Natriuretic peptide receptor 1 expression influences blood pressures of mice in a dose-dependent manner

Activation of the natriuretic peptide system lowers blood pressure and causes the excretion of salt. Atrial natriuretic peptide and B-type natriuretic peptide are the humoral mediators of this effect; they act primarily by binding to membrane-bound natriuretic peptide receptor A (NPRA) and stimulating its intrinsic guanylate cyclase activity. To study whether genetically determined differences in NPRA expression affect blood pressure we have generated mice with one, two, three, or four copies of the gene encoding NPRA (Npr1 in the mouse). Atrial natriuretic peptide-dependent guanylate cyclase activity ranged progressively from approximately one-half normal in one-copy animals to twice normal in four-copy animals (P < 0.001). On different diets (0.05%, 2%, and 8% NaCl), the blood pressures of F1 male mice having only one copy of Npr1 averaged 9.1 mmHg (1 mmHg = 133 Pa) above those of wild-type two-copy males (P < 0.001), whereas males with three copies of the gene had blood pressures averaging 5.2 mmHg below normal (P < 0.01). The blood pressures of the one-copy F1 animals were significantly higher (by 6.2 mmHg; P < 0.01) on the high-salt than on the low-salt diet. The blood pressures of four-copy F3 males were significantly lower (by 7 mmHg; P < 0.05) on the high-salt than on the low-salt diet. These results demonstrate that below normal Npr1 expression leads to a salt-sensitive increase in blood pressure, whereas above normal Npr1 expression lowers blood pressures and protects against high dietary salt.     

Opposite role of interferon-gamma and interleukin-4 on the regulation of blood pressure in mice

There is growing evidence that T-lymphocyte dysfunction contributes to the development of hypertension. IL-4 and IFN-gamma are important regulators of T-lymphocyte function. Therefore, we investigated the effect of neutralizing antibodies against IL-4 (alpha-IL-4) and IFN-gamma (alpha-IFN-gamma) on the development of hypertension in NZBNZWF1 hybrid compared to normotensive NZW control mice. Antibody-producing cells were encapsulated and injected intraperitoneally in mice at 6,8 and 10 weeks of age. This treatment resulted in significant levels of antibody in the serum. At 12 weeks of age blood pressure was recorded under anesthesia. Mean arterial blood pressure (MAP) increased in NZBNZWF1 hybrids between the age of 6 and 12 weeks. This increase was inhibited by treatment with alpha-IL-4, but was not affected by alpha-IFN-gamma. Treatment with alpha-IL-4 did not influence MAP in normotensive NZW or C57B1/6J mice. However, in these mice, treatment with alpha-IFN-gamma increases MAP. This increase in MAP by alpha-IFN-gamma was prevented by simultaneous treatment with alpha-IL-4. The present study demonstrates the influence of endogenous IL-4 and IFN-gamma on blood pressure.     

Participation of renal, but not of submaxillary renin in the homeostasis of the blood pressure after experimentally induced hypotension in mice

While hypotension elicited a marked increase in plasma renin concentration in conscious normal mice, no increase was provoked in previously nephrectomized mice in spite of the high renin content of their submaxillary glands. The role of the increased release of renal renin for the homeostasis of the blood pressure was shown by the decrease in pressure which followed blockade of the renin system. Contrary to Saralasin which did not change the blood pressure in nephrectomized mice, injections of SQ 20.881 did in some mice result in a decrease in blood pressure, which was probably caused by its ability to inhibit bradykininases. Both Saralasin and SQ 20.881 elicited marked increases in plasma renin in normal, but not in nephrectomized mice, showing that, while renal renin release is controlled by the plasma angiotensin II concentration, this does not apply to submaxillary renin release.     

