The importance of pigs' castration strategy on carbon footprint of feed intake, nitrogen and phosphorus efficiency under different management conditions.

The environmental impact of livestock production is under scrutiny nowadays and is being situated both on a global level and local level. On a global level, the global warming potential (GWP) of meat production is criticised. On a local level, the excretion of nitrogen (N) and phosphorus (P) is of concern as excess nutrients may lead to water eutrophication and soil acidification. The ERA-NET project SuSI evaluated if immunocastration may act as an ecologically, socially and economic more sustainable alternative compared to pork production with surgical castrates (SCs) and boars (BOs). Here, we report the environmental impact of immunocastrates (ICs) vs SC and BO, based on four trials carried out by European SuSi partners. More specifically, we aimed to compare IC with SC and BO in terms of GWP, N and P excretion per kg of pork production and test if this differed between experiments. There was an interaction between trial and sex category (PTrial × Sex category < 0.005) for all environmental sustainability parameters. Surgical castrates performed worse (higher carbon footprint of the feed intake, N and P excretion, lower N and P efficiency) compared to IC and BO, but the size of the effect was trial dependent. Immunocastrates scored intermediate, with mostly no significant differences from BO in most trials, but with significantly better values compared to SC. Over trials, the carbon footprint of the feed intake (land use change inclusive) per kg lean meat gain in the growing-finishing phase was 9-16% lower for IC vs SC and 9-22% lower for BO vs SC. Nitrogen efficiency of IC and BO was 7-10% and 9-14%, respectively, higher compared to SC. Phosphorus efficiency of IC and BO was higher than that of SC by 6-14% and 9-17%, respectively. Per kg of lean meat gain in the growing-finishing phase, IC excreted between 14 and 19% less N and between 14 and 24% less P than SC. For BO, it was between 14 and 27% less N and between 14 and 31% less P than SC. Differences between trials were larger than differences between castration strategies and trial design may have amplified the observed effects. Improving feed efficiency, adapting the feed to the needs of the animal (avoiding excess nutrients) and choosing low-impact ingredients are key for improving the environmental sustainability of pig production. Ending physical castration is another step to attain this goal.

Effect of dietary energy level in finishing phase on performance, carcass and meat quality in immunocastrates and barrows in comparison with gilts and entire male pigs.

Immunocastration, a technique consisting of two vaccinations against gonadotropin-releasing hormone (GnRH), can be used as alternative to surgical castration of piglets. It reduces boar taint and allows higher economic and ecological efficiency compared to barrows. The feeding strategy of immunocastrates, however, can still be improved. After second vaccination, when immunisation becomes fully effective, feed intake of immunocastrates increases sharply. This study aimed to investigate whether energy intake of immunocastrates after second vaccination could be reduced by lowering the dietary energy level of the finishing phase, without negatively affecting animal performance and quality of pork production. We hypothesised that immunocastrates already reach their limits in voluntary feed intake after second vaccination, and therefore would not be able to compensate the lower dietary energy level, in contrast to barrows. Therefore, this study aimed to assess the effect of high-energy diet (HE, net energy (NE) = 10.2 MJ/kg) compared to low-energy diet (LE, NE = 8.8 MJ/kg) in barrows and immunocastrates and as a reference, gilts and entire male pigs on a standard high-energy diet were included. CP and standardised ileal digestible amino acid levels were similar in both diets. For each treatment, eight pen replicates of six pigs per pen were evaluated on performance, carcass quality, meat and fat quality, digestibility, economic and ecological sustainability, behaviour and effectiveness of immune response. No difference in feed intake of immunocastrates between LE and HE could be demonstrated. As a result, daily energy intake of immunocastrates was higher on HE compared to LE, which resulted in a higher daily gain on HE. Feed conversion ratio (FCR) of immunocastrates on HE did not differ significantly with FCR of entire males. Barrows did not show higher average daily gain on HE compared to LE. Nitrogen efficiency was better in HE compared to LE, without negative effects on digestibility, carcass quality, economic parameters, behaviour or immune response. Small positive effects on the palatability of the meat of immunocastrates on HE were observed, although consumers did not prefer one of both feeds. Immunocastration was successful in reducing sexual and aggressive behaviour as well as in lowering the prevalence of boar taint from 15% in EM to 0% in immunocastrates. However, in two out of 96 immunocastrates (one on HE and one on LE), the immunocastration was not fully effective. In conclusion, this study did not show advantages of feeding immunocastrates or barrows a low-energy diet.

