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.

Different response of intracerebroventricular cadmium administration on blood pressure in normal and low urinary kallikrein rats.

Cadmium intracerebroventricular (i.c.v.) administration, at definite concentrations, induces a dose-dependent increase in the systemic blood pressure. Kallikreins are suggested to be important regulators of cardiovascular function. We evaluated the effects of 10 microg i.c.v. cadmium on mean blood pressure (MBP) and several urinary parameters such as 24h urine volume, sodium and potassium excretion and osmolality in a rat strain inbred for low urinary kallikrein and in normal-kallikrein Wistar rats. Low-kallikrein rats (LKR) showed an increase in MBP that, after an initial peak (27% from baseline), persisted higher than basal levels (10%) over 24h. In normal-kallikrein rats (NKR) a different reaction of blood pressure to cadmium was observed, causing a temporary increase (26% from baseline) of the systemic blood pressure, that returned to normal values within 2h. In addition, LKR showed a considerable reduction in the urinary volume (UV; 43.0+/-20 ml/24h versus 13.2+/-6 ml/24h, P<0.006), with an increase in the urinary osmolality (U(Osm); 500+/-210 mOsm/l versus 1391+/-245 mOsm/l, P<0.0002). Sodium (U(Na); 1761+/-432 microEq/24h versus 1156+/-522 microEq/24h, P<0.03) and potassium excretion (U(K); 2186+/-482 microEq/24h versus 936+/-299 microEq/24h, P<0.0006) were both significantly reduced. No changes in UV, U(Osm) and U(K) were observed in normal urinary kallikrein rats with the exception of U(Na) excretion that was significantly increased (667+/-274 microEq/24h versus 1725+/-300 microEq/24h, P<0.03). These results suggest that a genetically determined defect in urinary kallikrein excretion leads to a different hypertensive response to i.c.v. cadmium and to a different renal excretion of electrolytes. Perhaps the differences of blood pressure response could be due, at least in part, to a different sensitivity of LKR to cadmium: this implies a complex and articulate hypertensive effect of cadmium involving more systems than those supposed so far.

Evidence for oxidative activation of c-Myc-dependent nuclear signaling in human coronary smooth muscle cells and in early lesions of Watanabe heritable hyperlipidemic rabbits: protective effects of vitamin E.

BACKGROUND: Oxidized LDL (oxLDL) promotes atherogenesis, and antioxidants reduce lesions in experimental models. OxLDL-mediated effects on c-Myc are poorly characterized, and those on c-Myc nuclear pathways are completely unknown. c-Myc stimulates smooth muscle cell (SMC) proliferation and could be involved in atherosclerosis. We investigated the early effects of oxLDL and alpha-tocopherol on c-Myc, its binding partner Max, and the carboxy-terminal domain-binding factors activator protein-2 and elongation 2 factor in human coronary SMCs. We also investigated whether 9-week treatment of Watanabe heritable hyperlipidemic (WHHL) rabbits with diet-enriched alpha-tocopherol reduces c-Myc expression and oxLDL in the left coronary artery. METHODS AND RESULTS: OxLDL enhanced c-Myc/Max expression and transcription by cotransfection assay and the nuclear activities of E2F and activator protein-2 by binding shift and supershift in coronary SMCs. alpha-Tocopherol significantly reduced these molecular events. Furthermore, alpha-tocopherol reduced early lesions, SMC density, and the immunohistochemical presence of c-Myc, which colocalized with oxLDL/foam cells in the coronaries of WHHL rabbits. CONCLUSIONS: We provide the first evidence that oxLDL and alpha-tocopherol may influence c-Myc activation and several c-Myc-dependent signaling pathways in human coronary SMCs. The observation that in vivo, an antioxidant reduces both c-Myc and oxLDL in early coronary lesions of rabbits is consistent with, but does not prove, the hypothesis that c-Myc-dependent factors activated by oxidative processes contribute to atherogenesis and coronary heart disease.

