ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:To examine whether the altered regulation of adenylyl cyclase that has been reported in vascular tissues from spontaneously hypertensive rats is also evident in the Milan hypertensive (MHS) rat strain.Design:The plasma membranes of vascular smooth muscle cells derived from thoracic aortae from adult (60-day-old) MHS and Milan normotensive (MNS) strain rats were studied.Methods:Guanine nucleotide regulatory protein (G-protein) function was inferred from adenylyl cyclase activity studies, and levels of G-protein subunits were assessed by immunoblotting. β-Adrenergic receptor number and affinity were measured from the binding of the antagonist [125l]-cyanopindolol.Results:Basal adenylyl cyclase activity was increased significantly in MHS rat cell membranes, and stimulation by 0.1 mmol/l isoproterenol and 0.01 mmol/l prostaglandin E1was significantly greater in MHS than in MNS rat cell membranes. Forskolin (at 0.1 mmol/l) resulted in a significantly greater stimulatory response in MHS membranes, which was eliminated by 0.01 mol/l NaF. Biphasic effects of GTP on isoproterenol-stimulated membranes demonstrated similar Gifunction in MHS and MNS rat cell membranes, although a greater stimulatory GTP response was observed in MHS rat cell membranes. The levels of Gsα(both forms), Gi3αand the β-subunit were reduced in MHS rat cell membranes, whereas the levels of Gi2αand Gqαand G11αwere unchanged. The number of β-adrenoceptors was increased significantly in MHS rat cell membranes, whereas receptor affinity for the antagonist was unaltered.Conclusions:There are differences in adenylyl cyclase stimulatory responses in MHS rat vascular smooth muscle cell membranes. We have found evidence of reduced levels of particular G-protein subunits, altered β-adrenoceptor-Gscoupling and increased β-adrenoceptor number.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:Evidence suggests that calcium antagonists may suppress vascular smooth muscle cell (VSMC) growth and proliferation, which may be a crucial step in the pathogenesis of hypertension and atherosclerosis.Design:The effects of the dihydropyridine calcium antagonists nifedipine, nitrendipine, nisoldipine, nimodipine and isradipine on cell growth induced by platelet-derived growth factor (PDGF)-AB and angiotensin II (Ang II), and expression of the transcription factorsc-fosand early-growth response gene 1 (egr-1) were investigated.Methods:Proliferation of VSMC in culture was measured by [3H]-thymidine incorporation into cell DNA and by cell count. Expression ofc-fosandegr-1messenger RNA (mRNA) was determined by the Northern blot technique.Results:All of the calcium antagonists blunted the PDGF-induced rise in VSMC DNA synthesis. The inhibitory potency of isradipine on PDGF-stimulated DNA synthesis was approximately 10-fold that of the other calcium antagonists used, isradipine having a half-maximal inhibitory concentration (IC50) of (4.2 ± 0.16) x 10-7mol/l. The calcium antagonists investigated also inhibited Ang II-induced DNA synthesis. Isradipine (10-6mol/l) completely abolished the PDGF-induced cell proliferation. Both PDGF (50 ng/ml) and Ang II (10-7mol/l) inducedc-fosandegr-1mRNA expression, having maximum effect after 30 min. In the case ofc-fos, pre-incubation with 5 x 10-6mol/l isradipine led to a decrease in both Ang II- and PDGF-induced expression of this immediate-early gene. The expression ofegr-1was not affected by pre-incubation with 5 x 10-6mol/l isradipine.Conclusions:All calcium antagonists investigated in the present study inhibited cell growth. Isradipine was more potent in blocking growth factor-induced cell growth than the other calcium antagonists studied. The inhibitory effect of the dihydropyridine calcium antagonists appears to be dependent on the expression ofc-fos.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:A large population of F2rats, obtained from a cross between male Lyon hypertensive (LH) rats and female Lyon normotensive (LN) rats, was studied in order to assess the relationship between increased body weight, hyperlipidaemia and high blood pressure which characterize LH rats.Methods:Mean arterial pressure (MAP) was recorded in male, conscious, freely moving LH, LN, F1and F2rats aged 30 weeks. Plasma total cholesterol, high-density lipoprotein-, low-density lipoprotein- and very low-density lipoprotein-cholesterol, phospholipids, triglycerides, insulin and glucose were measured.Results:In the F2cohort it was observed that high MAP was a recessive trait that depends on several genes and was unrelated to body weight. The left ventricular weight, corrected for tibia length, was correlated with MAP. Plasma total and high-density lipoprotein-cholesterol and phospholipids concentrations were lower in the F1rats than in the LN rats, suggesting an overdominance of the LN alleles. In the F2rats MAP was related to total, high-density lipoprotein- and low-density lipoprotein-cholesterol. Plasma triglycerides, insulin and the insulin: glucose ratio, which were higher in the LH rats than in the LN rats, were also correlated with MAP in the F2cohort. Using stepwise multiple regression analysis, MAP remained correlated with plasma total cholesterol, insulin and the insulin: glucose ratio, but not with triglycerides.Conclusions:Hypertension in LH rats is a recessive trait that is independent of body weight. In addition, the cosegregation of blood pressure with plasma cholesterol and, to a lesser degree, with insulin levels, which was observed in the present study provides the first direct evidence that these phenotypes are associated and are not due simply to genetic drift in the Lyon model.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:The hypotensive and hormonal responses of an ATT-subtype angiotensin II receptor antagonist, SR 47436, were investigated and compared with those of DuP 753 (losartan), the leading AT1-receptor antagonist, and captopril and enalapril, two major angiotensin converting enzyme (ACE) inhibitors, in conscious, sodium-replete and sodium-depleted non-human primates.Design and method:Blood pressure and heart rate were measured in conscious, chronically instrumented sodium-replete (n = 3–5) and sodium-depleted (n = 4) cynomolgus monkeys (Macaca fascicularis). Plasma renin activity (PRA), active renin and angiotensin II plasma concentrations were determined.Results:SR 47436 induced a dose- and time-related fall in blood pressure in sodium-depleted monkeys; the blood pressure-lowering effect was obtained at a range of doses from one-third to one-tenth the equihypotensive dose of DuP 753 after intravenous and oral administrations. The hypotensive effect obtained with SR 47436 was similar to that of captopril and was sustained in sodium-replete monkeys, although it was weaker and less long-lasting than that of enalaprilat. In both sodium-depleted and sodium-replete monkeys the AT1antagonist and ACE inhibitors caused similar increases in PRA and active renin. However, although angiotensin II levels increased after SR 47436 or DuP 753 treatment, they decreased after treatment with enalaprilat. Modest decreases in the heart rate sometimes accompanied the hypotension, irrespective of the compound tested.Conclusion:These data demonstrate that the AT1antagonist SR 47436 is an effective hypotensive agent in both sodium-replete and sodium-depleted monkeys, with an intrinsic potency three to 10 times that of DuP 753 and similar to that of ACE inhibitors.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:Nailfold capillary density was measured at rest and after 4 min circulatory arrest in order to investigate the relationship between sodium-sensitive hypertension and microvessel density.Design:Seventeen sodium-sensitive and 28 sodium-resistant young borderline hypertensive males and 10 normotensive controls were studied. All of the subjects ate a diet containing 120 mmol/day sodium during the week preceding the investigation.Methods:Capillary density was investigated by means of intravital videomicroscopy. Blood pressure, cardiac index, plasma volume and humoral factors, such as plasma renin activity, plasma aldosterone and atrial natriuretic peptide, were also determined.Results:No differences in capillary density were found under basal conditions. However, during hyperaemia the sodium-resistant subjects had significantly fewer perfused capillaries than both the sodium-sensitive and control subjects, whereas (apart from blood pressure) macrocirculatory parameters and humoral factors did not differ among the three groups.Conclusion:Sodium-resistant borderline hypertensives seem to be characterized by a (possibly structural) reduction in nailfold capillarity, a phenomenon that is, as yet, unexplained.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:To gain insight into the relationship between vascular compliance and sodium sensitivity.Design:Arterial and venous compliance was determined in 17 sodium-sensitive and 28 sodium-resistant, young, borderline hypertensive males and in 10 age-matched normotensive controls, during regular sodium intake.Methods:The carotid, femoral and brachial arteries were studied using a non-invasive ultrasound vessel wall movement detector system, and venous compliance was determined using forearm strain-gauge plethysmography. Cardiac output, plasma volume and hormonal factors, such as plasma renin activity, were also measured to assess their possible influence on vascular compliance.Results:Large artery compliance was significantly less in the sodium-sensitive than in the sodium-resistant subjects in all arteries studied. Compared with controls, arterial compliance was reduced significantly in the sodium-sensitive group, whereas the sodium-resistant group did not differ significantly from the controls. Venous compliance was reduced equally in the two hypertensive groups compared with the controls, although the differences did not reach statistical significance. Cardiac output, blood pressure, plasma volume and hormonal factors did not differ between sodium-sensitive and sodium-resistant subjects and could not have been responsible for the observed differences in arterial compliance.Conclusions:The results of this study suggest that sodium-sensitive borderline hypertensives have reduced large artery compliance compared with age-matched sodium-resistant subjects. Since this finding could not be explained by differences in haemodynamic or hormonal factors between the groups, this suggests alterations to the viscoelastic properties of the arterial walls in sodium-sensitive subjects.