The effect of immunocastration on adipose tissue deposition and composition in pigs.

Immunocastrated pigs (IC) exhibit intensive fat deposition after immunisation, but the underlying mechanisms of intensified fat metabolism and deposition are not yet fully understood. Moreover, there is also a lack of comparative studies performed on IC, entire males (EM) and surgical castrates (SC). The main objective of our research was, therefore, to characterise the adipose tissue from the quantitative, histo-morphological and biochemical perspectives in IC 5 weeks after their immunisation in comparison to EM and SC. Immunocastrated pigs had an intermediate position in carcass fatness traits between EM (the leanest) and SC (the fattest). The histo-morphological traits of the subcutaneous adipose tissue of IC were similar to those of SC and differed from those of EM; i.e., they exhibited larger adipocytes in the outer backfat and a larger lobulus surface area in both backfat layers than EM. Intensive fat tissue development in IC was corroborated with higher activities of lipogenic enzymes (i.e., fatty acid synthase, malic enzyme, glucose 6-phosphate dehydrogenase, citrate cleavage enzyme), which was especially pronounced in the subcutaneous adipose tissue of IC (1.5- to 2.7-fold higher activity than in EM or SC). The fatty acid composition of the backfat in IC was similar to that in EM pigs. Both IC and EM exhibited less saturated and more polyunsaturated fatty acids than SC. In contrast, the fatty acid composition of the intramuscular fat of longissimus dorsi muscle in IC pigs was more similar to SC than to EM (higher monounsaturated and lower polyunsaturated fatty acid content in IC and SC than EM). In this study, it was demonstrated that immunocastration notably influenced lipid metabolism. This was shown by increased quantity of lipid depots and with changes in adipose tissue cellularity compared to EM, with changes in the fatty acid composition of the intramuscular fat and enhanced lipogenic activity compared to both EM and SC. These results provide new insights into the specificity of adipose tissue development and deposition in IC compared to EM and SC.

Non-invasive stress evaluation in domestic horses (Equus caballus): impact of housing conditions on sensory laterality and immunoglobulin A.

The study aimed to evaluate sensory laterality and concentration of faecal immunoglobulin A (IgA) as non-invasive measures of stress in horses by comparing them with the already established measures of motor laterality and faecal glucocorticoid metabolites (FGMs). Eleven three-year-old horses were exposed to known stressful situations (change of housing, initial training) to assess the two new parameters. Sensory laterality initially shifted significantly to the left and faecal FGMs were significantly increased on the change from group to individual housing and remained high through initial training. Motor laterality shifted significantly to the left after one week of individual stabling. Faecal IgA remained unchanged throughout the experiment. We therefore suggest that sensory laterality may be helpful in assessing acute stress in horses, especially on an individual level, as it proved to be an objective behavioural parameter that is easy to observe. Comparably, motor laterality may be helpful in assessing long-lasting stress. The results indicate that stress changes sensory laterality in horses, but further research is needed on a larger sample to evaluate elevated chronic stress, as it was not clear whether the horses of the present study experienced compromised welfare, which it has been proposed may affect faecal IgA.

Glucocorticoid receptor number and affinity differ between peripheral blood mononuclear cells and granulocytes in domestic pigs.

The aim of the present study was to characterize the number and affinity of glucocorticoid receptors (GR) in peripheral blood mononuclear cells (PBMC) and granulocytes of domestic pigs because glucocorticoid signaling is considered important for animal health and welfare. To investigate GR binding characteristics in intact porcine immune cells, blood samples of 6 castrated male pigs were collected via indwelling vein catheters. Porcine PBMC and granulocytes were isolated using two-layer density gradients, followed by radioligand binding assays to determine the number of GR sites per cell and the dissociation constant Kd as a measure for GR binding affinity. The present study revealed a greater number of GR sites per cell (P = 0.039) in PBMC (mean ± SEM: 1,953 ± 207 sites/cell) compared to granulocytes (1,561 ± 159 sites/cell) in domestic pigs. Furthermore, porcine PBMC had a higher GR binding affinity than porcine granulocytes (P = 0.003) as the dissociation constant Kd of PBMC (1.8 ± 0.2 nM) was lower than that of granulocytes (3.5 ± 0.4 nM). Our results point to differences in underlying mechanisms of glucocorticoid signaling in different porcine leukocyte populations.