Modulation by alpha- and gamma-tocopherol and oxidized low-density lipoprotein of apoptotic signaling in human coronary smooth muscle cells.

Apoptosis may play an important role in atherogenesis. Oxidized low-density lipoprotein (oxLDL) promotes apoptosis in the arterial wall in addition to several other proatherogenic effects. Tocopherol supplements have been suggested to protect against coronary heart disease (CHD) in epidemiological studies. The effects of oxLDL and alpha- and gamma-tocopherol on apoptotic signaling pathways are poorly understood. Thus, the goal of the study was to investigate these pathways in the presence of copper-oxidized LDL and tocopherols in human coronary smooth muscle cells (SMC). We showed that oxLDL-mediated apoptosis, assessed by DNA fragmentation, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, and caspase activation stimulated several transcription factors and proapoptotic dynamic movements of the Bcl-2 family proteins through the mitogen-activated protein kinase (MAPK) and Jun kinase pathways. alpha-Tocopherol and gamma-tocopherol significantly reduced these molecular events and cell death effectors caspase-3 and -8. Under our experimental conditions, alpha-tocopherol was significantly more effective than gamma-tocopherol, and oxLDL-mediated apoptosis increased c-Jun, cyclic AMP-responsive element-binding, Ets-like element kinase-dependent 7, and activating transcription factor-2 proteins as well as nuclear activity of the activated protein-1 complex in human coronary SMC. Moreover, our results demonstrate that tocopherols may exert their antiatherogenic effects at least in part via reduction of the MAPK and JunK cascade together with a protective profile of apoptotic genes of the Bcl-2 family. These data are consistent with the beneficial effects of tocopherols on atherogenesis seen in experimental studies and on CHD in epidemiological surveys.

Relationship between cerebrospinal fluid pressure and plasmatic ADH.

In a healthy human being, the extracellular volume is kept constant by homeostatic systems. One of these is represented by the antidiuretic hormone (ADH). ADH release is modulated by osmoreceptors and baroreceptors which respond to an increase in osmolality of extracellular fluid and a decrease in blood volume, respectively. In previous studies we investigated the existence of additional structures sensitive to plasma volume modifications. We found evidence of the presence of such receptors in the inner ear, with nervous connections to supraoptic and paraventricular nuclei. However, the possibility that the cerebral ventricle wall contained stretch sensors could not be excluded. To test our hypothesis, we studied 19 rats divided into three groups: Group 1 (n =7), Group 2 (n =7) and Group 3 (control group n =5). In each rat, under total anaesthesia, a femoral cannula was inserted into the left artery and a 22 gauge stainless steel cannula was implanted into the left cerebral ventricle. In the first group an isotonic fluid, similar to the animal's cerebrospinal fluid (CSF), was infused intracerebroventricularly (ICV) at a rate of 0.6 microl min-1 continuously for 6 h. In the second group, under the same conditions, CSF was aspirated; the third group was used as the control. In all animals, plasma modifications of ADH (pADH), osmolality (pOSM), Na+(pNa+) and K+(pK+) were evaluated before and after the experimental procedures. Mean arterial pressure (MAP) and heart rate (HR) were recorded throughout the experiment. At the end of the experiment no significant changes in pNa+, pK+, MAP and HR were observed. Plasma osmolality was significantly lower in Group 2 before and during the experimental procedure, since we deliberately expanded the volume in animals of Group 2 to partially suppress ADH, in order to evaluate its modifications. Plasma ADH fell in the first experimental group (-37.4%+/-6.3 sem) after the ventricular pressure had been increased, and rose in the second (+47.3%+/-14.7 sem) after ventricular decompression. These changes were statistically significant in comparison with those occurring in control subjects (-0.9+/-18.9 sem;P =0.07 and P =0.03, respectively). These results suggest the presence of additional volume receptors probably located in the cerebral ventricles, capable of controlling ADH. The importance of these receptors in physiological situations of plasma volume contraction or expansion remains to be established.

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.

