Bisphenol A and Bisphenol S Oxidative Effects in Sheep Red Blood Cells: An In Vitro Study.

Bisphenols (BPs) are plastic components widely used worldwide and occurring in the environment. Exposure to these compounds is known to be harmful for animals and humans at different levels. The aim of this study was to evaluate and compare the oxidative effects of bisphenol A (BPA) and bisphenol S (BPS) in sheep. Reactive oxygen species (ROS) production and correlated structural alterations in sheep erythrocytes were investigated in vitro. Blood samples from four ewes were collected at fasting from the jugular vein using vacuum collection tubes containing EDTA. For ROS assay in erythrocytes, blood was properly diluted and BPA or BPS was added to obtain final bisphenol concentrations in the range between 1 and 300 µM. 2',7'-Dichlorodihydrofluorescein diacetate (H2DCF-DA) 3 µM was added to the samples, and fluorescence was read in four replicates using a microplate reader. To evaluate erythrocyte shape, blood smears of blood treated with the different concentrations of BPS and BPA were prepared. A significant increase in ROS production was observed when concentrations of BPS and BPA increased from 1 to 100 µM (p < 0.05). At the higher concentrations of the two studied BPs (300 µM of BPS and 200-300 µM of BPA), a ROS decrease was observed when compared to the control group (p < 0.01). Erythrocytes' shape alterations were observed in cells treated with BPS and BPA 200-300 µM 4 hours after the beginning of the treatment. This study confirms that BPA and BPS exhibit oxidative effects on sheep erythrocytes. At higher concentrations, BPA was able to modify erythrocytes' shape, while BPS altered their membrane as a sign of a protein clustering that could lead to eryptosis. These BPs' effects are consequent to intracellular ROS increase.

Pharmacokinetic/pharmacodynamic assessments of 10 mg/kg tramadol intramuscular injection in yellow-bellied slider turtles (Trachemys scripta scripta).

In reptiles, administration of opioid drugs has yielded unexpected results with respect to analgesia. The aims of this study were to assess the pharmacokinetic/pharmacodynamic (PK/PD) properties of tramadol and its active metabolite M1 and to evaluate the effect of the renal portal system on the PK/PD parameters in yellow-bellied slider turtles. Turtles (n = 19) were randomly assigned to four treatment groups, according to a masked, single-dose, four-treatment, unpaired, four-period crossover design. Group A (n = 5) received a single i.m. dose of tramadol (50 mg/mL) at 10 mg/kg in the proximal hindlimb. Group B (n = 5) received the same i.m. dose but in the forelimb. Groups C (n = 5) and D (n = 4) received a single i.m. injection of saline (NaCl 0.9%) of equivalent volume to the volumes of tramadol injected in the hind- and forelimb, respectively. Groups were rotated (1-month washout period) until the completion of the crossover study. Tramadol plasma concentrations were evaluated by a validated HPLC-FL method. An infrared thermal stimulus was applied to the plantar surface of the turtles' hindlimbs to evaluate the thermal withdrawal latency (TWL). The two PK profiles of tramadol differed in the first 2 h following administration, but overlapped in the elimination phases. The metabolite M1 was formed in both the treatment groups, showing similar pharmacokinetic trends, although the amount of M1 was significantly higher (20%) in the hindlimb vs. forelimb group. Turtles given tramadol in the hind- and forelimb showed a significant increase in TWL over the periods of 0.5-48 and 8-48 h, respectively. The calculated % maximal possible response (% MPR) was low (about 24%). The PK/PD correlations between M1 plasma concentrations vs. % MPR appeared to show a counterclockwise hysteresis loop shape.

Carboplatin sustained delivery system using injectable microspheres.

A controlled carboplatin delivery system using biodegradable polymer has been used in this study. The purpose was to evaluate the local and systemic effects of injectable, biodegradable microspheres containing carboplatin when injected as aqueous suspension subcutaneously in rats. Biocompatibility and toxicity of empty microspheres and microspheres loaded with carboplatin were evaluated by clinical and histological examination. The diffusion of carboplatin in tissues and time of drug release were evaluated by platinum determination in plasma and tissues over the time. The results of the study suggest that microspheres provide a sustained slow release of carboplatin and that multiple inoculations of microspheres containing drug and no evidence of local or systemic toxicity is found. This device may be useful in the treatment of solid tumours.

