Metabolic clearance rates of oxyntomodulin and glucagon in the rat: contribution of the kidney

The half-life (t1/2) and metabolic clearance rate (MCR) of exogenous natural porcine oxyntomodulin (porcine OXM) and the synthetic analog of rat oxyntomodulin, [Nle27]-OXM (rat OXM), were compared with that of glucagon in control, sham-operated and acutely nephrectomized rats using the primed-continuous infusion technique. The half-disappearance times for porcine OXM (8.2 +/- 0.5 min) and rat OXM (6.4 +/- 0.5 min) were 3-fold slower than that of glucagon (1.9 +/- 0.1 min). Acute bilateral nephrectomy significantly prolonged the half-disappearance time of rat OXM (8.2 +/- 0.7 min) and glucagon (3.6 +/- 0.4 min) compared with that of sham-operated animals (6.5 +/- 0.8 min and 2.5 +/- 0.2 min, respectively). The mean MCRs were similar for porcine and rat OXM (11.3 +/- 0.7 and 11.9 +/- 0.5 ml.kg-1.min-1) but were 3 times lower than that measured with glucagon (36 +/- 5 ml.kg-1.min-1). Bilateral nephrectomy reduced the MCR of OXM and glucagon by 38% and 34%, respectively. No significant increase in C-terminal glucagon immunoreactivity was noticed during infusion of either porcine or rat OXM, measured directly in plasma, with a specific C-terminal glucagon antiserum or after HPLC. In the course of the glucagon infusion, blood glucose was increased 2-fold, while the same dose of porcine OXM or of rat OXM induced only a small increase over the values in phosphate buffer-infused rats. 10 times higher doses of rat OXM were necessary to obtain a similar hyperglycemic effect. These results indicate that: (1) the metabolism of OXM is 3-fold slower than that of glucagon, (2) renal clearance contributed close to 35% of the overall metabolic plasma extraction for OXM and glucagon and (3) OXM, although effective at a higher dose, when compared with glucagon, displays a hyperglycemic effect probably through the glucagon receptors.     

Growth hormone secretion in the rat as a function of age.

The first appearance of rat growth hormone (RGH) in serum was in the 19 day-old foetus. The level was high on the 21st day of gestation (129 +/- 7 ng/ml serum), it decreased after birth and descended to 17 +/- 2 ng/ml in the 15 day-old rat. After weanling it again rose to reach a plateau at 80 cays. The half-life and metabolic clearance rate (MCR) of RGH were compared in the 4 and 15 day-old rat and in normal and hypophysectomized adult rats after a single intravenous injection of hormone. As the MCR was essentially the same in all groups, serum RGH levels reflect the rate of hormonal secretion of the pituitary gland.     

Absorption of intragastrically administered DDAVP in conscious dogs

Plasma concentrations of DDAVP were measured after intragastric administration and intravenous infusion in dogs. Oral ingestion of DDAVP led to a dose dependent increase in peak plasma concentrations as well as area under the curve (AUC). Intravenous infusion of DDAVP (0.13 pmol/l min) resulted in a mean steady-state level of 20.3 pmol/l. Elimination half-lives for oral DDAVP were 77.6 and 76.1 min for low and high doses respectively. T1/2 estimated from the ascending part of the i.v. infusion curve was 50 min. A metabolic clearance rate (MCR) of 3.9 ml/kg . min was assessed from the i.v. steady-state level.     

The metabolic clearance of progesterone in the pregnant rat: absence of a physiological role for the lung

The metabolic clearance rate (MCR) of progesterone is among the highest for all steroid hormones studied, yet it is difficult to apportion this high MCR to specific organ contributions. The isolated lung has been shown to metabolize progesterone, and since this tissue receives the entire cardiac output, potentially it could make a major contribution to the overall MCR. This possibility was examined in the present study by measuring lung extraction of [3H]progesterone under steady-state conditions in the intact pregnant rat. Anesthetized rats (n = 6) were infused with [3H]progesterone via a femoral vein for 100 min on Day 16 of pregnancy. After the onset of steady state (40 min), four blood samples were obtained at 20-min intervals from the right ventricle and from the aorta, and the concentrations of [3H]progesterone and its metabolites were determined. Throughout the sampling period, mean arterial pressure and heart rate remained stable (two-way analysis of variance), as did the production rate (3.76 +/- 0.35 mg/day; mean +/- SEM) and the MCR (34.8 +/- 3.5 ml/min) of progesterone. Despite this high rate of clearance, there was no difference between the concentration of [3H]progesterone in arterial and right ventricular blood, indicating no net extraction of progesterone during passage through the lung. Furthermore, there was no change in the concentration of either lipid-soluble or aqueous-soluble [3H]progesterone metabolites during trans-lung passage. These observations demonstrate that the lung does not contribute to the MCR of progesterone when measured under physiological and steady-state conditions. Therefore, the relationship, MCR (ml/min) = whole-body extraction (%) x cardiac output (ml/min), is upheld for progesterone in the rat.     

Direct biphasic modulation of gonadotropin-stimulated testicular androgen biosynthesis by prolactin

Prolactin (PRL) exerts both stimulatory and inhibitory effects upon testicular steroidogenesis in vivo. The direct effects of PRL on biosynthesis of testicular androgen were studied in primary cultures of testicular cells obtained from adult, hypophysectomized or neonatal, intact rats. In cells from adult animals, treatment with human chorionic gonadotropin (hCG) (10 ng/ml) significantly increased testosterone and progesterone production relative to their respective controls. In contrast, neither steroid was increased by treatment with rat PRL (rPRL) or ovine PRL (oPRL) alone. Upon addition of 0.1-3 ng/ml of either rPRL or oPRL to the hCG-treated cultures, testosterone production was progressively increased up to a maximum of 70% greater than with hCG alone. However, when PRL exceeded 3 ng/ml, the testosterone response began to decline and was 39 or 24% less than from cells treated with hCG alone at 300 ng/ml of rPRL or oPRL, respectively. A similar biphasic response pattern was observed in cells from neonatal animals. In contrast to the biphasic effect of PRL on production of androgen, PRL treatment enhanced hCG-stimulated production of progesterone in a dose-related manner without exerting an inhibitory effect. At 3 and 300 ng/ml, rPRL augmented hCG action by 2.5- and 8-fold, respectively. Similarly, in the presence of inhibitors of pregnenolone metabolism, rPRL also enhanced hCG-stimulated production of pregnenolone. Quantitation of steroid intermediates in the testosterone biosynthetic pathway revealed that the stimulatory effect of 3 ng/ml rPRL on testosterone production was associated with 1.3- and 2.8-fold increases in accumulation of androstenedione and 17 alpha-hydroxyprogesterone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitric oxide decreases insulin resistance induced by high-fructose feeding.

The effect of nitric oxide (NO) on insulin resistance was studied in high-fructose-fed rats. A sequential hyperinsulinemic euglycemic clamp procedure was employed (insulin infusion rates: 3 and 30 mU/kg BW/min) in 12 high-fructose-fed rats and 12 chow-fed rats while awake. Half of the high-fructose-fed and the chow-fed rats, respectively, were continuously given sodium nitroprusside (SNP, 3 ng/kg BW/min) during the clamp study. Blood glucose was clamped at the fasting level in each rat. Plasma insulin levels during the 3 and 30 mU/kg BW/min insulin infusions were 30 and 400 microU/ml, respectively. Metabolic clearance rate of glucose (MCR) was regarded as an index of whole body insulin action. At both 3 and 30 mU/kg BW/min insulin infusions, high-fructose feeding showed a significant decrease in MCR compared with the chow-fed rats. However, decreased MCRs were stimulated by SNP administration and reached similar levels as the chow-fed rats. SNP infusion did not influence MCRs in the chow-fed rats. Therefore it could be concluded that NO can improve insulin resistance induced by high-fructose feeding.     

Metabolic clearance rate of adrenocorticotropin in the rat.

