Conzp.Biochem. Physiol.Vol. lOlA, No. I, pp. 177-182, 1992 Printed in Great Britain

GASTRIN

IN NEONATAL METABOLISM GROWER-PIGS RUO-JUN

School

0300-9629/92 $5.00 + 0.00 Q 1991 Pergamon Press plc

of Agriculture,

Xu*

La Trobe (Recked

PIGS

AND

and P. D. CRANWELL

University,

Bundoora,

Victoria

3083, Australia

14 February 1991)

Abstract-l. Half-life (1.7 k 0.1 min), distribution volume (146 & 12 ml/kg) and metabolic clearance rate (28 f I ml/kg/min) of little gastrin (G17) in neonatal pigs (N = 6; 3-12 days old) were significantly different from those in grower-pigs (N = 4; 161-170 days old) (2.4 k 0.1 min; 58 & 2 ml/kg; 7.9 + 0.3 ml/kg/min, respectively). 2. Half-life (33 k 4 min) and distribution volume (265 * 33 ml/kg) of big gastrin (G34) in neonatal pigs were greater but not significantly different from those in grower-pigs (24 + 2 min; 217 + 20 ml/kg, respectively). 3. Half-life of G17 in liver extracts from pigs 2-90 days old (40.4 & 4.2 min) was significantly longer than in kidney extracts (22.0 Ifr 1.7 min). Half-lives of G34 in liver and kidney extracts from pigs IO-90 days old (78 + 6; 74 + 4 min, respectively) were significantly shorter than the corresponding values for 2-day-old pigs (134 & 3; 149 + 9 min, respectively). 4. Since G34 is the major circulating form of gastrin in neonatal pigs the relative longer half-life of G34 to G17 in these animals may contribute to the higher circulating gastrin concentration compared with that in older animals.

INTRODUCTION

Ekvated concentrations of circulating gastrin (‘hyperga: trinaemia’) have been reported in neonatal anirnzls of several species, including humans (Rogers et ,zl., 1974; Sann et al., 1975), sheep (Lichtenberger et zl., 1981; Bell et al., 1984), dogs (Malloy et al., 19”9) and pigs (Cranwell and Hansky, 1980; Bunn an 1 Titchen, 1984; Xu and Cranwell, 1991). Shulkes et (11. (1982) demonstrated in sheep that the metabolic

cIe,irance rate of little gastrin (G17) was greater in neonates than in adults, and suggested that the nellnatal hypergastrinaemia was due to an increased syr thesis and secretion rate of gastrin in neonatal an- mals. ?lasma concentration of a hormone is determined by its rate of secretion, as well as by its distribution intl) extravascular spaces, and its rate of degradation. Ar increased production rate of a hormone may sullsequently produce an elevation of its concentra:ion in the circulation particularly if the storage callacity of the cells which produce the hormone are lirrited or are not fully developed. However, a slower metabolic clearance rate of the hormone may also result in an increased concentration in the circulation. 1jastrin, like many other peptide hormones, exists in multiple molecular forms. In a recent study we ob ,erved that big gastrin (G34) was the predominant mc~lecular form of immunoreactive gastrin in the plasma of neonatal pigs (Xu and Cranwell, 1991). To determine if neonatal hypergastrinaemia is related to the metabolic clearance rate of the hormone, degra*To whom correspondence should be addressed to at: Department of Physiology and Anatomy, Massey University, Palmerston North, New Zealand (Telephone: 64 63 69099; Fax: 64 63 505609)

dation rates of G34 and G17 were examined in neonatal and grower-pigs using both in viva and in vitro techniques.