Serum prolactin levels after administration of the alimentary opioid peptide gluten exorphin B4 in male rats.

Gluten Exorphins are opioid peptides identified in enzymatic digests of gluten. The effects of Gluten Exorphins are still largely unknown. It has been shown that Gluten Exorphin B5 (Tyr-Gly-Gly-Trp-Leu) stimulates Prolactin secretion in male rats. In this study, we have evaluated the Prolactin response to Gluten Exorphin B4, another exorphin whose structure (Tyr-Gly-Gly-Trp) is identical to that of the NH(2)-terminal sequence of Gluten Exorphin B5. To this aim, five groups of male rats were given the following intravenous treatments: vehicle, Gluten Exorphin B5 3 mg kg-1 body weight, Gluten Exorphin B4 at the doses of 3, 6 and 9 mg kg-1 body weight. At the dose of 3 mg kg-1 body weight, Gluten Exorphin B5 induced a significant increase in Prolactin levels. Gluten Exorphin B4 could not modify Prolactin secretion, even when administered at doses three times higher than those effective for Gluten Exorphin B5. The present study: (1) indicates that Gluten Exorphin B4 does not modify Prolactin secretion in male rats; (2) confirms the ability of Gluten Exorphin B5 to exert a stimulatory action on Prolactin release; (3) suggests that the presence of the carboxy-terminal leucine in Gluten Exorphin B5 is essential for its action on Prolactin secretion.

Renal blood flow in hypercholesterolemic pigs is increased by chronic antioxidant treatment.

Oxygen radical species can influence vascular tone, and antioxidants may have hemodynamic and vascular effects. To date, the vascular effects of chronic intervention with a combination of antioxidant vitamins E and C on renal blood flow (RBF) in hypercholesterolemia (which increases oxidative stress) have not been fully defined. The aim of this intervention study was to explore the involvement of increased oxidative stress in pig RBF disturbance by using chronic dietary antioxidant vitamin intervention. Responses of RBF to the acetylcholine (Ach) were measured in vivo using electron beam computed tomography (EBCT). Acetylcholine significantly increased RBF in normal and hypercholesterolemic + vitamins (P < 0.05 for both), but not in hypercholesterolemic pigs (P=0.1). In normocholesterolemic + vitamins pigs, Ach infusion did not induce any further increase in RBF, but RBF was similar to that observed in normal and hypercholesterolemic + vitamins under the same conditions, and tended to be higher than in hypercholesterolemic pigs (P=0.06). Thus, antioxidants improve RBF in hypercholesterolemic pigs and this effect may help to prevent renal diseases and hypertension in animals.

Enhanced blood pressure sensitivity to deoxycorticosterone in mice with disruption of bradykinin B2 receptor gene.

The renal kallikrein-kinin system is activated under conditions of mineralocorticoid excess. To evaluate whether endogenous kinins exert a protective role against the development of mineralocorticoid-induced hypertension, we studied the cardiovascular effects induced by long-term administration of deoxycorticosterone (DOC; 0.3 micromol/g body wt s.c. once per week for 6 weeks) or vehicle in transgenic mice (Bk2r-/-) lacking the bradykinin B2 receptor gene and in wild-type controls (Bk2r+/+). Under basal conditions, Bk2r-/- mice showed higher systolic blood pressure (tail-cuff plethysmography) than wild-type Bk2r+/+ and heterozygous Bk2r+/- mice (121+/-2 versus 114+/-2 and 115+/-2 mm Hg, respectively; P<0.05 for both comparisons). Heart rate was higher in Bk2r-/- and Bk2r+/- than in Bk2r+/+ (459+/-12 and 418+/-7 versus 390+/-7 bpm; P<0.05 for both comparisons). Systolic blood pressure was increased by DOC in transgenic as well as in wild-type mice, whereas no change was induced by the vehicle. The pressor response to DOC was more rapid and pronounced in Bk2r-/- than in Bk2r+/+ and Bk2r+/- (30+/-5 versus 15+/-4 and 6+/-3 mm Hg, respectively, at 3 weeks; P<0.01 for both comparisons). The difference in systolic blood pressure was consistent with that detected by direct intra-arterial measurements of mean blood pressure. Neither DOC nor its vehicle altered heart rate or gain in body weight over time. Under basal conditions, urinary sodium excretion did not differ between strains. During DOC administration, cumulative urinary sodium excretion was lower in Bk2r-/- than in Bk2r+/+ (2.59+/-0.15 versus 3.31+/-0.22 mmol, respectively, during the first week; P<0.05). Urinary kinin excretion was increased by DOC in both Bk2r-/- (from 0.65+/-0.17 to 4.27+/-0.80 pmol/24 h; P<0.01) and Bk2r+/+ (from 0.55+/-0.09 to 6.27+/-1.48 pmol/24 h; P<0.05). The increase in urinary kinin excretion was similar between strains. These results show that integrity of the bradykinin B2 receptor is essential for regulation of blood pressure and heart rate under basal conditions. In addition, they indicate that activation of the kallikrein-kinin system represents a compensatory response against the development of hypertension induced by mineralocorticoid excess.

Role of nitric oxide synthase inhibition in the acute hypertensive response to intracerebroventricular cadmium.

1. In the rat, intracerebroventricular (i.c.v.) injection of cadmium, a pollutant with long biological half-life, causes a sustained increase in blood pressure at doses that are ineffective by peripheral route. Since cadmium inhibits calcium-calmodulin constitutive nitric oxide (NO) synthase in cytosolic preparations of rat brain, this mechanism may be responsible for the acute pressor action of this heavy metal. 2. To test this possibility, we evaluated the effect of i.c.v. injection of 88 nmol cadmium in normotensive unanaesthetized Wistar rats, which were i.c.v. pre-treated with: (1) saline (control), (2) L-arginine (L-Arg), to increase the availability of substrate for NO biosynthesis, (3) D-arginine (D-Arg), (4) 3-[4-morpholinyl]-sydnonimine-hydrochloride (SIN-1), an NO donor, or (5) CaCl2, a cofactor of brain calcium-calmodulin-dependent cNOS(I). In additional experiments, the levels of L-citrulline (the stable equimolar product derived from enzymatic cleavage of L-Arg by NO synthase) were determined in the brain of vehicle- or cadmium-treated rats. 3. The pressor response to cadmium reached its nadir at 5 min (43+/-4 mmHg) and lasted over 20 min in controls. L-Citrulline/protein content was reduced from 35 up to 50% in the cerebral cortex, pons, hippocampus, striatus, hypothalamus (P<0.01) of cadmium-treated rats compared with controls. Central injection of N(G) nitro-L-arginine-methylester (L-NAME) also reduced the levels of L-citrulline in the brain. 4. Both the magnitude and duration of the response were attenuated by 1.21 and 2.42 micromol SIN-1 (32+/-3 and 15+/-4 mmHg, P<0.05), or 1 micromol CaCl2 (6+/-4 mmHg, P<0.05). Selectivity of action exerted by SIN-1 was confirmed by the use of another NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). Both L-Arg and D-Arg caused a mild but significant attenuation in the main phase of the pressor response evoked by cadmium. However, only L-Arg reduced the magnitude of the delayed, pressor response. Despite their similarity in ability to attenuate the cadmium-induced pressure effect, L-Arg and its isomer exerted differential biochemical changes in brain L-citrulline, as L-Arg normalized cadmium-induced reduction in L-citrulline levels, whereas i.c.v. D-Arg did not. 5. We conclude that the pressor effect of i.c.v. cadmium is due, at least in part, to reduced NO formation, consequent to inhibition of brain NO synthase. Accumulation of cadmium in the central nervous system could interfere with central mechanisms (including NO synthase) implicated in the regulation of cardiovascular function.

Cardiovascular phenotype of a mouse strain with disruption of bradykinin B2-receptor gene.