The metabolic clearance rate (MCR) of adrenocorticotropin (ACTH) was estimated after the intravenous infusion of graded rates of the hormone (40-2560 muU/min per 100 g body weight) in rats pretreated with chlorpromazine, morphine, and Nembutal, a preparation which proved effective in blocking endogenous ACTH release. The hormone was infused over a period of 45 min, at which time the plasma ACTH concentration had reached a steady state. A specific and sensitive bioassay, based on the corticosterone production of dispersed adrenal cells, was used to measure the plasma ACTH concentration. With increasing infusion rates of ACTH, a threefold decrease in the MCR of ACTH was observed. Previous studies of our group have shown that the MCR of corticosterone increases as a function of the infusion rate of the steroid. It appears, therefore, that the metabolism of these two hormonal links of the hypothalamo-pituitary-adrenocortical axis vary in opposite fashions as a function of the secretion rate of the hormone.     

Pharmacokinetics and organ catabolism of cholecystokinin octapeptide in pigs

The pharmacokinetics and organ catabolism of cholecystokinin octapeptide (CCK8) were studied in pigs. In conscious animals, intravenous infusion of increasing doses of CCK8 (2.9-232.3 pmol.kg-1.min-1) resulted in a linear increase of plasma CCK-like immunoreactivity (CCK-LI). At the cessation of infusion of the largest dose of CCK8, plasma CCK-LI promptly returned to near basal values. The half-disappearance time (t1/2), metabolic clearance rate (MCR) and distribution volume (DV) were estimated to be 0.55 +/- 0.03 min, 134.8 +/- 10.8 ml.kg-1.min-1 and 107.9 +/- 13.0 ml.kg-1, respectively. In another group of anesthetized animals, infusion of CCK8 at similar doses produced higher plateau plasma CCK levels and the t1/2, MCR and DV were calculated to be 0.68 +/- 0.06 min, 32.5 +/- 3.9 ml.kg-1.min-1 and 45.2 +/- 5.6 ml.kg-1, respectively. Estimates of first-pass immunological degradation through various vascular beds were in the range 27-66%, with in decreasing order the kidney, liver, hindleg, followed by the brain and gut. These results indicate that immunoreactive CCK8 is rapidly cleared from plasma during passage through several vascular beds. The peptide is only partly inactivated during hepatic transit and so may exert hormonal effects upon its release from intestinal stores.     

Body water handling in response to hypertonic-saline induced diuresis in fasting northern elephant seal pups (Mirounga angustirostris)

During natural fasting conditions in postweaned northern elephant seal (NES) (Mirounga angustirostris) pups, urinary water loss is minimized and percent total body water (TBW) is maintained constant. However, following infusion of hypertonic saline, glomerular filtration rate (GFR) and urine output increased in fasting pups. Therefore, we quantified the magnitude of the hypernatremia-induced diuresis relative to the animal's total body water (TBW) pool and the percentage of filtered water reabsorbed. Following a 24 h control period, naturally fasting NES pups (n=7) were infused (4 ml min(-1)) with hypertonic saline (16.7%) at a dose of 3 mmol NaCl kg(-1) body mass. Total body water was estimated prior to infusion by tritium dilution, GFR was estimated by standard creatinine clearance, and urine output (V) was measured for 24 h during the control and post infusion periods. Percentage of filtered water reabsorbed was calculated as (1-(V/GFR))x100. Twenty-four hours following the infusion, GFR (control: 69+/-12 ml min(-1) and post-infusion: 118+/-19 ml min(-1); mean+/-S.E.) increased 77+/-28% above control and the percentage of filtered water reabsorbed was decreased 0.4+/-0.1%. The increase in urine output (control: 218+/-47 ml d(-1) and post-infusion: 883+/-92 ml d(-1)) accounted for 1.7+/-0.2% of the pups' TBW. The hypernatremia-induced diuresis was accompanied by the loss of body water indicating the lack of water retention. Although the 77% increase in GFR was only associated with a 0.4% decrease in the percentage of filtered water reabsorbed, this decrease was significant enough to result in a 4-fold increase in urine output. Despite the observed diuresis, fasting NES pups appear to possess an efficient water recycling mechanism requiring only a small percentage of body water to excrete an excess salt load. This water recycling mechanism may allow pups to avoid negative perturbations in body water as they initiate feeding in a marine environment following the fast.     