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:To study the acute effects of cyclosporin on blood pressure, renal function and hormones within the first few hours of drug ingestion in healthy man.Design:A therapeutic (12mg/kg) and a supratherapeutic (30mg/kg) dose of cyclosporin were administered orally to 10 salt-replete normal healthy volunteers. Their renal haemodynamic parameters were assessed by inulin andpara-aminohippurate clearances, and their blood pressure was recorded every 20min.Results:Cyclosporin had an acute hypertensive effect while having no effect on sodium excretion or renal function. The earliest renal effect of cyclosporin was on water handling, with a marked antidiuretic effect.Conclusions:Our findings contradict previous data and currently held views regarding the pathogenesis of cyclosporin-induced hypertension. In particular, we have demonstrated that hypertension precedes any measurable change in renal haemodynamic parameters and occurs without apparent overall alterations in renal sodium excretion. We have also found that an antidiuresis is a very early renal effect of cyclosporin.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:To test whether the activation of the sympathetic nervous system that is common in essential hypertension derives from subcortical noradrenergic neuronal excitation.Design and methods:We performed a radionuclide cerebral venous sinus scan, using technetium-99m, to establish which internal jugular vein predominantly drained the cortical (the major jugular vein) and which the subcortical (minor jugular vein) brain regions. Blood samples were then collected simultaneously from catheters placed percutaneously in the brachial artery or radial artery and high in the internal jugular vein in 11 untreated hypertensive patients and 18 normotensive subjects, for determination of the plasma concentrations of noradrenaline, its precursor dihydroxyphenylalanine (DOPA) and its metabolite dihydroxyphenylglycol (DHPG) to calculate their rates of overflow into the cerebrovascular circulation.Results:In normotensive subjects blood flow determined by thermodilution was significantly higher in the major than in the minor jugular vein. The noradrenaline spillovers into the major and minor jugular veins calculated during infusions of L-[3H]-7-noradrenaline were similar in healthy subjects. The noradrenaline spillover from subcortical regions into the minor jugular vein was significantly higher in the hypertensives than in the normal subjects, as was the overflow of DHPG. In contrast, cortical noradrenaline and DHPG overflows into the major jugular vein were similar in hypertensive and normotensive subjects. Overflow of DOPA into the minor jugular vein, which derives largely from precursor turnover in dopaminergic neurons, was similar in hypertensive and normotensive subjects. Subcortical noradrenaline spillover correlated with neurochemical indices of sympathetic nervous system activity, with total body noradrenaline spillover (r=0.56,P<0.05) in normal and hypertensive subjects combined, and with renal noradrenaline spillover in the six hypertensive patients tested (r=0.91,P<0.05).Conclusion:These results suggest that increased subcortical noradrenaline release is a possible cause of peripheral sympathetic activation in essential hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:Dietary supplementation with marine oils attenuates the responses to noradrenaline and angiotensin II in human forearm resistance arteries. The mechanisms underlying these effects were the subject of the present study.Methods:Twenty-two normal male adults were allocated to one of three groups. The first group (n = 11) received 10 g/day marine oil capsules (maxEPA) for 28 days. The second group (n = 7) received maxEPA plus 25 mg indomethacin three times a day on days 28 and 29. The third group (n = 4) received 10 g/day mixed-oil placebo capsules for 28 days, plus indomethacin on days 28 and 29 as in group 2. Forearm venous occlusion plethysmography was performed before and immediately after each treatment period.Results:Responses to acetylcholine, sodium nitroprusside or reactive hyperaemia (area under the time-response curve: pre-maxEPA 14 850 ± 3502, post-maxEPA 17 118 ± 4576 units) were unaffected by maxEPA. The suppressive effect of maxEPA on responses to noradrenaline and angiotensin II (from group 1) was no longer apparent in the group receiving indomethacin in addition to maxEPA. Indomethacin, in subjects on placebo capsules, had no effect on the responses to either agonist.Conclusion:We conclude that the suppressive effects of maxEPA result from alterations toin vivoprostanoid profiles.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID