Tubular response to hormones is blunted in weanling rats

The renal responses to atrial natriuretic peptide (ANP), parathyroid hormone (PTH) and arginine vasopressin (AVP) were studied in anaesthetized weanling and adult rats with clearance methods. In rats receiving PTH, thyroparathyroidectomy (TPTX) was performed prior to the study. The results showed that GRF remained unchanged in both age groups during infusion with ANP, AVP and PTH after TPTX as well as with TPTX alone. During ANP infusion, the urine flow rate increased from 0.01 +/- 0.002 to 0.029 +/- 0.004 ml (100 g body wt)-1 min-1 (P less than 0.001) and the fractional sodium excretion increased from 0.48 +/- 0.1 to 3.0 +/- 0.4% (P less than 0.001) in the adult rats; no significant changes were observed in the weanling rats. Phosphate excretion was not influenced by ANP in either age group. After TPTX, both net and fractional phosphate excretion decreased in both age groups. During PTH infusion in TPTX rats, both net and fractional phosphate excretions increased significantly in the adult rats but were unchanged in the weanling rats. In rats of the same age, the renal concentrating capacity and urinary excretion of prostaglandin E2 (PGE2) were determined after dehydration. The renal concentrating capacity was lower, and the renal excretion of PGE2 was higher, in the weanling than in the adult rats. Furthermore, the concentrating mechanism seems not to be influenced by indomethacin treatment in either age group. It is concluded that the tubular responses to ANP and PTH are blunted in the immature kidney and that the renal excretion of PGE2 is not an important factor in the regulation of the concentrating capacity in the weanling rat.     

Prostaglandins but not nitric oxide protect renal medullary perfusion in anaesthetised rats receiving angiotensin II

Angiotensin II (Ang II) fails to constrict renal medullary vasculature, possibly due to the counteraction of local vasodilators, such as prostaglandins or nitric oxide (NO). The effects of exogenous Ang II on intrarenal circulation were determined in anaesthetised rats that were untreated or pretreated with indomethacin (Indo) or l -NAME. The total renal blood flow (RBF), representing cortical perfusion, and outer and inner medullary blood flow (OMBF and IMBF) were measured. In untreated rats, Ang II decreased RBF in a dose dependent manner. Intravenous administration of 30 ng kg⁻¹ min⁻¹ Ang II decreased RBF by 38 % and OMBF by 9 % (both significant); IMBF was unaffected. Indo (5 mg kg⁻¹ i.v. ) significantly and similarly decreased OMBF and IMBF without affecting RBF. Ang II decreased IMBF by 27 % in Indo-pretreated rats, but caused no change in rats without pretreatment. The decreases in OMBF and RBF were comparable with or without Indo pretreatment. Inhibition of NO synthesis with l -NAME (0.6 mg kg⁻¹ i.v. ) significantly decreased RBF, OMBF and IMBF. Ang II infusion into l -NAME-pretreated rats induced a further significant decrease in RBF and OMBF without changing IMBF. We conclude that within the inner medulla, but not the outer medulla or cortex, prostaglandins effectively counteract the vasopressor effect of circulating Ang II.     

Prelimbic but not infralimbic cortex is involved in the pressor response to chemoreflex activation in awake rats

The ventral portion of the medial prefrontal cortex comprises the prelimbic cortex (PL) and the infralimbic cortex (IL). Several studies have indicated that both the PL and the IL play an important role in cardiovascular control. Chemoreflex activation by systemic administration of potassium cyanide (KCN) evokes pressor and bradycardiac responses in conscious rats, in addition to an increase in respiratory frequency. We report here a comparison between the effects of pharmacological inhibition of PL and IL neurotransmission on blood pressure and heart rate responses evoked by chemoreflex activation using KCN (i.v.) in conscious rats. Bilateral microinjection of 200 nl of the unspecific synaptic blocker CoCl(2) (1 mm) into the PL evoked a significant attenuation of the pressor response, without affecting the chemoreflex-induced heart rate decrease. However, IL local synapse inhibition evoked no changes in cardiovascular responses induced by chemoreflex activation. Thus, our results suggest that the pressor but not the bradycardiac response to chemoreflex activation is, at least in part, mediated by local neurotransmission present in the PL cortex, without influence of the IL cortex.     

Renal hypertension following aortic constriction is abolished by angiotensin II converting enzyme inhibitor,but not by low-salt diet

This study evaluates the role of different sodium intakes and the role of angiotensin II in the development and the maintenance of renovascular hypertension in rats with constriction of the aorta proximal to the renal arteries. The rats were studied 3 weeks after surgery when the hypertension was well established. Glomerular filtration rate was decreased and filtration fraction was increased in rats with proximal aortic constriction. Low and high salt intakes had no effect on glomerular filtration and filtration fraction. Treatment with angiotensin II converting enzyme inhibitor increased the glomerular filtration rate and reduced the filtration fraction in rats with proximal aortic constriction to the same levels as in control rats. Serum levels of angiotensin II were about the same in rats with proximal aortic constriction as in control rats.     

Medullary serotonergic neurones modulate the ventilatory response to hypercapnia, but not hypoxia in conscious rats

Serotonergic neurones in the mammalian medullary raphe region (MRR) have been implicated in central chemoreception and the modulation of the ventilatory response to hypercapnia, and may also be involved in the ventilatory response to hypoxia. In this study, we ask whether ventilatory responses across arousal states are affected when the 5-hydroxytryptamine 1A receptor (5-HT_1A) agonist ( R )-(+)-8-hydroxy-2(di- n -propylamino)tetralin (DPAT) is microdialysed into the MRR of the unanaesthetized adult rat. Microdialysis of 1, 10 and 30 m m DPAT into the MRR significantly decreased absolute ventilation values     during 7% CO₂ breathing by 21%, 19% and 30%, respectively, in wakefulness compared to artificial cerebrospinal fluid (aCSF) microdialysis, due to decreases in tidal volume ( V _T) and not in frequency ( f ), similar to what occurred during non-rapid eye movement (NREM) sleep. The concentration-dependence of the hypercapnic ventilatory effect might be due to differences in tissue distribution of DPAT. DPAT (30 m m ) changed room air breathing pattern by increasing f and decreasing V _T. As evidenced by a sham control group, repeated experimentation and microdialysis of aCSF alone had no effect on the ventilatory response to 7% CO₂ during wakefulness or sleep. Unlike during hypercapnia, microdialysis of 30 m m DPAT into the MRR did not change the ventilatory response to 10% O₂. Additionally, 10 and 30 m m DPAT MRR microdialysis decreased body temperature, and 30 m m DPAT increased the percentage of experimental time in wakefulness. We conclude that serotonergic activity in the MRR plays a role in the ventilatory response to hypercapnia, but not to hypoxia, and that MRR 5-HT_1A receptors are also involved in thermoregulation and arousal.     

Physiological response in rats to protein conjugates of angiotensin II during long-term immunization

P. K. Anokhin Research Institute of Normal Physiology, Academy of Medical Sciences of the USSR. Institute of Biological and Medical Chemistry, Academy of Medical Sciences the USSR, Moscow. (Presented by Academician of the Academy Medical Sciences K. V. Sudakov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 110, No. 12, pp. 563–565, December, 1990.     

Realized immune response is enhanced in long-lived puc and chico mutants but is unaffected by dietary restriction

The immune system is vital for the immediate survival of multicellular organisms by protecting them from the damaging effects of bacterial infections, viruses, and toxic molecules. It has been hypothesized that the immune system plays a pivotal role in determining longevity. We investigated the efficiency of the innate immune system in Drosophila carrying the longevity extending mutations puc (JNK signaling pathway, stress response) and chico (insulin signaling pathway), as well as animals subjected to dietary restriction (DR), which also extends lifespan. We found that puc heterozygous animals, as well as chico homozygous and heterozygous flies, have enhanced pathogen resistance. Surprisingly, diet manipulation did not reproducibly alter pathogen resistance, despite its significant effect on the expression of many immunity-related genes. Considering that chronic or frequent activation of the immune system results in reduced longevity, we postulate that the longevity extending potential of the above mutations may be partially obscured by parallel activation of the immune system. Such upregulation is not observed during DR, suggesting the presence of a mechanism that suppresses immune activity in diet-restricted animals.     

