摘要:

SUMMARY1. A ‘second generation’ of centrally acting antihypertensive agents has recently been developed. Unlike the ‘first generation’ of these agents (e.g. α‐methylodopa, clonidine, guanabenz), which act predominantly by an agonist action at α‐adrenoceptors, these agents (e.g. rilmenidine, moxonidine) are believed to exert their antihypertensive effects chiefly by an interaction at putative imidazoline (I) receptors of the I1‐type, and so have a reduced profile of α‐adrenoceptor‐mediated side effects. There is also evidence from studies in experimental animals that activation of I1‐receptors mediates a natriuretic effect. This review evaluates the evidence that they mediate renal effects different from those of α‐adrenoceptors that could contribute to their long‐term efficacy.2. Data from binding studies suggest that I1‐binding sites are heterogeneous. There is conflicting evidence concerning whether any of there binding sites are truly receptors. Indeed, the best evidence for the existence of I1‐receptors comes fromin vivoexperiments receptive sites in the central nervous system to reduce sympathetic drive and blood pressure.3. There are a wide range of potential sites and mechanisms through which centrally acting antihypetensive agents can affect renal function, including actions mediated within the central nervous system, heart, systemic circulation and within the kidneys themselves. ‘First generation’ centrally acting anti‐hypertensive agents cause diuresis and natriuresis in rats, while in dogs and humans a diuresis is often seen with variable effects on sodium excretion.4. Evidence from studies in anaesthetized rats indicates that rilmenidine and moxonidine can promote sodium excretion by interacting with both central nervous system and renal putative I1‐receptors. This does not appear to necessarily be the case in other species. At this time there are few or no published data from clinical studies to suggest that ‘second generation’ centrally acting antihypertensive agents affect salt and water balance

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01132.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Our aim was to determine the role of nitric oxide (NO) in regulating ceebral blood flow (CBF) in foetal sheep under conditions of both hypoxaemia and normaxaemia.2. Aseptic surgery was performed on 11 pregnant sheep at 125 ± 1.1 days of gestational age (g.a.) when foetal vascular catheters were implanted for the measurement of CBF using coloured microspheres. Additionally, each ewe was prepared for one of two procedures for inducing foetal hypoxaemia; either an adjustable clamp was placed around the maternal common internal iliac artery to reduce uterine blood flow, or a catheter was implanted into the maternal trachea for insufflation of N2. At 131 ± 0.3 days g.a., in control foetuses (n = 5), CBF and cerebral vascular resistnace (CVR) were measued under basal (normoxaemic) conditions and after 3h of hyposaemia. In ohter foetuses (n = 6) CBF and CVR were measured under basal conditions and after 3h of hypoxsaemia; in these foetuses NO synthesis was inhibited with N‐nitro‐L‐arginine (NOLA) between 2‐3h of hypoxaemia.3. In the hypoxaemia experiments foetal Sao2and Pao2were reduced (P<0.05) in both control and NOLA‐treated foetuses, from normoxaemic values of 69.5 ± 2.1% and 23.8 ± 1.0 mmHg, respectively, to 29.3 ± 1.0% and 14.6 ± 0.4 mmHg during the period of hypoxaemia. In control foetuses, CBF (mL/min) was increased by 82.7% during hpoxaemia; in NOLA‐treated foetuses CBF increased by 55.3, which was less (P<0.05) than in control foetuses. In control foetuses CVR (mmHg/mL/min) was reduced by 43.5% during hypoxaemia, whereas in NOLA‐treated foetuses there was no significant change.4. In five of the 11 foetuses, the role of NO in regulating CBF under basal (normoxaemic) conditions was determined at 132 ± 0.3 days g.a. Cerebral blood flow and CVR did not significantly change from basal values after NOLA treatment.5. We conclude that in foetal sheep NO plays an important role in regulating cerebral vascular tone and hence CBF during hypoxaemia, but its contribution during normoxae

