Increase in atrial natriuretic peptide in response to physical exercise

Circulating atrial natriuretic peptide (ANP) level was determined during physical exercise to investigate the correlation between changes in ANP level and heart rate increases. Six subjects exercised at a work level of 75% VO2max for 30 min, two also performed two successive exercises at 75% VO2max while two more exercised for longer at 55% VO2max. Plasma ANP levels and heart rate increased in all the exercising subjects. At the end of the exercise, the ANP level fell immediately, suggesting an immediate reduction in ANP secretion by the heart. Pre-exercise values were reached after 30 min. Successive exercises gave the same heart rate related ANP patterns without previous secretory episodes having any effect. These results lead to the conclusion that ANP intervenes in the cardiovascular adjustments to exercise.     

Cardiovascular responses of heart transplant recipients to graded exercise testing.

A group of orthotopic heart transplant (OHT, n = 28) and heart surgery (n = 19) patients, with similar ejection fractions and left ventricular end-diastolic pressures, were exercised to symptom-limited maximum to describe differences in cardiovascular and gas exchange responses. Testing was performed at a mean of 3 and 6 mo after surgery, respectively (P less than 0.05). OHT patients have a greater resting systolic and diastolic blood pressure (P less than 0.01) and a significantly greater (P less than 0.01) heart rate (HR) at rest in the supine and standing positions and during minutes 2 through 7 of supine recovery. Peak treadmill time was significantly less (P less than 0.01) in OHT patients. No significant differences were found for systolic blood pressure (SBP) during recovery, peak HR, ventilation, relative O2 uptake (VO2), body weight, ventilatory equivalents for O2 and CO2, O2 pulse, and HR-SBP product (peak HR x peak SBP). Peak pulse pressure, heart rate reserve, total VO2, and absolute VO2 at ventilatory threshold were significantly lower (P less than 0.01) in the OHT patients. We concluded that 1) complete cardiac decentralization is evident, 2) the significantly reduced VO2 at ventilatory threshold should be considered when activities of daily living are prescribed, and 3) SBP response is more appropriate than HR for assessing recovery of the decentralized heart after maximal exercise.     

Impaired pulmonary oxygen uptake kinetics and reduced peak aerobic power during small muscle mass exercise in heart transplant recipients.

We examined peak and reserve cardiovascular function and skeletal muscle oxygenation during unilateral knee extension (ULKE) exercise in five heart transplant recipients (HTR, mean +/- SE; age: 53 +/- 3 years; years posttransplant: 6 +/- 4) and five age- and body mass-matched healthy controls (CON). Pulmonary oxygen uptake (Vo(2)(p)), heart rate (HR), stroke volume (SV), cardiac output (Q), and skeletal muscle deoxygenation (HHb) kinetics were assessed during moderate-intensity ULKE exercise. Peak exercise and reserve Vo(2)(p), Q, and systemic arterial-venous oxygen difference (a-vO(2diff)) were 23-52% lower (P < 0.05) in HTR. The reduced Q and a-vO(2diff) reserves were associated with lower HR and HHb reserves, respectively. The phase II Vo(2)(p) time delay was greater (HTR: 38 +/- 2 vs. CON: 25 +/- 1 s, P < 0.05), while time constants for phase II Vo(2)(p) (HTR: 54 +/- 8 vs. CON: 31 +/- 3 s), Q (HTR: 66 +/- 8 vs. CON: 28 +/- 4 s), and HHb (HTR: 27 +/- 5 vs. CON: 13 +/- 3 s) were significantly slower in HTR. The HR half-time was slower in HTR (113 +/- 21 s) vs. CON (21 +/- 2 s, P < 0.05); however, no significant difference was found between groups for SV kinetics (HTR: 39 +/- 8 s vs. CON 31 +/- 6 s). The lower peak Vo(2)(p) and prolonged Vo(2)(p) kinetics in HTR were secondary to impairments in both cardiovascular and skeletal muscle function that result in reduced oxygen delivery and utilization by the active muscles.     

Forearm vascular resistance increases during static exercise in heart transplant recipients.

