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.

Cardiovascular effects of brain kinin receptor blockade in spontaneously hypertensive rats.

We studied the role of brain kinins in the regulation of cardiovascular function. Intracerebroventricular injection of 380 pmol bradykinin increased mean blood pressure by 20 +/- 2 mm Hg (P < .01) in normotensive Wistar-Kyoto (WKY) rats. Complete inhibition of this effect was achieved with intracerebroventricular administration of the newly synthesized, long-acting B2 receptor antagonist D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140). On a molar basis, Hoe 140 was two orders of magnitude more potent than antagonists of the first generation. Baroreceptor sensitivity, estimated as the heart rate response to blood pressure changes induced by intravenous injection of phenylephrine or sodium nitroprusside, was not altered by Hoe 140 in WKY rats. In spontaneously hypertensive rats (SHR), baroreceptor reflex sensitivity to increments in mean blood pressure was reduced by Hoe 140 (mean slope value: -0.47 +/- 0.07 versus -0.92 +/- 0.13 beats per minute per millimeter of mercury in controls, P < .05). Hoe 140 did not affect the tachycardic component of the baroreceptor reflex. Two-week intracerebroventricular infusion of Hoe 140 did not alter systolic blood pressure or heart rate in WKY rats. In SHR, systolic blood pressure increased (P < .01) similarly during the infusion of Hoe 140 or vehicle (from 174 +/- 6 to 220 +/- 5 mm Hg and 178 +/- 4 to 210 +/- 4 mm Hg at 2 weeks, respectively), whereas heart rate did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Early blockade of bradykinin B2-receptors alters the adult cardiovascular phenotype in rats.

We evaluated whether long-term inhibition of bradykinin B2-receptors by the long-acting antagonist Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) affects the blood pressure of normotensive rats. Neither Hoe 140 (at 75 nmol/d for 8 weeks) nor its vehicle altered systolic pressure of adult rats on a normal or high sodium intake. In further experiments, pairs of Hoe 140-treated rats were mated and their offspring maintained on Hoe 140 and a normal sodium diet. Controls were given vehicle instead of Hoe 140. At 9 weeks of age, rats given Hoe 140 during prenatal and postnatal phases of life showed greater systolic pressures, heart rates, and body weights than controls (122 +/- 1 versus 113 +/- 1 mm Hg, 444 +/- 6 versus 395 +/- 8 beats per minute, 258 +/- 7 versus 213 +/- 3 g, respectively, P < .01), whereas urinary creatinine excretion was reduced (1.13 +/- 0.05 versus 1.36 +/- 0.04 mumol/100 g body wt in controls, P < .05). The difference in blood pressure (confirmed by direct intra-arterial measurement) persisted after 20 days of dietary sodium loading, whereas it was nullified by sodium restriction. In additional experiments, the offspring of untreated rats received Hoe 140 or vehicle from 2 days to 11 weeks of age. At this stage, systolic pressure and body weight were significantly greater in Hoe 140-treated rats compared with controls, and heart rate was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of kinin blockade on the blood pressure of salt-loaded pregnant rats.

We evaluated whether chronic inhibition of bradykinin B2 receptors by the long-acting antagonist D-Arg, [Hyp3, Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140) affects blood pressure of salt-loaded pregnant rats. Pairs of rats fed a high sodium diet (0.84 mmol sodium per gram chow) were mated at 14 weeks of age. Infusion of vehicle or Hoe 140 (300 nmol/d per kilogram body weight) was performed throughout each dam's pregnancy by use of an Alzet osmotic pump implanted in the abdominal cavity. In both groups, no significant change in systolic pressure (tail-cuff plethysmography) or renal blood flow (Doppler flow-meter) was observed from that in the unmated state to that at midterm pregnancy. In the control group, systolic pressure decreased at the 21st day of pregnancy (from 126 +/- 2 to 97 +/- 2 mm Hg, P < .01), and renal blood flow increased (from 6.1 +/- 0.1 to 7.5 +/- 0.2 kHz, P < .01). These changes were nullified by the administration of Hoe 140 (systolic pressure changing from 124 +/- 2 to 118 +/- 4 mm Hg, P = NS; renal blood flow changing from 6.3 +/- 0.2 to 6.2 +/- 0.1 kHz, P = NS). In the group given Hoe 140, placental weight was greater (0.50 +/- 0.01 versus 0.43 +/- 0.01 g in controls, P < .01) and the fetal/placental weight ratio was reduced (4.53 +/- 0.09 versus 5.31 +/- 0.17 in controls, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Brain kinins are responsible for the pressor effect of intracerebroventricular captopril in spontaneously hypertensive rats.

The role of the brain kallikrein-kinin system in the regulation of arterial blood pressure of normotensive and spontaneously hypertensive rats was evaluated. Intracerebroventricular administration of the kinin antagonist [DArg0]Hyp3-Thi5,8[DPhe7]bradykinin caused no change in mean blood pressure in Wistar-Kyoto, Sprague-Dawley, or spontaneously hypertensive rats. The antagonist proved to be very potent in blocking the pressor effect of intracerebroventricular bradykinin (32 +/- 3 vs. 3 +/- 1 mm Hg, p less than 0.01). It was specific, as the pressor effect induced by other unrelated peptides was similar during the infusion of either vehicle or kinin antagonist (angiotensin II, 25 +/- 4 vs. 26 +/- 2 mm Hg; prostaglandin E2, 48 +/- 3 vs. 47 +/- 8 mm Hg; norepinephrine, 17 +/- 2 vs. 18 +/- 2 mm Hg; leucine-enkephaline, 15 +/- 2 vs. 16 +/- 1 mm Hg; neurotensin, 18 +/- 2 vs. 19 +/- 1 mm Hg; substance P, 19 +/- 2 vs. 19 +/- 2 mm Hg). Intracerebroventricular administration of 1 mg captopril, an inhibitor of kininase II (one of the enzymes responsible for kinin degradation), caused no change in mean blood pressure in normotensive rats, whereas it increased mean blood pressure by 44 +/- 9 mm Hg (p less than 0.01) in spontaneously hypertensive rats. This increase in mean blood pressure was blocked and then reversed into a hypotensive effect (22 +/- 6 mm Hg, p less than 0.05) during the infusion of kinin antagonist. Our data suggest that the pressor effect induced by intracerebroventricular captopril is due to a transient elevation in endogenous brain kinin levels, supporting the hypothesis that the brain kallikrein-kinin system plays a role in the central regulation of blood pressure in spontaneously hypertensive rats.

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.

Chronic kinin receptor blockade induces hypertension in deoxycorticosterone-treated rats.

1. The contribution of endogenous kinins to the regulation of blood pressure and renal function of Wistar rats was evaluated by use of the new B2-receptor antagonist, Hoe 140, (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin). 2. Neither Hoe 140 (4 micrograms h-1 s.c., for 6 weeks), nor vehicle altered systolic blood pressure (SBP, tail-cuff plethysmography) or renal function in rats, under normal conditions. 3. Chronic administration of deoxycorticosterone (DOC, 25 mg kg-1 s.c., weekly) increased SBP slightly only after 6 weeks (from 124 +/- 2 to 133 +/- 3 mmHg, P < 0.05). An earlier and greater rise in SBP (P < 0.01) occurred when DOC was combined with chronic infusion of Hoe 140 (from 125 +/- 1 to 154 +/- 3, P < 0.01). The hypertensive effect of Hoe 140 was confirmed by direct measurement of mean blood pressure (143 +/- 2 vs 122 +/- 2 mmHg in controls, P < 0.01). 4. DOC caused an initial fall, followed by a transitory increase in urinary volume and sodium excretion; thereafter, both parameters returned to baseline. The initial antidiuretic and antinatriuretic effects were enhanced by Hoe 140 (P < 0.05). 5. Urinary prostaglandin E2 excretion was increased by DOC (from 106 +/- 3 to 153 +/- 4 ng 24 h-1, P < 0.01) and this effect was prevented by Hoe 140 (from 95 +/- 3 to 104 +/- 3 ng 24 h-1, NS). By contrast, the high urinary vasopressin excretion and suppressed plasma renin activity found in DOC-treated rats were not altered by Hoe 140. 6. These data suggest that endogenous kinins play an important role in the regulation of arterial blood pressure under conditions of mineralocorticoid excess.