BACKGROUND: To evaluate the role of kinins in the regulation of cardiovascular function, we studied the phenotype of a mouse strain with disruption of the bradykinin B2-receptor gene (Bk 2r-/-). METHODS AND RESULTS: Under basal conditions, tail-cuff blood pressure was higher in Bk2r-/- than in wild-type Bk2r+/+ and heterozygous Bk2r+/- mice (124+/-1 versus 109+/-1 and 111+/-2 mm Hg, respectively; P<.01 for both comparisons), a difference that was confirmed by measurements of intra-arterial blood pressure in unanesthetized mice. Heart weight was greater in Bk2r-/- than in Bk2r+/+ and Bk2r+/- mice (505+/-10 versus 449+/-12 and 477+/-10 mg/100 g body wt, P<.05). Chronic blockade of B2-receptors by Icatibant (50 nmol/100 g body wt twice a day S.C.) or inhibition of nitric oxide synthase by nitro-L-arginine-methyl ester (0.14 mmol/100 g body wt orally) increased the blood pressure of Bk2r+/+ to the levels of Bk2r-/- mice. Compared with the wild-type strain, both Bk2r-/- and Bk2r+/- mice showed exaggerated vasopressor responses to angiotensin II. In addition, chronic administration of an angiotensin AT1-receptor antagonist reduced the basal blood pressure of Bk2r-/- by 21+/-3 mmHg (P<.05) to the levels of Bk2r+/+. No difference was detected between strains as far as plasma renin activity and the expression of renin and AT1-receptor genes are concerned. Chronic salt loading (0.84 mmol/g chow for 15 days) increased the blood pressure of Bk2r-/- and Bk2r+/- by 34+/-3 and 14+/-6 mm Hg, respectively, whereas it was ineffective in Bk2r+/+. CONCLUSIONS: Our results suggest that a normally functioning B2-receptor is essential for the maintenance of cardiovascular homeostasis in mice. Dysfunction of the kallikrein-kinin system could contribute to increase blood pressure levels by leaving the activity of vasoconstrictor agents unbalanced.

Regulation of bradykinin B2-receptor expression by oestrogen.

1. Tissue kallikrein is overexpressed in the kidney of female rats, this sexual dimorphism being associated with a greater effect of early blockade of bradykinin B2-receptors on female blood pressure phenotype. We evaluated the effect of ovariectomy and oestradiol benzoate (50 micrograms kg-1 every two days for two weeks) on the vasodepressor response to intra-arterial injection of bradykinin (150-900 ng kg-1) and on the expression of bradykinin B2-receptors. 2. Ovariectomy reduced the magnitude of the vasodepressor response to bradykinin and unmasked a secondary vasopressor effect. Oestrogen replacement restored the vasodepressor response to bradykinin in ovariectomized rats. 3. The vasodepressor responses to sodium nitroprusside (3-18 micrograms kg-1), acetylcholine (30-600 ng kg-1), desArg9-bradykinin (150-900 ng kg-1) or prostaglandin E2 (30-600 ng kg-1) were significantly reduced by ovariectomy. Oestrogen restored to normal the responses to desArg9-bradykinin, acetylcholine and prostaglandin E2, but not that to sodium nitroprusside. 4. B2-receptor mRNA levels were decreased by ovariectomy in the aorta and kidney and they were restored to normal levels by oestrogen. Neither ovariectomy nor oestradiol affected receptor expression in the heart and uterus. 5. These results indicate that oestrogen regulates B2-receptor gene expression and function. Since kinins exert a cardiovascular protective action, reduction in their vasodilator activity after menopause might contribute to the increased risk of pathological cardiovascular events. Conversely, the cardioprotective effects of oestrogen replacement might be, at least in part, mediated by activation of the kallikrein-kinin system.

Kallikrein-kinin system and blood pressure sensitivity to salt.