Blood pressure responses to acute or chronic captopril in mice with disruption of bradykinin B2-receptor gene.

OBJECTIVE: To evaluate the role of kinins in the hypotensive response to angiotensin converting enzyme inhibition, we compared the blood pressure effects induced by acute or chronic captopril administration in a mouse strain (Bk2r-/-) with disruption of the bradykinin B2 receptor gene and in wild-type controls (J129 Sv mice). A second aim was to determine whether Icatibant, a selective bradykinin B2-receptor antagonist, prevented the blood pressure changes induced by acute captopril administration in Swiss, c57/B16, J129 Sv and Bk2r-/- mice. METHODS AND RESULTS: Under basal conditions, tail-cuff systolic blood pressure (SBP) and intra-arterial mean blood pressure (MBP) were higher in Bk2r-/- than in J129 Sv (SBP: 132+/-2 versus 113+/-3 mmHg; MBP: 144+/-6 versus 122+/-10 mmHg, P< 0.05 for both comparisons). Acute captopril administration (1 mg/kg body weight, intra-arterially) reduced the MBP of Bk2r-/- and J129 Sv by 36+/-8 and 31+/-7 mmHg, respectively. Swiss and c57/B16 mice showed similar decreases in MBP following captopril. Pretreatment with Icatibant (10 nmol/kg body weight, intra-arterially) did not influence the MBP responses to acute captopril in all the strains. Chronic administration of captopril (approximately 120 mg/kg body weight per day for 2 weeks in drinking water) reduced SBP in either Bk2r-/- or J129 Sv. The magnitude of this response was higher in Bk2r-/- than in J129 Sv (65+/-3 versus 47+/-4 mmHg, respectively, P < 0.01). CONCLUSIONS: Our results suggest that endogenous kinins do not participate in the hypotensive response to angiotensin converting enzyme inhibition in mice; in Bk2r-/-, the exaggerated blood pressure response to chronic captopril appears to be attributable to interference with unbalanced vasoconstrictor action of the renin-angiotensin system.

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.

Sexual dimorphism of cardiovascular responses to early blockade of bradykinin receptors.

To assess whether the cardiovascular effects induced by early blockade of bradykinin B2-receptors with Hoe 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) are influenced by sex, Wistar rats of both sexes received the antagonist (300 nmol/d per kilogram body wt) or vehicle from 2 days to 7 weeks of age by subcutaneous injection and then by intraperitoneal infusion. Compared with control rats, Hoe 140-treated female rats showed higher systolic blood pressure levels at 7 and 9 weeks of age (125 +/- 2 versus 111 +/- 2 mm Hg and 132 +/- 3 versus 116 +/- 2 mm Hg, respectively, P < .05), whereas in male rats a difference was found at 7 weeks (122 +/- 4 versus 108 +/- 4 mm Hg, P < .05) but not at 9 weeks. At this stage, the mean blood pressure of Hoe 140-treated rats was higher than that of control animals, and this difference was more pronounced at 12 weeks in female rats (121 +/- 2 versus 100 +/- 3 mm Hg in control animals, P < .01) compared with males (116 +/- 3 versus 104 +/- 2 mm Hg in control animals, P < .05). After the first week of life, body weight gain was greater in Hoe 140-treated female rats than in control rats, whereas a group-difference was detected in male rats only after weaning. In Hoe 140-treated female rats, heart weight was already increased at 9 weeks (330 +/- 6 versus 305 +/- 5 mg/100 g body wt in control rats, P < .05), whereas it was necessary to prolong Hoe 140 administration in male rats to develop heart hypertrophy (300 +/- 4 versus 275 +/- 4 mg/100 g body wt in control rats at 12 weeks, P < .05). Tissue kallikrein mRNA levels were higher in the kidney of adult female rats, whereas no sex difference was detected in the heart. The finding of a sexual dimorphism in the cardiovascular response to early blockade of bradykinin receptor suggests that endogenous kinins play a role in the regulation of cardiovascular function in both sexes, but they may be functionally more important in the female rat.