MATERIALS

AND METHODS

Animals and procedures Experiment 1. A total of 12 Large White x Landrace pigs were used. Eight were neonatal pigs (four males and four females, 3-12 days old and 1.45-3.90 kg body-weight) and four were grower-pigs (two males and two females, 161-170 days old and 8492 kg body-weight). The neonatal pigs were suckled by their sows. The grower-pigs were fed ad lib. with

a commercial grower-pig ration containing 16% crude protein (Barastoc, Victoria, Australia). Under general anaesthesia each pig was prepared with femoral arterial and femoral venous catheters according to the following procedure. An incision was made in the inner side of the thigh and two polyvinyl catheters (i.d. 0.86-l.OOmm; o.d. 1.27-1.50mm) were tied into the femoral artery and vein. The catheters were inserted so that the tips were in the abdominal aorta and inferior vena cava. The catheters were taken subcutaneously and exteriorized dorsally at a point near the mid-lumbar region. The external parts of the catheters were placed in a pouch which was held in place by first attaching one side of the pouch to the skin with an adhesive (White Bostic; Bostic Australia, Victoria, Australia), and then wrapping one layer of elasticized self-adhesive tape (Leukoplast; BDF Intanin Co. Ltd, Thailand) around the body of the pig and the pouch. Following surgery a recovery period of at least 3 days was allowed prior to the first experimental procedure. In addition, at least 2 days rest was allowed between experimental procedures on the same animals. All experiments were completed within 2 weeks. Two types of experimental procedures were performed to determine firstly the half-lives (I,~,) and distribution volumes of G17 and G34, and secondl; &e metabolic clearance rate (MCR) of G17. Prior to each experimental procedure neonatal pigs were removed from the sow and fasted for

178

RUO-JUN Xu and P. D. CRANWELL 3000

4 hr;

the grower-pigs were fasted for 16 hr. The fasting periods for the neonatal pigs and the grower-pigs were chosen so that the circulating gastrin in both groups were at basal levels prior to the commencement of the procedure. Six neonatal pigs and four grower-pigs received a bolus of 100 pmol/kg body-weight synthetic human Cl7 (Sigma Chemical Co., St Louis, MO, U.S.A.) via the venous catheter. The same pigs received a bolus of 50 pmol/kg body-weight synthetic human G34 gastrin (G34) (Sigma Chemical Co., St Louis, MO, U.S.A.) on a separate day. Blood samples were taken, via the arterial catheter, at 1.5 to 30 min intervals from 30 min before and up to 2 hr after the administration of the bolus. The experimental procedures with both Cl7 and G34 were repeated in the same pigs during the following week. Eight neonatal pigs and three grower-pigs each received an intravenous infusion of Cl7 at a dose rate of 250 pmol/kg body-weight per hr for 2 hr. Arterial blood samples were taken at 15 to 30 min intervals before, during and after completion of the infusion. Following collection, blood samples were transferred into tubes containing 50 units of heparin which were placed in a container of crushed ice for up to 3 hr. Plasma was then obtained by centrifugation at 4°C and stored at -20°C until analysed for gastrin. Experiment 2. Ten Large White x Landrace pigs, 2-90 days old and 1.9-33.8 kg body-weight, were killed with an overdose of sodium pentobarbitone prior to the removal of samples of liver. kidney, skeletal muscle and blood. Immediately after collection the tissue samples were immersed in liquid nitrogen and stored and -70°C until extraction. Plasma was obtained and stored as described above. Small pieces of frozen tissue were minced in a Teflon glass homogenizer with 10 vol. of sodium phosphate buffer (pH 7.4) containing 0.2% gelatine and IOmM EDTA. The extracts were centrifuged and the supernatants were decanted and stored at 4°C for not more than 2 hr prior to being used for further analysis. One quarter millilitre synthetic human Cl7 or G34 (2 pmoljml) were mixed with 0.25 ml liver, kidney or muscle extract (100 mg/ml) or with 0.5 ml plasma in plastic tubes which were incubated for periods of 60-90min in a 37°C water bath. The final incubation volume was made up to I ml with the sodium phosphate buffer. Prior to incubation the tissue extracts and the hormone solutions were equilibrated to 37°C in the water bath. During the incubation period duplicate subsamples of 30~1 were removed at 10 min intervals into plastic tubes which were placed in a boiling water bath for 1 min to stop further enzymic activity. The amount of immunoreactive gastrin in these subsamples was determined by radioimmunoassay. Gastrin analysis Gastrin was determined by a commercially available radioimmunoassay using antiserum RPN 1651 (Amersham, Bucks, U.K.). The antiserum is specific to the mid-to-Cterminal regions of Cl7 and has an equal cross-reactivity with both Cl7 and G34. The intra-assay coefficient of variation was 6.1-8.6% and the inter-assay coefficient of variation was I 1.9~14.1%. Gel chromatograph) In Experiment I plasma samples, obtained from one neonatal pig and one grower-pig at 3 and 15 min following the bolus of G34, were subjected to gel filtration on a Sephadex G50 superfine column under the conditions described previously (Xu and Cranwell, 1991). Data analysis The disappearance rate constant and the distribution volume were determined from the decline curve of plasma gastrin concentrations following the bolus of Cl7 and G34. The disappearance rate constant (k) was estimated for