Immunoreactive cholecystokinin in human and rat plasma: correlation of pancreatic secretion in response to CCK

Immunoreactive cholecystokinin (CCK) levels in human and rat plasma are described using a radioimmunoassay specific for the biologically active sulfated end of CCK. This assay detected significant changes in plasma cholecystokinin levels during intrajejunal administration of amino acids and intravenous infusions of CCK-8 which were followed by increased pancreatic secretion. In humans, the concentration (pg/ml) of plasma cholecystokinin increased from 10.8 to 18.9 following intrajejunal amino acid instillation and from 15.4 to 31.1 during CCK infusion, while pancreatic trypsin secretion increased more than 15 fold. Ingestion of a test meal also caused a rapid and significant elevation (P less than 0.05) in both plasma CCK (14.5-21.7 pg/ml) and gastrin (50-160 pg/ml) levels. In the rat, an injection of 46 ng of CCK-8 produced a 300% increase in immunoreactive plasma CCK levels (2 min) and caused peak pancreatic protein secretion within 5 min; 4 fold lower doses (11.5 ng) elevated plasma CCK by 38% and pancreatic protein secretion to a small but significant extent. The ability of this assay to detect various forms of sulfated CCK in human plasma was also determined. Following gel chromatography on Sephadex G-50, at least three different immunoreactive peaks were found in plasma from fasted subjects and after intrajejunal amino acid stimulation. While the lower molecular weight CCK peptides (CCK-8 and CCK-12) were detected in plasma from both fasted and stimulated subjects, the larger form (CCK-33) was only present in measurable concentrations after amino acid infusion. The simultaneous measurement of increased plasma CCK levels and pancreatic secretion and the changes in the distribution of CCK peptides following amino acid infusion provides strong support that this assay detects physiologically relevant changes in biologically active CCK peptides.     

Effects of acutely increased plasma testosterone concentrations on pulsatile luteinizing hormone secretion in the male rat

To assess the role of testosterone (T) in regulating the minute-to-minute release of pulsatile luteinizing hormone (LH) secretion in the adult male rat, we investigated the negative feedback of acute increases in plasma T concentrations on pulsatile LH secretion in acutely castrated male rats. At the time of castration, we implanted T-filled Silastic capsules, s.c., which maintained plasma T concentrations at approximately 1.8 ng/ml and suppressed LH pulses. On the next day, the capsules were removed; blood sampling (every 6 min) was started 8 h after implant removal, thereby allowing LH pulses to be reinitiated. Immediately following a control bleeding interval of 2 h, either T or vehicle alone was infused s.c., and blood sampling continued for another 4 h. In animals receiving vehicle alone, LH pulse frequency and mean LH levels increased over the 6 h bleeding period. The administration of 200 ng T/min caused a rapid rise in plasma T concentrations of about 4 ng/ml ("physiological") and prevented the increase in pulse frequency that occurred in the control group; it did not, however, reduce pulse frequency over the 4 h infusion period. When T was infused at the rate of 400 ng/ml, plasma T concentrations rose to approximately 18 ng/ml ("supraphysiological") and LH pulse frequency was significantly reduced, but not completely inhibited, during the last 2 h of the infusion. The pulse amplitude of luteinizing hormone did not change significantly in any of the groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic clearance rate and half-time disappearance rate of human N-terminal and adrenocorticotropin of pro-opiomelanocortin in the rat: a comparative study

In metabolic clearance rate (MCR) and plasma half-time disappearance rate (t 1/2) of human N-terminal (1-76) and adrenocorticotropin(hACTH 1-39) of pro-opiomelanocortin were compared after intravenous bolus injection of both peptides simultaneously into rat. The level of immunoreactive (IR) hNT and IR-ACTH in plasma and urine samples were measured by specific and homologous radioimmunoassays (RIAs). The MCR and hNT and hACTH were 3.01 +/- 0.20 ml/min (M +/- S.D., N = 4) and 2.04 +/- 0.06 ml/min, respectively (p less than 0.05), The curve for the disappearance rate of IR-hNT was triphasic (rapid t 1/2 = 0.96 +/- 0.39 min, intermediate t 1/2 = 6.7 +/- 2.25 min, and slow t 1/2 = 74 +/- 15.8 min), while that of IR-ACTH was biphasic (rapid t 1/2 = 3.3 +/- 0.68 min, and slow t 1/2 = 41.5 +/- 3.03 min) as analyzed by the non-linear least-squares methods. Statistically significant difference (p less than 0.01) was found between IR-hNT and IR-hACTH in the rapid t 1/2 and in the slow t 1/2. Subsequent analysis of pooled plasma sample (30 min post-injection) by molecular sieve chromatography on Sephadex G-50 superfine column revealed that the majority of IR-hNT (90-95%) and IR-ACTH (60-70%) are co-chromatographed with [125I]iodo hNT and [125I]iodo ACTH respectively. Similarly, gel filtration of pooled urine sample (120 min post-injection) on Sephadex G-50 superfine revealed that 80-90% of IR-hNT and less than 50% of IR-ACTH co-eluted with [125I]iodo hNT and [125I]iodo ACTH, respectively. Smaller molecular forms of IR-hNT and IR-ACTH were definitely apparent in the urine sample. In conclusion, hNT has a larger MCR and a longer half-time disappearance rate (t 1/2) than IR-hACTH in rat plasma and it appears that hNT is more resistant to degradation by plasma and by kidney than hACTH.     

Adrenocorticotropin secretion rates following histamine injection in adult and newborn dogs.

The metabolic clearance rate (MCR) for ACTH in adult dogs was previously shown not to vary significantly with varying plasma ACTH concentrations or among dogs. This is confirmed here for pups aged 1-7 days. Hence, ACTH secretion rates can be continuously calculated from a continuous function of plasma ACTH vs. time. Each of seven adult dogs under Nembutal anesthesia received two or three intravenous (i.v.) injections of histamine with increasing doses. The first injections in each dog ranged from 7 to 50 mug/kg, while the last dose was 62-108 mug/kg. A total of 16 injections were given. Twelve pups (two litters of six) aged 1-7 days each received one injection of histamine of 76-116 mug/kg (i.v.). ACTH concentrations in plasma were determined by an adrenal cell suspension bioassay before, and 6 times after each injection. Nine pups also underwent determinations of their MCR for ACTH, with plateau concentrations determined at three times during an ACTH infusion. Continuous curves of ACTH secretion rates were calculated for all 28 histamine injections, showing that all except the 1-day-old pups secrete considerable ACTH when stressed. Compared to adult dogs, the pups show lower secretion rate peaks and shorter periods of rapid secretion. Changes in plasma glucocorticoids also suggest that the adrenal cortex of newborn dogs can respond to ACTH by increased glucocorticoid secretion.     

Effects of insulin infusion on glucose kinetics in normal and burned guinea pigs

The effects of a constant infusion of insulin (12 mu/kg·min for 90 min) on glucose turnover (determined by means of the primed-constant infusion of 6-³H-glucose) was evaluated in normal and burned (50% BSA) guinea pigs (gp). In burned, untreated gp, the mean plasma glucose level (gl) was increased from 129±8.2 to 205±13.7 mg/dl 90 min after burning, whereas gl was 140±14.5 mg/dl in the burned + insulin-infused animals at 90 min. The insulin infusion reduced gl from 120±5.6 to 69±5.8 mg/dl in unburned gp; the rate of glucose appearance (R_a) was reduced and the metabolic clearance rate (MCR) was increased. In the B+I gp, the insulin effectively minimized the increase in R_a which followed burning in the burned, untreated gp. However, insulin did not increase the MCR of the burned + insulin-infused group above that of the burned, untreated group. On the day following the burn, the insulin infusion decreased gl in the burned gp to the same extent as in the unburned animals and also increased MCR. We concluded that whereas there was a lack of peripheral responsiveness to the insulin infusion in the first 90 min after burning (during the shock phase), no such lack of responsiveness was evident on the second day.     

Changes in the blood concentrations of progesterone and 20 alpha-hydroxypregn-4-en-3-one during late pregnancy in the conscious rat: a specific role for metabolic clearance rate

Near term in the rat, the blood concentration of progesterone falls while that of 20 alpha-hydroxypregn-4-en-3-one (20 alpha-DHP) increases. This is generally attributed to changes in ovarian secretion alone, but altered rates of hormone metabolism could also have a role. In the present study, therefore, metabolic clearance rate (MCR), production rate, and peripheral interconversion of progesterone and 20 alpha-DHP were measured on Day 16 of pregnancy, the time of maximal progesterone secretion, and on Day 22, one day prior to parturition. Conscious rats (n = 8 per group) were infused with either [3H]progesterone or [3H]20 alpha-DHP and the dynamics of progestin metabolism were calculated from the resultant isotopic and endogenous progesterone and 20 alpha-DHP concentrations. The blood concentration of progesterone declined by 69% between Day 16 (54 +/- 2 ng/ml) and Day 22 (17 +/- 2 ng/ml), and this was due to the combined effect of a 48% increase in the MCR and a 54% decrease in production rate of progesterone. In contrast, the production rate of 20 alpha-DHP was twofold greater on Day 22 compared to Day 16. As a result, the blood concentration of 20 alpha-DHP increased from 28 +/- 3 ng/ml on Day 16 to 40 +/- 6 ng/ml on Day 22, and this change would have been greater but for a concomitant increase (41%) in the MCR of 20 alpha-DHP. Although peripheral conversion of progesterone to 20 alpha-DHP was similar on Day 16 (transfer constant, 12.8 +/- 0.6%) and Day 22 (12.3 +/- 0.9%), the contribution of this conversion to total 20 alpha-DHP production fell from 32% to 7% between the two days.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo reopening of the neonatal ductus arteriosus by a prostanoid EP4-receptor agonist in the rat

Prostaglandin E1 is used to reopen the constricted ductus arteriosus in neonates with ductus-dependent circulation. To clarify possible prostanoid receptor agonists that can reopen the neonatal ductus with fewer side effects, we studied in vivo reopening of the neonatal ductus arteriosus by AE1-329, a prostanoid EP4-receptor agonist, in the rat. Neonatal rats were incubated at 33 degrees C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing. Intraesophageal pressure was measured with a Millar micro-tip transducer. The ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 and 0.08 mm at 0 and 60 min after birth. PGE1 and AE1-329, injected subcutaneously at 60 min after birth, dilated the ductus dose-dependently. Thirty minutes after injection of 10 ng/g of PGE1 and AE1-329, the ductus diameter was 0.52 and 0.65 mm, respectively. The ductus-dilating effect of PGE1 was maximal at 15-30 min, and disappeared at 2 h. The ductus-dilating effect of AE1-329 was prolonged, the ductus was widely open at 6 h, and closed at 12 h after injection of 10 ng/g AE1-329. AE1-259-01 (EP2 agonist) (100 ng/g) did not dilate the neonatal ductus. Respiration was depressed by PGE1, but not by AE1-329. These results indicate the major role of EP4 in the neonatal ductus and that AE1-329, an EP4 agonist, can be used to dilate the neonatal constricted ductus without the side effects shown by EP3, including apnea.     

Effects of insulin and glucose on the production and utilization of glucose in sheep (Ovis aries)

1. The rates of appearance (RA) and metabolic clearance rates (MCR) of glucose were determined during the infusion of insulin plus glucose in sheep. 2. During euglycaemia 50% inhibition of RA of endogenous glucose occurred at insulin concentrations of 60 microU/ml in arterial plasma. 3. During euglycaemia the MCR of glucose doubled with an increment of about 100 microU/ml of insulin. 4. Hypoglycaemia was associated with a reduction in insulin's suppression of RA of endogenous glucose and hyperglycaemia significantly reduced the increase in MCR due to insulin.     

Effects of calcitonin gene-related peptide on renal blood flow in the rat

The effects of alpha-rat calcitonin gene-related peptide (alpha-rCGRP) on systemic and renal hemodynamics and on renal electrolyte excretion were examined in normal anesthetized rats. In one group of rats (n = 7), infusions of alpha-rCGRP at doses of 10, 50, 100, and 500 ng/kg/min for 15 min each produced dose-related and significant decreases in mean arterial pressure from a control of 130 +/- 3 mm Hg to a maximal depressor response of 91 +/- 2 mm Hg. During the first three doses of alpha-rCGRP, renal blood flow progressively and significantly increased from a control of 5.0 +/- 0.3 ml/min to a peak level of 6.3 +/- 0.3 ml/min achieved during the 100 ng/kg/min infusion. With the highest infusion rate of 500 ng/kg/min, renal blood flow fell below the control level to 4.5 +/- 0.2 ml/min (P less than 0.05). The responses in renal blood flow and mean arterial pressure were associated with reductions in renal vascular resistance. After cessation of alpha-rCGRP infusions, arterial pressure, renal blood flow, and renal vascular resistance gradually returned toward the baseline values. In another group of rats (n = 9), infusion of alpha-rCGRP for 30 min at 100 ng/kg/min produced a significant reduction in urinary sodium excretion from 0.28 +/- 0.06 to 0.14 +/- 0.5 muEq/min (P less than 0.05). Urine flow and urinary potassium excretion also appeared to decrease, but the changes were not significantly different (P greater than 0.05) from their respective baselines. These results demonstrate that alpha-rCGRP is a potent and reversible hypotensive and renal vasodilatory agent in the anesthetized rat. The data also suggest that alpha-rCGRP may have significant effects on the excretory function of the kidney.     

Failure of IGF-1 to affect protein turnover in muscle from growth-retarded neonatal rats

To investigate the response of the growth retarded neonatal rat to insulin-like growth factor-I (IGF-I) we have measured the effect of IGF-I on in vitro muscle protein synthesis and degradation rates in growth retarded and control neonatal rat pups. The growth retarded pups were growth retarded in utero by ligation of the uterine blood supply at day 17 of gestation. Basal levels of muscle protein synthesis in vitro were significantly lower in growth retarded pups compared with controls. Protein degradation rate were not different in muscles taken from the two groups. IGF-I stimulated protein synthesis in muscle from control pups by 12% and 15% at 20 ng/ml and 200ng/ml respectively. Net protein degradation was inhibited by 20% in the presence of 20ng/ml IGF-I. IGF-I had no effect on net protein synthesis or degradation in muscle from growth retarded pups. Neither Multiplication Stimulating Activity (at 20ng/ml or 200ng/ml) nor insulin (at 40ng/ml or 800ng/ml) was able to increase synthesis or decrease degradation of protein. Specific receptors for IGF-I are present on muscle membranes from both groups. Unlabelled IGF-I was more effective than MSA or insulin in competing with 125I-IGF-I for binding to the receptor. The relative affinities are consistent with type I IGF receptors. The affinity of these receptors for IGF-I was similar (Kd approximately 5nM) in both groups and the receptor concentration in both cases was approximately 250 fmol/mg protein. The refractility of tissue from growth retarded pups to IGF-I may be partially responsible for the lack of catch up growth in growth retarded neonates.     

Infusion of a novel peptide, calcitonin gene-related peptide (CGRP) in man. Pharmacokinetics and effects on gastric acid secretion and on gastrointestinal hormones

Calcitonin gene-related peptide (CGRP) is a recently discovered widespread regulatory peptide which is encoded in the same gene as calcitonin. We assessed the effect of systemic infusion of synthetic rat CGRP at low dose (range 0.32-2.56 pmol/kg per min) on submaximal pentagastrin-stimulated gastric secretion and on gastrointestinal hormones. To assess its pharmacokinetic parameters in man the MCR and plasma half-life were estimated by the continuous infusion method. Gastric acid output and pepsin secretion were significantly reduced by CGRP (-29% of basal, P less than 0.01 and -40% of basal, P less than 0.005, respectively). There was a significant fall in basal levels of gastrin (-39%, P less than 0.001); gastric inhibitory peptide (-44.7%, P less than 0.001); enteroglucagon (-25%, P less than 0.001) and neurotensin (-33%, P less than 0.05). There was no significant change in plasma levels of insulin, motilin, pancreatic polypeptide or glucose. Suppression of gastric secretion and the fall in gastrointestinal hormones was prolonged and basal levels were not re-established after stopping the CGRP infusion. The disappearance curve of immunoreactive CGRP from the plasma was bi-exponential. The plasma half-life of immunoreactive CGRP was calculated as 6.9 +/- 0.9 min for the fast decay and 26.4 +/- 4.7 min for the slow decay. The calculated MCR was 11.3 +/- 1.2 ml/kg per min. Except for flushing of the face no untoward effects were observed. The results of this study suggest the possibility that CGRP could play a role in the regulation of gastric secretion and gastrointestinal hormone release.