Chronic blockade of angiotensin II action prevents glomerulosclerosis, but induces graft vasculopathy in experimental kidney transplantation

Long-term renin-angiotensin system blockade is beneficial in a variety of renal diseases. This study examines the long-term (34 weeks) effects of the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor type I blocker L158,809 in the Fisher to Lewis rat model of chronic renal transplant failure. Treatment in allografted rats with lisinopril or L158,809 was initiated 10 days after transplantation, or at the time when proteinuria exceeded 50 mg/24 h. Untreated allografts and syngrafts served as controls. In contrast to syngrafts, untreated allografts developed proteinuria, hypercholesterolaemia, interstitial damage, and glomerulosclerosis. Lisinopril or L158,809 treatment in allografts starting at day 10 after transplantation completely prevented this, with the exception of interstitial damage, but this treatment also caused a reduction in blood pressure and renal function. Moreover, the intimal surface area of the renal arteries was dramatically increased in allografts treated with either lisinopril or L158,809 compared with untreated allografted rats. Treatment once proteinuria had developed was less effective in preventing glomerulosclerosis, but also caused less intimal expansion. Thus, chronic renin-angiotensin system blockade preserves glomerular morphology in the absence of proteinuria, but enhances intimal hyperplasia and reduces renal function in experimental transplantation. In view of these results, it should be questioned whether such treatment benefits renal transplant patients in the long term.     

Sexual motivation is demasculinized, but not feminized, in prenatally stressed male rats

Sexual motivation and copulation in male rats are associated with dopamine release in the nucleus accumbens. Demasculinized copulatory behavior has been demonstrated in prenatally stressed adult male rats. We have previously reported that approximately 80% of prenatally stressed male rats do not exhibit copulation and that no significant changes in nucleus accumbens dopamine release are seen during exposure to estrous females. In the present study, we investigated whether prenatal stress affects sexual motivation in these animals as adults. Pregnant Wistar rats were subjected to immobilization stress for two hours daily from day 15-19 of gestation. The prenatally stressed male offspring at the age of 3 months were allowed contact with receptive female rats for a 30 min period per week for 10 weeks; then, between the age of 5 and 6 months, their sexual motivation and copulatory activity were measured. Sexual motivation was measured in terms of sexual partner preference. The number of visits and the duration of each visit to an estrous female (stimulus female) or to a sexually active male rat (stimulus male) were recorded. Compared with control males, prenatally stressed male rats showed a significantly lower number of visits and a shorter duration of each visit to stimulus females. Prenatally stressed males showed no preference for male or female stimulus rats in terms of the number of visits and the duration of each visit, whereas control rats showed a significantly higher number of visits and duration of visits to female stimulus rats than male stimulus rats. A significant decrease in copulatory activity was observed in the prenatally stressed male offspring compared with control male rats, with most of the prenatally stressed males failing to show copulation. In vivo microdialysis experiments were performed on the nucleus accumbens with concurrent observation of sexual behavior. The prenatally stressed rats that did not exhibit copulation showed no significant changes in nucleus accumbens dopamine release during exposure to a stimulus male behind a wire-mesh barrier and the amount of dopamine release remained at the basal levels during actual physical contact. These results, combined with those of our previous report, indicate that sexual motivation in prenatally stressed male rats is demasculinized, but not feminized.     

Pre-weaning handling reduces adrenocorticotropin response to novel but not to noxious stimuli in adult rats

Effects of handling stimuli given to the rat during pre-weaning period were investigated on plasma immunoreactive (ir) adrenocorticotropin (ACTH) level after electric footshocks or novel audiovisual stimuli in adult life. Plasma ir-ACTH levels after footshocks did not significantly differ between non-handled control and previously handled rats, while the hormone level after novel audiovisual stimuli was significantly lower in handled than in the control rats. These results demonstrate that pre-weaning handling reduces ACTH response to novel audiovisual stimuli but not to footshocks in adult life, and thus suggest the possibility that stress during pre-weaning period affects differentially the developmental plasticity of the hypothalamo-pituitary axis.     

In the rat, citrullinated autologous fibrinogen is immunogenic but the induced autoimmune response is not arthritogenic

Conversion of arginyl to citrullyl residues (citrullination) is essential for the formation of the epitopes recognized by rheumatoid arthritis (RA)-associated autoantibodies to citrullinated proteins (ACPA). ACPA are secreted by plasma cells of the rheumatoid synovial tissue where their major target, citrullinated fibrin, is abundant. Although numerous arguments suggest that ACPA play an important role in RA, their pathological relevance remains to be established. In the present study, we assessed the immunogenicity and arthritogenicity of complete Freund's adjuvant-emulsified autologous citrullinated (C-rFBG) or non-citrullinated (NC-rFBG) fibrinogen in Lewis (LEW) and Brown-Norway rats, which exhibit drastic differences in their susceptibility to induced autoimmune diseases. NC-rFBG induced no antibody response. In contrast, a single injection of C-rFBG induced an IgG response directed mainly to citrullinated determinants of rFBG. However, all rat strains remained devoid of clinical and histological signs of arthritis up to 3 months after C-rFBG inoculation. Next, in LEW rats, we tested whether autoimmunity to C-rFBG could aggravate acute ankle arthritis triggered by intra-articular injection of incomplete Freund's adjuvant (IFA). However, such arthritis evolved identically in the presence or absence of anti-C-rFBG autoantibodies. However, IFA-injected joints were devoid of citrullinated fibrin deposits. Therefore, citrullination allows breakdown of immunological tolerance but the autoimmune response developed is not spontaneously arthritogenic. Whether or not it can aggravate arthritis with citrullinated fibrin deposits remains to be evaluated.     

Hormone-dependent aggression in male rats is proportional to serum testosterone concentration but sexual behavior is not

Male hooded rats were castrated and implanted with Silastic capsules (1.57 mm i.d.; 3.18 mm o.d.) having a testosterone-filled space 0, 7, 22, 60, or 90 mm long. All animals were returned to their original group cages for a three-week period to allow hormone concentrations and behavioral tendencies to stabilize. Each male was then housed with an intact female in a large cage. Aggression by the male toward an unfamiliar male was tested at weekly intervals for three weeks. Sexual behavior with an estrogen/progesterone-primed ovariectomized female was tested on each of the subsequent two weeks. Serum testosterone was measured during the following week. The frequency of aggression was correlated with serum testosterone concentration up to the normal level and did not increase with higher serum testosterone concentrations. In contrast, sexual behavior was virtually absent in animals with no testosterone replacement and normal in all other groups. These results demonstrate a clear dissociation in the dependence of hormone-dependent aggression and sexual behavior on serum testosterone concentration. In a male cohabiting with a female, sexual experience activates hormone-dependent aggression toward an unfamiliar male but the level of aggression that develops depends on the serum testosterone concentration in the resident male.     

Hippocampal long-term potentiation is reduced in mature compared to young male rats but not in female rats

Aging is associated with a decline in cognitive function which could be due to reduced synaptic plasticity. Hippocampal long-term potentiation (LTP) is an activity-dependent form of increased transmission efficacy at synapses that is considered the basis for some forms of learning and memory. We studied the N-methyl-d-aspartic acid (NMDA) receptor-dependent LTP in the CA1 region of hippocampus in young (2 months) and mature (8 months) male and female rats. We have found that in young male rats the tetanus increased the magnitude of excitatory post-synaptic potentials to 204+/-10% of basal while in mature male rats the magnitude of the LTP was significantly lower reaching only 153+/-11% of basal. This decrease did not occur in female rats. Similar changes occurred in the content of the NMDA receptor subunits NR1 and NR2A in hippocampus. The amount of both subunits was reduced significantly (15-16%) in hippocampus of 8-month-old compared with 2-month-old male rats. This decrease was not observed in female rats. Moreover, there is a significant correlation between the content of NR1 subunit and the magnitude of the potentiation. These data suggest that some of the neurobiological changes induced in hippocampus by aging are different in males and females.     

Effects of an angiotensin inhibitor on adrenocortical response to angiotensin II, ACTH, and K.

A competitive inhibitor of angiotensin II has been studied in nephrectomized dogs treated with dexamethasone to suppress ACTH secretion. The inhibitor, [1-sarcosine, 8-alanine]angiotensin II (P113), has been shown by previous investigators to inhibit the pressor action of angiotensin II but not the pressor effect of other pressor agents. The present experiments demonstrate that P113 inhibits the stimulation of aldosterone secretion by angiotensin II but not by ACTH or potassium infusions. Therefore, P113 appears to be a specific inhibitor of angiotensin's action on both vascular and adrenocortical tissue. In this dog preparation, P113 has a mild nondose-related agonistic action on the blood pressure and a nonsignificant action on aldosterone secretion, although in some dogs P113 appears to have a definite agonist effect.     

Central but not peripheral glucoprivation is impaired in monosodium glutamate-treated rats

In the present study, newborn male Wistar rats were injected, subcutaneously, five times, every other day, with monosodium glutamate (MSG, 4 g/kg bw) or saline (as control, C), during the neonatal period. MSG animals developed destruction of the arcuate nuclei (ARC) with absence of NPY-immunoreactive cell bodies, which impaired both the food intake (baseline) and the 2-deoxy-D-glucose (2DG) glucoprivic feeding response. Increases in the immunoreactivity of corticotropin-releasing hormone-cell bodies in the paraventricular nuclei might have developed to compensate for the atrophy of the pituitary in MSG-treated rats. After systemic 2DG injection, neither the C nor the MSG rats increased their food intake, but they showed similar hyperglycemic responses, whereas plasma free fatty acids (FFA) increased only in the C group. In other groups, 2DG, norepinephrine (NE), neostigmine (NEO) and saline were intracerebroventricularly (i.c.v.) administered. In this condition, impairment of the hyperglycemic and food intake responses, associated to a lower increase in plasma FFA levels, were observed. As opposed to this, the MSG treatment gives support to NE effects, enhancing food intake, as well as plasma glucose and FFA levels. After NEO, plasma glucose increased only in the MSG group, while plasma FFA levels were elevated in the C rats. Taken together, the results obtained after MSG treatment point to a separate neural control of the hyperglycemic response and of the lipid mobilization when stimulated by central 2DG, NE or NEO administration. It seems likely that the excitatory neural pathway that controls lipid metabolism and is present in C rats was destroyed by the MSG treatment.     

Zona incerta lesions: regulatory drinking deficits to intravenous NaCl, angiotensin, but not to salt in the food

Rats with bilateral damage to the anterior zona incerta (ZI) showed small and delayed drinking responses after IP hypertonic NaCl injection, but they normally excreted most of the salt load within 6 hr. The impaired drinking responses were also evident after nonpainful intravenous (IV) NaCl infusions. After nephrectomy, rats with complete ZI lesions did not drink within 24 hr of the NaCl infusion. Rats with less complete lesions showed reduced and delayed drinking. In contrast to these profound osmoregulatory drinking impairments, all of the lesioned rats increased their water to food ratio when fed a 3% NaCl-supplemented diet. ZI lesioned rats did not drink in response to IV infusions of angiotensin II. The role of the ZI in drinking behavior is discussed in terms of the paradigm-dependent nature of these results, and parallels with other findings are considered.     

Endurance enhancement related to the human angiotensin I-converting enzyme I-D polymorphism is not due to differences in the cardiorespiratory response to training

Human physical performance is strongly influenced by genetic factors. We have previously reported that the I variant of the human angiotensin I-converting enzyme (ACE) gene is associated with greater endurance performance in mountaineers and Olympic runners and improved performance in army recruits. In this study we examined whether this effect is mediated by improvements in cardiovascular fitness with training in 58 army recruits homozygous for the insertion (I, ACE genotype II) or deletion (D, ACE genotype DD) allele. A submaximal and maximal exercise protocol was used to calculate both the heart rate/oxygen uptake ( ) relationship and changes in maximal oxygen uptake ( ), respectively. There was no significant intergroup difference in at baseline (P=0.19) or after training (P=0.22). There was no difference between genotypes with training in the heart rate/ elevation (P=0.79 for the mean difference in mean adjusted heart rates). However, at all exercise intensities in the submaximal test was lower for all subjects after training and at 80 W the reduction in was greater for the II subjects compared to DD subjects [mean(SEM)] [1.6 (0.27) and 0.68 (0.27) ml kg^–1 min^–1, respectively; P=0.02 for mean difference]. The I/D polymorphism may play a role in enhanced endurance performance but this is not mediated by differences in or the heart rate/ relationship in response to training. Electronic Publication