IO

^ :

E

cz

300

v

It-i

z z

30

2 2

0

3 !xtL

0

30

20

10

TIME (min)

Fig. 1. Mean increment of plasma gastrin above basal concentration in six neonatal pigs (0) and four grower-pigs (0) following a bolus of synthetic human Cl7 at a dose rate of 100 pmol/kg body-weight. The regression equation for neonatal pigs was C = 1251 emo.433’,where C = gastrin concentration (fmol/ml), t = time (min). The regression

equation for grower-pigs was C = 2669 e&‘.267’. both mono- and double-exponential models (Reeder et al., 1972), using the computer program MLP (Ross, 1980). The half-life (t,J was calculated using the formula t,,* = 0.693/k (In 2 = 0.693). The distribution volume was determined by the ratio of the amount of gastrin given as a bolus and the estimated (extrapolated) plasma gastrin concentration at time zero (Straus and Yalow, 1974). The mean of the two replicate experiments for each animal was used for the statistical analyses, The metabolic clearance rate (MCR) was determined from the continuous infusion of Cl7 using the formula MCR = D/C; where D = continuous infusion rate; C = plateau concentration of plasma gastrin minus the basal concentration (Shulkes et a/., 1982). RESULTS

Experiment

1. Catabolism of G 17 and G 34 in vivo

The decline curve of plasma gastrin concentration after the bolus of G17 (Fig. 1) fitted best to a mono-exponential model as determined by the least squares method. The t,,2 and the distribution volumes of G17 estimated from the mono-exponential model are presented in Table 1. The t,!, of G17 in neonatal pigs was significantly shorter than in grower-pigs (P < 0.001). The distribution volume of G17 in neonatal pigs was significantly larger than in grower-pigs (P < 0.001). The decline curve of plasma gastrin concentration after the bolus of G34 showed an initial mixing phase followed by a catabolic phase (Fig. 2). For both neonatal pigs and grower-pigs the curve fitted best to a double-exponential model as determined by the least squares method. The t,iz and the distribution volumes of G34, estimated from the double-exponential model, are presented in Table 2. In the neonatal pigs the tl,* of the mixing phase was significantly shorter than in the grower-pigs (P < 0.05). In both Table

1,Half-lives and distribution volumes of synthetic human G17 in neonatal

pigs and grower-pigs

(mean ?r. SEM)

Pigs

N

Half-life (min)

Neonates

6

1.7+0.1 *

146 + 12

Growers

4

2.4 f 0.1

58 + 2

*Differences between the neonatal cant P < 0.001.

Distribution

volume

(ml/kg)

l

and the grower-pigs

were signifi-

179

Gastrin metabolism in pigs

=

500

E : 5v

50

5

1

0

25

I

50

75

I

100

I

125

I

500 400

I

-

JI

“““..$.._...”

i

P,

1

150

0 ,

TIME @in) Fig 2. Mean increment of plasma gastrin above basal conl:entration in six neonatal pigs (0) and four growerpig>, (0) following a bolus of synthetic human G34 at a dos: rate of 50 pmol/kg body-weight. The regression eqtrltion for neonatal pigs was C = 446 e-“M56’+ 193 e-” 0561 , where C = gastrin concentration (fmol/ml), t = time (min). The regression equation for the grower-pigs was C z 551 e-02*2’r+ 273 e~“0324’. neclnatal pigs and grower-pigs the t,,, during the cat tbolic phase was significantly longer than during the mixing phase. Also, the t,!, during the catabolic ph:l se was longer in the neonates than in the grower-

pig’; but the difference was not significant (P = 0.08) po:#sibly due to the small sample size. However, the ratio of the t,:, (catabolic phase) for G34 to the tliZ for G17 in neonatal pigs (28.6 f 3.7) was significan tly greater (P = 0.016) than that in grower-pigs (12 4 + 1.5). Both the initial and the equilibrium distribution volumes of G34 were greater in the neonatal pigs than in the grower-pigs but the difl:rences were not significant. Ilasma obtained from a neonate and a grower-pig 3 min after receiving a bolus of G34 yielded a single peak of immunoreactive gastrin which corresponded to the elution volume of G34. Samples taken 15 min later, from the same pigs, also yielded a single peak with the same elution volume as that of the samples taken at 3 min. However during the 12 min interval the concentration of immunoreactive gasirin had decreased to 54 and 38% of the concentraion at 3 min in the neonate and the grower-pig, respectively. 11 both neonatal pigs and grower-pigs plasma gas.rin concentrations reached a plateau within 30 min of commencement of the constant intravenous infiision of G17 (Fig. 3). Gastrin concentrations rettuned to basal levels within 30 min of cessation of the infusion. The plateau concentration in growerpig,; was approximately 3 times higher than that in neonatal pigs, despite both the neonates and growerpig,; having received the same dose rate per unit hoc y-weight. The calculated MCR for G17 in the neonatal pigs was 27.8 f 1.2ml/kg body-weight per Table 2. Half-lives and distribution

.. B

6oo~ Start of infusion

I

-45

0

I

45

I

90

I

135

TIME (min) Fig. 3. Plasma gastrin concentration (mean f. SEM) in eight neonatal pigs (0) and three grower-pigs (0) before, during and after a continuous infusion of synthetic human G17 at a dose rate of 250 pmol/kg body-weight per hour for 2 hr.

min, which was significantly higher (P < 0.001) than that observed in the grower-pigs (7.9 f0.3 ml/kg body-weight per min). Experiment 2. Catabolism of G17 and G34 in vitro Human G17 was found to be stable when it was incubated in plasma from pigs of all ages, also there was only a slight decrease (10%) in G17 concentration following 60 min incubation with muscle extracts from the same pigs. However, when human G17 was incubated with kidney and liver extracts there was a rapid and progressive decrease in G17 concentration, with the decrease in kidney extracts being twice as rapid as that in liver extracts from pigs l&90 days of age (Table 3). Human G34 was found to be stable when incubated in plasma and muscle extracts from pigs of all ages. When incubated with liver extracts from pigs 10-90 days of age G34 was stable for the first 20min after which its concentration decreased in a linear manner. In the presence of kidney extracts from l&90-day-old pigs the concentration of G34 decreased progressively with time. At the end of the 90 min incubation period the G34 immunoreactivity in the media containing the liver and kidney extracts had decreased by about 50% (Table 3). When incubated in liver and kidney extracts from 2-day-old pigs G34 concentration did not decrease significantly until after 30min incubation; by the end of the 90 min incubation period the G34 concentration was reduced to 63-70% of this initial concentration. The t,,* of G34 when incubated in kidney and liver extracts from 2-day-old pigs were similar and significantly longer than those in older pigs (Table 3). The relative weight of the kidneys per unit body weight at 2 days of age was 8.2 g/kg; it decreased progressively with increasing age and in pigs of 90 days of age it was 4.2 g/kg.

volumes of synthetic human G34 in neonatal pigs and grower-pigs (mean + SEM) Half-life (min)

Distribution volume (ml/kg)

Pigs

N

Mixing phase

Metabolic phase

Neonates

6

1.8 k 0.4

33 * 4

95*17

265 of:33

Growers

4

3.6 k 0.5

24 f 2

68 f 9

217 f 20

Mixing phase

*Differences between the neonatal pigs and the grower-pigs were significant P < 0.05.