Social stress, dominance and blood cellular immunity.

The impact of chronic social coexistence on distribution and function of blood immune cells was examined in Long Evans rats. At the beginning of a 7 day period of chronic coexistence (confrontation), a wall was removed between two neighboring cages each consisting of a male-female pair. Winner and loser males were classified based on differences in their defensive behavior. On day 2 and 7 of confrontation, losers showed reductions in numbers of blood CD4 and CD8 T cells as well as profound suppression of in vitro NK activity and lymphocyte (LYM) proliferation. Numbers of granulocytes (GRAs) were more than doubled. Winner males showed similar immunological alterations only on day 2 of confrontation. On day 7 most changes were reversed. The persistent changes in loser males may reflect a less favorable state for effective immune response.

Long-term colony housing in Long Evans rats: immunological, hormonal, and behavioral consequences.

The distribution pattern and the function of blood immune cells were investigated for 10 weeks in three mixed-sex colonies of Long Evans rats. After colony formation, a despotic dominance system was established between the males. This paper focuses on differences between subdominant colony and pair-housed control males. A reduced body mass development and hormonal status in subdominant males indicate stressful colony conditions. Subdominant males had lower numbers of CD4 and CD8 T cells, pronounced granulocytosis and reduced lymphocyte proliferation rates as compared with controls. The persistency of changes in subdominant males offers the opportunity to investigate the effects of long-term immuno-modulation on health.

A new quantitative assay for the determination of complement activity.

The suitability of the algal assay and the hemolysis method for the determination of complement activity was investigated with regard to reproducibility and quantification. It was shown that the day-to-day reproducibility is higher in the algal assay than in the hemolysis method in test tubes. The lysis of algal cells depends on serum concentrations. The extensive linear relationship between cytotoxic activity and serum concentration prevails at lysis rates between 20 and 80%. Therefore, it is often sufficient to measure the lysis rate at one serum concentration only. The algal assay enables the investigation of changes in complement activity, even if the changes are not expected to be drastic.

Social stress in laboratory rats: hormonal responses and immune cell distribution.

Previous experiments with chronically coexisting groups of Long-Evans rats indicated differences in many aspects of blood cellular immunity between winner and loser rats. The present study investigated the specific hormonal response patterns of winners and losers in relation to changes in numbers of blood immune cells. At the beginning of a 7 day period of chronic confrontation, a partition wall was removed between two neighboring rat groups, each containing a male-female pair. Fights for dominance between the males resulted in fast establishment of stable dominance relationships. At day 7 of the confrontation, winner males showed stable concentrations of CBG (corticosteroid-binding globulin) and even reduced titers of total CORT (corticosterone). In contrast, a marked decrease in CBG and unaffected total CORT concentrations were determined in loser males. Increased norepinephrine (NE) and epinephrine (E) titers were evident only in losers. In addition, reduced testosterone titers were observed in the bitten loser male subgroup. All male subgroups lost body mass with most pronounced reductions in loser males. Confrontation caused a marked granulocytosis, especially in loser males. NE concentrations in loser males correlated with the percentage of granulocytes. Numbers of CD4 T-cells were lowered in all loser males and in non-biting winners. In not-bitten losers also a reduced number of CD8 T-cells was determined. Interestingly, higher pre-confrontational NE titers were detected in future bitten loser and future biting winner males relatively to not-bitten losers and non-biting winners. The present report indicates that differential hormonal response patterns may play an important role in some of the immunological differences observed between winner and loser males under stressful social conditions.

Social stress in loser rats: opposite immunological effects in submissive and subdominant males.

The impact of chronic confrontation on behavior, body weight, and aspects of blood cellular immunity was investigated in 24 Long Evans intruder rats. At the beginning of a 1-week confrontation period, an adult male was introduced into a one male-one female resident group which resulted in fights for dominance. Although most intruders became losers in this situation, their specific behavior differed. Two groups of losers were defined: subdominant (N = 11) and submissive intruders (N = 9). In contrast to subdominant intruders, submissive males often displayed behaviors indicating social defeat. They were frequently involved in agonistic interactions and lost 7% of their initial body weight. Confrontation provoked marked changes in many measures of blood cellular immunity. Importantly, the immunological effects differed significantly in magnitude and direction depending on the individuals' behavior. Submissive males reacted with reduction in lymphocyte proliferation in response to ConA and shifts in lymphocyte subsets (decline in percentage of CD4 and CD8 T cells, increase of B cells), but with little change in lymphocyte numbers. In addition, a pronounced increase in granulocytes was evident. In contrast, in subdominant males lymphocyte, T cell, and B cell counts were lowered but no change in subset composition occurred. The effects on T and B cell composition were not fully reversible within 7 days after end of the confrontation period indicating long-term consequences for migration of lymphocyte subsets. These data show that a detailed behavioral analysis is required for a meaningful biological evaluation of social stress-induced immune changes in rats, because different coping strategies result in different immunological consequences.

Social stress in laboratory rats: behavior, immune function, and tumor metastasis.

This report summarizes data from social confrontations studies in laboratory rats dealing with the effects of psychosocial stress on immune functioning and tumor metastasis. The paper focuses on the physiological alterations observed in subdominant males after 2 days of continuous social confrontation. A significant loss of body mass and elevated plasma concentrations of adrenal hormones in subdominant males indicate a stressful social environment. Subdominant males showed lower numbers of blood CD4 and CD8 T cells as well as reduced activity levels of T cells and natural killer (NK) cells relative to control subjects. In order to evaluate the possible health impact of suppressed NK functioning, we used the MADB 106 tumor model. A 10-fold lower tumor clearance in subdominant males demonstrates suppression of the animals' capacity to prevent metastatic development. The relationship between individual behavior and immunological outcome is briefly discussed. Together, the study of male rats in social confrontations appears to be a good model to investigate stress-induced immune modulation and tumor metastasis under relatively naturalistic social conditions.

Social confrontation in male guinea pigs: behavior, experience, and complement activity.

Because aggressive encounters are known to affect immune function in rodents, we hypothesized that individual behavior and social experience would contribute importantly to the impact of confrontation on the activity of the complement system (CA) in guinea pigs. CA was determined by lysis of Euglena gracilis cells (triggered by alternative pathway mechanisms). Males with different social experience were used: i) individually housed males (IH), ii) socially less-experienced males (LE), raised in large groups in the absence of adult animals; and iii) socially experienced males (EX) with additional fighting experience. An IH and LE male, respectively, was introduced into a group of EX residents (consisting of one male and two females). During a 26-day confrontation period the behavior of all animals was quantitatively recorded. IH and LE males showed a significant and persistent decrease in CA after confrontation (mean +/- SEM lysed cells/100 cells; IH: -16.5 +/- 4.0, LE: -16.5 +/- 3.5), whereas no significant changes from baseline were observed in EX males (-2.5 +/- 3.0). However, in social situations characterized by unstable dominance, EX males showed a lowered CA (-11.3 +/- 4.0) as well. Plasma cortisol concentrations determined in LE males were significantly elevated 4 h after confrontation but did not correlate with the long-term decrease in CA. The data indicate that the activity of the complement system can be influenced by psychosocial stressors, and suggest the importance of prior social experience for the guinea pig's ability to cope with social conflicts.

Effects of acute and chronic social stress on blood cellular immunity in rats.

The study compares the impact of acute and chronic social confrontation on aspects of blood cellular immunity in Long-Evans intruder rats. An adult male was introduced for either 2 h or 48 h into a male-female resident group, which resulted in fights for dominance. Thirty-eight of the 42 intruders became losers. For immunologic measurements, blood samples were taken from the intruders before confrontation (baseline) and 2 h or 48 h after the beginning of confrontation. Two h of confrontation resulted in increased granulocyte (+65%) and decreased lymphocyte numbers (-60%), as well as in differential reductions in CD4, CD8, and B cell numbers. CD4/CD8 and T/B ratios were elevated. T cell responsiveness to ConA was markedly suppressed in proliferation assays using either whole blood (-90%) or PBMC (-50%). The direction of changes in leukocyte and lymphocyte subsets after 48 h resembled in many aspects the 2 h changes, although with lower magnitude. In contrast to acute stress, a lowered T/B cells ratio and unaffected CD4/CD8 ratio was determined after 48 h. Proliferative response of T cells was lowered by about 25% in the whole blood assay; but unaffected in the PBMC assay. Significant correlations were found between the amount of submissive behavior displayed by the losers and several immunologic measures after 2 h of confrontation. The data suggest that acute and chronic stressful conditions may not necessarily result in similar effects on immune functioning. This should be considered when evaluating the biologic and evolutionary consequences of social stress-induced immune alterations.