We evaluated the blood pressure response to chronic salt loading in a rat strain inbred for low urinary kallikrein excretion. Low-kallikrein rats showed greater systolic blood pressure values (130 +/- 1 versus 114 +/- 2 mm Hg in controls; P < .05) at 9 weeks of age. Systolic blood pressure was increased after 10 days of dietary sodium loading in the low-kallikrein group and remained unchanged in controls (153 +/- 1 versus 112 +/- 2 mm Hg, P < .01). In additional experiments, blood pressure sensitivity to salt was tested in low-kallikrein rats receiving a chronic infusion of rat glandular kallikrein (1.7 micrograms/day per 100 g body weight, IV) or vehicle. Systolic blood pressure of vehicle-treated rats was increased by salt loading (from 138 +/- 1 to 158 +/- 2, 153 +/- 1, and 145 +/- 2 mm Hg at 5, 10, and 15 days, respectively; P < .01), while it remained unchanged in the kallikrein-treated group (from 136 +/- 2 to 146 +/- 5, 140 +/- 2, and 134 +/- 4 mm Hg at 5, 10, and 15 days, respectively; P = NS). Urinary kallikrein excretion was increased by kallikrein infusion (from 13.6 +/- 1.4 to 17.8 +/- 2.1 nanokatals per 24 hours; P < .01). Plasma immunoreactive kallikrein levels were higher in the kallikrein-treated group (66.4 +/- 4.4 versus 57.7 +/- 1.4 ng/mL in vehicle-treated rats; P < .05). On normal sodium diet, the ratio of kidney weight to body weight was lower in low-kallikrein rats (329 +/- 5 versus 370 +/- 8 mg/100 g body weight in controls; P < .01). This difference was associated with a decreased number of glomeruli per unit square area and increased width of Bowman's space. These results indicate that kallikrein replacement prevents the exaggerated blood pressure increase observed in rats with a genetically determined defect in urinary kallikrein excretion. Histological abnormalities are present at different levels in the nephron, and they may be functionally related to the altered cardiovascular and renal phenotype of this strain.

Effect of atrazine administration on spontaneous and evoked cerebellar activity in the rat.

The effect of atrazine oral administration on cerebellar forelimb projection area was studied in rats in vivo. Rats acutely treated with atrazine (100 mg kg-1, BW) showed a significant decrease in spontaneous Purkinje cell firing rate. Atrazine also decreased the cerebellar potentials evoked by electrical stimulation of the ipsilateral radial nerve, affecting mostly the response to climbing fiber input. These results demonstrate that atrazine exerts a toxic action on central nervous system. The effects on the cerebellar somatosensory cortex could be responsible for motor disorders frequently observed in animals intoxicated with atrazine.

Metabolic and renal effects of Laevo-carnitine and propionyl-carnitine in rats with subtotal nephrectomy.

The renal and metabolic effects of chronic carnitine administration were evaluated in the early stages of experimentally-induced renal failure. Laevo-carnitine (n = 5), Propionyl-carnitine (n = 5) both at 200 mg kg-1 of body weight, or vehicle (physiological saline solution, 0.4 ml kg-1 body weight, n = 5) were administered daily for 3 days prior to 2/3 nephrectomy and for 25 days thereafter, by intraperitoneal route. At the end of the experiment, no significant differences were found in systolic blood pressure and heart rate among groups. During the 25 days after nephrectomy, body weight increased by 71 +/- 13 g in the control group and by 50 +/- 26 g and 42 +/- 9 g in Laevo-carnitine and Propionyl-carnitine groups, respectively (P < 0.05 vs control for both comparisons). Urinary sodium excretion was increased in carnitine-treated rats (Laevo-carnitine: from 1.03 +/- 0.3 to 1.36 +/- 0.3 mEq day-1, Propionyl-carnitine: from 1.2 +/- 0.2 to 1.66 +/- 0.2 mEq day-1, P < 0.05 for both comparisons), but not in those given vehicle. Twenty-five days after nephrectomy, plasma creatinine was lower in carnitine-treated rats (Laevo-carnitine: 0.98 +/- 0.12 mg dl-1, Propionyl-carnitine: 1.06 +/- 0.15, vehicle: 1.52 +/- 0.09, P < 0.05 vs control for both comparisons). Plasma triglycerides and VLDL were decreased by nephrectomy and this effect was prevented by carnitine treatment. The data indicate that the carnitine blunts the increase in plasma creatinine that occurs early after partial nephrectomy and normalizes the plasma lipoprotein pattern. Thus, carnitine might protect against the development of renal failure in this experimental model.