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01133.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Plasma gastrin relesing peptide (GRP) is elevated in the foetal and maternal circulations of pregnant sheep. To determine the mechanisms for this increase the synthesis, secretion rate, metabolism and placental transfer of GRP were measued.2. Foetal metabolic clearance rate of GRP was significantly increased (P<0.05) compared to the non‐pregnant eve (1909 ± 2.6 (s.e.m.) and 11.8 ± 2.0 mL/min per kg, respectively). Production rate of GRP in the foetus was four in the foetus was four‐fold higher than in the non‐pregnant ewe reflecting the combination of the increased basal concentration and metabolic celarance rate in the foetus.3. Infused GRP did not cross the placenta. However, endogenous GRP was higher in the umbilical vein than in the umbilical artery, suggesting a uteroplacental origin for some of the GRP in the foetal circulation.4. Gastrin releasing peptide mRNA was synthesized in the pregnant endometrium with lower amounts found in the pregnant myometrium. No GRP mRNA was detected in the amnoin or chorioallantois.5. The results show that the previously reported increase in foetal concentration of GRP is from foetal and uteroplacental sources and is not a result of immaturity of clearance mechanims but rather from an increased production of GRP. With the demonstation that the uteroplacenatal unit synthesizes and stores GRP, additional studies on the regulation of GRP production from these sources are wa

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01134.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Baroreflex responses to changes in aortic pressure were measured simulataneously in three main coronary regions of awake dogs.2. Pulsed Doppler flow probes were mounted at prior surgery on the right, circumflex and anterior descending coronary arteries; the animals were placed in complete heart block and the left ventricle was placed. After 2‐4 weeks recovery, baroreflexes were evoked by inflating a balloon catheter placed in the mid‐thoracic aorta via the femoral arteriotomy. Flow and pressure data were collected at rest, and during acute (8 s) and steady‐state (25 s) baroreflex challenge.3. Changing ventricular rate alone caused a fall in aortic pressure at low rates; however, over the range 60 to 180 b.p.m., circumflex and anterior descending coronary flow and conductance changed directly with ventricular rate, but right coronary flow and conductance remained unchanged.4. Acute aortic pressure elevation increased flow at 8 s in all beds at all rates. Conductance effects at 60 b.p.m. were negligible in all three beds, but rose at 100 and 180 b.p.m. in the right and circumflex beds.5. Sustained aortic pressure elevation (25 s) caused flow to return towards control in all beds at all ventricular rates, but in the right coronary at 60 b.p.m. flow fell below control. Conductance at this time was unchanged at all rates in the anterior descending bed, fell modestly in the circumflex, and decreased to below resting in the right coronary bed.6. Baroreflex control of coronary flow and conductance thus varies between territories, and within territories, depending on ventricular rate. The right coronary bed appears to be regulated by a bidirectional, baroreflex‐linked mechanism, which is functionally opposite in action to that found in most vascul

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01135.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. The role of the renal dopaminergic system in water‐sodium metabolism in heart failure remains unclear.2. In this study, the urinary free dopamine excretion (uDA), delivery ofl‐dopa X creatinine clearance (Cer)), and the production of dopamine in the kidney [uDA/(plasmal‐dopa x Cer)] were investigated in patients with congestive herat failure (n= 30) and in normal controls (n = 12). In both groups, endogenous Ccr, urinary excretion of sodium (UNaV), fractional excretion of sodium (FENa), plasma noradrenaline concentration (pNA) and plasmal‐dopa and dopamine production in the kidney showed successively lower values in congestive heart failure with progression in NYHA functional class.4. UNaV (r = 0.48, P<0.05) and Cer (r = 0.539, P<0.01) positively correlated with uDA. Linear correlations were found between left ventricular ejection fraction and uDA (r = 0.574, P<0.01), pNA)r = ‐0.495, P<0.01) or plasmal‐dopa (r = 0.423, P<0.05).5. From these findings, it was suggested that (i) uDA was clearly suppressed in patients with CHF, and (ii) the possible mechanisms of its suppression might be due to decrease of delivery ofl‐dopa into the proximal tubulles and suppressed production of dopamine froml‐dop