Allogeneic bone marrow transplantation for acute leukaemia--IGCI experience. International Group for Chemo-Immunotherapy

1. The influence of strain and sex on the effect of enflurane and isoflurane and administration on heme metabolism was investigated to identify the animal model which could best reproduce the biochemical signs of acute intermittent porphyria. 2. Enflurane produced 35% and 80% increases in ALA-S activity only in CF1 male and female mice, respectively, whereas isoflurane induced 40% enzyme activity in CF1 male. 3. CF1 males showed around 35% decrease in blood PBGase and PBG-deaminase after administration of enflurane, whereas isoflurane provoked a striking inhibition (70%) in males of the C57 strain. 4. Enflurane produced alterations in heme synthesis, which would fit a model of acute porphyria in CF1 male mice. On the other hand, isoflurane would mimic biochemical alterations of this porphyria in C57 males.     

Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2

Thromboxane A2 (TXA2) is a labile metabolite of arachidonic acid that has potent biological effects. Its actions are mediated by G protein-coupled thromboxane-prostanoid (TP) receptors. TP receptors have been implicated in the pathogenesis of cardiovascular diseases. To investigate the physiological functions of TP receptors, we generated TP receptor-deficient mice by gene targeting. Tp-/- animals reproduce and survive in expected numbers, and their major organ systems are normal. Thromboxane agonist binding cannot be detected in tissues from Tp-/- mice. Bleeding times are prolonged in Tp-/- mice and their platelets do not aggregate after exposure to TXA2 agonists. Aggregation responses after collagen stimulation are also delayed, although ADP-stimulated aggregation is normal. Infusion of the TP receptor agonist U-46619 causes transient increases in blood pressure followed by cardiovascular collapse in wild-type mice, but U-46619 caused no hemodynamic effect in Tp-/- mice. Tp-/- mice are also resistant to arachidonic acid-induced shock, although arachidonic acid signifi-cantly reduced blood pressure in Tp-/- mice. In summary, Tp-/- mice have a mild bleeding disorder and altered vascular responses to TXA2 and arachidonic acid. Our studies suggest that most of the recognized functions of TXA2 are mediated by the single known Tp gene locus.     

Total cholesterol and high-density lipoprotein cholesterol in patients with non-insulin-dependent diabetes mellitus

Non-insulin-dependent diabetics often have quantitative changes in plasma lipid profiles characterised by higher triglycerides and lower HDL-cholesterol than the average population. This paper summarises the cross-sectional data (reported by the general practitioners participating in Medicos-Sentinela) concerning total and HDL-cholesterol in a cohort of non-insulin-dependent diabetics treated at primary care settings in Portugal. Total cholesterol and High Density Lipoprotein (HDL) associated cholesterol were significantly higher in women. Total cholesterol increased significantly with age (in women), regular alcohol intake, body mass index, systolic blood pressure and diastolic blood pressure (in males). HDL-cholesterol showed significant increase with age (both sexes and males only), gender, and alcohol intake in males. The increase in total cholesterol found in patients with regular alcohol intake is an infrequently reported finding.     

Evidence for an initial, thymus independent and a chronic, thymus dependent phase of DOCA and salt hypertension in mice

Treatment with desoxycorticosterone acetate (DOCA) and 1 per cent saline as drinking water for 21 days caused a significant and similar increase in blood pressure in haired mice, with a normal thymus function, as in nude mice with genetical aplasia of the thymus. After 57 and 78 days there was, however, a significantly more pronounced increase in blood pressure in haired than in nude mice. A marked degree of round cell infiltration around intrarenal vessels and degenerative changes including wedge-shaped infarcts were observed in the kidneys of the haired mice, commencing after 57 days of treatment, while no such changes were found in nude mice. Thymus grafting in nude mice, successively treated with DOCA and salt, conferred the ability to react with chronic hypertension and intrarenal vascular disease, equal to the reaction seen in haired mice. The present investigation has provided evidence for the existence of an initial thymus independent and a chronic thymus dependent phase of DOCA and salt hypertension in mice. It still remains an unsolved problem whether the secondary blood pressure fall observed in nude athymic mice is a direct consequence of the lack of perivascular cellular immune reactions, or caused by other defects in this strain of mice.     

Single lead acetate insult, testosterone therapy, and erythropoiesis in mice

Lead acetate (PbAc) was tested for its effects on the production and release of erythrocytes-that is, erythropoiesis-in ICR mice. Dose-survival data indicate that a dosage of 20 mg PbAc/100 g body weight represents the maximum tolerable treatment level. No differences in survival at the various levels of the salt were observed with regard to sex or age. For erythropoietic effects of PbAc, mice were injected on day O, and radioiron (59Fe) incorporation percentages were determined at daily intervals through day 8 for both erythrocytes and splenic tissue. Control mice received isotonic saline as the injectate. On day 3, the percentages obtained from PbAc-treated mice showed a decline, reaching their minimum value by day 4. Recovery from erythropoietic suppression appeared to be complete by day 6 or 7; no positive overshoots in 59Fe percentages were found following recovery. These trends were typical for both peripheral red blood cells and spleen. Testosterone was administered to mice receiving saline or PbAc on two consecutive days (days -1 and O). Radioiron uptake percentages for females receiving testosterone and saline showed an abrupt increase on day 4. No accelerative effect due to testosterone was found in recipient males. For females treated with testosterone and PbAc, the radioiron percentages for erythrocytes and spleen paralleled those for females receiving saline only. Male mice treated with both androgen and PbAc demonstrated 59Fe percentages typical of males treated with PbAc alone.     

Angiotensinogen in human essential hypertension

The candidacy of angiotensinogen for a role in the genetic basis of hypertension is supported by the observation that plasma angiotensinogen levels track with raised blood pressure through families. In addition, transgenic mice with overexpression of a rat angiotensinogen gene develop hypertension, and knockout mice with a disrupted gene and absent angiotensinogen production develop low blood pressure. There are now two studies in populations of white European origin and one in African Caribbeans providing support for a role of the angiotensinogen gene locus in human essential hypertension.     

Arterial hypertension in relation to life style and other cardiovascular risk factors. Epidemiologic study of a population of blood donors. Project AVIS

The objectives of this research were to determine the prevalence of essential and borderline hypertension in a population of blood donors and their families and to determine if there is a correlation between blood pressure and lifestyle and/or other cardiovascular risk factors. The study was comprised of 1976 individuals, of whom 1290 were men and 686 were women, aged 18-65 years. The prevalence of essential hypertension was 15.1% for males and 12.5% for females: the prevalence of borderline hypertension was 22.3% for males and 15.7% for females. The population was divided into two groups: the first group included only subjects (1170 men, 543 women) who did not regularly use drugs that could modify the blood pressure and the heart rate, the second group included the entire population. In the first group, the multiple regression analysis indicated, in order of importance: age, BMI (body mass index), and heart rate. These variables were important in determining the systolic blood pressure in both sexes, uricemia for males and glycemia for females. The diastolic blood pressure was dependent on BMI, heart rate, and alcohol in both sexes, and glycemia, LDL cholesterol, and uricemia in the men. In the second group, primary and borderline hypertension are significantly correlated with age, BMI, and uricemia in both sexes and glycemia in females. A program of health and nutritional education could modify some factors related to blood pressure, such as obesity and alcohol consumption. The result would be a reduction of the prevalence not only of essential and borderline hypertension, but also of metabolic diseases such as dyslipidaemias, diabetes and hyperuricemia, with a global reduction of the cardiovascular risk.     

Satisfying solutions? A review of some unresolved issues in the measurement of patient satisfaction

The present study was conducted to assess the pattern of body mass index (BMI) prevalence of obesity, and the association between obesity and other health-related problems in a Saudi population. The study was conducted in Queza district of Jeddah, Saudi Arabia. A systematic random sample of Saudi nationals aged 16 years and above were selected (total number 1037; 611 males and 426 females). The study population was clinically examined and a specially-designed questionnaire was administered to obtain the information. Anthropometric measurements, blood pressure and urine analysis were carried out. The collected data were analyzed using simple as well as multivariate statistical methods. It was observed that BMI significantly increased with age. The crude mean BMI was significantly greater in females compared to males. Prevalence of Grade I obesity among different age groups in males ranged from 15.7% to 43.0%, while in females the range was from 22.8% to 45.7%. Similar patterns for both genders were found for Grade II obesity (5.2%-18.9%; and 11.1%-47.8% respectively). Obesity was significantly associated with an increase in both systolic and diastolic blood pressure, where increase in BMI by one unit increased systolic blood pressure by 0.617 mm Hg, and diastolic blood pressure by 0.484 mm Hg. This relationship held true even after allowing for other confounding factors. The present study concluded that obesity is a problem prevalent in the community of Queza district. It is recommended that health education programs be implemented through primary health care services in the community to prevent this problem.     

Major histocompatibility complex class II expression and parathyroid autoantibodies in primary hyperparathyroidism

We evaluated whether kinins exert a protective action against the development of two-kidney, one clip (2K1C) hypertension, a model characterized by an activated renin-angiotensin system in the ischemic kidney and increased expression of the bradykinin (BK) B2 receptor in the contralateral kidney. BK B2-receptor knockout (B2-/-), wild-type (B2+/+), and heterozygous (B2+/-) mice underwent clipping of the left renal artery, with the other kidney remaining untouched. Basal systolic blood pressure (SBP, via tail-cuff plethysmography) was higher in B2-/- mice than in B2+/- or B2+/+ mice (121+/-2 versus 113+/-2 and 109+/-1 mm Hg; P<0.05 for both comparisons). SBP did not change from basal values after sham operation, but it increased in mice that underwent clipping. The increase in SBP was greater in 2K1C B2-/- mice than in B2+/- or B2+/+ mice (28+/-2 versus 14+/-2 and 14+/-2 mm Hg, respectively, at 2 weeks; P<0.05 for both comparisons). Blockade of the BK B2 receptor by Icatibant enhanced the pressure response to clipping in B2+/+ mice (29+/-2 mm Hg at 2 weeks). Intra-arterial mean blood pressure (MBP) was higher in 2K1C than in respective sham-operated mice, with the MBP difference being higher in B2-/- mice (32 and 38 mm Hg, at 2 and 4 weeks, respectively), and higher in B2+/+ mice given Icatibant (30 and 32 mm Hg) than in B2+/+ mice without Icatibant (17 and 18 mm Hg). At 4 weeks, acute injection of an angiotensin type 1 receptor antagonist normalized the MBP of 2K1C hypertensive mice. A tachycardic response was observed 1 week after clipping in B2-/- and B2+/- mice, but this effect was delayed in B2+/+ mice. However, the HR response to clipping in B2+/+ mice was enhanced by Icatibant. Within each strain, heart weight to body weight ratio was greater in 2K1C hypertensive mice than in sham-operated control animals (B2-/-: 5.7+/-0.1 versus 5.2+/-0.1; B2+/+: 5.1+/-0.1 versus 4.5+/-0.1; P<0.01 for both comparisons). The clipped kidney weight to nonclipped kidney weight ratio was consistently reduced in mice with 2K1C hypertension. Our results indicate that kinins acting on the BK B2 receptor exert a protective action against excessive blood pressure elevation during early phases of 2K1C hypertension.     

The relationship of education to blood pressure: findings on 40,000 employed Chicagoans

The relationship of education to both actual blood pressure and the prevalence of high blood pressure, based on a systolic pressure of 160 mm Hg or greater or a diastolic pressure of 95 mm Hg or greater, was analyzed among 27,033 men and women, white and black, age 25-44 and 45-64, from the Chicago Heart Association Detection Project in Industry. The educational status of each individual was categorized as not a high school graduate, high school graduate, some college, or college graduate. A statistically significant inverse association between education and high blood pressure was present in all groups of whites. This association could not be "accounted for" by differences in age, relative weight, and heart rate among the educational strata. Controlling for these variables did, however, lessen the association. Among black males a significant inverse association between education level and blood pressure was found for the younger group. For the older black males there was a clear inverse association although with the small numbers it did not achieve statistical significance. For black females there was no clear association.     

Steroid content in endometrial tissue

Recent studies indicate beneficial effects of androgen depletion in male mice, before trauma-hemorrhage on cell-mediated immunity following soft-tissue trauma and hemorrhagic shock. Nonetheless, it remains unknown whether androgen receptor blockade following the insult has any salutary effects. To study this, male C3H/HeN mice were either sham-operated or subjected to soft-tissue trauma (i.e., 2.5 cm midline laparotomy) followed by hemorrhagic shock (blood pressure 35 +/- 5 mmHg for 90 min) and then adequately resuscitated (shed blood and lactated Ringer's). Immediately after the completion of resuscitation, as well as 24 and 48 h thereafter, the animals received either vehicle, 10 mg/kg body weight (BW) flutamide or 25 mg/kg BW flutamide subcutaneously. At 72 h after resuscitation, all animals were killed. The spleens and peritoneal macrophages (M phi) were then harvested and cultures established to determine IL-2 and IL-3 release, splenocyte proliferative capacity, as well as splenic and peritoneal M phi IL-1 release. Moreover, plasma testosterone and corticosterone levels were measured. Our results indicate that trauma-hemorrhage resulted in significant depression of splenocyte and M phi functions in vehicle-treated and animals receiving 10 mg/kg BW flutamide. Treatment with 25 mg/kg BW flutamide following trauma-hemorrhage, however, resulted in levels of cytokine release which were comparable with those found in sham-operated animals. No significant alterations in plasma corticosterone and testosterone levels were observed in any of the experimental groups. These findings indicate that short-term therapy of males with the androgen receptor blocker, flutamide at 25 mg/kg BW, following trauma-hemorrhage has protective effects on immune functions. This protective effect is dose dependent, since 10 mg/kg BW flutamide did not produce significant salutary effects. Thus, flutamide represents a novel and safe agent for improving the depressed functions in male trauma patients suffering severe blood loss.     

Male acceleration of puberty in female mice (Mus musculus).

Nine experiments investigated various aspects of the acceleration of puberty in female ICR/Alb house mice (N?=?754) produced by the presence of a male mouse or urine from males. Grouping males had no effect on the urinary chemosignal that accelerates puberty, except that urine from dominant males produced greater acceleration than urine from subordinates. Young female mice must be exposed to the male urine for at least 2–3 hrs/day or to the presence of a male for 1 hr/day to produce acceleration of first vaginal estrus. Females were accelerated to the same extent in attaining puberty whether treated with urine from the same male or a different male each day. Urine from the father or a full brother, or the presence of those close relatives, exerted no differential acceleratory or retarding effect on puberty when compared with urine from or the presence of unrelated males. Excreted or bladder urine from adrenalectomized males accelerated puberty to the same extent as urine from intact males, but the presence of an adrenalectomized male did not produce the same degree of acceleration as when an intact male was present. Behavioral observations indicate that adrenalectomized males pursued young females less and attempted fewer mounts during a brief test period. Implications are noted for the understanding of both the mechanisms of acceleration of puberty in the house mouse and the population and reproductive biology of these mice. (35 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Arachidonate-induced thrombosis in mice: effects of gender or testosterone and estradiol administration

Sodium arachidonate (i.v.) has previously been shown to induce pulmonary emboli formation and a dose dependent cyanosis and respiratory depression in mice. Subsequently, we found that male mice are significantly more sensitive to arachidonate than females. Aspirin given orally 2 hours prior to arachidonate administration inhibits the responses of both males and females. Pretreatment with depo-testosterone markedly increases the effect of arachidonate in both males and females and depo-estradiol pretreatment reduces the responses in all mice. This exacerbation by testosterone of the arachidonate response and the attenuating effects of estradiol is consistent with data reported using other thrombogenic techniques.     