In heart transplant recipients but not in normal humans, total peripheral vascular resistance increases during static exercise. To determine whether this augmented vasoconstriction limits the vasodilation normally seen in the nonexercising forearm, we measured arterial pressure, heart rate, and forearm blood flow during 30% maximal static handgrip in 9 heart transplant recipients and 10 control subjects. Handgrip evoked comparable increases in mean arterial pressure in the transplant recipients and control subjects (+19 +/- 2 vs. +20 +/- 2 mmHg). Heart rates increased by 14 +/- 3 beats/min in the control subjects but did not change in the transplant recipients. Directionally opposite patterns of forearm vascular resistance were observed in the two groups. In the control subjects, forearm resistance fell during handgrip (-8.8 +/- 1.9 units, P less than 0.05). In contrast, in the transplant recipients, forearm resistance rose during this intervention (+9.0 +/- 2.9 units, P less than 0.05). Thus the vasodilation that normally occurs in the nonexercising forearm during static handgrip is reversed in heart transplant recipients. Vasoconstriction in the forearm contributes to the increase in total peripheral resistance that occurs during static exercise in these individuals.     

Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients

Grassi, Bruno, Claudio Marconi, Michael Meyer, Michel Rieu,and Paolo Cerretelli. Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients. J. Appl. Physiol. 82(6): 1952-1962, 1997.Metabolicand cardiovascular adjustments to various submaximal exercises wereevaluated in 82 heart transplant recipients (HTR) and in 35 controlsubjects (C). HTR were tested 21.5 ± 25.3 (SD) mo (range1.0-137.1 mo) posttransplantation. Three protocols were used:protocol A consisted of 5 min of rectangular 50-W load repeatedtwice, 5 min apart [5 min rest, 5 min 50 W (Ex 1), 5 minrecovery, 5 min 50 W (Ex 2)]; protocol B consistedof 5 min of rectangular load at 25, 50, or 75 W; protocol Cconsisted of 15 min of rectangular load at 25 W. Breath-by-breathpulmonary ventilation (E),O₂ uptake (O₂),and CO₂ output(CO₂) were determined.During protocol A, beat-by-beat cardiacoutput () was estimated by impedance cardiography. The half times (t_1/2) of the on- andoff-kinetics of the variables were calculated. In all protocols,t_1/2 values forO₂ on-,E on-, andCO₂ on-kinetics were higher(i.e., the kinetics were slower) in HTR than in C, independently ofworkload and of the time posttransplantation. Also,t_1/2 on- was higher in HTRthan in C. In protocol A, no significant difference of t_1/2 O₂on- was observed in HTR between Ex 1 (48 ± 9 s) and Ex2 (46 ± 8 s), whereas t_1/2 on- was higher during Ex 1 (55 ± 24 s)than during Ex 2 (47 ± 15 s). In all protocols and for all variables, the t_1/2 off-values were higher in HTRthan in C. In protocol C, no differences of steady-stateE,O₂, andCO₂ were observed in bothgroups between 5, 10, and 15 min of exercise. We conclude that1) in HTR, a "priming" exercise, while effective inspeeding up the adjustment of convective O₂ flow to muscle fibers during a second on-transition, did not affect theO₂ on-kinetics, suggestingthat the slower O₂ on- inHTR was attributable to peripheral (muscular) factors; 2) thedissociation between on- andO₂ on-kinetics in HTRindicates that an inertia of muscle metabolic machinery is the mainfactor dictating theO₂ on-kinetics; and 3) theO₂ off-kinetics was slowerin HTR than in C, indicating a greater alactic O₂ deficitin HTR and, therefore, a sluggish muscleO₂ adjustment.

     

Immunoreactive forms of natriuretic peptides in ovine brain: response to heart failure

In order to elucidate how brain natriuretic peptides (NPs) are affected by experimentally induced heart failure, we have measured the immunoreactive (IR) levels of the NP in extracts from 10 regions of ovine brain, including pituitary, and clarified their molecular forms using high performance liquid chromatography (HPLC). Using species-specific radioimmunoassay (RIA), atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were all detected in extracts taken from control animals and sheep that had undergone rapid ventricular pacing for 7 days to induce heart failure. CNP was the most abundant NP as assessed by specific RIA, and the pituitary contained the highest IR levels for all three NP. Compared with control animals, the pituitary content of BNP in animals with heart failure was reduced by 40% (control, 0.26±0.02 pmol/g wet weight versus heart failure 0.16±0.01; P<0.01, n=7). No other significant changes were observed. The molecular forms of ANP and CNP in whole brain extracts as assessed by HPLC were proANP and CNP22, CNP53 and proCNP, respectively. BNP in pituitary extracts was assessed to be primarily proBNP with a minor component of mature BNP26.     

Characterization of immunoreactive human C-type natriuretic peptide in brain and heart.

Amino acid sequence of human C-type natriuretic peptide (CNP) has recently been deduced to be identical to those of porcine and rat CNPs in the bioactive unit of C-terminal 22 residues (CNP-22) (1). Thus, tissue concentrations and molecular forms of immunoreactive (ir-) CNP in human brain and heart were determined or characterized using a radioimmunoassay established for porcine CNP. In human brain (hypothalamus and medullapons), ir-CNP was detected at a concentration of 1.04 pmol/g, being about 25 times or 70 times higher than ir-atrial (A-type) natriuretic peptide (ANP) or ir-brain (B-type) natriuretic peptide (BNP). CNP was present mainly as CNP-53, with CNP-22 as well as 13K CNP (presumed to be pro-CNP) as minor components. In heart, 1 approximately 5 pmol/g of ir-CNP was detected in both atrium and ventricle, but this ir-CNP was shown to be derived from crossreactivity of ANP. These results demonstrated that human CNP functions exclusively in the central nervous system in contrast to ANP and BNP which mainly function in the circulation system.     

The presence of brain natriuretic peptide of 12,000 daltons in porcine heart

Brain natriuretic peptide (BNP) and its N-terminally six amino acid extended form (BNP-32) have been identified in porcine brain. These peptides exert diuretic-natriuretic and hypotensive effects, and have remarkably high sequence homology to atrial natriuretic peptide (ANP). We have set up a radioimmunoassay system specific to BNP and surveyed immunoreactive (ir-) BNP in peripheral tissue. In porcine cardiac atrium, we found the highest concentration of ir-BNP. By using gel filtration and reverse phase high performance liquid chromatography, ir-BNP was characterized. Most of ir-BNP in the atrium was found to exist as a high molecular weight form of 12,000 daltons; less than 15% of the total ir-BNP exist as low molecular weight forms such as BNP and BNP-32. These results suggest that BNP functions as a circulating hormone in addition to the neuropeptide function in brain.     

Evaluation of atrial natriuretic peptide and brain natriuretic peptide in atrial granules of rats with experimental congestive heart failure.

The natriuretic peptides are believed to play an important role in the pathophysiology of congestive heart failure (CHF). We utilized a quantitative cytomorphometric method, using double immunocytochemical labeling, to assess the characteristics of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in atrial granules in an experimental model of rats with CHF induced by aortocaval fistula. Rats with CHF were further divided into decompensated (sodium-retaining) and compensated (sodium-excreting) subgroups and compared with a sham-operated control group. A total of 947 granules in myocytes in the right atrium were analyzed, using electron microscopy and a computerized analysis system. Decompensated CHF was associated with alterations in the modal nature of granule content packing, as depicted by moving bin analysis, and in the granule density of both peptides. In control rats, the mean density of gold particles attached to both peptides was 347.0 +/- 103.6 and 306.3 +/- 89.9 gold particles/microm2 for ANP and BNP, respectively. Similar mean density was revealed in the compensated rats (390.6 +/- 81.0 and 351.3 +/- 62.1 gold particles/microm2 for ANP and BNP, respectively). However, in rats with decompensated CHF, a significant decrease in the mean density of gold particles was observed (141.6 +/- 67.3 and 158.0 +/- 71.2 gold particles/microm2 for ANP and BNP, respectively; p<0.05 compared with compensated rats, for both ANP and BNP). The ANP:BNP ratio did not differ between groups. These findings indicate that the development of decompensated CHF in rats with aortocaval fistula is associated with a marked decrease in the density of both peptides in atrial granules, as well as in alterations in the quantal nature of granule formation. The data further suggest that both peptides, ANP and BNP, may be regulated in the atrium by a common secretory mechanism in CHF.     

Distribution and molecular forms of brain natriuretic peptide in porcine heart and blood

Although brain natriuretic peptide (BNP) is a novel natriuretic peptide originally identified in porcine brain, recent investigation has verified the presence of BNP in porcine heart. In order to identify BNP as a circulating hormone, we analyzed the regional distribution and molecular form of immunoreactive (ir-) BNP in heart and blood. Tissue concentration of ir-BNP was high in atrium, but low in ventricle, in a manner similar to that of atrial natriuretic peptide (ANP). However, the concentration of ir-BNP in atrium was only about 1/50 that of ir-ANP. In plasma, ir-BNP was found at a concentration of 1-3 fmol/ml, which was about 1/20 that of ir-ANP. Both ir-BNP and ir-ANP were present as low molecular weight forms. Three forms of ir-BNP of about 3K daltons, including BNP-26, BNP-29 and BNP-32, are thought to circulate in blood.     

Dimensional analysis of heart rate variability in heart transplant recipients

Periodicities in the heart rate have been known for some time. We discuss these periodicities in normal and transplanted hearts. We then consider the possibility of dimensional analysis of these periodicities in transplanted hearts and problems associated with the record.     

Relationship between levels of brain natriuretic peptide in blood and immune response in subjects

Elevated concentrations of Nt-pro-BNP were revealed in 11% of apparently healthy subjects aged 19–24 years and 22% of middle-aged (34–55 years) subjects. An increase in Nt-pro-BNP blood concentration was detected in 90% of patients with metabolic syndrome. Elevated levels of Nt-pro-BNP in peripheral blood occur with age. Higher concentrations of the peptide were revealed in women. Inhibition of lymphocytes proliferation and differentiation accompanied by increasing concentration of Nt-pro-BNP in blood is associated with a deficiency of the IL-2 level due to increased IL-10 concentration. Immunosuppressive effect of IL-10 declares itself at the level of innate immune reactions as a decrease in blood counts of naive CD45RA+ T lymphocytes, natural killer cells, T cells with adhesion receptor (CD56+) and adhesion receptor ligand (CD62L+). To prevent a loss of the intercellular pool, the effect of Nt-pro-BNP is activated. No statistically significant correlations between the increased Nt-pro-BNP concentration in blood and the content of serum IgM, IgG, IgA, IgE, IL-6, TNF-α, IFN-γ, CEC C1q, or С3d, as well as glucose, hemoglobin, transferrin, iron, or free fatty acids were revealed in apparently healthy subjects.     

Cardiac allograft vasculopathy in Dutch heart transplant recipients

Background

Cardiac allograft vasculopathy (CAV) is a multifactorial disease and a major cause of graft failure after heart transplantation. However, the impact of CAV may vary according to the definition and the regional differences in transplantation settings.

Objectives

We sought to assess CAV prevalence, predictors and prognosis in Dutch heart transplant recipients based on coronary angiography, following the 2010 standard nomenclature of the International Society for Heart and Lung Transplantation.

Methods

Patients ≥18 years who underwent heart transplantation at our centre with at least one coronary angiography during follow-up were included in the analysis. Clinical variables were collected prospectively.

Results

Among 495 analysed recipients, there were 238 (48?%) with CAV. The prevalence of CAV was 18, 47 and 70?% at 4, 12 and 20 years, respectively. In the multivariable proportional hazards regression analysis, only male donor gender and increasing donor age were significantly associated with the risk of CAV. The long-term prognosis of the patients with CAV at fourth-year angiography was significantly worse as compared with that of CAV-free patients, independently of the severity of CAV (p < 0.001).

Conclusion

The prevalence of CAV increased gradually over time, with a similar trend as in other registries. Post-transplant survival is decreased in patients with any degree of early CAV, indicating that management strategies should start with donor selection and preventive measures immediately after transplantation.

     

Interaction between brain natriuretic peptide and atrial natriuretic peptide in caecal circular smooth muscle cells

Guinea pig caecal circular smooth muscle cells were used to determine whether brain natriuretic peptide (BNP) can inhibit the contractile response produced by cholecystokinin-octapeptide (CCK-8). In addition, we examined the effect of an inhibitor of cAMP-dependent protein kinase, an inhibitor of particulate or soluble guanylate cyclase, an atrial natriuretic peptide (ANP) antagonist (ANP 1-11), and selective receptor protection on the BNP-induced relaxation of these muscle cells. The effect of BNP on cAMP formation was also examined. BNP inhibited the contractile response produced by CCK-8 in a dose-response manner, with an IC50 value of 8.5 nM, and stimulated the production of cAMP. The inhibitor of cAMP-dependent protein kinase and the inhibitor of soluble guanylate cyclase significantly inhibited the relaxation produced by BNP. In contrast, the inhibitor of particulate guanylate cyclase did not have any significant effect on the relaxation produced by BNP. ANP 1-11 significantly but partially inhibited the relaxation produced by BNP. The muscle cells where CCK-8 and ANP binding sites were protected completely preserved the inhibitory response to ANP, but partially preserved the inhibitory response to BNP. The muscle cells where CCK-8 and BNP binding sites were protected completely preserved the inhibitory response to both ANP and BNP. This study demonstrates that BNP induces relaxation of these muscle cells via both ANP binding sites coupled to soluble guanylate cyclase and distinct BNP binding sites coupled to adenylate cyclase.     

Age differences in renal response to atrial natriuretic peptide in rabbits

Plasma levels of atrial natriuretic peptide (ANP) and the effect of exogenous ANP on renal function have been studied in newborn and adult rabbits. In order to investigate an age difference in responsiveness to ANP, we studied the renal effects of alpha-human ANP (1-28) administered at the same dose per kg body weight in adult and neonatal rabbits. Plasma basal ANP levels were similar in 18 newborn (4- to 11-day-old) compared to 7 adult rabbits (150 +/- 16 and 151 +/- 28 pg/ml, resp.). Eleven newborn and 11 adult rabbits were anesthetized and mechanically ventilated. After a control period, each animal received an hANP loading dose (3 micrograms/kg i.v.), followed by an infusion of 0.3 micrograms/kg/min. Blood gases remained stable throughout the experiment in both groups. Mean blood pressure decreased in newborn (28.5 +/- 0.8 to 26.2 +/- 1.0 mmHg) and adult (92 +/- 3 to 84 +/- 3 mmHg) animals. Percent hANP-induced changes in renal functions in newborn and adult rabbits were, respectively: urine flow rate: -21 +/- 4% and +57 +/- 8%; urinary sodium excretion: +4 +/- 7% and +81 +/- 11%; glomerular filtration rate (GFR): -19 +/- 4% and -4 +/- 6%; renal blood flow (RBF): -22 +/- 4% and -11 +/- 5%. As expected, diuresis and natriuresis increased in adult rabbits. Failure of hANP to increase natriuresis and diuresis in newborn rabbits could be related to the marked decrease in GFR, receptor immaturity and/or interactions with other hormonal systems.     

Cardiovascular responses of heart transplant patients to exercise training

Orthotopic heart transplantation (OHT) represents an effective alternative for individuals with end-stage heart disease. The current literature reports only the responses of OHT patients to greater than or equal to 4 mo of exercise training (ET) and frequently lacks adequate controls. Most programs currently treating OHT patients usually provide 6-12 wk of ET. This study describes the effects of a 10-wk supervised ET program in 12 male OHT patients and 5 other male OHT patients who served as a comparison group. Graded exercise tests were performed before and after ET. After ET, maximal O2 consumption was significantly greater for the ET group than the comparison group (P less than 0.05) and the mean increase in peak heart rate was 18 +/- 4 and 6 +/- 4 (SE) min-1 for ET and comparison groups, respectively (P less than 0.05). Maximal ventilation was also significantly greater for the ET group at after ET, while resting heart rate and blood pressure and peak blood pressure, O2 pulse, respiratory rate, and ventilatory equivalents for O2 and CO2 were not significantly changed. We conclude that after OHT a 10-wk ET program improves maximal O2 consumption and, by improving peak heart rate, improves O2 delivery.     