Catabolic phase

180

RUO-JUNXu and P. D. CRANWELL Table

3. Half-lives

(min) of synthetic human Gl7 and synthetic human G34 when incubated liver and kidney from pigs 2-90 days old Gl7 N

Liver

Kidney

Liver

2

2

30.3 + 0.2’

26.6 + 0.4

134+3

8 IO

43.0 * 4.9t 40.4 f 4.2$

20.9 & 2.0 22.0 + I .7

Differences Differences

of

G34

Age (days)

IO-90 2-90

with extracts

Kidney 149*9

§ 78 + 6 89 f 9

5 74 * 4 89+ II

between the liver and the kidney were significant *P < 0.05; tP < 0.01; $P < 0.001 between 2-day-old pigs and l&90-day-old pigs were significant $P < 0.001.

DISCUSSION

Catabolism of G 17 In the present study the t,,, of 2.4 min for synthetic human G17 in grower-pigs is comparable with the values of 1.7 to 3.7 min reported in adult dogs (Schrumpf and Semb, 1973; Straus and Yalow, 1974; Walsh et al., 1974; Carter et al., 1979; Dockray et al., 1982) and is 2-3 times shorter than that found in adult humans (Walsh et al., 1975, 1976; Eysselein et al., 1984). Liver and kidney extracts from pigs of all ages were very effective in catabolizing G17. Previous studies in dogs and pigs have also shown that the liver and the kidney are very effective in metabolizing circulating G17 (Clendinnen et al., 1971, 1973; Christiansen, 1984; Feurle et al., 1984). In addition several other organs including stomach, small intestine and lung, have been shown to metabolize circulating G17 (Temperley et al., 1971; Becker et al., 1973; Korman et al., 1973; Evans ef al., 1974). In a later study in dogs Strunz et al. (1978) observed that not only did the kidney, liver and the gastrointestinal tract remove circulating G17, but there were also large arteriovenous differences in gastrin concentrations across the head and the hind limbs. In uivo studies similar to those of Strunz et al. (1978) have not been done in the pig. The observations that G17 has a shorter t,,, and a faster MCR in neonatal pigs than in grower-pigs are in agreement with the findings in sheep by Shulkes et al. (1982). In their study the MCR of human G17 in I-lCday-old lambs was 2.54.0 times faster than in adult sheep. The mechanisms responsible for the faster MCR of G17 in neonatal animals compared with that in older animals could be associated with their relative body size. In studies on the metabolism of synthetic human G17 in three different species of widely different body-weights Boniface et al. (1976) found that there was an inverse allometric relationship between the MCR of G17 and the bodyweight of animals. Makhlouf (1973) proposed that MCR is determined by the functional size of the eliminating organs which in turn is related to bodyweight by an allometric function. The results of the present study agree with the proposal of Makhlouf (1973), and show that the MCR of G17 per unit metabolic body-weight (BWt0.65) are similar in both neonatal and mature pigs, 38.4 + 3.1 and 38.0 + 1.6 ml/kg0.65/min, respectively. In the present study and that of Sarkar et al. (1977) the relative weight of kidney tissue per unit body-weight was found to decrease progressively with increasing age. Also, although the liver-weight to body-weight ratio is relatively constant at about 3%

