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Biomedical subjects

D A Blizard

Publications and source records attributed to D A Blizard.

At least 19 recordsLinked to original sources
PubMed1992

Maternal influences on cardiovascular pathophysiology.

Elevated blood pressure (BP) is of special clinical significance because of its association with pathophysiologies such as heart disease, renal failure, and stroke. We described the development of a protocol for use with hypertensive rats in which prepubertal exposure to a high salt (8% NaCl) diet results in a pathophysiological syndrome including rapid increase in BP, failure to maintain normal weight gain, renal damage, cerebrovascular lesions, and early mortality. These phenomena are described for the inbred spontaneously hypertensive rat (SHR), and for reciprocal F1 hybrids of a cross between SHR and the Dahl salt-sensitive (SS/Jr) inbred strain. The study with reciprocal F1s revealed striking effects of maternal environment on pathophysiological response to a high salt diet. F1s nurtured by SHR mothers weighed less at 35 days of age, and after exposure to the high salt diet suffered more rapid BP increases, greater incidence of stroke, body weight loss, and mortality, than F1s nurtured by SS/Jr dams. These results suggest that maternal mediation of the nutritional status of the animal may play an important role in determining susceptibility to elevated BP and subsequent pathophysiology associated with exposure to a high salt diet. The implication of these findings for human hypertension is briefly discussed.

Animals↗
PubMed1992

Recombinant-inbred strains: general methodological considerations relevant to the study of complex characters.

If appropriately determined, recombinant-inbred (RI) strain means provide an excellent method for determining genetic correlations among complex characters. However, little systematic attention has been paid to important environmental influences on strain means such as random effects due to litter membership or systematic maternal influences, which are inevitably confounded with genetic effects. It is suggested that users of RI strains would do well to control for litter effects by sampling appropriately from many litters and assessing the potential role of maternal influences by appropriate fostering procedures. Concern for these and other environmental sources of variation has caused reliability of strain means to emerge as an important issue in studies with RIs which focus on complex characters. Examples of estimating the reliability of RI strain means are provided to draw attention to the value of this kind of information in both gene-mapping studies and genetic correlational analyses. In addition, particularly in the case of behavioral tests which are susceptible to considerable day-to-day variation, repeated testing of the same animals can serve to diminish the influence of extreme deviations which are due to random variations in the manner in which the test is conducted on any given day. The advantages of RIs for gene mapping are well established. However, via the power of genetic correlational analysis, the RI methodology is emerging as a major alternative method, e.g., as distinct from lesion studies, pharmacological interventions, etc., in the bio-behavioral sciences to explore relationships between different domains of inquiry. Via its cumulative and integrative power, it is likely to make a major contribution to investigations of relationships between complex characters at various levels of and this application which should be considered separately from its application to gene mapping.

Animals↗
PubMed1991

Genetic and maternal influences in rat models of spontaneous and salt-induced hypertension.

Genetic and maternal influences on hypertension were studied by comparing the SHR and SS/Jr inbred rat strains and their reciprocal F1 hybrids under identical conditions. When raised on a low salt (LS) diet (0.3% NaCl), SHR rats had higher systolic blood pressure (SBP) than SS/Jr rats by 9 weeks of age. Direct recordings from freely moving rats at 18-24 weeks confirmed this difference. Placement on a high salt (HS) diet (8% NaCl) at 5 weeks of age significantly increased SBP within 3 weeks in all groups, although the degree of increment was significantly smaller in SHR females. Inbred strains had higher SBP than their F1 hybrids when measured indirectly and directly from arterial cannulae. After exposure to HS diet, F1 females reared by SHR dams exhibited larger increments in SBP, greater weight loss, and greater debilitation and associated mortality than F1 females reared by SS/Jr dams. Differences between inbred strains and F1s maintained on LS diet were consistent with dominance for low BP, and differential genetic control of hypertension in each inbred strain. F1 differences demonstrated that maternal factors affected body weight in weanlings, pressor response to HS diet, and associated debilitation.

Animals↗
PubMed1991

Circadian rhythms of heart rate and mean arterial pressure in chronically instrumented pregnant rats.

With the use of a chronic preparation to directly monitor blood pressure and heart rate in pregnant rats, continuous data were obtained over the last half of gestation in normotensive rats. Over this time span, the animals showed significant decreases in blood pressure and increases in heart rate. Heart rate exhibited marked and consistent circadian rhythmicity with peaks occurring near the midportion of the dark phase of the 24-hour cycle. Blood pressure rhythms were less prominent and peaked later. The trends observed in blood pressure and heart rate over gestation suggest that the pregnant rat is a useful model for studying the cardiovascular effects of pregnancy.

Animals↗
PubMed1991

Ethanol preference in the Harrington derivation of the Maudsley Reactive and Non-Reactive strains.

Ethanol intake was explored in the Harrington derivation of the Maudsley Reactive and Maudsley Non-Reactive rat strains (MR/Har and MNRA/Har). When 5% and 10% ethanol solutions were presented as the sole source of fluid (1-bottle test), MR/Har rats, respectively, ingested 15% more, or 9% less, than their baseline water intake, whereas MNRAs ingested 6% less, or 42% less than their baseline intake. However, because MNRA/Har rats drank significantly more water than MR/Har's under ad libitum conditions (MNRA/Har, 46.6 +/- 1.83 ml; MR/Har 32.45 +/- 1.64 ml/24 hr), males and females of the two strains ingested a similar amount of ethanol in the 1-bottle test (5% ethanol, 4-7; 10% ethanol, 6-12 g/kg body weight/24 hr). In 2-bottle free-choice tests administered after an extended period of forced ethanol consumption, MR/Har male and female rats exhibited a strong ethanol preference (X = 80%) and consumed a larger amount of ethanol (MR/Har, 7-13; MNRA/Har, 6-9 g/kg body weight/24 hr) than MNRA/Har's. Across all conditions, females of both strains ingested a greater relative amount of ethanol than males. The strain difference in ethanol preference was found to be independent of prior exposure to ethanol because it was also found when 2-bottle free-choice tests were carried out in naive animals (Experiment 2). The pattern of development of ethanol preference in individual animals was characterized by abrupt onset, after variable periods of exposure to the 2-bottle choice test, and maintenance of strong ethanol preference thereafter. The extensive behavioral and biological definition of the Maudsley strains is a valuable asset in attempting to elucidate the biobehavioral correlates of ethanol preference.

Alcohol Drinking↗
PubMed1991

The effect of a high salt diet and gender on blood pressure, urinary protein excretion and renal pathology in SHR rats.

A high salt diet produced increases in SBP, urinary protein excretion (UPE) and renal vascular lesions (RVL) across groups of male and female SHR rats which were allowed to develop moderate or excessive increases in SBP. A highly significant linear relationship between SBP and log-transformed UPE was found when the data from all groups were analyzed together. Males developed high blood-pressure more rapidly, and exhibited more severe RVL and greater UPE than females. Two results prevent the conclusion that the elevated UPE was simply due to the adverse effects of high BP on the kidney. First, the relationship between SBP and UPE across groups could not be demonstrated when regression analyses were performed within individual dietary sub-groups. Secondly, gender differences in UPE were highly significant by analysis of covariance adjusting for individual differences in SBP. The increases in SBP and UPE may be independent consequences of ingestion of a high salt diet.

Animals↗
PubMed1991

Dietary salt and accelerated hypertension: lack of sub-line differentiation in spontaneously hypertensive rat stocks from the United States.

We compared the ability of a high-NaCl diet to produce blood pressure elevation in spontaneously hypertensive rats (SHR) from the major North American commercial suppliers (Harlan, Taconic Farms, Charles River) and SHR and stroke-prone SHR (SHRSP) from the National Institutes of Health (NIH). Animals were raised on a low-NaCl diet containing 0.30% NaCl and placed on an 8.0% NaCl diet at 37 days of age. In males, the high-NaCl diet produced large increments in blood pressure within 2-4 weeks, which were similar in magnitude for all SHR derivations. In females, increments in blood pressure occurred more slowly than in males but, in most SHR derivations, the absolute blood pressure level eventually reached was similar to that seen in males. The present findings provide no evidence of sub-line differentiation among SHR stocks from the United States regarding the blood pressure-augmenting effects of increased levels of NaCl and are consistent with the results of DNA fingerprinting studies, which have not found any genetic variation between SHR from different colonies. We speculate that the pervasive gender differences in the blood pressure response to the high-NaCl diet in SHR may reflect gender differences in food intake, and hence the dose of NaCl received, rather than intrinsic differences between males and females. On the other hand, the lack of significant gender differences in blood pressure response to the high-NaCl diet in SHRSP may reflect the genetic differences which are known to exist between this strain and the main SHR stemline.

Animals↗
PubMed1990

Resource sharing in rat gestation: role of maternal cardiovascular hemodynamics.

There is a substantial decrease in blood pressure (BP) in late pregnancy in the laboratory rat. It is so pronounced that manipulations that produce sustained elevations in BP in nonpregnant animals have little or no effect during pregnancy. It is commonly believed that this decrease in BP is a consequence of a large decrease in total peripheral resistance resulting from the passive combination of the placental vasculature with a preexisting maternal vasodilation. An alternative view is presented here. We suggest that, in small mammals like the laboratory rat, pregnancy severely challenges the ability of the maternal cardiovascular system to meet its metabolic demands, so that during the last stages of maturation of the low-resistance placental circulation delivery of vital metabolic or nutritional substances to the maternal vasculature becomes marginal. When the so-called maternal hemodynamic preservation threshold is reached, a pronounced and wide-spread vasodilation occurs to maintain adequate perfusion of maternal organs. The late-gestational decrease in BP thus reflects a dynamic interaction between the maternal and placental circulations rather than reflecting their passive combination. The hypothesis provides a framework for the integrated discussion of a number of important phenomena: the fact that hypertensive rats exhibit a larger decrease in BP in late gestation than normotensive rats; the existence of a positive association between litter size and the magnitude of the late-gestational decrease in BP; and, finally, the well-established ability of the food-restricted pregnant rat to compartmentalize its nutritional resources.

Animals↗
PubMed1990

Modification of stroke susceptibility by genotype-dependent maternal influences.

The influence of the prenatal and postnatal maternal environment on stroke susceptibility was evaluated by reciprocally crossing the spontaneously hypertensive (SHR) and the Dahl salt-sensitive (SS/Jr) inbred rat strains to produce reciprocal F1 hybrids that were nurtured, respectively, during prenatal and postnatal life by SHR or SS/Jr mothers. Following placement on a high-salt diet containing 8% NaCl at 35 days of age, F1 rats reared by SHR mothers had shorter survival times and were more likely to die with cerebral hemorrhage than F1s reared by SS/Jrs. Across reciprocal F1 female groups, enhanced susceptibility to stroke was associated with greater elevations of systolic blood pressure, but this association was not seen across reciprocal F1 male groups. There was also an association between blood pressure and stroke within each F1/gender subgroup: Rats eventually suffering strokes developed higher blood pressure after placement on the high-salt diet than rats that did not suffer stroke. Lower day 35 body weights (before exposure to the high-salt diet) were associated with greater likelihood of stroke both across the reciprocal F1 groups, and within three of the four F1/gender subgroups. The differences in stroke susceptibility between the reciprocal F1 groupings may be due to systematic differences in the prenatal and/or postnatal environments of SHR and SS/Jr mothers and may be mediated by variations in the nutritive capacity of the two inbred mothers.

Animals↗
PubMed1990

Microtransferrinuria and microalbuminuria. II. In the rat.

We studied albumin and transferrin excretion in the normal and diabetic rat: (1) The rat secretes small concentrations of albumin and transferrin in the urine. (2) The secretion depends on the strain and was highest in the Kyoto spontaneously hypertensive rat. (3) The secretion of these two proteins in the rat is quite dependent on age and sex. The level increases dramatically with age. The secretion is much higher in the male compared to the female. This difference is observed after puberty. The changes in transferrin relative to those in albumin are much higher. (4) In streptozotocin-induced diabetes, the concentration of albumin and transferrin expressed as milligrams per liter decreases; however, the output/24 h or per gram creatinine is increased with a greater increase in transferrin output relative to that of albumin. The similarities and differences between excretion of these two proteins in the human and the rat as well as their importance are discussed.

Aging↗
PubMed1988

The locus ceruleus: a possible neural focus for genetic differences in emotionality.

