No abstract

SUMMARY To examine the role of angiotensin II in the maintenance of blood pressure and the control of aldosterone secretion in man, eight normal subjects were studied on a tilt table in sodium replete and sodium depleted states prior to and subsequent to the intravenous infusion of an angiotensin converting enzyme inhibitor (CEI). In both the sodium replete or sodium depleted state, upright tilting resulted in an increase in heart rate and a narrowing of pulse pressure. None of the sodium replete or depleted subjects fainted. Tilting was accompanied by a rise in plasma renin activity with an associated rise in plasma aldosterone concentration. When converting enzyme inhibitor was administered, wbich blocked the generation of angiotensin II, sodium replete subjects were able to compensate for an upright tilt, despite the absence of angiotensin 11, without significant hemodynamic change when compared to control state. In sodium depleted subjects, after the administration of converting enzyme inhibitor, there was a sharp and significant decrease THE PRECISE ROLE of the renin-angiotensin system in the maintenance of blood pressure in normal human subjects remains unclear. The recent availability of effective competitive inhibitors of the angiotensin converting enzyme has permitted a critical examination of this question. Recent experiments in rats, rabbits, and trained conscious dogs' have demonstrated the importance of angiotensin II in the maintenance of blood pressure in the sodium depleted animal. In the experiments described here, the role of the renin-angiotensin system in the maintenance of blood pressure and in the regulation of aldosterone in relation to sodium depletion, diuretic administration, and posture was examined in normal human subjects. Methods Subjects Eight normal subjects (seven men, one woman), ranging in age from 19 to 27 years, were studied. All subjects were in in systolic and diastolic blood pressure associated with a significant rise in heart rate. All but one sodium depleted subject fainted within seven minutes. Both plasma aldosterone concentration and plasma renin activity rose on tilting in both sodium replete and sodium depleted subjects. After the administration of converting enzyme inhibitor, plasma aldosterone failed to rise in association with a rise in plasma renin activity. In supine subjects, after the administration of converting enzyme inhibitor, plasma renin activity rose but plasma aldosterone concentration fell. In sodium depleted subjects, after the administration of CEI, aldosterone fell to a level significantly lower than that in supine controls and to a level no different from the supine sodium replete subject. These results indicate that angiotensin II is essential for blood pressure maintenance in sodium depleted individuals, that angiotensin II exerts a direct feedback control on renin secretion, and that angiotensin It is the primary stimulus to aldosterone secretion in response to both sodium depletion and to posture.good health by history, had a normal physical ...

SummaryPlatelet counts, coagulation factors, and the fibrinolytic system were studied in seven regular dialysis patients during the course of haemodialysis by parallel flow (Gambro-Alwall) and coil (Travenol Ultra-Flo 100) dialysers. Significant falls in the patients' platelet counts and rises in their factor V levels were found with both dialysis systems. The changes were more pronounced over the course of a Gambro-Alwall dialysis, when significant falls in the partial thromboplastin clotting time and in the plasminogen levels were also noted. These haemostatic changes were associated with the retention of platelets on the dialysis membranes and, in the case of the Gambro-Alwall dialyser, with the formation of plateletfibrin thrombus. This thrombus formation may take place in spite of efficient heparin anticoagulation and may cause excessive blood loss to the regular dialysis patient.