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.

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.

Effects of Hoe 140, a bradykinin B2-receptor antagonist, on renal function in conscious normotensive rats.

1. The present study was designed to determine if endogenous kinins are involved in the regulation of arterial blood pressure and renal function in conscious rats given deoxycorticosterone enantate (DOC, 25 mg kg-1, s.c., weekly) or vehicle for two weeks. 2. The bradykinin B2-receptor antagonist, D-Arg[Hyp3,Thi5,D-Tic7,Oic8]- bradykinin (Hoe 140), at a dose of 300 micrograms kg-1, s.c., blocked the hypotensive effect of 300 ng kg-1 bradykinin i.a., but it did not alter the blood pressure lowering action of 300 ng kg-1 acetylcholine or prostaglandin E2. Inhibition of the response to bradykinin persisted up to 6 h after the administration of Hoe 140. 3. Administration of 300 micrograms kg-1 Hoe 140 s.c. four times a day did not alter mean blood pressure, renal blood flow, or renal function in rats given DOC-vehicle. However, it decreased urinary volume by 70% (from 48.2 +/- 3.8 to 14.3 +/- 3.7 ml 24 h-1, P less than 0.01) and urinary secretion of sodium by 54% (from 1.02 +/- 0.05 to 0.47 +/- 0.16 mmol 24 h-1, P less than 0.01) and potassium by 30% (from 2.93 +/- 0.15 to 2.04 +/- 0.15 mmol 24 h-1, P less than 0.05) in DOC-treated rats. Mean blood pressure, glomerular filtration rate and total renal blood flow remained unchanged. 4. Our results suggest that endogenous kinins play a role in the regulation of renal excretion of water and sodium in the presence of elevated levels of DOC.

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.

Verapamil prevents the acute hypertensive response to intracerebroventricular cadmium in conscious normotensive rats.

Cadmium, a trace element from natural and industrial sources, may contribute to the pathogenesis of arterial hypertension. We evaluated the effect induced by acute intracerebroventricular (icv) administration of cadmium on mean blood pressure of normotensive conscious rats. Intracerebroventricular cadmium (1 to 10 micrograms) produced a dose-dependent, sustained increase in mean blood pressure. The hypertensive response to icv cadmium was significantly (P < .01) prevented by icv pretreatment with verapamil (10 to 100 micrograms). A preventive effect was exerted also by icv nifedipine (100 micrograms); however, this result was attributable, at least in part, to the antihypertensive action of the vehicle, polyethylene glycol. The hypertensive response to icv cadmium was blunted by icv administration of 10 ng clonidine, 10 micrograms vasopressin antagonist, or 10 micrograms bradykinin antagonist (P < .05), but it was not altered by icv enalaprilat (100 micrograms). These results indicate that brain calcium channels play a role in the hypertensive action induced by icv cadmium. Accumulation of cadmium in the brain caused by prolonged exposure to this heavy metal might lead to chronic arterial hypertension.

Chronic inhibition of bradykinin receptors alters cardiovascular function in rats with an excess of circulating vasoconstrictors.