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01136.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. The haemodynamic mechanisms by which infusion of angiotensin II (AngII), either into the lateral cerebral ventricles (i.c.v.) or intravenously (i.v.), increased arterial pressure were studied in conscious sheep.2. Sheep were previously fitted with flow probes for measurement of cardiac output and coronary, mesenteric, renal and iliac blood flows.3. Intracerebroventricular AngII (10 nmol/h for 1 h) increased arterial pressure by 11 ± 4 mmHg (P<0.001) due to vasoconstriction, predominantly in the mesenteric vasculature. These effects developed over 30 min and took 2 h to return to control. Following the infusion renal conductance increased continuously for 3 h, resulting in a parallel increase in renal blood flow (to 75 ± 18 mL/min above control, P<0.001).4. Intracerebroventricular AngII increased plasma vasopressin from 0.8 ± 0.3 to 7.2 ± 1.8 pg/mL (P<0.01), and reduced plasma renin concentration from 0.9 ± 0.3 to<0.4 nmol/L/h.5. The pressor effect of i.v. AngII (5, 10, 25, 50 nmol/h) also depended on peripheral vasoconstriction, but the pattern of responses was different. The greatest degree of vasoconstriction occurred in the renal, followed by the mesenteric and iliac vascular beds; these effects were rapid in onset and offset.6. In conclusion, the pressor responses to both i.c.v. and i.v. angiotensin depended on peripheral vasoconstriction, but there were contrasting regional haemodynamic changes. ICV AngII caused a prolonged pressor response, mainly due to mesenteric vasoconstriction possibly partly due to vasopressin release, and following the infusion there was a pronounced, long‐lasting renal vasodilatation. In contrast, i.v. AngII caused vasoconstriction preferentially in the renal vascular bed and its effects were short l

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01137.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. During the destruction of articular cartilage, fibrinolytic enzymes and matrix metalloproteinases (MMP) may contribute to the related pathology. The activities, antigens and messenger RNA (mRNA) levels of urokinase‐type plasminogen activator (uPA) and plasminogen activator inhibitor‐1 (PAI‐1) in articular cartilage were measured in patients with no history of joint diseases (control), those with osteoarthritis (OA) classified into osteophyte‐formed site (OS) and weight‐bearing site (WS), and in patients with rheumatoid arthritis (RA).2. The uPA content was higher in WS and RA compared to normal. The PAI‐1 content was higher in OS and RA compared to normal. Weight‐bearing site patients expressed a high uPA mRNA level but a low PAI‐1 mRNA level. Osteophyte‐formed site patients expressed a low uPA mRNA level but a high PAI‐1 mRNA level.3. The levels of the MMP and mRNA of tissue inhibitors of metalloproteinases (TIMP) were measured in WS, OS and RA. In WS, the levels of MMP were high and levels of TIMP mRNA expression low. In OS, the levels of TIMP were high and levels of MMP mRNA were low. In RA, the levels of MMP and TIMP mRNA were high.4. These findings suggest that regulation of fibrinolysis may play an important role in the matrix of articular cartila

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01138.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Cortical spreading depression (CSD) was induced by direct current stimulation of the lateral frontal cortex in awake and freely moving rats.2. Regional cerebral blood flow (rCBF) was continuously measured by a laser Doppler flowmeter using an acrylic cup which was chronically fixed on the surface of the cerebral cortex. Under the resting condition rCBF remained constant throughout the observation period and showed a high reproducibility.3. rCBF increased to approximately 190% of control values during 1‐3 min after CSD, and decreased to approximately 80% of control values, before returning to normal values 60 min after CSD.4. These results are consistent with those found in anesthetized animals. This is the first study which has continuously monitored cortical hypoperfusion after CSD in awake and freely moving rats. The model is a useful system for studying migraine with aur

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01139.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. The anticonvulsant phenytoin (PHT) has been used with variable success in animal models of cerebral ischaemia. Although PHT has been reported to alter glucose regulation in man, this potential effect has been largely ignored in animals. Because hyperglycaemia strongly influences the outcome of cerebral ischaemia, we sought to systematically delineate the effects of PHT on serum glucose in several rat strains.2. We have studied the PHT dose‐response curve for serum PHT and glucose concentrations and several physiological variables. Phenytoin induces a significant, concentration‐dependent hyperglycaemia, even in the ranges commonly used for humans and in animal models.3. Hypothermia of several degrees was observed during PHT administration, but no hypotension or bradycardia was found.4. Both hyperglycaemia and hypothermia must be considered when PHT is studied as a neuroprotective agent in animal mod

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01140.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. This review explores the complexity of skeletal muscle function mainly from the perspective of work performed by the author over the past two decades.

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb01141.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY