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Three patients with congenital, nephrogenic diabetes insipidus (NDI) from two unrelated families were tested for haemostatic and fibrinolytic responses to DDAVP infusion and venous occlusion. None of the three patients showed a response of factor VIII:C, vWF:Ag or t-PA to DDAVP, a V2-agonist. However, the baseline levels of these factors in the patients' plasma were normal and during venous occlusion a rise in t-PA antigen and t-PA activity was observed in all patients. One patient showed a definite response of the t-PA antigen level to exercise. It is concluded that (extrarenal) V2-receptor-mediated responses are absent in these patients, but that baseline homeostasis and the response to venous occlusion and physical exertion are intact. Presumably, these depend on other mechanisms. This observation denies a central role for vasopressin receptors in the on-demand regulation of clotting and clot dissolving properties of the blood.

Human plasma contains a non-dialyzable factor which is not enzymatically active in its native form but shows renin-like activity after exposure to low pH (inactive renin). In 3 out of 13 patients with renovascular hypertension the renal to peripheral vein ratio for inactive renin on the affected side was above 1.40, indicating renal release of this form of renin. In 4 cases a high renal to peripheral vein ratio for active renin was associated with a ratio for inactive renin below 0.80, indicating renal activation of circulating inactive renin. The results suggest a renal mechanism for modulating the degree of activation of renin. They have some practical implications for the pre-operative evaluation of patients with renovascular hypertension.

Information on the levels of angiotensin II (Ang II) and its receptors in the various renal tissue compartments is still incomplete. A model is presented describing the kinetics of Ang II production, distribution, and disposal in the renal cortex. Basic features are: (1) the model is designed to derive, from Ang II measurements in blood and in whole tissue, estimates of the local densities of the Ang II type 1 (AT(1)) and type 2 (AT(2)) receptors, and to calculate the concentrations of endocrine and paracrine Ang II they actually 'see'; (2) glomerular and peritubular tissue are conceived as separate regions (glomerular region (Glom), peritubular region (Pt)); (3) in Glom and in Pt, Ang II is homogeneously distributed in capillary blood and in interstitial fluid; (4) the model allows for local Ang II concentration gradients between interstitium and blood; (5) Ang II from the circulation diffuses into the interstitium of Glom after convective transcapillary transport; (6) Ang II produced in tubules or Pt enters the microcirculation through diffusive overflow from interstitium; (7) the presence of cell-surface-bound Ang II depends on the reaction with AT(1) and AT(2) receptors, and the presence of intracellular Ang II depends on the internalization of Ang II - AT(1) receptor complex; and (8) the model provides for glomerular filtration, vasopeptidase-mediated degradation, and intracellular degradation as mechanisms of elimination. This model can serve as a framework for detailed quantitative studies of the renin-angiotensin system in the kidney.

Information on the regional concentrations of angiotensin (Ang) II and its type-1 and -2 receptors (AT 1 R, AT 2 R) in the kidney is still incomplete. Published data on the levels of arterially delivered Ang I and II (Ang Ia, Ang IIa) and intrarenally produced Ang I and II (Ang Ii, Ang IIi) in the renal vein and in whole tissue were analyzed by using a kinetic model of Ang production and distribution in the glomerular and peritubular cortical tissue regions (Glom, Pt). (1) 90% of Ang II is cell-associated, due to its binding to AT 1 R and AT 2 R; (2) most Ang II in the renal cortex is Ang IIi; (3) Ang IIa is mainly localized in Glom; (4) Ang Ii rather than Ang Ia is a substrate of renal angiotensin-converting enzyme; (5) Ang IIi is localized in Pt and its concentration in interstitial fluid is 5–15 times the Ang II concentration in arterial plasma; and (6) in Glom the interstitial concentration of cell surface-bound AT 1 R is above 200 K d , and in Pt the AT 1 R and AT 2 R concentrations are above 10 K d . In conclusion, endocrine Ang II mainly acts in Glom, whereas Pt is exposed to paracrine Ang II generated by the conversion of intrarenally produced Ang I. High AT 1 R concentrations in Glom and Pt favor diffusion-limited binding, so that the apparent binding rate constant at sites closest to the source of Ang II delivery is greatly increased. Results may explain why the kidney is responsive to low levels of endocrine Ang II, despite its high content of paracrine Ang II.

Item does not contain fulltext BACKGROUND: Renal artery stenosis is among the most common curable causes of hypertension. The definitive diagnosis is made by renal angiography, an invasive and costly procedure. The prevalence of renal artery stenosis is less than 1% in non-selected hypertensive patients but is higher when hypertension is resistant to drugs. OBJECTIVE: To study the usefulness of standardised two-drug regimens for identifying drug-resistant hypertension as a predictor of renal artery stenosis. DESIGN AND SETTING: Prospective cohort study carried out in 26 hospitals in The Netherlands. PATIENTS: Patients had been referred for analysis of possible secondary hypertension or because hypertension was difficult to treat. Patients < or =40 years of age were assigned to either amlodipine 10 mg or enalapril 20 mg, and patients >40 years to either amlodipine 10 mg combined with atenolol 50 mg or to enalapril 20 mg combined with hydrochlorothiazide 25 mg. Renal angiography was performed: (1) if hypertension was drug-resistant, ie if diastolic pressure remained > or =95 mm Hg at three visits 1-3 weeks apart or an extra drug was required, and/or (2) if serum creatinine rose by > or =20 micromol/L (> or =0.23 mg/dL) during ACE inhibitor treatment. RESULTS: Of the 1106 patients with complete follow-up, 1022 had been assigned to either the amlodipine- or enalapril-based regimens, 772 by randomisation. Drug-resistant hypertension, as defined above, was identified in 41% of the patients, and 20% of these had renal artery stenosis. Renal function impairment was observed in 8% of the patients on ACE inhibitor, and this was associated with a 46% prevalence of renal artery stenosis. In the randomised patients, the prevalence of renal artery stenosis did not differ between the amlodipine- and enalapril-based regimens. CONCLUSIONS: In the diagnostic work-up for renovascular hypertension the use of standardised medication regimens of maximally two drugs, to identify patients with drug-resistant hypertension, is a rational first step to increase the a priori chance of renal artery stenosis. Amlodipine- or enalapril-based regimens are equally effective for this purpose.

Background —The mechanisms behind the beneficial effects of renin-angiotensin system blockade after myocardial infarction (MI) are not fully elucidated but may include interference with tissue angiotensin II (Ang II). Methods and Results —Forty-nine pigs underwent coronary artery ligation or sham operation and were studied up to 6 weeks. To determine coronary angiotensin I (Ang I) to Ang II conversion and to distinguish plasma-derived Ang II from locally synthesized Ang II, 125 I-labeled and endogenous Ang I and II were measured in plasma and in infarcted and noninfarcted left ventricle (LV) during 125 I-Ang I infusion. Ang II type 1 (AT 1 ) receptor–mediated uptake of circulating 125 I-Ang II was increased at 1 and 3 weeks in noninfarcted LV, and this uptake was the main cause of the transient elevation in Ang II levels in the noninfarcted LV at 1 week. Ang II levels and AT 1 receptor–mediated uptake of circulating Ang II were reduced in the infarct area at all time points. Coronary Ang I to Ang II conversion was unaffected by MI. Captopril and the AT 1 receptor antagonist eprosartan attenuated postinfarct remodeling, although both drugs increased cardiac Ang II production. Captopril blocked coronary conversion by >80% and normalized Ang II uptake in the noninfarcted LV. Eprosartan did not affect coronary conversion and blocked cardiac Ang II uptake by >90%. Conclusions —Both circulating and locally generated Ang II contribute to remodeling after MI. The rise in tissue Ang II production during angiotensin-converting enzyme inhibition and AT 1 receptor blockade suggests that the antihypertrophic effects of these drugs result not only from diminished AT 1 receptor stimulation but also from increased stimulation of growth-inhibitory Ang II type 2 receptors.

Objective The angiotensin-converting enzyme (ACE) gene I/D polymorphism accounts for part of the variation in ACE concentration; subjects with one or two D alleles have approximately 25 and 50% higher ACE levels, respectively, than subjects with two I alleles. Data from studies on the pressor effects of angiotensin (Ang) I in DD compared with II subjects are inconsistent, because enhanced conversion in DD subjects may have been masked by a decreased responsiveness to Ang II. Here we quantify ACE genotype-related Ang I to Ang II conversion in the human forearm and leg using non-pressor 125 I-Ang I infusions. Design and methods Infusions were given to 12 women and 17 men (age 24-67 years) who were undergoing renal vein sampling followed by renal angiography for diagnostic purposes. 125 I-Ang I was infused for 20 min into the right antecubital vein, and blood samples for the measurement of 125 I-labelled and endogenous Ang I and Ang II were taken from the aorta, the left antecubital vein and a femoral vein under steady-state conditions. Genotype frequencies were determined by polymerase chain reaction. Results Fractional conversion (i.e. the percentage of arterially delivered 125 I-Ang I that is converted to 125 I-Ang II) in the forearm (38 ± 4, 30 ± 3 and 31 ± 6% in 8 II, 16 ID and 5 DD subjects, respectively; mean ± SEM) and leg (52 ± 4, 48 ± 3 and 42 ± 5%) was similar in all three groups. In addition, no genotype-related differences in plasma Ang II/I ratio (a measure of ACE activity) were observed at the three sampling sites. Conclusions Regional Ang I to Ang II conversion does not parallel the previously described D allele-related differences in ACE concentration, suggesting that effects other than enhanced conversion may underlie the reported associations between the D allele and various cardiovascular diseases.

Experimental evidence indicates that the renal circulation is more sensitive to the effects of nitric oxide (NO) synthesis inhibition than other vascular beds. To explore whether in men the NO-mediated vasodilator tone is greater in the renal than in the systemic circulation, the effects of three different intravenous infusions of NG-nitro-l-arginine methyl ester (l-NAME; 1, 5, and 25 μg ⋅ kg−1⋅ min−1for 30 min) or placebo on mean arterial pressure (MAP), systemic vascular resistance (SVR), renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR), and fractional sodium and lithium excretion (FENaand FELi) were studied in 12 healthy subjects, each receiving randomly two of the four treatments on two different occasions. MAP was measured continuously by means of the Finapres device, and stroke volume was calculated by a model flow method. GFR and RBF were estimated from the clearances of radiolabeled thalamate and hippuran. Systemic and renal hemodynamics were followed for 2 h after start of infusions. During placebo, renal and systemic hemodynamics and FENaand FELiremained stable. With the low and intermediate l-NAME doses, maximal increments in SVR and RVR were similar: 20.4 ± 19.6 and 23.5 ± 16.0%, respectively, with the low dose and 31.4 ± 26.7 and 31.2 ± 14.4%, respectively, with the intermediate dose (means ± SD). With the high l-NAME dose, the increment in RVR was greater than the increment in SVR. Despite a decrease in RBF, FENaand FELidid not change with the low l-NAME dose, but they decreased by 31.2 ± 11.0 and 20.2 ± 6.3%, respectively, with the intermediate dose and by 70.8 ± 8.1 and 31.5 ± 15.9% with the highl-NAME dose, respectively. It is concluded that in men the renal circulation is not more sensitive to the effects of NO synthesis inhibition than the systemic circulation and that the threshold for NO synthesis inhibition to produce antinatriuresis is higher than the threshold level to cause renal vasoconstriction.

The dependence of uraemic solute clearance on the hydraulic and diffusive permeability index of an AN-69 capillary haemofilter is investigated during the treatment of patients with continuous arterio-venous haemodiafiltration (CAVHD). A mathematical model is presented to calculate solute clearance and the hydraulic and diffusive permeability index parameters from clinical data and to predict the blood flow rate entering the extra-corporeal circuit from the manufacturer's specifications and blood viscosity. By measuring the flow rates, the patient's mean arterio-venous pressure difference and uraemic solute clearance under different clinical and operational conditions, mathematical model equations are evaluated. During the average survival time of an AN-69 capillary haemofilter of about five days, it is found that both the hydraulic permeability index and the diffusive permeability index decline over treatment time, independent of the haemofilter resistance to blood flow. The measured haemofilter resistance to blood flow is three times higher than the haemofilter resistance predicted from the manufacturer's specifications and blood viscosity. Predicting the blood flow rate entering the extra-corporeal circuit from the arterial haematocrit, plasma protein concentration and temperature and the manufacturer's specifications is not reliable.

Background A local renin-angiotensin system in the heart is often invoked to explain the beneficial effects of ACE inhibitors in heart failure. The heart, however, produces little or no renin under normal conditions. Methods and Results We compared the cardiac tissue levels of renin-angiotensin system components in 10 potential heart donors who died of noncardiac disorders and 10 subjects with dilated cardiomyopathy (DCM) who underwent cardiac transplantation. Cardiac levels of renin and prorenin in DCM patients were higher than in the donors. The cardiac and plasma levels of renin in DCM were positively correlated, and extrapolation of the regression line to normal plasma levels yielded a tissue level close to that measured in the donor hearts. The cardiac tissue-to-plasma concentration (T/P) ratios for renin and prorenin were threefold the ratio for albumin, which indicates that the tissue levels were too high to be accounted for by admixture with blood and diffusion into the interstitial fluid. Cell membranes from porcine cardiac tissue bound porcine renin with high affinity. The T/P ratio for ACE, which is membrane bound, was fivefold the ratio for albumin. Cardiac angiotensinogen was lower in DCM patients than in the donors, and its T/P ratio was half that for albumin, which is compatible with substrate consumption by cardiac renin. Conclusions These data in patients with heart failure support the concept of local angiotensin production in the heart by renin that is taken up from the circulation. Membrane binding may be part of the uptake process.

The beneficial effects of angiotensin converting enzyme (ACE) inhibitors in heart failure appear to be independent, at least in part, of their effect on blood pressure. The existence of a local cardiac renin angiotensin system is often suggested as an explanation. It has been known for some time that a substantial proportion of arterially delivered angiotensin I is converted to angiotensin II by ACE of the coronary vascular endothelium. The levels of angiotensin II in cardiac tissue are several times the levels of angiotensin II in circulating blood. Recent evidence suggests that most of the angiotensin II in the heart is not derived from angiotensin I in the circulation, and that most of the angiotensin I in cardiac tissue is generated in the tissue itself. On the other hand, renin mRNA levels are very low or undetectable in the normal heart. In addition, studies on the effects of bilateral nephrectomy on the cardiac tissue levels of renin, angiotensin I, and angiotensin II in pigs have indicated that cardiac renin originates from the kidney and that cardiac generation of angiotensin I and angiotensin II depends on renin from the kidney. Intracardiac synthesis of renin may occur under pathological conditions and during fetal development. The fact that angiotensins are generated by the heart raises the possibility of local mechanisms to regulate the concentrations of these peptides at certain tissue sites. For example, preliminary evidence suggests that binding of renin to cardiac membranes is a mechanism by which renin is taken up by the heart. A specific renin binding protein has been identified in cardiac tissue. Cardiac ACE levels may also influence local angiotensin II formation and are, in part, determined by the so called insertion/deletion ACE gene polymorphism. More detailed knowledge on the site of angiotensin generation and on its regulation will improve our understanding of the role of the renin-angiotensin system in cardiac function, hypertrophy, and postinfarction remodelling.

Newly developed IRMAs to measure the plasma concentrations of renin and prorenin were validated for clinical use and compared with a classical enzyme kinetic assay. The IRMAs involve two monoclonal antibodies, one that reacts equally well with renin and prorenin and one that recognizes renin well but prorenin only minimally. Prorenin reactivity with the second antibody was enhanced by adding the renin inhibitor, Remikiren, to plasma. The complex of prorenin with this active-site ligand undergoes a conformational change, whereby prorenin is converted into a form that cannot be differentiated from renin by the IRMA. The linear working range of the assay was 4.0-3000 mU/L. The concentration of prorenin was calculated by subtracting the assay result obtained without Remikiren (i.e., renin) from the result obtained with Remikiren (i.e., renin plus prorenin). No more than 2% of prorenin present in plasma was detected as renin. The interassay CVs for renin quantification were 18%, 13%, and 8% at low, medium, and high concentrations, respectively. The interassay CV for calculated prorenin was 8% at both low and high concentrations. The IRMA results were highly correlated with those of an enzyme kinetic assay in healthy subjects; in patients with such conditions as primary hyperaldosteronism, renovascular hypertension, and low-, medium-, and high-renin essential hypertension; and in women undergoing gonadotropin stimulation.

1. The role of the renin-angiotensin system in the regulation of myocardial contractility is still debated. In order to investigate whether renin inhibition affects myocardial contractility and whether this action depends on intracardiac rather than circulating angiotensin II, the regional myocardial effects of systemic (i.v.) and intracoronary (i.c.) infusions of the renin inhibitor remikiren, were compared and related to the effects on systemic haemodynamics and circulating angiotensin II in open-chest anaesthetized pigs (25-30 kg). The specificity of the remikiren-induced effects was tested (1) by studying its i.c. effects after administration of the AT1-receptor antagonist L-158,809 and (2) by measuring its effects on contractile force of porcine isolated cardiac trabeculae. 2. Consecutive 10 min i.v. infusions of remikiren were given at 2, 5, 10 and 20 mg min-1. Mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), systemic vascular resistance (SVR), myocardial oxygen consumption (MVO2) and left ventricular (LV) dP/dtmax were not affected by remikiren at 2 and 5 mg min-1, and were lowered at higher doses. At the highest dose, MAP decreased by 48%, CO by 13%, HR by 14%, SVR by 40%, MVO2 by 28% and LV dp/dtmax by 52% (mean values; P < 0.05 for difference from baseline, n = 5). The decrease in MVO2 was accompanied by a decrease in myocardial work (MAP x CO), but the larger decline in work (55% vs. 28%; P < 0.05) implies a reduced myocardial efficiency ((MAP x CO)/MVO2). 3. Consecutive 10 min i.c. infusions of remikiren were given at 0.2, 0.5, 1, 2, 5 and 10 mg min-1. MAP, CO, MVO2 and LV dP/dtmax were not affected by remikiren at 0.2, 0.5 and 1 mg min-1, and were reduced at higher doses. At the highest dose, MAP decreased by 31%, CO by 26%, MVO2 by 46% and LV dP/dtmax by 43% (mean values; P < 0.05 for difference from baseline, n = 6). HR and SVR did not change at any dose. 4. Thirty minutes after a 10 min i.v. infusion of the AT1 receptor antagonist, L-158,809 at 1 mg min-1, consecutive 10 min i.c. infusions (n = 5) of remikiren at 2, 5 and 10 mg min-1 no longer affected CO and MVO2, and decreased LV dP/dtmax by maximally 27% (P < 0.05) and MAP by 14% (P < 0.05), which was less than without AT1-receptor blockade (P < 0.05). HR and SVR remained unaffected. 5. Plasma renin activity and angiotensin I and II were reduced to levels at or below the detection limit at doses of remikiren that were not high enough to affect systemic haemodynamics or regional myocardial function, both after i.v. and i.c. infusion. 6. Remikiren (10(-10) to 10(-4) M) did not affect contractile force of porcine isolated cardiac trabeculae precontracted with noradrenaline. In trabeculae that were not precontracted no decrease in baseline contractility was observed with remikiren in concentrations up to 10(-5) M, whereas at 10(-4) M baseline contractility decreased by 19% (P < 0.05). 7. Results show that with remikiren i.v., at the doses we used, blood pressure was lowered primarily by vasodilation and with remikiren i.c. by cardiac depression. The blood levels of remikiren required for its vasodilator action are lower than the levels affecting cardiac contractile function. A decrease in circulating angiotensin II does not appear to be the sole explanation for these haemodynamic responses. Data support the contention that myocardial contractility is increased by renin-dependent angiotensin II formation in the heart.

In renal transplant recipients, hypertension and a diminished nocturnal blood pressure fall are frequently found. To investigate whether this diminished nocturnal blood pressure fall is related to the use of cyclosporin A or to other factors, such as the use of glucocorticoids, we measured 24-hour ambulatory blood pressure in 18 renal transplant recipients both before and 16 weeks after conversion from cyclosporin A to azathioprine. Renal blood flow and glomerular filtration rate were estimated from 131 I-hippurate and 125 I-iothalamate clearances, respectively, and plasma concentrations of renin, atrial natriuretic peptide, norepinephrine, prostaglandin E 2 , and thromboxane B 2 were determined. During cyclosporin A treatment, mean 24-hour blood pressure was 117±3 mm Hg, and the nocturnal fall in blood pressure was 4±9 mm Hg. A nondipping diurnal blood pressure pattern was present in 13 patients. After conversion to azathioprine, mean 24-hour blood pressure decreased to 109±3 mm Hg ( P 2 and thromboxane B 2 decreased after conversion, as did plasma atrial natriuretic peptide. Renal blood flow and glomerular filtration rate increased after conversion. In conclusion, cyclosporin A appears to be involved in the disturbance of the circadian blood pressure rhythm in renal transplant recipients. Although the precise mechanism is unclear, the elevated plasma atrial natriuretic peptide and slightly suppressed plasma renin concentrations suggest that intravascular volume expansion may contribute to the observed hemodynamic alterations.

Improvements in methodologies for measuring concentrations of catecholamines (CA) have led to an increasing use of these compounds as markers in the screening of patients and in long-term clinical trials. Because of the associated logistical problems, we have investigated the unresolved question of optimal conditions for sample preparation and for storage of plasma and urine samples. Results show that blood should be centrifuged within 1 h after collection; the use of a refrigerated centrifuge is not necessary. Once plasma is prepared, CA are stable for 1 day at 20 degrees C, 2 days at 4 degrees C, 1 month at -20 degrees C (or 6 months with added glutathione), and up to 1 year at -70 degrees C. CA are stable at 4 degrees C for 1 month in unpreserved urine and for 4 months in urine preserved with EDTA and sodium metabisulfite. In acidified urine, CA were nearly unchanged after 1 year at 4 and -20 degrees C.

Enhanced GH secretion and hyperglycemia are suggested to play a role in the pathogenesis of glomerular hyperfiltration in insulin dependent diabetes mellitus. In this study we measured the GH response to GHRH (1 microgram/kg body weight), metabolic control, and renal function in 44 patients in order to explore a possible association between these parameters. Hyperfiltration [glomerular filtration rate (GFR) > 130 ml/min/1.73 m2] was present in 21 patients and normofiltration in 23. The duration of diabetes, plasma concentrations of renin, catecholamines, insulin-like growth factor-1 and blood glucose during renal function measurements were not different. GH response was significantly higher in patients with hyperfiltration. There was a positive relation between GH response and GFR (r = 0.51, P < 0.001) and effective renal plasma flow (r = 0.39, P < 0.01). GFR was correlated with insulin dose (r = 0.48, P < 0.001). There was no difference in glycosylated hemoglobin between the two groups. Patients with hyperfiltration used more insulin, had more frequent blood glucose values below the threshold level for activation of GH secretion, and had greater glycemic excursions than patients with normofiltration. The results suggest that GH hypersecretion and glomerular hyperfiltration are related and they support the possibility of a linkage between GH hypersecretion and glucose variability.

We wished to determine whether ibopamine, a dopaminergic prodrug with weak agonist activity on alpha- and beta-adrenoceptors, improves orthostatic tolerance in autonomic insufficiency. Three subjects with severe orthostatic hypotension resulting from pure autonomic failure (PAF) were studied. Direct arterial blood pressure (ABP) and heart rate (HR) were recorded continuously. Orthostatic tolerance was evaluated by 60 degrees passive head-up tilting. Tilting was performed before and after a single oral 100-mg dose of ibopamine. Blood samples for measurement of plasma catecholamines, free epinine (the active metabolite of ibopamine), and conjugated epinine were taken at regular intervals. In all 3 subjects, orthostatic tolerance was greatly improved by ibopamine. This improvement occurred as soon as 10-30 min after administration of ibopamine and lasted 20-50 min. alpha-Adrenoceptor blockade with phentolamine abolished the effect of ibopamine. The interindividual pharmacokinetics of ibopamine varied considerably: Peak plasma concentrations of ibopamine in the three subjects were 2.8, 4.5, and 35.4 ng/ml, respectively. The high level of epinine in one patient was associated with severe hypertension and tachycardia. Ibopamine may be a valuable new pharmacologic treatment for orthostatic hypotension in PAF, but in light of the highly variable interindividual pharmacokinetics further studies must be performed before use of the compound can be advocated in this disorder.

To study regional metabolism and production of angiotensin II, we measured steady-state plasma levels of 125I-angiotensin I and II and endogenous angiotensin I and II in the aorta and the antecubital, femoral, renal, and hepatic veins during systemic infusion of 125I-angiotensin I or II. Extraction of arterially delivered angiotensin II ranged from 30-50% in the limbs to 80-100% in the renal and hepatomesenteric vascular beds both in essential hypertension (n = 13) and in unilateral renal artery stenosis (n = 7). Across the limbs, 20-30% of arterially delivered angiotensin I was converted to angiotensin II in both groups, and there was no arteriovenous gradient in endogenous angiotensin II. No conversion of arterially delivered angiotensin I was detected across the renal and hepatomesenteric beds, and there was net extraction of angiotensin II from the systemic circulation by these beds. Although regional production of angiotensin I at tissue sites made a significant contribution to its level in the veins, little of this locally produced angiotensin I reached the regional veins in the form of angiotensin II, even in the kidney with artery stenosis, where the venous levels of locally produced angiotensin I were particularly high. These results provide no evidence for a source of circulating angiotensin II other than blood-borne angiotensin I and illustrate the high degree of compartmentalization of angiotensin I and II production.

In patients who were treated with continuous arteriovenous haemodiafiltration (CAVHD), using the AN-69 capillary dialyser, we measured the clearance rates of uraemic solutes and drugs at dialysate flo

To estimate the contribution of angiotensin (ANG) I and II production at tissue sites to the circulating levels, ANG I and II and their radiolabeled counterparts were measured in arterial and venous plasma across various vascular beds during constant infusion of 125I-ANG I into the left cardiac ventricle of anesthetized pigs. In the combined systemic vascular beds, ANG I production was closely correlated with plasma renin activity (PRA) and ANG II production was greater than in the lungs. In the lungs virtually no ANG I but 31% of ANG II in venous plasma was derived from de novo production, which could be fully accounted for by conversion of circulating ANG I. In myocardium, head, skin, skeletal muscle, and kidney, respectively, 40, 58, 55, 67, and 94% of venous ANG I, and 32, 49, 40, 59, and 85% of venous ANG II were derived from de novo production. In these extrapulmonary beds part of de novo produced ANG I and II appeared not to be generated, respectively, by PRA and by conversion of circulating ANG I. These results indicate that production of ANG I at tissue sites contributes to its circulating level and that some circulating ANG II may not be derived from circulating ANG I.

Epinine (N-methyldopamine) is the pharmacologically active hydrolysis product of the prodrug ibopamine, which is currently being widely studied for the treatment of congestive heart failure. This paper reports a sensitive and reliable method for the simultaneous determination of free catecholamines and epinine in plasma and urine. The compounds are isolated from plasma or urine by a specific liquid—liquid extraction, derivatized with the selective fluorogenic agent 1,2-diphenylethylenediamine, and quantitated by high-performance liquid chromatography with gradient elution and fluorimetric detection. The limits of detection for the derivatized catecholamines and epinine are 0.3–0.6 pg of injected compound. Intra- and inter-assay coefficients of variation of all four compounds are good (1–8%), as are the accuracy and linearity. A method is also reported for the determination of total dopamine and epinine in plasma and urine based on the same principle. This method, in which deconjugation is accomplished by acid hydrolysis at 95°C, also shows good sensitivity and reproducibility.

Nonparallel effects of renin inhibitor treatment on plasma renin activity (PRA) and the plasma levels of angiotensins (ANG), as well as on blood pressure, have been observed in subjects with hypertension. This study addresses the possibility that renin inhibitors may show a high degree of plasma protein binding in vivo and that displacement of protein-bound inhibitor during the assay of PRA in vitro may lead to overestimation of renin inhibition. Indeed, with the ultrafiltration technique it was found that 96% of the novel renin inhibitor Ro 42-5892, when added to EDTA plasma, was bound to protein. The angiotensinase inhibitors phenylmethylsulfonyl fluoride (PMSF) and 8-hydroxy-quinoline sulfate (8-OHQ), which are currently used in PRA assays, caused a displacement of protein-bound inhibitor, thereby increasing its free concentration. This displacement was sufficient to explain the reduction in IC 50 of Ro 42-5892, which was seen in the PRA assay when PMSF and 8-OHQ were added to plasma. Such reductions in IC 50 were also seen with the renin inhibitors CGP 29-287, CGP 38-560A, and SR 43-845. When Ro 42-5892 was given, 1 mg/kg intravenously in 10 min, to subjects with hypertension, it appeared that plasma ANG I and II returned to baseline after 6-8 h, whereas PRA measured in the presence of PMSF and 8-OHQ was still suppressed. However, when PRA was measured without these angiotensinase inhibitors, the inhibition of PRA was parallel to the suppression of ANG I and II.(ABSTRACT TRUNCATED AT 250 WORDS)

We report a sensitive and reliable assay for the determination of the urinary catecholamines norepinephrine, epinephrine and dopamine, based on selective extraction by a liquid—liquid extraction procedure, followed by selective derivatization with the fluorigenic agent 1,2-diphenylethylenediamine and quantification by high-performance liquid chromatography with fluorimetric detection. Comparison with a method using electrochemical detection shows that interference of an unknown compound, most probably N-methylepinephrine, which is an often-overlooked problem with methods using electrochemical detection and results in falsely high epinephrine concentrations, does not occur with the described fluorimetric method.

Summary. To investigate the origin of the prorenin peak that occurs during the normal menstrual cycle, plasma levels of prorenin, renin, oestradiol, progesterone, LH and FSH were measured serially in a nephrectomized woman having regular hacmodialysis. The prorenin peak coincided with the LH surge and preceded the rise of progesterone, whereas renin was below the detection limit during the whole cycle. These findings indicate that the rise in prorenin during the menstrual cycle is not of renal origin but is probably due to increased production by the ovary and supports the increasing evidence for the existence of a local renin-angiotensin system in the ovary.

A mathematical model of continuous arteriovenous hemodiafiltration is presented, by which the diffusive mass transfer coefficient (Kd) for a solute may be calculated from blood, filtrate and dialysate flow rates and solute concentrations. The model was applied to clinical data obtained with 0.6-m2 AN69 capillary dialyzers that had been used for up to 5 days. The diffusive mass transfer coefficient proved to depend on dialysate flow rate. Furthermore, it was related to the membrane index of ultrafiltration, as measured in the clinic, and to the filter resistance to blood flow. Measurement of these filter characteristics allowed a reasonable prediction of solute clearance.

In normotensive nonpregnant women (n = 23), the plasma concentrations of immunoreactive endothelin-1 (ir-ET-1) were not different from nonpregnant women with essential hypertension (n = 15): 3.6 (2.0-5.4) ng/L (mean, range) versus 3.8 (2.4-5.8) ng/L. In normotensive pregnant women (n = 25), the plasma level of ir-ET-1 was 2.1 (1.3-3.4) ng/L (p less than 0.01) lower than in normotensive nonpregnant women. Pre-eclamptic patients (n = 25) had elevated ir-ET-1 plasma levels of 5.0 (2.1-12.4) ng/L (p less than 0.001 for normotensive pregnant women, p less than 0.01 for nonpregnant women). The low level of ir-ET-1 in normotensive pregnant women may be explained by the increase in the distribution volume of ir-ET-1 during the course of pregnancy. Damage of vascular endothelium is a consistent morphological abnormality in pre-eclampsia. Elevated ir-ET-1 in plasma might be a biochemical marker of this abnormality and may contribute to the pathogenesis of pre-eclampsia.

Objective To investigate the mechanisms of vascular uptake of prorenin and renin and to explore the possibility of vascular activation of prorenin. Design and methods Human umbilical vein endothelial cells (HUVECs) cultured in a chemically defined medium were incubated with recombinant human prorenin or renin in the presence or absence of putative inhibitors of renin internalization. Cell surface-bound and internalized prorenin or renin were separated by the acid-wash method and were quantified by enzyme-kinetic assays. The activation of prorenin was also monitored by a direct immunoradiometric assay (IRMA) with use of a monoclonal antibody directed against the -p24-Arg to -1p-Arg C-terminal propeptide sequence of prorenin. Results Prorenin and renin were internalized at 37 degrees C in a dose-dependent manner; with 1000 microU prorenin/ml medium, the quantity of cell-associated prorenin after 3 h of incubation was 9.3 +/- 1.0 microU/4 x 10(5) cells, and with 75,000 microU/ml medium it was 670 +/- 75 microU/4 x 10(5) cells (mean +/- SD; n = 5). Results for renin were similar. Prorenin that had been treated with endoglycosidase H to remove N-linked oligosaccharides was not internalized. Addition of mannose 6-phosphate (M-6-P) to the medium caused a dose-dependent inhibition of renin and prorenin internalization. Fifty per cent inhibition was observed at 70 micromol/M-6-P, whereas mannose 1-phosphate, glucose 6-phosphate and alpha-methylmannoside at this concentration had no effect Ammonium chloride (50 mmol/l) and monensin (10 micromol/l) also inhibited internalization. Prorenin was activated by HUVECs, and cell-activated prorenin was only found in the internalized fraction, whereas the surface-bound prorenin remained inactive. Thus, it appears that the activation of prorenin took place at the time of its internalization or thereafter. The results of the prorenin IRMA indicated that activation was associated with proteolytic cleavage of the propeptide. Conclusions Our findings provide evidence for M-6-P receptor-dependent endocytosis of (pro)renin and proteolytic prorenin activation by vascular endothelial cells.

Plasma renin concentrations are an important factor in cardiovascular risk profiling.To investigate the effects of sex, medication, and anthropometric factors that may contribute to the interindividual variation in the plasma concentrations of renin and its precursor prorenin.Prorenin and renin levels in 327 men and 383 women, aged 52-69 years, who participated in a 1994 reexamination of a previous population survey in Bavaria, were measured by immunoradiometric assay.Prorenin and renin levels in men were significantly higher than those in women, those in women without estrogen replacement therapy were significantly higher than those in women with estrogen replacement therapy, and those in diabetics were significantly higher than those in nondiabetics. Prorenin level was correlated negatively to blood pressure and positively to age and the use of diuretics; it was normal in subjects using angiotensin converting enzyme inhibitors and beta-adrenergic antagonists (beta-blockers). Renin level was correlated negatively to atrial natriuretic peptide level and the use of beta-blockers, and it was elevated above normal levels in subjects using angiotensin converting enzyme inhibitors and diuretics as well as in subjects who had previously suffered myocardial infarction. After exclusion of data for women being administered estrogen replacement therapy, multivariate analysis revealed that sex (P0.001), age (P0.02), blood pressure (P0.002), diabetes (P0.05), and the use of angiotensin converting enzyme inhibitors (P0.002), beta-blockers (P0.001), and diuretics (P0.05) were independent determinants of plasma prorenin. Plasma renin was independently related to atrial natriuretic peptide level (P0.01) and the use of angiotensin converting enzyme inhibitors (P0.001), beta-blockers (P0.001), and diuretics (P0.05).These data demonstrate that there is a sexual dimorphism of prorenin levels in humans, suggesting that sex hormones affect the regulation of the renin gene. Data confirm previous reports of elevated prorenin levels in diabetics and older subjects, as well as of lower than normal prorenin levels in subjects with hypertension in smaller populations. Our findings may help to clarify the potential (patho)physiologic functions of prorenin and to identify the factors that influence the constitutive secretion and intracellular processing of this prohormone.

Abstract We used a modification of the isolated perfused rat heart, in which coronary effluent and interstitial transudate were separately collected, to investigate the uptake and clearance of exogenous renin, angiotensinogen, and angiotensin I (Ang I) as well as the cardiac production of Ang I. The levels of these compounds in interstitial transudate were considered to be representative of the levels in the cardiac interstitial fluid. During perfusion with renin or angiotensinogen, the steady-state levels (mean±SD) in interstitial transudate were 64±34% ( P P P

Objective: Semicarbazide-sensitive amine oxidase (SSAO) is present in various mammalian tissues, especially in vascular smooth muscle cells, but also in plasma. The enzyme has been suggested to play a role in vascular endothelial damage through conversion of amines into cytotoxic aldehydes, ammonia and hydrogen peroxide. Endothelial dysfunction is present in diabetes mellitus (DM) and congestive heart failure (CHF). Elevated plasma SSAO activities have been reported in patients with DM, bur no data on patients with CHF are as yet available. Methods and Results: Plasma SSAO was measured in 271 patients with CHF and compared to values in 77 controls. SSAO was found to be elevated in patients with CHF compared to controls (589 +/- 252 vs. 355 +/- 114 mU/l; P

Heute ist allgemein anerkannt, das ein erhohter peripherer Gesamtwiderstand das hamodynamische Kennzeichen nahezu aller Formen der klinischen Hypertonic in alien Stadien der Erkrankung ist. Es erscheint daher logisch, diese Erkrankung mit Antihypertensiva zu behandeln, die einen oder mehrere vasokonstriktorische Mechanismen beeinflussen, um die zugrundeliegende hamodynamische Anomalie zur Umkehr zu bringen. Tatsachlich scheinen die meisten antihypertensiven Substanzklassen eine solche Wirkung auf die Widerstandsgefase aufzuweisen. In einem neueren und umfassenden Uberblick zum Thema stellte Lund- Johansen, einer der Pioniere auf dem Gebiet der hamodynamischen Forschung bei Hypertonic, 154 Arbeiten zur Hamodynamik bei Hypertonic und zu deren medikamentoser Behandlung zusammen [1]. Aus seiner Arbeit und der anderer Autoren geht hervor, das tatsachlich die meisten Gruppen von Antihypertensiva vasokonstriktorische Mechanismen beeinflussen, da die Mehrzahl den Gefaswiderstand bis zu einem gewissen Grad senkt (Abb. 1).

Synthetic human atrial natriuretic peptide (ANP) (102-126) 0.01 microgram/kg per minute or vehicle was intravenously infused for 2 h in 10 patients with insulin-dependent diabetes mellitus and microalbuminuria (albumin excretion, 20 to 200 micrograms/min) and in 10 healthy subjects. In the diabetic group, the immunoglobulin G clearance was higher, but both size index and charge index as calculated from albumin and immunoglobulin clearances were equal compared with normal values. The fractional clearances of small dextrans (3.6 nm) were lower in diabetics, which was compatible with a depressed hydraulic permeability (Kf). During ANP infusion, the excretion of albumin and immunoglobulin G increased in the diabetic subjects (189 +/- 12 to 521 +/- 84 and 7.1 +/- 3.5 to 21 +/- 8.1 micrograms/min, respectively; both P0.05) only. In the diabetics, the clearance of dextrans54 A increased and our calculations indicated an increase in "shut-flow" (omega o). The transcapillary escape rate of albumin, which was elevated in the diabetics at baseline, increased in the diabetic group only. Thus, ANP uncovers altered size selectivity of the filtration barrier in a phase that is otherwise characterized by charge-selective changes only. Moreover, the increased susceptibility of the glomerular capillaries in diabetics to ANP seems to be part of a more generalized capillary abnormality, because ANP also increases the transcapillary escape of albumin.

BACKGROUND An attenuated or absent nocturnal decline in blood pressure has repeatedly been documented in cardiac transplant recipients. The present study was aimed at investigating the hemodynamic mechanism underlying this abnormality. METHODS AND RESULTS In 23 cardiac transplant recipients (11 to 36 months after transplantation) and in 23 control subjects matched for age and 24-hour mean arterial pressure, invasive 24-hour ambulatory blood pressure was measured by means of the Oxford technique. Beat-to-beat relative values of stroke volume were determined by means of a pulse-contour method, and relative changes of cardiac output (stroke volume x heart rate) and total peripheral vascular resistance (blood pressure/cardiac output) over the 24-hour period were calculated. The nocturnal decline in blood pressure was 20 +/- 8% (mean +/- SD) in control subjects but only 5 +/- 9% (P < .001) in cardiac transplant recipients. In control subjects, the nocturnal decline in blood pressure was associated with a nocturnal fall in cardiac output of 24 +/- 13%, whereas vascular resistance compared with daytime value did not change. The small nocturnal decline in blood pressure in cardiac transplant recipients was associated with an attenuated nocturnal fall in cardiac output of 14 +/- 12% (P < .05 versus control subjects). In addition, vascular resistance compared with daytime value was increased by 9 +/- 9% (P < .05) during the night. Both in cardiac transplant recipients and in control subjects, the nocturnal changes in blood pressure were correlated with the nocturnal changes in cardiac output but not with the nocturnal changes in total peripheral vascular resistance. CONCLUSIONS This study confirms the attenuated nocturnal fall in blood pressure in cardiac transplant recipients. Hemodynamically, this attenuated blood pressure decline is characterized by a reduced nocturnal fall in cardiac output, and it is associated with a nocturnal increase in vascular resistance.

We noted rapid breakdown at 4 degrees and 20 degrees C of dopamine (DA) (but not of (nor)epinephrine and epinine) in pig plasma, but not in human plasma. The enzyme responsible appears to be a semicarbazide-sensitive amine oxidase (SSAO) because the breakdown can be inhibited by semicarbazide, but not by pargyline, clorgyline, EDTA, or (extra) glutathione. Among catecholamines tested, only DA and 3,4-dihydroxybenzylamine (DHBA, the internal standard of most catecholamine assays using high-performance liquid chromatography (HPLC) with electrochemical detection) were good substrates for the pig plasma SSAO. At 37 degrees C, especially after prolonged storage, all catecholamines break down. This breakdown results from autoxidation since it can be prevented by addition of extra glutathione (but not by semicarbazide) for all catecholamines except DA and DHBA. Breakdown at 37 degrees C of these two compounds cannot be prevented by addition of extra glutathione or semicarbazide, but only by addition of both. For reliable measurements of DA concentrations in pig plasma, blood should be collected in tubes containing not only glutathione, but also semicarbazide. The possibility of similarly high plasma SSAO activity in other species should be investigated further.

Endothelial cell damage, which is associated with local thrombin formation and inflammation, can lead to the release of endothelium-synthesized factors into plasma, such as vWFAg, TM, ACE and ET-1. These markers of endothelial damage are increased in some patients with diabetes mellitus, but the differences with normal are often small and not closely correlated with the severity of microvascular disease, as judged from the degree of albuminuria and the severity of retinopathy. Prorenin, which may also be related to abnormal endothelial cell function or endothelial damage, is elevated in many patients with diabetes, both type I and II, and its level is more closely correlated with the severity of microvascular disease. It is already elevated at an early stage. Further studies will reveal whether, in diabetes, an increased plasma prorenin is a reliable predictor of progressive microvascular disease. It is even conceivable that prorenin is not only a marker of diabetic microvascular disease but also has a role in its pathogenesis, via local proteolytic or non-proteolytic prorenin activation.

We report a reliable fluorimetric assay for the simultaneous determination of norepinephrine, epinephrine, dopamine and dobutamine in human plasma and urine, based on liquid—liquid extraction and derivatization with the fluorogenic agent 1,2-diphenylethylenediamine prior to chromatography. The method is sensitive (detection limit 0.3–0.8 pg injected) and reproducible (coefficients of variation 1–10%), and shows good accuracy (93–98%). The method should also be used when one only wants to measure the concentrations of the natural catecholamines, in order to avoid interference by metabolites of dobutamine and by the late-eluting dobutamine itself.

To quantify regional conversion of angiotensin (ANG) I to ANG II and its degradation to peptides other than ANG II, monoiodinated 125I-labeled ANG I was given to anesthetized pigs by constant infusion into the left cardiac ventricle. At steady state, blood samples were taken from the aorta and various regional veins. Distribution volume of ANG I appeared to be 24% of body weight. After angiotensin-converting enzyme (ACE) inhibitor treatment, fractional ANG I metabolism (fraction of arterially delivered ANG I that was metabolized during a single passage of blood) was 10% in the lungs (conversion 4%), compared with 56% in the combined systemic vascular beds (conversion 1%). Fractional ANG I metabolism during ACE inhibition was 93% in the kidney; 50-70% in myocardium, skeletal muscle, head, and skin; 21% in the left cardiac cavity; and 14% in the right cardiac cavity. Without ACE inhibition, fractional ANG I metabolism was 29% in the lungs (conversion 25%); 49% in the combined systemic vascular beds (conversion 10%); 38% in the left cardiac cavity (conversion 11%); and 14% in the right cardiac cavity (conversion 0%). It may thus be concluded that 1) extrapulmonary vascular beds make an important contribution to the conversion of circulating ANG I and 2) there is rapid extrapulmonary ANG I degradation that does not depend on ANG I-II conversion.

We measured blood flow, ultrafiltration rate and uraemic solute clearance at different dialysate flow rates during CAVHD using the AN-69 0.43 m2 flat plate haemofilter. As filter performance depends on clinical conditions and operational characteristics, data were analysed in terms of resistance to blood flow, membrane index of ultrafiltration, and diffusive mass transfer coefficients. An attempt was made to construct nomograms that may be used both to predict filter performance and to compare different haemofilters with each other.

The kidney is important in blood-pressure regulation, but its role in the development of essential hypertension is still subject to debate. We compared renal hemodynamics, measured in terms of the clearance of para-aminohippuric acid and inulin, and the characteristics of the renin-angiotensin-aldosterone system in three groups of normotensive subjects at different degrees of risk for hypertension: 41 subjects with two normotensive parents, 52 with one normotensive and one hypertensive parent, and 61 with two hypertensive parents. The subjects ranged in age from 7 to 32 years.The mean renal blood flow was lower in the subjects with two hypertensive parents than in those with two normotensive parents (mean difference [+/- SE], 198 +/- 61 ml per minute per 1.73 m2 of body-surface area; P = 0.002). Moreover, both the filtration fraction and renal vascular resistance were higher in the subjects with two hypertensive parents (filtration fraction: mean difference, 3.0 +/- 1.1 percentage points; P = 0.006; renal vascular resistance: mean difference, 2.7 +/- 0.8 mm Hg per deciliter per minute per 1.73 m2; P = 0.006). The subjects with two hypertensive parents had lower plasma concentrations of renin (mean difference, 3.3 +/- 1.6 mU per liter; P = 0.03) and aldosterone (mean difference, 111 +/- 36 pmol per liter; P = 0.003) than those with two normotensive parents. The differences could not be explained by the small differences in blood pressure between the groups. The values in the subjects with one hypertensive and one normotensive parent fell between those for the other two groups.Renal vasoconstriction is increased and renin and aldosterone secretion is decreased in young persons at risk for hypertension. These findings support the hypothesis that alterations in renal hemodynamics occur at an early stage in the development of familial hypertension.

First-pass radiocardiography, by single probe or gamma camera, has the theoretic potential to be an attractive non-invasive indicator dilution method of measuring cardiac output. Registrations, once programmed, require little time to perform and entail hardly any risk for the subject. At the same time, they are to varying degrees inaccurate. As long as technology is not standardized, each institution that wishes to employ these measurements has to do its own critical validation before results can be accepted. As with any other indicator dilution technique, precision of radiocardiography is served by repetitive measurements. However, radiation dose and disturbing background radioactivity preclude taking multiple measurements within a short period. This holds particularly for the gamma camera. The speed and simplicity of the probe system make this device very suitable for serial evaluation of cardiac function at the bedside. Depending on collimation of the probe and extracardiac background activity, a correction factor has to be derived empirically to avoid overestimation of cardiac output. The major advantage of the gamma camera linked to a data system is that an infinite number of first-pass curves can be obtained from different parts of the heart. Provided that appropriate regions of interest are selected, first-pass studies can yield reasonably accurate and reproducible determinations of cardiac output. In addition, functional image analysis during the equilibrium phase enables calculation of other cardiac variables such as ejection fraction and chamber size. Nevertheless, standardization of ‘hardware’ and ‘software’ is imperative.

To estimate the renal extraction and de novo production of angiotensin I and to assess the contribution of blood-borne renin to renal angiotensin I production, the aortic and renal venous plasma levels of renin and intact [125I]angiotensin I and endogenous angiotensin I during continuous systemic intravenous infusion of monoiodinated [125I]angiotensin I were measured in subjects with unilateral renal artery stenosis (n = 8) who were treated with captopril (50 mg b.i.d.). Results demonstrated that 80% of angiotensin I delivered by the renal artery was extracted both by the affected and the unaffected kidney and that on both sides a major part of angiotensin I in the renal vein was derived from intrarenal de novo production. Production of plasma angiotensin I was in excess over extraction (p less than 0.01) on the affected side, whereas extraction was in excess over production (p less than 0.01) on the contralateral side. The plasma level of de novo intrarenally produced angiotensin I in the renal vein was seven times higher on the affected side than the contralateral side. This difference was by far too big to be explained by a difference in the transit time of blood between the two kidneys, by an augmented production of angiotensin I in the circulating blood passing through the affected kidney due to the higher level of venous plasma renin activity in that kidney, or by the combination of both.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE--To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. DESIGN--Exploratory study in which active treatment was preceded by placebo. SETTING--Inpatient unit of teaching hospital. PATIENTS--Nine men with uncomplicated essential hypertension who had a normal sodium intake. INTERVENTIONS--Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. RESULTS--With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. CONCLUSIONS--The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II.

This study evaluates the vasoactive effects and mode of action of ketanserin, a selective 5HT2 receptor antagonist, on digital circulation in 11 patients with primary Raynaud's phenomenon. Reflex digital vasoconstriction was induced by moderate body cooling. We found that ketanserin given intravenously in a dose of 10 mg, normalized digital skin temperature and digital blood flow as estimated by venous occlusion plethysmography and laser-Doppler flowmetry. However, effects of ketanserin on transcutaneously measured oxygen pressure were modest. This could imply a preferential effect of ketanserin on arteriovenous shunt flow. Pretreatment with high doses of the selective and nonselective alpha-adrenoreceptor antagonists prazosin and phentolamine did not abolish the effects of ketanserin on digital blood flow. However, under alpha-adrenoceptor blockade the small effects of ketanserin on normal blood pressure disappeared. Thus, in contrast to the effects in the systemic circulation, the principal mechanism underlying digital vasodilation after ketanserin is unlikely to involve alpha-adrenoceptor antagonism. We conclude that 5HT2 receptors are present in the digital vasculature. In patients with primary Raynaud's phenomenon, their activation plays an important role in cold-induced digital vasoconstriction.