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O Isaksson

Publications and source records attributed to O Isaksson.

At least 37 records · Page 2Linked to original sources
PubMed1992

Growth hormone induces multiplication of the slowly cycling germinal cells of the rat tibial growth plate.

To study the effect of locally infused growth hormone (GH) or insulin-like growth factor I(IGF-I) on slowly cycling cells in the germinal cell layer of the tibial growth plate, osmotic minipumps delivering 14.3 microCi of [3H]thymidine per day were implanted s.c. into hypophysectomized rats, and GH (1 microgram) or IGF-I (10 micrograms) was injected daily through a cannula implanted in the proximal tibia. The opposite leg served as a control. After 12 days of treatment, the osmotic minipumps were removed, and three rats in each group were given GH (20 micrograms/day, s.c.) for an additional 14 days to chase the labeled cells out of the proliferative layers. Labeled cells remained in the germinal layer, in the perichondrial ring, and on the surface of the articular cartilage close to the epiphyseal plate. GH administered together with labeled thymidine significantly increased the number of labeled cells in the germinal cell layer compared to that in the control leg (ratio = 1.95 +/- 0.13), whereas IGF-I showed no stimulatory effect (ratio = 0.96 +/- 0.04). Therefore GH but not IGF-I stimulates the multiplication of the slowly cycling (label-retaining) cells in the germinal layer of the epiphyseal plate. IGF-I acts only on the proliferation of the resulting chondrocytes.

Animals↗
PubMed1992

High frequency of mammary adenocarcinomas in metallothionein promoter-human growth hormone transgenic mice created from two different strains of mice.

Transgenic mice were developed by injecting a mouse metallothionein promoter-human growth hormone (Mt-hGH) gene fragment into the pronucleus of C57Bl x DBA/2J-f2 or C57Bl x CBA-f2 one cell embryos. Six founder animals with the C57Bl x DBA genetic background grew 1.3-2.2 times larger than littermate controls and had higher levels of hGH in plasma (4.6-279 mU/l). Three of the four female transgenic founders developed malignant papillar adenocarcinomas of mammary origin at 27-43 weeks of age. One male transgenic founder was successfully mated and two of three female transgenic offsprings developed mammary tumors. To examine if the tumor induction was dependent on the strain of mice used the experiments were repeated using animals with different genetic background. Fourteen female hGH transgenic mice from five founder animals were generated using C57Bl x CBA-f2 mice. Thirteen of the animals had elevated levels of hGH in plasma (7-1960 mU/l) and grew larger than control animals. Nine of the animals developed mammary adenocarcinomas. Four of the hGH expressing animals did not demonstrate macroscopic tumor formation but have not yet been analyzed histologically. The present study suggests that markedly elevated endogenous levels of GH cause mammary carcinoma in hGH transgenic mice. The present animal model might prove useful for studying molecular mechanisms involved in the development of hormonally induced mammary tumors.

Adenocarcinoma, Papillary↗
PubMed1992

Effects of tri-iodothyronine and insulin-like growth factor-I (IGF-I) on alkaline phosphatase activity, [3H]thymidine incorporation and IGF-I receptor mRNA in cultured rat epiphyseal chondrocytes.

The effects of tri-iodothyronine (T3) and insulin-like growth factor-I (IGF-I) on [3H]thymidine incorporation, alkaline phosphatase (ALP) activity and IGF-I receptor mRNA levels were studied in rat epiphyseal chondrocytes cultured in monolayer. Chondrocytes from enzymatically digested rat tibia epiphyseal growth plates were seeded in monolayer culture and precultured for 7-14 days in Ham's F-12 medium supplemented with 10% (v/v) newborn calf serum and 1% (v/v) of a serum substitute. After preculture the medium was changed to Ham's F-12 medium containing 1% (v/v) serum from hypophysectomized rats, and the effects of T3 and/or IGF-I on DNA synthesis ([3H]thymidine incorporation), ALP activity (a late marker of differentiated epiphyseal chondrocytes) and IGF-I receptor mRNA levels were studied. ALP activity was increased by T3 in a dose-dependent manner with a maximal response at 10 micrograms T3/l (678 +/- 86% compared with control culture). The increase in ALP activity was accompanied by a concomitant decrease in [3H]thymidine incorporation (52 +/- 14% compared with control culture). Human GH (hGH; 50 micrograms/l) and IGF-I (25 micrograms/l) had no stimulatory effect on ALP activity. However IGF-I (10 micrograms/l) exerted an inhibition on the T3 (10 micrograms/l)-induced increase in ALP activity (64 +/- 9% compared with T3-treated culture). T3 (3 micrograms/l) inhibited the increase in [3H]thymidine incorporation caused by 25 micrograms IGF-I/l (51 +/- 13% compared with IGF-I-treated culture). Furthermore, IGF-I receptor mRNA levels were increased by 10 micrograms T3/l (137 +/- 4.2% compared with control culture) while no effect of hGH (50 micrograms/l) or IGF-I (25 micrograms/l) was demonstrated. Both T3 and IGF-I were shown to interact with epiphyseal chondrocytes and both substances seemed to affect cell proliferation and maturation and therefore longitudinal bone growth. Furthermore, the results indicated that IGF-I is important for proliferation of the cells while T3 initiates the terminal differentiation of epiphyseal chondrocytes.

Alkaline Phosphatase↗
PubMed1991

On the role of the peptide galanin in regulation of growth hormone secretion.

The effects of the peptide galanin on growth hormone secretion were studied in vitro using cultured rat and human anterior pituitary cells, and in vivo by iv administration of galanin in both rats and humans. Galanin in concentrations from 10 nmol/l to 1 mumol/l did not alter basal GH release, but slightly inhibited GHRH-stimulated GH release from cultured rat anterior pituitary cells. Galanin (1 mumol/l) did not significantly change basal or GHRH-stimulated GH secretion from cultured human anterior pituitary cells. In contrast, iv injection of 1 microgram (300 pmol) galanin to rats induced an increase in plasma GH that was reproducible at repetitive injections. The galanin-induced GH release in rats was of a lower magnitude than the increase in plasma GH after iv injections of GHRH, and was seen with a 5-15 min delay in comparison to iv administered GHRH. In man, iv infusions of galanin (40 pmol.kg-1.min-1.(40 min)) also caused a significant increase in plasma GH, but it occurred 25-30 min after the beginning of the infusion. These results suggest an indirect action of galanin on GH release in both rats and humans, i.e. galanin does not directly affect the somatotropes. In agreement with a central action, no binding sites for galanin could be demonstrated in the rat anterior pituitary by autoradiography. Since galanin did not affect somatostatin release from fragments of rat mediobasal hypothalamus, the stimulatory effects of galanin on GH release are most likely mediated via a stimulatory effect on GHRH neurons.

Animals↗
PubMed1988

Immunohistochemical localization of insulin-like growth factor I in the adult rat.

Rabbit antisera against native human insulin-like growth factor I (IGF-I; somatomedin C) or a synthetic tetradecapeptide, representing the carboxyterminal amino acids 57-70 of human IGF-I, were used to map immunohistochemically the distribution of IGF-I immunoreactive material in adult rats. Both antisera were specific for IGF-I, as characterized by immunoabsorption, immunoblotting and radioimmunoassay. There was no cross-reactivity to IGF-II, relaxin or pro-insulin; substances having a high degree of structural homology with IGF-I. High IGF-I immunoreactivity was observed in spermatocytes of the testis; in oocytes, granulosa and theca interna cells of the ovary during early stages of follicle development; in some lymphocytes and in reticular cells of lymphoid and hematopoietic organs; in salivary gland duct cells; in the adrenal medulla, the parathyroid gland and the Langerhans' islets. Chondrocytes in the epiphyseal and rib growth plates and at articular surfaces showed strong IGF-I immunoreactivity. Brown but not white fat cells were stained. Nerve cells in the peripheral and autonomic nervous system showed faint to intense IGF-I immunoreactivity. In contrast, neurons and neuroglial cells in the central nervous system were generally negative; motor neurons being an exception. Erythropoietic, thrombocytopoietic and myeloic cells in the bone marrow showed IGF-I immunoreactivity, but only at defined developmental stages. Hepatocytes showed faint IGF-I immunoreactivity, but became more intensely stained after pretreatment with colchicine. The present results suggest that IGF-I is synthetized by cells in several tissues and organs in the adult rat. There was an apparent association between the localization of IGF-I and cell differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of unilateral arterial infusion of GH and IGF-I on tibial longitudinal bone growth in hypophysectomized rats.

We have studied the effect of local arterial infusion of bacterially produced human growth hormone (hGH), insulinlike growth factor I (IGF-I), or pituitary-derived ovine prolactin (oPRL) on longitudinal bone growth of hypophysectomized rats. The substances were infused during a 14-day period by osmotic mini-pumps through a catheter which was implanted into the femoral artery of one hindlimb. Longitudinal bone growth was measured by the intravital marker tetracycline. Infusion of 1 microgram hGH per day stimulated bone growth only of the treated limb and not of the uninfused contralateral limb. Infusion of 10 micrograms hGH per day also stimulated unilateral longitudinal bone growth, but the uninfused contralateral limb also showed a significant growth response, probably because local administration of GH at this dose caused a significant elevation of GH in the systemic circulation. As a result, the differential growth response between the GH-treated and untreated limbs decreased compared to rats that were infused with 1 microgram hGH per day. Unilateral arterial infusion of 5 micrograms human IGF-I or 10 micrograms oPRL per day did not produce a significant growth response. The results of the present study confirm the observation by Schlechter and co-workers, who demonstrated that unilateral arterial infusion of GH maintained tibial cartilage width following hypophysectomy in the rat. The results of Schlechter and coworkers and the results of the present study show that GH in vivo stimulates epiphyseal cartilage growth directly. However, an increased local production of insulinlike growth factors is probably of importance for the expression of the direct effect of GH on longitudinal bone growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Isolation of three electrophoretic variants of rat pituitary growth hormone.

A procedure has been developed for the isolation of rat pituitary growth hormone and for the subsequent resolution of the preparation into three variants by preparative electrophoresis. The starting material was whole frozen glands and the process involved homogenization and extraction at pH 6.2, ammonium sulfate fractionation and molecular-sieve chromatography on Sephadex G-100. The separation into charge variants was achieved by zone electrophoresis in agarose suspension at alkaline pH. The purification was monitored by radioimmunoassay and the specific activities were expressed in terms of the rat growth hormone reference preparation (RP-1) supplied by the NIADDK, Bethesda, U.S.A. The three-component preparation and its constituents all had activities in the same range, exceeding the activity of the reference by a factor up to 20 times. Bioassay of the three-component preparation, based on measurement of longitudinal bone growth in hypophysectomized rats gave a potency of 4-5 IU/mg. The reference was the 1st International Standard (bovine) for growth hormone. The yield of the three-component preparation was 3.3 mg per gram pituitary tissue. Different electrophoretic analyses revealed the efficiency of the preparative procedure in separating the variants. The results of the analyses also support the view that difference in electrophoretic behaviour is due to a difference of a single net charge between adjacent variants. In addition, growth hormone was prepared from two side extracts (at pH 7.0 and pH 9.8, respectively), provided by a procedure developed earlier for rat prolactin. The three preparations gave electrophoretic patterns of equal appearance although the relative proportions of the activity peaks differed.

Animals↗
PubMed1987

Endogenous testosterone enhances growth hormone (GH)-releasing factor-induced GH secretion in vitro.

The influence of endogenous gonadal steroids in male and female rats on basal and growth hormone-releasing factor (GRF)-stimulated GH secretion from perifused anterior pituitaries was studied. After 75 min of perifusion with basal medium, freshly dissected pituitaries were exposed to human GRF(1-44) (10 nmol/l) for 15 min. Neonatal (day 1-2) or prepubertal (day 25) gonadectomy of male rats suppressed baseline GH release (ng/min per mg dry weight) as well as GRF-stimulated GH release by 40-70%. This effect was slightly more pronounced in neonatally gonadectomized animals. In prepubertally gonadectomized male rats, the suppression of GH release was completely reversed by testosterone replacement therapy. In female rats, prepubertal gonadectomy did not affect GH secretion from perfused pituitaries. However, treatment of ovariectomized female rats with oestradiol reduced baseline and GRF-induced GH release to levels lower than those observed in sham-operated or vehicle-treated ovariectomized animals. The data suggest that testicular androgen secretion in adult male rats increases the pituitary GH release in response to GRF in vitro, whereas ovarian oestrogen secretion is of less importance for the GRF responsiveness of female rat pituitaries.

Animals↗
PubMed1987

Growth hormone and experimental cancer cachexia.

Plasma levels of growth hormone (GH) and the effect of GH treatment have been evaluated in adult nongrowing sarcoma-bearing mice (C57BL/6J). Prepubertal tumor-bearing mice, tumor-bearing hypophysectomized Sprague-Dawley rats, and malnourished non-tumor-bearing animals served as additional groups of study and control animals. Adult sarcoma-bearing mice showed an increase in plasma levels of GH early following tumor implantation. GH levels increased further with tumor progression. The anorexia and the state of malnutrition in sarcoma-bearing mice were the major factors behind increased GH levels. Muscle wasting and body composition in the tumor-bearing host were not improved by GH treatment at doses that increased growth rate in normal growing mice with intact pituitaries or partially normalized growth rate in hypophysectomized rats. Exogenous GH supported tumor growth and host body growth to the same extent in hypophysectomized rats. Exogenous GH in excess of endogenous GH did not stimulate tumor growth further. It is suggested that increased GH production in a tumor-bearing host acts in concert with other hormones to stimulate endogenous substrate mobilization and in tumor-bearing animals to prevent substrate deficiency and hypoglycemia. On the basis of this conclusion, it is unlikely that GH supplementation to a freely eating tumor-bearing host will support replenishment of host tissues.

Animals↗
PubMed1986

Specific binding of human growth hormone but not insulin-like growth factors by human adipocytes.

Binding of human GH (hGH) and insulin-like growth factors I and II (IGFI and II) to isolated human adipocytes from adult subjects was studied. Binding equilibrium for hGH at 24 degrees C was reached at 120 min and half-maximal specific binding at 6-8 ng/ml. Apparent Ka was 2.1 X 10(9) M-1 and Bmax 7.3 X 10(-11) M/10(6) cells. The human fat cell growth hormone receptor recognized neither bovine, ovine or rat GH nor human prolactin or placental lactogen. No specific receptors for human IGFII could be demonstrated. Thus, human adipocytes do not possess IGF receptors but have specific GH receptors which recognize hGH but not GH from lower species.

Adipose Tissue↗
PubMed1985

Changes in growth hormone binding and metabolic effects of growth hormone in rat adipocytes following hypophysectomy.

Growth hormone (GH) binding and the effect of GH and insulin on glucose metabolism in rat adipocytes were studied at various time periods following hypophysectomy. Male rats were hypophysectomized at 33-34 days of age. After 6 h, 20 h or 3, 7 and 14 days adipocytes were prepared from epididymal fat pads by mild collagenase digestion (0.5 mg X ml-1, 60 min, 37 degrees C). Glucose metabolism was studied by determining the production of CO2 from [14C]glucose and the incorporation of [14C]glucose into lipids. GH binding was measured in cell aliquots using [125I]hGH. No difference in GH binding to adipocytes was observed between control rats and rats hypophysectomized or sham-operated 6 h earlier. GH binding was significantly decreased 20 h after hypophysectomy and declined further with time after hypophysectomy. Adipose tissue from normal rats is usually refractory to the insulin-like effect of GH. Adipocytes isolated from normal rats were, however, usually responsive to GH immediately after cell isolation, suggesting that refractoriness to the insulin-like effect of GH was lost during the time required for the preparation of adipocytes. The magnitude of the response to GH in adipocytes progressively declined with time after hypophysectomy. The decreased responsiveness to GH with time after hypophysectomy parallelled the decrease in GH binding. The results suggest that the pituitary, directly or indirectly, is necessary for the maintenance of GH binding sites in adipose tissue and that these binding sites are related to the insulin-like effect of GH.

Adipose Tissue↗
PubMed1985

Sexual dimorphism in the control of growth hormone secretion.

The secretory pattern of GH in the mature rat is sexually differentiated. In male rats GH is secreted in pulses occurring at regular 3- to 4-h intervals. In females the pulses are lower and plasma GH levels between the pulses are higher than in males. The continuous presence of testosterone appears to be necessary to maintain low basal GH levels in adult male rats. Neonatal, but not prepubertal, gonadectomy decreases GH pulse height in adult male rats to female levels. Administration of testosterone neonatally to castrated animals returns GH pulse height to normal suggesting that neonatal testicular androgen secretion is one determinant for GH pulse height in adult male rats. Administration of testosterone neonatally or during adult life to neonatally ovariectomized rats also produces higher GH pulses. In contrast to testosterone, estrogens elevate basal plasma GH levels and suppress the GH pulses under some conditions. Estrogens may stimulate basal GH secretion by acting directly on the pituitary. The physiological significance of the secretory pattern of GH has been investigated in hypophysectomized rats by simulating different plasma patterns of GH. The results suggest that high, infrequent GH pulses with low plasma GH levels in between (i.e. a masculine plasma GH pattern) promotes growth more effectively than an intermediate, rather constant level of plasma GH (i.e. a feminine plasma GH pattern). Since male sex steroids masculinize the secretory pattern of GH and have only minor growth-promoting effects in hypophysectomized animals it appears that the growth promoting effect of androgens is indirect and is due to an altered secretory pattern of GH. Presumably, neonatal androgen secretion stimulates body growth during adult life by irreversibly masculinizing the secretory pattern of GH. In contrast, estrogens appear to influence body growth by mechanisms that are mainly independent of the secretory pattern of GH. Evidence is accumulating that the secretory pattern of GH in the rat also affects various sexually differentiated hepatic characteristics such as steroid metabolism and prolactin receptor concentration. Thus, a feminization of the liver develops after continuous, but not intermittent, administration of GH to hypophysectomized rats. GH secretion is predominantly regulated by two hypothalamic peptides; GRF, and the GH-release-inhibiting factor, somatostatin.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1985

Effect of insulin treatment of hypophysectomized rats on adipose tissue responsiveness to insulin and growth hormone.

The effects of insulin treatment and dietary glucose on the responsiveness of adipose tissue to insulin and GH after hypophysectomy were studied. Male rats, 130-150 g, were hypophysectomized. Glucose metabolism was measured by determining the production of CO2 from [14C]glucose and the incorporation of glucose into lipids in the epididymal fat pad. Basal levels of glucose oxidation as well as the response to insulin were markedly decreased 7 days after hypophysectomy. In hypophysectomized animals given drinking water containing 10% glucose, insulin responsiveness was partially restored, and an enhanced response to the insulin-like effect of GH was observed. Plasma insulin levels decreased after hypophysectomy. Additional glucose caused a significant increase in plasma insulin levels, but these levels were still lower than those in sham-operated animals. To examine the possibility that endogenous insulin levels are important for the capacity of adipose tissue to metabolize glucose and respond to insulin and GH, hypophysectomized rats were injected with different, progressively increasing doses of insulin for 7 days, beginning on the day after the operation. Basal levels of glucose oxidation were decreased in hypophysectomized control animals and gradually increased in a dose-dependent manner in insulin-treated animals. Basal levels were normalized when the total dose of insulin injected was 16.5 U. In these animals, the response to insulin was enhanced, and there was an increase in the magnitude of the response to GH. Similar results were obtained when glucose incorporation into lipids was determined. The decrease in basal and insulin-stimulated glucose oxidation levels after hypophysectomy were most pronounced when measured at a high glucose concentration (50 mM), when glucose transport is not rate limiting. The results indicate that the changes in glucose metabolism and hormonal responsiveness of adipose tissue after hypophysectomy are, at least in part, dependent upon the decrease in endogenous insulin levels.

Adipose Tissue↗
PubMed1985

Imprinting of growth hormone secretion, body growth, and hepatic steroid metabolism by neonatal testosterone.

The influence of endogenous sex steroids and exogenous testosterone treatment on pulsatile GH secretion, body weight, longitudinal bone growth, and hepatic steroid metabolism was studied in male and female adult rats. Blood samples were obtained from the tip of the tail, and maximum and minimum GH levels were determined in individual rats to evaluate pulse heights and baseline levels. Longitudinal bone growth was measured using the intravital marker tetracycline, and hepatic steroid metabolism was evaluated by determining the enzyme activities of 16 alpha-hydroxylase and 5 alpha-reductase. Neonatal, but not prepubertal, gonadectomy of male rats suppressed maximum and mean plasma GH levels during adult life. The body weight and the rate of longitudinal bone growth were also decreased. Testosterone treatment neonatally reversed all of these effects. Neonatal gonadectomy of male rats also caused an elevation of minimum plasma GH levels, an effect, however, which was not reversed by testosterone replacement during neonatal life. Neonatally gonadectomized females treated with testosterone neonatally or during adult life increased their maximum and decreased their minimum GH levels. Their longitudinal bone growth was increased. The body weight of these rats was increased by neonatal, but not adult, testosterone treatment. There was no effect of neonatal ovariectomy on plasma GH levels in 3- to 4-month-old female rats. However, neonatal ovariectomy did increase the maximum and mean plasma GH levels immediately postpubertally, suggesting that the effect of the ovaries on GH secretion differs among mature female rats of different ages. Prepubertal gonadectomy of male rats feminized their hepatic steroid metabolism by decreasing 16 alpha-hydroxylase and increasing 5 alpha-reductase activities. Neonatal gonadectomy caused an even more pronounced feminization, which was partly reversed in rats given testosterone replacement therapy neonatally. In neonatally gonadectomized female rats, treatment with testosterone during adult life increased 16 alpha-hydroxylase and decreased 5 alpha-reductase to levels seen in intact male rats. The present results indicate that neonatally secreted testicular androgens imprint the high amplitude pulses characteristic of GH secretion in adult male rats. Neonatal androgens also stimulate somatic growth and partially account for the masculinized hepatic steroid metabolism in the adult animal. It is proposed that imprinting of the GH secretory pattern contributes to the influence of neonatal testicular androgens on body growth and hepatic steroid-metabolizing enzymes.

Animals↗
PubMed1985

Effect of human growth hormone on proteoglycan synthesis in cultured rat chondrocytes.

We have previously demonstrated that hGH stimulates DNA synthesis in cultured chondrocytes in the absence of serum. The present study is concerned with the effects of hGH on proteoglycan synthesis by cultured chondrocytes. Chondrocytes were isolated from rat rib growth cartilage by collagenase digestion, plated in plastic dishes, transferred to serum-free MCDB 104 medium, and incubated for 24 h to establish growth arrest. The cultures were then preincubated for 0-24 h with various concentrations of hGH and ovine prolactin (oPrl) and finally pulse-labelled for 30 min with radioactive sulphate in the presence of hormone. hGH, but not oPrl, stimulated sulphate incorporation with an apparent maximum at 50 ng/ml (approximately 170%). The stimulatory effect was apparent after 2 h and maximal after 3h preincubation. After 12 h the stimulatory effect had decreased to insignificant levels. Qualitative analysis of isolated proteoglycans indicated that the stimulation of sulphate incorporation by hGH is exerted at the level of protein synthesis with little effect on glycosylation and sulphation. Further experiments are required to demonstrate whether the stimulatory effect on proteoglycan synthesis is a specific phenomenon or represents one aspect of a general stimulation on cell metabolism in preparation for DNA synthesis.

Animals↗
PubMed1985

Intravenous growth hormone: growth responses to patterned infusions in hypophysectomized rats.

Young hypophysectomized rats were maintained with chronic indwelling i.v. cannulae attached via swivels to a multichannel pumping system programmed to deliver GH in a continuous or pulsatile pattern for several days. Continuous i.v. infusions of human GH for 5 days produced dose-dependent increases in body weight and tail length, without increasing food intake. A comparison of GH infusions by the s.c. or i.v. route showed that the direct i.v. route was threefold more effective. Pulsatile i.v. infusions of human or bovine GH at two doses (12 or 36 mu./day, eight pulses/day, 5-min duration, every 3 h) produced greater increases in body weight than continuous i.v. infusions of GH at the same daily dose. Continuous infusions of bovine GH produced a lower growth rate in the second of two consecutive 5-day treatment periods, whereas the responses to pulsatile GH did not diminish with time. Both body weight gain and long-bone growth were affected by the frequency of GH pulses; nine pulses per day were more effective than three pulses per day which in turn produced larger growth responses than one pulse per day. Keeping GH pulse frequency constant and varying pulse duration (4, 16 or 64 min) did not affect growth rates. In conclusion, long-term pulsatile i.v. infusions of GH mimic the endogenous secretory pattern, and are most effective when given at the physiologically appropriate pulse frequency.

Animals↗