Social confrontation and tumor metastasis in rats: defeat and beta-adrenergic mechanisms.

The effect of social confrontation on the susceptibility to metastatic development was studied in rats. An intruder male Fischer 344 (F344) was introduced to a male-female Long-Evans pair and the behavior was recorded during the first 30 min of a 7-h confrontation session. Mammary tumor cells (MADB106), syngeneic to the inbred F344 rat, were injected i.v. to the intruder 1 h after the beginning of the confrontation session, and the lung retention of tumor cells was determined 24 h later. In this tumor model, metastases develop only in the lungs. Retention of tumor cells and the consequent development of lung colonies are known to be highly controlled by the activity levels of natural killer cells during the first 24 h after tumor inoculation but not later. Twenty of the 21 intruders were attacked by resident males and 19 displayed submissive behavior. A significant increase in lung tumor retention was evident in intruders compared to both control groups: home cage and new environment. The magnitude of this increase was higher in intruders that frequently displayed submissive behavior (indicating social defeat). Pretreatment with the beta-adrenergic antagonist, butoxamine, reduced the effects of social confrontation by approximately 50%, and adrenal demedullation almost abolished it without significantly affecting the social interaction. These findings suggest that the nature of intruder-resident interaction, rather than being subdominant or exposure to an unfamiliar environment, has a marked influence on the intruder's susceptibility to metastatic development. These effects of social confrontation seem to be mediated by adrenergic mechanisms, possibly via adrenergic influence on NK function and distribution.

Characterization of the adaptive immune response following immunization in pregnant sows (Sus scrofa) kept in two different housing systems.

Housing conditions might differentially affect the adaptive immune responses to a neoantigen in pregnant sows with possible consequences for the success of vaccinations. Therefore, this study aimed at characterizing antigen-specific T cell and B cell responses of pregnant sows (German Landrace) either housed in a social group (GP; n = 22) or confined in individual gestation crates (CR; n = 11). All sows were immunized with the neoantigen keyhole limpet hemocyanin (KLH) 7 and 5 wk prepartum. Blood samples were taken 7, 6, 4, and 2 wk prepartum, thus before and after the first as well as second immunization. This study aimed at identifying both the resulting cellular as well as humoral KLH-specific immune response in the pregnant sows. We therefore analyzed total IgG and anti-KLH IgG concentrations and the KLH-specific lymphocyte proliferation as well as the KLH-specific production of the T helper cell type 1 (TH1)-related cytokines tumor necrosis factor (TNF) α and interferon (IFN) γ in main T cell subsets before and after the immunization. Anti-KLH IgG titers significantly increased during the experimental procedure (P < 0.001) reflecting the activation and differentiation of KLH-specific B cells on immunization. However, CR-housed sows showed greater anti-KLH IgG concentrations compared to GP-housed sows (P < 0.05). Keyhole limpet hemocyanin-specific TNFα-producing cytotoxic T cells (CTL) and T helper (TH) cells were detectable in CR-housed sows not before the second immunization (both P < 0.05), whereas those cells were detectable already after the first immunization in GP-housed sows (CTL: P < 0.01 and TH: P < 0.05). Similarly, KLH-specific TNFα/IFNγ-double producing CTL and TH cells were detectable earlier in GP-housed sows than in CR-housed sows (both P < 0.05). Keyhole limpet hemocyanin-induced lymphocyte proliferation and total IgG concentrations were not affected by the housing system. Our results show that housing conditions affect the adaptive immunity to a neoantigen in pregnant sows. Whereas GP housing of pregnant sows induced a rather TH1-mediated cellular response, individual housing in CR resulted in a T helper cell type 2 (TH2)-pronounced humoral response to KLH. The greater anti-KLH IgG concentration and the delayed activation and differentiation of KLH-specific TH1 cells in CR-housed sows support the hypothesis of a shifted TH1:TH2 ratio in individually housed sows of this study. We presume differences in the stressfulness of the housing system to be mainly responsible for the occurring effects.

Social rearing conditions before weaning influence numbers and proportions of blood immune cells in laboratory rats.

The influence of the early social rearing environment on blood cellular immunity was investigated in the male offspring of Long-Evans rats. Sons of females housed in pair groups (P-males) and sons of females living in a mixed sex colony (C-males) were studied. After weaning at the age of 21 days, offspring were housed individually to ensure identical experiences until the age of 100 days when immunological assessments were conducted. C-males had significantly higher numbers of blood CD4 and CD8 T cells as well as higher numbers of granulocytes and monocytes than P-males. In contrast, the number of B cells and NK cells was similar in P- and C-males. T-cell responsiveness to ConA, determined in the peripheral blood mononuclear cells and whole blood assays, did not differ significantly between the two groups. The study indicates that the early social environment affects numbers and proportions of many blood immune cell subsets in later life.

Impact of social confrontation on rat CD4 T cells bearing different CD45R isoforms.

The impact of social defeat on lymphocyte subpopulations and T helper subsets was investigated in Long Evans rats. CD4 T helper cell subsets with distinct functional properties and different cytokine profiles can be distinguished by using the mAbs OX-22 (anti-CD45RC) and OX-7 (anti-CD90, Thy1.1). Male intruders were exposed for 2, 6, or 48 h to aggressive resident pairs. All intruders were attacked upon introduction and were defeated as indicated by frequent display of full submissive postures. After 2 and 48 h of confrontation, drastic but differential effects on blood leukocyte numbers, CD4 and CD8a cells, and CD4 subsets were evident. However, after 6 h of confrontation most lymphocyte subset numbers corresponded to baseline levels. Focusing on CD4 subsets after 2 h of confrontation, we demonstrated that only the number of the CD45RC-CD90(-) subset declines, whereas neither the number of the CD45RC+CD90(-) subset nor the number of the CD45RC-CD90(+) subset (recent thymic emigrants) was influenced. Con A stimulation of sorted subsets identified the CD45RC-CD90(-) as a poor producer of IFN-gamma. The data clearly demonstrate that social factors might differentially influence not only T cell subsets but also T helper cell subsets with distinct cytokine profiles in a possibly time-dependent manner. Such a stress-induced shift toward a CD45RC+CD90(-)-dominated milieu may have important consequences in interpreting results obtained from mitogenic stimulation of blood lymphocytes and cytokine production profiles measured after such a stimulation. In addition, a shift toward a CD45RC+CD90(-) dominance may modify the type and magnitude of immune response, at least temporarily.

Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and beta-adrenoceptors.

Although acute stress has been reported to suppress natural killer cell activity (NKA) and host resistance to metastasis, it is unclear whether the sympathetic nervous system (SNS) has a role in these effects. The current study in Fischer 344 rats assessed the involvement of adrenal catecholamines and beta(1)- and beta(2)-adrenoceptors in mediating these deleterious effects of swim stress. In addition to assessing the number and activity of NK cells following swim stress, we used a tumor model based on the MADB106 mammary adenocarcinoma line: this syngeneic tumor metastasizes only to the lungs, and its lung tumor retention (LTR) and metastatic colonization are highly sensitive to NKA. The findings indicate that stress increased both LTR, assessed 24 h after inoculation, and the number of lung metastases, counted 3 weeks later. These effects were attenuated or completely abolished by the ganglionic blocker chlorisondamine (3 mg/kg i.p.), by adrenal demedullation, by a selective beta-adrenergic antagonist (nadolol, 0.4 mg/kg), and additively by a selective beta(1)- (atenolol, 1-6 mg/kg) and a selective beta(2)-antagonist (either butoxamine 4-32 mg/kg or ICI-118,551 0.3-8 mg/kg). Stress also suppressed NKA, and adrenal demedullation prevented this suppression. Administration of adrenaline (0.1-1 mg/kg) or of a beta-adrenergic agonist (metaproterenol, 0.8 mg/kg), in physiologically relevant doses, suppressed NKA in a dose-dependent manner, and increased LTR to levels characteristic of swim stress. Taken together, these findings suggest that acute stress, by releasing catecholamines from the adrenal glands and activating beta(1)- and beta(2)-adrenoceptors, suppresses NKA and consequently compromises resistance to NK-sensitive metastasis.