A B S T R A C T A radioimmunoassay for fibrinopeptide A (FPA) has been developed. This assay uses rabbit antibodies induced by injection of native FPA-human serum albumin conjugates and 1"I introduced into tyrosine-FPA synthesized in our laboratory. Plasma FPA is separated from fibrinogen by TCA extraction. The assay is capable of detecting as little as 50 pg/ml of FPA.In 20 normal donors this assay revealed a mean concentration of 0.9 ng/ml (0.3 SD). In five patients with disseminated intravascular coagulation, FPA concentrations ranged from 13.0 to 346 ng/ml. Two groups of patients with systemic lupus erythematosus (SLE) whose disease had achieved complete remission were studied; one consisted of four patients with no history of lupus nephritis and another with a history of nephritis. Mean FPA concentrations of 1.5 ng/ml (range, 0.7-1.8 ng/ml) and 2.7 ng/ml (range, 1.1-5.6 ng/ml) were found in these two groups, respectively. Another group of nine patients with active SLE, but without evidence of lupus nephritis, had a mean FPA concentration of 4.5 ng/ml (range, 2.4-7.8 ng/ml). Finally, a group of seven patients with active SLE, including active nephritis, had a mean FPA concentration of 10.2 ng/ml (range, 5.3-17.0 ng/ml).A positive correlation was found between the concentration of plasma FPA and serum DNA-binding activity and an inverse correlation was found between plasma FPA and the concentration of serum C3. No correlation existed between plasma FPA and concentration of serum creatinine. Several possibilities for the origin of plasma FPA in patients with SLE were considered; at present it seems most likely that FPA arises through the action of thrombin on fibrinogen.

The angiotensin substrate analog Pro-HisPro-Phe-His-Phe-Phe-Val-Tyr-Lys has no significant effect on blood pressure in sodium-replete monkeys (Macaca fascicularis) but blocks the pressor response to infused human renin. Pressor responses to angiotensin I and angiotensin II are not attenuated. In five studies in sodium-depleted monkeys, an infusion of 2 mg of the peptide per kg of body weight resulted in a reduction of mean arterial pressure (MAP) from 105 i 4 to 79 + 3 mm Hg, which is not significantly different from the response to 1 mg of the angiotensin I-converting enzyme inhibitor teprotide per kg. In uninephrectomized monkeys, inflation of a suprarenal aortic cuff caused an increase in MAP from 107 + 3 to 131 + 3 mm Hg. Infusion of 0.6 mg of the renin-inhibitory peptide per kg was followed by a return of blood pressure to 107 + 4 mm Hg-a depressor response similar to that observed with teprotide. This specific in vivo inhibitor of renin can now be applied to a wide variety of physiologic studies.The renin-angiotensin system plays an important role in normal cardiovascular homeostasis and in some forms of hypertension. Clear definition of this role remains elusive, partly because of the inability to inhibit specifically the initial steps in this pathway by pharmacologic methods. Competitive inhibitors of angiotensin II binding have varying agonist/antagonist activity (1, 2), which undermines their effectiveness. Angiotensin I-converting enzyme inhibitors have been studied (3, 4), but their potential interaction with the kallikrein system (5, 6) and their inhibition of other enzymes unrelated to the renin-angiotensin system clouds interpretation of physiologic responses (7). Competitive inhibitors of renin, based on the sequence of the natural substrate (angiotensinogen), have been synthesized (8), but they have been of insufficient potency and solubility for in vivo studies (9). We have synthesized a decapeptide with a modification of'the amino acid sequence between positions 6 and 13 of equine natural substrate. This peptide, unlike previous analogs, is not only a potent competitive inhibitor but also exhibits adequate solubility and has a prolonged in vio halflife. Additionally, specific in vio blockade of the pressor response to exogenous renin but not to angiotensin I or II has been demonstrated.We report the administration of this renin inhibitory peptide to sodium-depleted normotensive and renin-dependent hypertensive monkeys. The results demonstrate the potential utility of this peptide for evaluating the role of renin in cardiovascular homeostasis and renin-dependent hypertension. METHODSSynthesis and Characterization of the Renin-Inhibitory Peptide. A soluble peptide with the sequence Pro-His-ProPhe-His-Phe-Phe-Val-Tyr-Lys was prepared as described (8). After synthesis and lyophilization under sterile conditions, the peptide was dissolved in physiologic saline (2 mg/ml) for animal studies. Plasma concentrations of infused 3H-labeled peptide were measured and the half-life was determined to...