The Maudsley Reactive and Non-Reactive strains have been developed as a model for the study of individual variations in stress-reactivity, and many differences in biobehavioral systems have been found between them. This review discusses limitations of the 'emotionality' construct in accounting for differences between the Maudsley strains and offers an alternative, theoretical approach. Amaral and Sinnamon have proposed that the locus ceruleus (LC) plays a stress-attenuating role in mediating behavioral, physiological and neuroendocrine response to prepotent, emergency-provoking stimuli and, building upon this formulation, it is proposed that the LC has been an important focus for gene action in the Maudsley model. It is suggested that the LC of the Non-Reactive strain is more strongly activated by stressful stimuli than the LC of Reactive rats, and is the basis of many of the behavioral and physiological differences between them. Behavioral and biochemical evidence consistent with this proposition is reviewed. Identification of the LC as a target for gene-action in the Maudsley model has an important advantage. It substitutes variations at a specific anatomic location in the brain for a loosely defined construct like emotionality, and the hypothesis is amenable to empirical tests by a variety of experimental approaches.

Animals↗
PubMed1988

Genetic influences on agonist binding to cardiac beta-receptors.

Regulation of beta-adrenoceptor-agonist function in the Maudsley Reactive (MR/Har) and the Maudsley Non-Reactive (MNRA/Har) rat strains was assessed by comparison of isoproterenol competition for [125I]iodocyanopindolol (ICYP) binding sites in crude left ventricular homogenate preparations. Non-linear, least-squares analysis of isoproterenol competition for ICYP binding in the absence of guanine nucleotide revealed different proportions of high- and low-affinity receptors in the two strains; MR/Har rats (59 +/- 3.3%) had a significantly greater proportion of receptors in the high-affinity state than the MNRA/Har rats (41 +/- 4.5%). Addition of the non-hydrolyzable guanine nucleotide analog guanylylimidodiphosphate (Gpp(NH)p) converted receptors to the low-affinity state. Analysis of Gpp(NH)p concentration-response curves in left ventricular homogenates of the two strains revealed that the MR/Har strain had a significantly (P less than 0.02) lower EC50 for guanyl nucleotide inhibition of isoproterenol competition for ICYP binding than the MNRA/Har. Confirming previous experimental results, a significantly (P less than 0.04) greater density of ventricular beta-receptors was found in MR/Har rats (13.16 +/- 0.92 fmol/mg protein) than in MNRA/Har rats (10.81 +/- 0.63 fmol/mg protein). Left ventricular catecholamine levels were found to be correlated inversely with beta-adrenoceptor density in the two strains; norepinephrine (NE) and epinephrine (EPI) concentrations (ng/mg protein) in left ventricle were 12.19 +/- 0.94 for NE and 0.165 +/- 0.038 for EPI in MNRA/Har, and 8.73 +/- 0.95 and 0.018 +/- 0.018, respectively, in MR/Har. All other parameters of agonist interactions with the cardiac beta-adrenoceptor for the MR/Har and MNRA/Har rat strains were similar [the IC50 for displacement of ICYP binding by isoproterenol, the accompanying Hill coefficients in the Gpp(NH)p present and absent condition, the Kd of the high- and low-affinity states in the absence of Gpp(NH)p, and the Kd of the uniform low-affinity state in the presence of Gpp(NH)p]. We hypothesize that the strain-dependent differences in high-affinity state formation reported here may account for some of the in vivo differences in cardiovascular function previously demonstrated in the Maudsley rats.

Adrenergic beta-Agonists↗
PubMed1988

Effects of stress and chronic propranolol infusion on cardiac beta-receptor function in the Maudsley Reactive and Non-Reactive rat strains.

The effects of beta-adrenoceptor blockade on left ventricular beta-receptor characteristics were evaluated in the Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rat strains. After propranolol infusion for one week administered by subcutaneously implanted osmotic minipumps, differences in beta-adrenoceptor-agonist interactions between strains were assessed by comparison of isoproterenol competition for [125I]iodocyanopindolol (ICYP) binding sites in crude left ventricular homogenate preparations from both strains. Propranolol exposure had no significant effect on the binding parameters investigated (Bmax, Kd, % receptors in high affinity state, IC50). In contrast to previous observations in naive animals, these experiments revealed no strain differences in the sham-implanted Maudsleys in any of the left ventricular beta-adrenoceptor parameters investigated. We hypothesize that the surgical procedures and/or presence of the plastic inserts acted as stressors in the Maudsley strains and thus altered beta-adrenoceptor function. This hypothesis is supported by the observation that exposure to another stress (footshock) also eliminated strain differences in ventricular beta-receptor binding variables.

