摘要:

Our purpose was to evaluate whether early treatment of spontaneously hypertensive rats (SHR) with the angiotensin converting enzyme inhibitor captopril could permanently alter the course of hypertension. Mating pairs of SHR were treated with captopril, and their pups were maintained on captopril until experimentation. Some captopril-treated rats were taken off treatment at 2 months of age, and then some of these rats were mated at 3 months of age. The mean arterial pressures of conscious captopril-treated rats, the rats removed from therapy, and the offspring of the rats removed from therapy were significantly smaller than control rats at 4 and 9 months of age. Central administration of angiotensin I or II induced significantly smaller increases in blood pressure and drinking in captopril-treated rats and the rats removed from therapy compared with control rats. The increase in blood pressure in response to intravenous Injection of angiotensin I or II was similar among all groups, with the exception that captopril-treated rats showed lesser pressor responses to angiotensin I. Early administration of captopril, even after administration was stopped, prevented the subsequent development of hypertension in SHR and altered the course of development of hypertension in their progeny. This effect was associated with decreased central responses to angiotensin I and II. Our data suggest that captopril may permanently alter the development of hypertension in SHR through an alteration in the central renln-angiotensin system.

ISSN:0194-911X    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Endothelium-dependent dilatation of cerebral arterioles is impaired during chronic hypertension. The goal of this study was to determine the effects of an angiotensin converting enzyme inhibitor, ciiazaprii, on endothelium-dependent dilatation in pial arterioles. Four-month-old Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP) received cilazapril in their drinking water (500 mg/L) for 3 to 6 months. Treatment with cilazapril reduced mean arterial pressure in both WKY rats and SHRSP and had no significant effect on baseline diameter of pial arterioles measured with a cranial window. Responses to bradykinin and A23187, but not to nitroglycerin and adenosine, were impaired in SHRSP. Cilazapril did not affect responses to bradykinin (3×10−7M) and A23187 (10−5M) in WKY rats but significantly increased cerebral vasodilatation in response to bradykinin (52 ±4% vs 27±5%) and A23187 (19±3% vs 8±3%) in SHRSP. Cilazapril also tended to increase dilator responses to nitroglycerin and adenosine in SHRSP. In another group of SHRSP, treatment with cilazapril for 4 days produced a moderate reduction in blood pressure and increased cerebral vasodilatation in response to bradykinin, A23187, and adenosine. Topical application of the active form of cilazapril (cilazaprilat) for 40 minutes also increased cerebral vasodilatation in response to bradykinin, A23187, and nitroglycerin in SHRSP. The data indicate that an angiotensin converting enzyme inhibitor enhances cerebral vasodilatation in response to endothelium-dependent agonists in SHRSP and may also increase responses to endothelium- independent agonists.

ISSN:0194-911X    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Nitric oxide mediates the vasodilator and hypotensive responses of acetylcholine infusion. It has been reported that nitric oxide could be protected from free radical destruction by forming anS-nitrosothiol compound. Furthermore, sulfhydryl donors such asN-acetylcysteine or thiosalicylic acid enhance nitric oxide production from nitroglycerin. Consequently, the hypotensive effect of intravenous acetylcholine infusion might be potentiated during the simultaneous administration of sulfhydryl donors. The objective of the present study was to test in Okamoto spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (1) whether the hypotensive effect of acetylcholine (10μg/kg per minute) was affected by the simultaneous administration ofN-acetylcysteine (10 μg/kg per minute) or thiosalicylic acid (10 μg/kg per minute), and (2) whetherNG-nitro-L-arginine-methyl ester (100 μg/kg per minute) administration was able to reverse the changes induced by acetylcholine plusN-acetylcysteine or acetylcholine plus thiosalicylic acid. The administration of acetylcholine reduced (P<.05) mean arterial pressure in WKY rats (13±2%) and SHR (14±2%) without affecting urine flow rate, urinary sodium excretion, and glomerular filtration rate. In the presence ofN-acetylcysteine, the acetylcholine-induced reduction in mean arterial pressure was potentiated (P<.05) in WKY rats (24±4%) and SHR (20±2%). These changes in mean arterial pressure were accompanied by significant reductions in urine flow rate and urinary sodium excretion in WKY rats, as well as in glomerular filtration rate in SHR. During the administration of thiosalicylic acid, the acetylcholine-induced hypotensive response was potentiated (P<.05) in both WKY rats (31±4%) and SHR (22±3%). These effects were also accompanied by significant reductions in urine flow rate, urinary sodium excretion, and glomerular filtration rate. The administration of NG-nitro-L-arginine-methyl ester reversed (P<.05) the changes induced by acetylcholine plusN-acetylcysteine and acetylcholine plus thiosalicylic acid in mean arterial pressure, glomerular filtration rate, urine flow rate, and urinary sodium excretion in both rat strains. Under these conditions, urine flow rate and urinary sodium excretion levels were significantly higher than those found during the infusions ofN-acetylcysteine and thiosalicylic acid, respectively. The administration ofN-acetylcysteine or thiosalicylic acid, at the doses indicated, did not modify any of the measured arterial pressure or renal responses when compared with saline infusion. These results suggest that sulfhydryl donors effectively potentiated the hypotensive action of acetylcholine through a nitric oxide-dependent mechanism.

ISSN:0194-911X    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Urinary kallikrein excretion has been shown statistically to be partially determined by a major gene in large Utah pedigrees with the use of segregation analysis. A previous twin analysis of environmental factors influencing urinary kallikrein level showed that urinary potassium twin differences were strongly related to differences in urinary kallikrein. The present study uses 769 individuals in 58 Utah pedigrees to analyze the association of urinary potassium with urinary kallikrein within statistically inferred kallikrein genotypes. Fitting genotype-specific curves relating urinary kallikrein level to 12-hour urinary potassium amount within a major gene, polygene, and common environment model, we showed a significant statistical urinary potassium interaction with the inferred major gene for kallikrein (P=0002). The heterozygotes (with a frequency of 50%) had a significant association between urinary kallikrein and potassium (slope, 0.51±0.04 SD), whereas there was no association with potassium in the low homozygotes, suggesting a genetic defect involving the kallikrein response to potassium. The model predicted that an increase in urinary potassium excretion of 0.8 SD above the mean in these pedigrees would be associated with high kallikrein levels in the heterozygotes similar to the high homozygotes. A decrease of 1.3 SD in urinary potassium excretion in heterozygous individuals was associated with kallikrein levels similar to the homozygous individuals with low kallikrein. Because in the steady state urinary potassium represents dietary potassium intake, this study suggests that an increase in dietary potassium Intake in 50% of these pedigree members, estimated to be heterozygous at the kallikrein locus, would be associated with an increase in an underlying genetically determined low kallikrein level. If kallikrein excretion is found to be a physiological marker related to the risk of developing hypertension, that risk may be able to be modified by achievable increases in dietary potassium intake in heterozygous individuals deficient in potassium intake.

ISSN:0194-911X    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

We studied the ontogenetic development of renal α1-, α2-,and β-adrenergic receptors and their coupling to inositol phosphate and cyclic AMP formation in spontaneously hypertensive and normotensive Wistar-Kyoto rats, α1-, α2-and β-Adrenergic receptor number was significantly increased in hypertensive compared with normotensive rats, but the increase did not precede blood pressure elevation. Despite increased α1-adrenergic receptors, basal and norepinephrine-stimulated inositol phosphate formation remained unchanged in all age groups. Rat kidney contains α1A- and α1B,-adrenergic receptors coupling to inositol phosphate formation by different mechanisms, but the relative contribution of α1A- and α1B-adrenergic receptors to norepinephrine-stimulated inositol phosphate formation was similar in normotensive and hypertensive rats. Despite increased β-adrenergic receptors, basal, isoproterenol-, and forskolin-stimulated cyclic AMP accumulation was similar in normotensive and hypertensive rats. We conclude that the number but not the functional responsiveness of renal adrenergic receptors increases in spontaneously hypertensive rats. Thus, the additional receptors are unlikely to contribute to the pathophysiology of elevated blood pressure in this model.

ISSN:0194-911X    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Ouabain has recently been identified as an endogenous Na+-K+pump inhibitor. We administered ouabain chronically to normotensive rats with varying degrees of reduced renal mass (RRM) and to normal two-kidney rats to see whether hypertension could be produced. Normal male Wistar rats and rats with 25%, 60%, and 70% RRM received ouabain (13.9 μg/kg per day IP) in normal saline for 4 weeks followed by ouabain (27.8 μg/kg per day IP) for 3 to 4 more weeks. Respective control animals received vehicle only. Blood pressure was recorded weekly by tail plethysmography. Animals received tap water and standard rat chow, except for 70% RRM rats, which received distilled water and sodium-free chow. After 6 to 8 weeks of treatment, with rats under thiobutabarbital anesthesia, direct blood pressure was determined. Plasma, tissue, and urinary ouabain levels were measured with a specific radioimmunoassay. Animals receiving ouabain developed significant increases in mean blood pressure compared with control animals (70% RRM, 147±4 vs 116±4 mm Hg; 60% RRM, 140±4 vs 107±3 mm Hg; 25% RRM, 131±5 vs 100±2 mm Hg; no RRM, 116±4 vs 98±5 mm Hg). Plasma ouabain levels measured 24 hours after the last ouabain dose were not different in animals receiving ouabain vs those receiving vehicle. However, kidney tissue ouabain levels were significantly greater (6.39±1.17 vs 2.36±0.52 μg/kg,P<.05) in animals receiving ouabain. In conclusion, ouabain, given chronically, is associated with the development of hypertension in RRM rats as well as in normal rats. Blood pressure was greater in animals with greater degrees of RRM for a given ouabain dose.

ISSN:0194-911X    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Converting enzyme inhibitors impair renal function of the kidney beyond a stenosis of the renal artery in humans and induce histologlcal lesions in the clipped kidney of renal hypertensive rats. In two-kidney, one clip hypertensive rats, we compared the time course and magnitude of the biochemical effects of angiotensin converting enzyme inhibition on the plasma renin-angiotensin system, cardiac hypertrophy, renal lesions, and 24-hour blood pressure decrease induced by either intermittent angiotensin converting enzyme inhibition administration (benazepril PO, 10 mg/kg once a day, n=93) or continuous administration (benazeprilat, 3 mg/kg per day via osmotic pumps, n=92). Control rats (n=91) received the drug vehicle intermittently or continuously. Mortality was significantly reduced by both intermittent (n=3/93) and continuous (n=3/92) inhibition compared with controls (n=18/91) (P<.001). Changes in the plasma renin-angiotensin system and blood pressure were parallel. A continuous suppression of the activity of the plasma renin-angiotensin system was associated with a 24-hour decrease in blood pressure with continuous inhibition, whereas intermittent inhibition induced a similar fall in blood pressure only for the first hours after gavage. Heart weight (5.12±0.12, 3.98±0.09, 4_32±0.12 g/kg in controls [n=8], continuous inhibition [n=18], and intermittent inhibition [n=18], respectively) was significantly reduced to the same extent by both treatments (P<.0001), and clipped kidney weight (3.28±0.11, 1.83±0.12, 2.20±0.15 g/kg in controls [n=8], continuous inhibition [n=18], and intermittent inhibition [n=18], respectively) was significantly reduced in both groups of treated rats (P<.0001). After removal of the undipped kidney, plasma creatinine was significantly increased in both treatment groups (p<.0001) compared with nephrectomized hypertensive control rats but to a significantly greater extent in the continuously inhibited rats (117±39, 317±8, 260±8 μmol/L in controls [n=8], continuous inhibition [n=18], and intermittent inhibition [n=18];P<.0001). Therefore, changes in blood pressure and the plasma renin-angiotensin system were parallel after either continuous or intermittent inhibition. It was possible to decrease blood pressure continuously during 24 hours only with continuous inhibition. Both treatments reduced heart weight to a similar extent. Damage to the clipped kidney, as revealed by elevated plasma creatinine levels after nephrectomy of the undipped kidney, was slightly reduced but not avoided by the intermittent inhibition.

ISSN:0194-911X    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Short-term effects of ridogrel, a combined thromboxane synthase inhibitor and receptor antagonist, were investigated in 16 patients with uncomplicated essential hypertension. After a 2-week placebo period without antihypertensive medication, patients were admitted to the hospital overnight on two occasions 3 weeks apart On each occasion, they received two doses of either placebo or ridogrel (300 mg) 12 hours apart according to a double-blind crossover protocol. Renal and systemic thromboxane A2and prostacyclin biosynthesis were investigated by measuring urinary excretion of thromboxane B2, 6-oxoprostaglandin F1α, and their respective 2,3-dinor metabolites using gas chromatography/mass spectrometry. Responses of platelets to a thromboxane A2mimetic and to adenosine diphosphate were studied turbidometrically. Blood pressure was measured automatically at 20-minute intervals. Ridogrel reduced excretion of 2,3-dinor-thromboxane B2and thromboxane B2compared with placebo (21±6 versus 279±28 and 14±4 versus 39±9 ng/g creatinine, respectively,P<.0001 andP<.05). Excretion of 2,3-dinor-6- oxoprostaglandin F1αand 6-oxoprostaglandin F1α, was increased by ridogrel compared with placebo (184±20 versus 146±11 and 86±9 versus 58±6 ng/g creatinine, respectively;P<.05). Ridogrel selectively antagonized platelet aggregation to the thromboxane mimetic (P<.0001). Blood pressure did not differ significantly between ridogrel and placebo treatment periods. Thus, in patients with essential hypertension, acute administration of ridogrel reduces renal and extrarenal thromboxane A2biosynthesis, increases renal and extrarenal prostacyclin biosynthesis, inhibits thromboxane receptor-activated platelet aggregation, but has no effect on systemic arterial pressure.

ISSN:0194-911X    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

To define the potential pathogenic role of hyperinsulinemia as a mediator of alterations in sodium transport, we have examined red blood cell Na+-H+and Na+-Li+exchanges in a young adult black population characterized for blood pressure and insulin-mediated glucose disposal. Normotensive and mildly hypertensive blacks (blood pressure, 120±2/76±2 and 139±3/94±2 mm Hg, respectively) with a mean age of 26.1 years were studied for insulin sensitivity with the euglycemic hyperinsulinemic clamp (molar index of insulin sensitivity, M/I=moles glucose metabolized/insulin in milliliters of plasma). Na+-H+exchange (U=mmol/L cell · h) was measured before and after the insulin clamp as a function of cell pH to determine the maximum transport rate. In the normotensive subjects, 18 were insulin sensitive (M/I=9.37±0.6×104) and 4 were insulin resistant (M/I=3.64±0.6×104). In the hypertensive subjects, 4 were insulin sensitive (M/I=9.15±1.1×104) and 16 were insulin resistant (M/I=3.02±03×104). The maximum rate of Na+−H+exchange was significantly higher in all hypertensive vs normotensive individuals (35±3 vs 23±3 U,p<.005). Na+−H+exchange activity was higher in insulin-resistant vs insulin-sensitive hypertensive subjects (40±3 vs 20±2 U,P<.001) but not in insulin-resistant normotensive subjects. Na+−Li+exchange was not different in hypertensive and normotensive individuals but was higher in all insulin-resistant compared with all insulin-sensitive subjects (0.26±0.03 vs 0.16±0.02 U,P<.01). Na+-Li+exchange also was higher in insulin-resistant vs insulin-sensitive normotensive subjects (0.35±0.03 vs 0.15±0.02 U,P<.001) and in insulin-resistant hypertensive subjects vs insulin-sensitive normotensive subjects (0.24±0.03 vs 0.15±0.02 U,P<.001). A stepwise multiple regression analysis for all variables revealed that with Na+−H+exchange as a dependent variable the main determinant was blood pressure, which in turn had insulin sensitivity as the main determinant In conclusion, these results indicate that in hypertensive blacks, insulin-resistant glucose disposal is strongly associated with elevated red blood cell Na+-H+exchange activity. Thus, despite impaired insulin-mediated glucose disposal, cellular Na+gain via enhanced activity of Na+-H+exchange is not blunted in hypertensive blacks.

ISSN:0194-911X    

出版商:OVID    

年代:1993

数据来源: OVID