1. The contribution of endogenous kinins to the regulation of blood pressure of angiotensin-treated rats was evaluated using the new bradykinin B2-receptor antagonist Hoe 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin). 2. Chronic intraperitoneal infusion of 20 nmol/day angiotensin II did not alter systolic blood pressure or plasma angiotensin II levels. A significant increase in plasma aldosterone and corticosterone levels was observed after 4 weeks (from 89 +/- 20 to 140 +/- 22 and from 147 +/- 30 to 225 +/- 33 pg/ml, respectively; P < 0.05). 3. Combined administration of 20 nmol/day angiotensin II and 75 nmol Hoe 140 induced a significant increase in systolic blood pressure from 126 +/- 3 to 142 +/- 3 and 137 +/- 3 mmHg, at 1 and 4 weeks, respectively (P < 0.05). This effect was not accompanied by significant changes in plasma angiotensin II concentration. The angiotensin-induced increase in plasma levels of aldosterone and corticosterone was not altered by the antagonist Hoe 140. 4. These findings indicate that blockade of endogenous kinin receptors enhances the slow pressor effect induced by angiotensin II. Therefore, endogenous kinins may play a role in preventing the cardiovascular effects of an excess of vasoconstrictors.

Diuretic agents related to indapamide. III--Synthesis and pharmacological activity of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydroisoquinolines.

A series of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinoline++ + (IV-1) and isoquinoline (IV-2) have been synthesized and their diuretic and antihypertensive activities evaluated. While none of the test compounds was found to be provided with antihypertensive properties, most of them displayed a diuretic activity comparable to (IV-2 a) or higher (IV-1 a,b) (IV-2 c) than those of indapamide and clopamide, taken as reference drugs.

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.

Synthesis and evaluation of gastroprotective and antiulcer activity of some 2-substituted-1H-imidazo[4,5-b] pyridines and -1H-benzimidazoles.

Several compounds possessing imidazo[4,5-b]pyridine and benzimidazole structure bearing substituents in position 2 were prepared in order to evaluate an anti-ulcer and gastroprotective activity in rat pylorus ligature, in comparison with omeprazole. Among sixteen compounds taken as representatives of the synthetised series only one (3d) showed a good activity by i.m. administration at 50 mg/kg, while by oral administration of 100 mg/kg a certain number was active and in some cases this activity was quite superior to that of omeprazole.

Synthesis and evaluation of gastroprotective activity of omeprazole related benzimidazole, imidazo[4,5-b]pyridine and quinoxaline 2-substituted derivatives.

Twenty compounds possessing benzimidazole, imidazo[4,5-b]pyridine and quinoxaline structure bearing either a substituted arylmethylmercapto- or an arylmethylsulfinyl group in position 2 were prepared in order to evaluate an antiulcer and gastroprotective activity in rat pylorus ligature, in comparison with omeprazole at the dose of 50 mg/kg after i.m. administration. One third of these compounds showed a moderate activity, being about half potent as omeprazole.

[Cadmium-induced changes in the activity of the dopaminergic and purinergic systems and in ascorbic acid catabolism in the rat striatum]. / Modificazioni da cadmio dell'attività dei sistemi dopaminergico e purinergico e del catabolismo dell'acido ascorbico nello striato del ratto.

Levels of dopamine (DA), 3-4-dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), uric acid (UA) and adenosine (ADO), were determined by HPLC in the striatum of male Wistar rats treated with repeated injections of cadmium (as sulfate) 3 mg/kg/day s.c. for 10 consecutive days. Cadmium treatment significantly reduced DOPAC levels with consequent decrease of the DOPAC/DA ratio; AA levels were significantly reduced, while DHAA levels were significantly increased, with consequent increase of DHAA/AA ratio: levels of UA and ADO were both significantly increased. It is concluded that cadmium, given systemically, reduces dopaminergic system activity in the rat striatum; such impairment occurs together with an increase of AA oxidation and of markers of purinergic system activity. The inhibition of striatal dopaminergic activity could be considered the neurochemical basis of behavioral changes induced by cadmium, while the increase of AA oxidation and of purinergic system activity could be considered an antitoxic metabolic response.