow. The change in the coefficient of variation from rest to exercise was unique in comparison to the changes in SDNN, and this merits further investigation.

Neuroendocrine activation in heart failure is modified by endurance exercise training.

OBJECTIVES: The purpose of this study was to determine whether endurance exercise training could buffer neuroendocrine activity in chronic heart failure patients. BACKGROUND: Neuroendocrine activation is associated with poor long-term prognosis in heart failure. There is growing consensus that exercise may be beneficial by altering the clinical course of heart failure, but the mechanisms responsible for exercise-induced benefits are unclear. METHODS: Nineteen heart failure patients (ischemic disease; New York Heart Association [NYHA] class II or III) were randomly assigned to either a training group or to a control group. Exercise training consisted of supervised walking three times a week for 16 weeks at 40% to 70% of peak oxygen uptake. Medications were unchanged. Neurohormones were measured at study entry and after 16 weeks. RESULTS: The training group (n = 10; age = 61 +/- 6 years; EF = 30 +/- 6%) and control group (n = 9; age = 62 +/- 7 years; EF = 29 +/- 7%) did not differ in clinical findings at study entry. Resting levels of angiotensin II, aldosterone, vasopressin and atrial natriuretic peptide in the training and control groups did not differ at study entry (5.6 +/- 1.3 pg/ml; 158 +/- 38 pg/ml; 6.1 +/- 2.0 pg/ml; 37 +/- 8 pg/ml training group vs. 4.8 +/- 1.2; 146 +/- 23; 4.9 +/- 1.1; 35 +/- 10 control group). Peak exercise levels of angiotensin II, aldosterone, vasopressin and atrial natriuretic peptide in the exercise and control groups did not differ at study entry. After 16 weeks, rest and peak exercise hormone levels were unchanged in control patients. Peak exercise neurohormone levels were unchanged in the training group, but resting levels were significantly (p < 0.001) reduced (angiotensin -26%; aldosterone -32%; vasopressin -30%; atrial natriuretic peptide -27%). CONCLUSIONS: Our data indicate that 16 weeks of endurance exercise training modified resting neuroendocrine hyperactivity in heart failure patients. Reduction in circulating neurohormones may have a beneficial impact on long-term prognosis.