Atrial natriuretic peptide in the heart and pancreas

We used antisera to pure atrial natriuretic peptide to localise this peptide by immunocytochemistry in rat and human tissue. We showed that both rat and human atrial cardiocytes gave a positive reaction while ventricular cardiocytes were consistently negative. Peripheral islet cells in rat but not in human pancreas also showed positive staining for ANP. We showed by double labelling techniques that the ANP was present in the glucagon containing cells.     

Atrial natriuretic peptide response to endurance physical training in the rat

The effect of an endurance physical training programme on the plasma and atrial natriuretic peptides (ANP) and on renal glomerular ANP receptors was evaluated in male normotensive Wistar rats. Maximal O2 uptake was significantly greater in the endurance trained (117.1 ml O2.kg-1.min-1, SEM 6.18 versus the control rats 84.2 ml O2.kg-1.min-1, SEM 4.88, P less than 0.01. In addition, various muscle oxidative enzymes were also significantly higher in endurance trained animals. An increase in resting plasma [ANP] was observed after 11 weeks of physical training (40.02 pg.ml-1, SEM 7.07 vs 22.8 pg.ml-1, SEM 3.83, P less than 0.05). Glomerular ANP receptor density was lower in trained rats (272 fmol.mg-1 protein, SEM 3.1 vs 380 fmol.mg-1 protein, SEM 6.1, P less than 0.05), whereas atrial tissue [ANP] was not significantly different between controls and trained animals. However, in trained rats, circulating [ANP] was closely correlated with left atrial [ANP] (r = -0.92, P less than 0.05). Resting systolic blood pressure had not changed at the end of this physical training programme. It is considered that under physiological conditions ANP may be involved in long-term extracellular fluid volume homeostasis through the regulation of renal glomerular ANP receptors, and that the left atrium might play a significant role in this long term fluid volume control.     

Expression of natriuretic peptide receptor mRNA and functional response to atrial natriuretic peptide and C-type natriuretic peptide in rainbow trout (Oncorhynchus mykiss) head kidney leucocytes

The stimulatory effect of vasomodulatory natriuretic peptide hormones on macrophages and peripheral blood leucocytes in mammals is well-established. However, the relationship in lower vertebrates has not been characterised. Expression of atrial natriuretic peptide, ventricular natriuretic peptide and C-type natriuretic peptide-1, and the guanylyl cyclase-linked (GC) natriuretic peptide receptor-A and -B-type receptors (NPR-A and NPR-B, respectively) was determined by PCR from the mRNA of rainbow trout head kidney leucocytes yielding gene fragments with 100% homology to the same respective natriuretic peptide and NPR-A and -B sequences obtained from other rainbow trout tissues. A mixed population of isolated rainbow trout head kidney leucocytes was stimulated in vitro with trout atrial natriuretic peptide (specific NPR-A agonist) and trout C-type natriuretic peptide (NPR-A and -B agonist) as well as the cGMP agonist 8-bromo-cGMP or the GC inhibitor 8-bromo-phenyl-eutheno-cGMP. Respiratory burst was stimulated by trout atrial natriuretic peptide, trout C-type natriuretic peptide-1 and 8-bromo-cGMP in a dose dependant manner with the highest activity as a result of stimulation with trout C-type natriuretic peptide-1 in excess of that achieved by phorbol myristate acetate (PMA). Equimolar concentrations of the inhibitor, inhibited the respiratory burst caused by the natriuretic peptides and 8-bromo-cGMP. The natriuretic peptide receptors on rainbow trout head kidney leucocytes appear to have a stimulatory function with regard to respiratory burst that is activated through a cGMP second messenger pathway and the natriuretic peptides expressed in the head kidney leucocytes may well act in a paracrine/autocrine manner.