Quinoxaline chemistry. Part 6--Synthesis and evaluation of antiulcer and gastroprotective activity of 2-[arylmethylmercapto-, arylmethylsulfinyl-, piperazinyl-3-R-substituted]quinoxalines.

Thirty compounds possessing quinoxaline structure bearing either substituted arylmethylmercapto-, arylmethylsulfinyl group or a piperazinyl moiety in position 2 were prepared in order to evaluate an antiulcer and gastroprotective activity in rat pylorus ligature, in comparison with omeprazole and ranitidine at the dose of 100 mg/kg after oral administration. Among the compounds of the first group one third showed a moderate activity being about half potent as omeprazole whereas in the second group compound 5b exibited an activity superior to that of ranitidine accompanied with the lowest incidence of lesions and mortality and another compound (5i) was equiactive as ranitidine.

Intracranial volume receptors: possible role on ADH homeostatic control.

Volume receptors are situated in many organs and are capable of modulating ADH secretion. We have evaluated the variation of plasma ADH concentration after an experimentally induced increase of cerebrospinal fluid (CSF) pressure (PCSF). The experiment was performed in controlled environmental conditions to avoid pain or stress-related ADH release. In 15 rats (10 experimental, 5 control) a cannula was positioned in the left cerebral ventricle: in the experimental group artificial CSF was infused at a rate of 0.6 (microliter/min for 6h: this manoeuvre, in a separate set of animals obtained an increase from 13.03 +/- 0.8 to 25.4 +/- 2.5 cmH2O of PCSF. The same conditions were reproduced in the control group without infusion into lateral ventricle. At the end of the experiment, plasma ADH had fallen significantly in the experimental group from 18.9 +/- 4.8 to 11.9 +/- 2.3 pg/ml (p < 0.05), while it was not changed in the control group (from 25.5 +/- 13.7 to 23.7 +/- 16.2 pg/ml). Heart rate, arterial pressure, plasma Na+ and osmolality, did not change significantly. Plasma K+ fell significantly in both groups: from 5.5 +/- 0.6 to 4.3 +/- 0.3 (p < 0.05) and from 5.4 +/- 0.7 to 4.3 +/- 0.15 mEq/l (p < 0.05) in the experimental and control group respectively. Plasma creatinine was normal, checked only at the end of the experiment. Our results demonstrate that a relationship exists between PCSF variations and plasma ADH concentration. We believe this relationship is due to the pressure receptors in the cerebral ventricles or in structures connected to it, such as the inner ear, and we hypothesize the existence of a control system of body fluids, more diffused than though to be, up till now.

Blood pressure sensitivity to salt in rats with low urinary kallikrein excretion.

We evaluated if a rat strain inbred for reduced urinary kallikrein excretion differs from normal-kallikrein Wistar rats regarding blood pressure in basal conditions and during alterations in sodium balance. Low-kallikrein rats showed greater systolic blood pressure values (125 +/- 3 vs. 114 +/- 2 mmHg in controls, P < 0.01) at 9 weeks of age. Systolic blood pressure was increased after 20 days of dietary sodium loading in the low-kallikrein group and remained unchanged in controls (150 +/- 6 vs. 112 +/- 2 mmHg, P < 0.01) and this effect was associated with a reduced cumulative excretion of sodium (23% less in the low-kallikrein group compared with controls, P < 0.01). Urinary creatinine excretion was decreased by sodium loading in both groups, and this effect was more pronounced in the low-kallikrein group. The group-difference in urinary kallikrein excretion found in basal conditions (2.49 +/- 0.10 vs. 7.78 +/- 0.53 Pkat/100 g body weight, P < 0.01) was enhanced by high salt diet (1.05 +/- 0.21 vs. 8.31 +/- 0.70 Pkat/100 g body weight, P < 0.01). The ratio of heart weight to body weight was significantly greater in low-kallikrein rats (331 +/- 7 vs. 275 +/- 4 mg/100 g body weight, P < 0.01), whereas the ratio of kidney weight to body weight was lower (329 +/- 5 vs. 370 +/- 8 mg/100 body weight, P < 0.01). Our results indicate that a genetically-determined defect in urinary kallikrein excretion is associated with a greater blood pressure sensitivity to salt, possibly due to altered renal sodium handling.

Urinary kallikrein: a marker of blood pressure sensitivity to salt.

We evaluated if a rat strain inbred for low urinary kallikrein excretion differs from normal-kallikrein Wistar rats regarding blood pressure levels in basal conditions and during alterations in sodium balance. Blood pressure was measured in unanesthetized rats on normal sodium intake. Then, blood pressure sensitivity to salt was evaluated over a period of 20 days of high sodium diet (0.84 mmol per g chow). Low-kallikrein rats showed greater systolic blood pressure levels (125 +/- 3 vs. 114 +/- 2 mm Hg in controls, P < 0.01) at nine weeks of age. Systolic blood pressure was increased after sodium loading in the low-kallikrein group and remained unchanged in controls (150 +/- 6 vs. 112 +/- 2 mm Hg, P < 0.01). This effect was associated with a reduced cumulative urinary excretion of sodium in the low-kallikrein rats. No group difference was found in the clearance of endogenous creatinine in basal conditions. Urinary creatinine excretion decreased during sodium loading, particularly in the low-kallikrein group. The group-difference in urinary kallikrein excretion found in basal conditions (6.85 +/- 0.31 vs. 20.74 +/- 1.71 nkat/24 hr in controls, P < 0.01) was enhanced by high salt diet (2.96 +/- 0.67 vs. 22.07 +/- 2.47 nkat/24 hr in controls, P < 0.01). In addition, renal kallikrein activity and content were reduced in low-kallikrein rats. The latter group showed a greater ratio of heart weight to body wt both in basal conditions and after sodium loading. The ratio of kidney weight to body wt was reduced after sodium loading. These results indicate that a genetically-determined defect in urinary kallikrein excretion is associated with a greater blood pressure sensitivity to salt, possibly due to altered renal sodium handling.

Prevention by blockade of angiotensin subtype1-receptors of the development of genetic hypertension but not its heritability.

1. We determined whether early inhibition of angiotensin II subtype1 (AT1) receptors by the newly synthesized nonpeptidic antagonist, A-81988, can attenuate the development of hypertension in spontaneously hypertensive rats (SHR) and if the altered blood pressure phenotype can be passed on to the subsequent generation, not exposed to the antagonist. 2. Pairs of SHR were mated while drinking tap water or A-81988 in tap water, and the progeny was maintained on the parental regimen until 14 weeks of age. At this stage, A-81988-treated rats showed lower systolic blood pressure and body weight values (136 +/- 5 versus 185 +/- 4 mmHg and 247 +/- 4 versus 283 +/- 4 g in controls, P < 0.01); while heart rate was similar. In addition, mean blood pressure was reduced (101 +/- 7 versus 170 +/- 7 mmHg in controls, P < 0.01), and the pressor responses to intravenous or intracerebroventricular angiotensin II were inhibited by 27 and 59%, respectively. Heart/body weight ratio was smaller in A-81988-treated rats (3.2 +/- 0.1 versus 3.8 +/- 0.1 in controls, P < 0.01). 3. The antihypertensive and antihypertrophic effect of A-81988 persisted in rats removed from therapy for 7 weeks (systolic blood pressure: 173 +/- 4 versus 220 +/- 4 mmHg, heart/body weight ratio: 3.4 +/- 0.1 versus 4.1 +/- 0.1 in controls at 21 weeks of age, P < 0.01 for both comparisons), whereas the cardiovascular hypertensive phenotype was fully expressed in the subsequent generation that was maintained without treatment. 4. These results indicate that chronic blockade of angiotensin AT1-receptors attenuates the development of hypertension in SHR but it does not prevent the transmission of hypertension to the following generation. Thus, heritability of the SHR's hypertensive trait is not affected by pharmacological manipulation of the cardiovascular phenotype.