Animals↗
PubMed1987

Contrasting effects of social stress and foot-shock on acute cardiovascular response in salt-sensitive rats.

Repeated defeat by an aggressive resident attacker rat produces a large decrement in systolic blood pressure (SBP) in male S/JR rats. The present experiments compared the cardiovascular (CV) response of male S/JR rats exposed either to repeated defeat, or to a common laboratory stressor, electric foot-shock. Using the tail-cuff method of determining SBP, the results of Experiment 1 replicated the previous finding that on the second and subsequent exposures, repeated defeat is followed by an acute decrement in SBP (30-40 mm Hg in magnitude). In contrast, repeated exposures to foot-shock were followed by acute increases in SBP (20-40 mm Hg) and in heart rate (HR). In Experiment 2, mean arterial blood pressure (MAP) and HR were measured directly from chronically cannulated male S/JR rats after defeat or exposure to foot-shock: again, defeated males exhibited an acute decrease in MAP, whereas the MAP of rats exposed to foot-shock tended to increase. In Experiment 3 we varied the parameters of shock intensity and the social context of shock exposure. Male S/JR rats exposed to more intense foot-shock than in the previous experiments or to foot-shock while paired with one of the resident attacker rats all exhibited acute increases in SBP. The results of these experiments indicate that CV response to defeat may be qualitatively different from CV response to foot-shock.

Aggression↗
PubMed1987

Acute stress increases plasma concentrations of atrial natriuretic peptides.

5 min exposure of inbred Maudsley Reactive male rats to intermittent foot-shock resulted in an approximate doubling of plasma atrial natriuretic peptides ANP (Control grp mean = 62.12 +/- 8.74; Stressed grp mean = 128.70 +/- 26.63 pg/ml) and 25 min exposure resulted in a three-fold increase (Stressed grp mean = 187.88 +/- 39.24 pg/ml). In the second experiment exposure of genetically heterogeneous Wistar male rats to 15 min of intermittent foot-shock produced a 10-fold increase in plasma ANP (Control grp mean = 45.76 +/- 6.05; Stressed grp mean = 471.20 +/- 58.49 pg/ml). The magnitude of the increase in plasma ANP produced by acute stress is as large as the increase caused by volume expansion and administration of various pharmacological agents and therefore delineation of biological role of ANP must take account of its potential role as a stress-hormone.

Animals↗
PubMed1986

Effects of social defeat on acute cardiovascular response in salt-sensitive and salt-resistant rats.

We studied the effects of social stress (SS) and a high salt diet on systolic blood pressure (SBP) and heart rate (HR): S/JR male rats (which exhibit marked elevations in SBP when placed on a high sodium diet) and R/JR male rats (which are resistant to the BP-elevating effects of a high sodium diet) were maintained on a low sodium diet (0.3% NaCl) or placed on a high sodium diet (8% NaCl). Within each dietary condition independent groups were either exposed to SS, by placement in the cage of a trained fighter male (Long-Evans breed) for 25 min, or exposed to no stress. The dietary regimen was imposed for 10 days with stress exposures on Days 1, 2, 3, 5, 7, and 9, with SBP and HR measured indirectly by tail plethysmography 3 min following exposure to SS. SS produced an acute decrease in SBP (20-30 mm Hg) in S/JR rats on the second and subsequent exposures, but did not affect HR. SS did not affect SBP of R/JR rats, but did produce a significant elevation of HR. Maintenance on the high sodium diet increased SBP in S/JR, but not R/JR, rats when it was measured on the eighth (no stress) day, but SS obscured the effects of diet on SBP on days when rats were stressed. Following exposure to attacks, defeated SS rats displayed an upright submissive posture relatively late during the first stress exposure when no change in SBP was observed after SS in S/JRs, but displayed the submissive posture immediately and with long duration on the second and subsequent exposures when a marked decrement in SBP was seen.

Aggression↗