Immunohistochemical detection of parathyroid hormone-related protein in human astrocytomas

Hypertension is more common among African Americans than Americans of European descent. However, the genetic etiology has not been defined. Similarly, lipoprotein (Lp) (a), an independent risk factor for cardiovascular disease, is higher among African Americans. To explore the relationship between Lp (a) and hypertension, we measured the blood pressure of transgenic mice expressing apolipoprotein(a), the unique protein moiety of lipoprotein(a). As controls, we also determined blood pressure for apoE deficient mice, low density lipoprotein-receptor (LDL-R) deficient mice, and wild type C57Bl/6 mice. Apo(a) expression was not associated with hypertension. Surprisingly, LDL-R deficient mice exhibited male-associated hypertension. This observation could explain the higher incidence of atherosclerosis in male LDL-R deficient mice and human familial hypercholesterolemia (FH) patients. LDL-R deficient mice were more sensitive to photochemically induced cerebral stroke. However, this hypersensitivity was only modestly associated with sexual dimorphism. The presented data suggest that LDL-R deficiency results in hitherto unrecognized changes in the vascular tone.     

Modifiable risk factors for coronary heart disease among young people in Addis Ababa

We report results of a cross-sectional survey of modifiable risk factors for coronary heart disease among young people (15-24 years of age) in Addis Ababa, conducted in 1994/95. A city-wide random sample of 1,436 (851 females and 585 males) young people participated in the study. Interviews using structured questionnaires, weight, height and blood pressure measurements were conducted using trained and supervised field workers. Current smoking was 11.8% for males and 1.1% for females. About 34% of the respondents consumed alcoholic beverages regularly, but 7.0% of these took more than 100 grams of alcohol per week. High fat intake and sedentary life-styles were registered in 4.5 and 8.4% of the respondents, respectively. About 6.0% of the females and 0.7% of the males were obese. The prevalence of elevated blood pressure (diastolic BP > 90 mmHG) was 7.1%. The prevalence of modifiable risk factors among young people in Addis Ababa indicates that there is need for initiation of primary preventive activities as soon as possible.     

Age relations of cardiovascular risk factors in a traditional Melanesian society: the Kitava Study

This study examined cross-sectional age relations of blood pressure, anthropometric indexes, serum lipids, and hemostatic variables in 203 subsistence horticulturists aged 20-86 y in Kitava, Trobriand Islands, Papua New Guinea. The population is characterized by extreme leanness (despite food abundance), low blood pressure, low plasma plasminogen activator inhibitor 1 activity, and rarity of cardiovascular disease. Tubers, fruit, fish, and coconut are dietary staples whereas dairy products, refined fat and sugar, cereals, and alcohol are absent and salt intake is low. Although diastolic blood pressure was not associated with age in Kitavans, systolic blood pressure increased linearly after 50 y of age in both sexes. Body mass index decreased with age in both sexes. Serum total cholesterol, triacylglycerol, low-density-lipoprotein cholesterol, and apolipoprotein B increased in males between 20 and 50 y of age, whereas high-density-lipoprotein cholesterol and apolipoprotein A-I decreased. There were no significant differences in these indexes with age in the few females studied. A slight linear age-related increase of lipoprotein(a) was present in males. Plasma fibrinogen, factor VII clotting activity, factor VIII clotting activity, and von Willebrand factor antigen increased with age in both sexes but plasminogen activator inhibitor 1 activity did not. The modest or absent relations between the indexes measured and age are apparently important explanations of the virtual nonexistence of stroke and ischemic heart disease in Kitava.