in pigs, O-50 days of age (Sarkar et al., 1977) it has been shown to decrease with age from 3.3% in 77-day-old pigs to 1.5% in 210-day-old pigs (Doornenbal and Tong, 1981). The relative weights of the gastrointestinal tract and lung also decrease with increasing age in pigs (Sarkar et al., 1977; Doornenbal and Tong, 1981). Thus the relative weight of organs which have been shown to catabolize G17, namely kidney, liver, lung, gastrointestinal tract, decrease with increasing body size whereas the relative weight of tissues such as skeletal muscle, which was found to have little catabolic activity for G17, makes up a significantly greater proportion of body-weight at 91 kg body-weight than it does at birth (Shields et al., 1983). The faster MCR of G17 in neonatal animals may also be related to their greater relative cardiac output. In pigs, 7-50 kg body-weight cardiac outputs per unit body-weight are 4-5 times greater than those in mature pigs (Pond and Houpt, 1978). Also, in neonatal lambs cardiac output per unit body-weight has been observed to be greater than that in adult sheep (Woods et al., 1978) Catabolism of G34 The disappearance curve of G34 consisted of a mixing and a catabolic component. The two component curve could not be attributed to the molecular modification of G34 in the circulation since gel filtration on a Sephadex G50 column of plasma, taken 3 and 15 min after bolus administration, revealed a single peak which corresponded to G34. Eysselein et al. (1984) also found that synthetic human G34 was not converted into other immunoreactive forms in the human circulation during a 2 hr continuous infusion of the hormone. During the initial mixing phase the t,,, of G34 was significantly shorter in neonatal pigs than in growerpigs. This difference may again be explained by the relatively greater cardiac output in neonatal animals (Pond and Houpt, 1978). The t,,, of G34 in both neonatal pigs and grower-pigs during the catabolic phase were very much longer than they were for G17, approximately 29 and 12 times, respectively. This is in agreement with observations in humans in which the t,,? of G34 was in the range 3942 min (Walsh et al., 1975, 1976; Eysselein et al., 1984) and in dogs in which the range was 9916min (Straus and Yalow, 1974; Walsh et al., 1974). In humans the t,,z of G34 is 5-9 times longer than that of G17 and in the dog it is 3-5 times longer. It would appear that the relative ability of the neonatal pig to catabolize G34 is not as well developed as it is in the grower-pig. This is born out in the results from the in vitro studies in which the G34 catabolic activity of liver and kidney extracts

Gastrin

wert: significantly lower in 2-day-old le’+O-day-old pigs. Rebltionship between and gastrin metabolism

neonatal

metabolism in pigs

pigs than in the

‘hypergastrinaemia’

As mentioned in the Introduction elevated concentrat ons of circulating gastrin or ‘hypergastrinaemia’ havl: been observed in neonates of several species. In the pig it has also been shown that G34 is the major mo;ecular form of circulating gastrin in fetal and neonatal animals (68~81%) with the balance being con prised of G17 and smaller fragments (Xu and Cra nwell, 1991). However, in the circulation of older pig: the molecular profile is very different with G17 berg the major form in both peripheral blood (53 -61%) and antral blood (88 k 1%) (Christiansen et L l., 1978; Hilsted and Hansen, 1988). Two other diff :rences between neonatal and older pigs relate to the concentration and molecular profile of gastrin in ant ,al tissue, the major site of gastrin synthesis in the pig (Xu and Cranwell, 1991). Both fetal and neonatal pig have significantly higher G34:G17 ratios (0.1 14.21:l.O) compared with those found in older pig (0.04-0.08: 1.O) (Christiansen et al., 1978; Hilsted ant Hansen, 1988; Xu and Cranwell, 1991). Howeve., despite the observation that the number of gas rin producing cells in the antrum of the pig reach ad1 It frequency just prior to birth (Alumets et al., 198 3), the gastrin concentration in antral tissue from fet: 1 and neonatal pigs is about 2 orders of magnitude loser than that in older pigs (Hilsted and Rehfeld, 19E7; Hilsted and Hansen, 1988; Xu and Cranwell, 195 1). The lower tissue concentration and the higler plasma concentration of gastrin in neonatal pig; would suggest that mechanisms regulating gasxin secretion and/or storage by the gastrin cells are not fully developed. Other reasons, suggested by Lit htenberger (1984), include a lower gastric acid sec,etory capacity (Xu and Cranwell, 1990) and the high level of dietary stimulation of gastrin release due to the concentration of protein and calcium in milk. The results of the present study would suggest that the relatively longer t,:, of G34 to G17 in net natal pigs may also contribute to the different plasma gastrin molecular profile and the higher plasma concentration compared with that in older ani nals. AC/ no&dgements-This work was supported by a CTEC Spc vial Research Grant. R.-J. Xu was ide recipient of a La Trc be University Postgraduate Research Scholarship. We tha lk Mr K. D. Chandler for expert assistance.

REFERENCES

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181

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Gastrin metabolism in neonatal pigs and grower-pigs.

1. Half-life (1.7 +/- 0.1 min), distribution volume (146 +/- 12 ml/kg) and metabolic clearance rate (28 +/- 1 ml/kg/min) of little gastrin (G17) in ne...
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