Twenty-four-hour blood pressure profile and blood pressure responses to head-up tilt tests in Parkinson's disease and multiple system atrophy.

OBJECTIVE: To investigate the 24 h blood pressure profile in patients with Parkinson's disease with intact autonomic function or with autonomic failure and patients with multiple system atrophy (MSA), and to assess whether these patients exhibit posture-related variations in blood pressure. PATIENTS AND METHODS: We studied 24 patients with Parkinson's disease (11 with autonomic failure) and 13 patients with MSA (all with autonomic failure). Autonomic failure was determined by autonomic tests. An oscillometric recorder was used for ambulatory blood pressure monitoring. Tilt-table tests were performed with a head-up tilt position of 60 degrees. RESULTS: An alteration in the normal 24 h blood pressure profile was observed in 82% of Parkinson's disease patients with autonomic failure and in 85% of those with multiple system atrophy, but not in the patients with intact autonomic function. Head-up tilt tests revealed a significantly higher supine blood pressure in Parkinson's disease patients with autonomic failure and in those with MSA than in Parkinson's disease patients with intact autonomic function. Tilting resulted in a marked fall in blood pressure in patients with MSA; in Parkinson's disease patients with autonomic failure, the fall was comparatively slighter. CONCLUSIONS: We conclude that autonomic failure contributes to the alterations in the day-night blood pressure profile that may possibly be ascribed to postural dysregulation of blood pressure. We hypothesize that nocturnal hypertension is a risk factor in the development of additional cerebrovascular disease in patients with Parkinson's disease or MSA who are affected by autonomic failure.

Cardiovascular and renin responses to head-up tilt tests in parkinsonism.

OBJECTIVES: We investigated cardiovascular and renin responses to head-up tilt tests in patients with Parkinson's disease (PD), multiple system atrophy (MSA), and in controls to determine variables for the assignment of parkinsonism to the potential underlying neurologic condition. PATIENTS AND METHODS: Sequential changes in sympathetic-mediated circulatory variables such as heart rate, blood pressure, and plasma renin concentration during head-up tilt tests were studied in 14 patients with PD and 11 patients with MSA. Twelve subjects with normal autonomic functions were studied as controls. RESULTS: Head-up tilt resulted in significant differences in blood pressure and heart rate responses between PD, MSA, and controls. The baseline plasma renin concentration was significantly lower in MSA than in controls. Twenty min head-up tilt revealed significant differences in plasma renin concentration between PD, MSA, and controls. CONCLUSION: We conclude that investigating sequential changes in mean arterial blood pressure, heart rate, and plasma renin concentration during head-up tilt test can potentially support differential diagnosis of PD and MSA.

Angiotensin I-forming angiotensinogenases in extrarenal vasculature and in the kidney.

The intention of this study was to characterize angiotensin I-forming angiotensinogenases (AIFAs) in rat extrarenal arterial walls and to clarify whether these enzymes are also present in the kidney. A further aim was to identify AIFAs in human vasculature and to establish whether they are affected in essential hypertension. Sprague-Dawley rats and vascular sections of patients undergoing corrective surgery were studied. Enzyme kinetic assays were performed using angiotensin I radioimmunoassay and purified natural angiotensinogens. Fast protein liquid chromatography was employed for biochemical characterization. A series of AIFAs with various isoelectric points, molecular weights and pH optima was detected in rat extrarenal vascular and, with differing distributions of enzyme activities, in renal tissues. In extrarenal arteries the main form of renal renin was present with a relatively low activity only. AIFAs were also demonstrable in human extrarenal vasculature and behaved like plasma renin in essential hypertension. The results indicate the existence of an intrinsic human vascular RAS in extrarenal (and renal) arteries. Extrarenal arterial AIFAs are not generally stimulated in essential hypertensives, as previously postulated.

Autoregulation of the glomerular filtration rate and the single-nephron glomerular filtration rate despite inhibition of tubuloglomerular feedback in rats chronically volume-expanded by deoxycorticosterone acetate.

Tubuloglomerular feedback (TGF) function and autoregulation (renal blood flow RBF; glomerular filtration rate, GFR; single-nephron glomerular filtration rate, SNGFR) were examined in rats chronically treated with deoxycorticosterone acetate (DOCA) and given isotonic saline to drink. DOCA treatment depressed arterial plasma renin activity, expanded plasma volume by 25% and increased arterial blood pressure. Autoregulation of RBF and GFR was maintained in the DOCA animals above 90 mm Hg and 110 mm Hg respectively, whereby both GFR and RBF were lower than in controls. Micropuncture experiments demonstrated the absence of TGF in the DOCA animals. There was no difference between SNGFR values measured in the distal and proximal tubules, nor was there a significant response of SNGFR when loops of Henle were perfused with Ringer's solution at 20 nl/min. Loop perfusion in control rats with tubular fluid collected in DOCA rats elicited a normal TGF response, showing that TGF inhibition in the DOCA animals is due to changes in the function of the juxtaglomerular apparatus. In contrast to control rats, proximal SNGFR was perfectly autoregulated. These results suggest that TGF is not primarily responsible for autoregulation and that the vasodilatation normally resulting from acute TGF interruption is therefore compensated by some other mechanism such that RBF and GFR are lower than in controls.

Reninlike enzymes in human vasculature.

The present study was designed to identify angiotensin I (Ang I)-forming angiotensinogenases in human extrarenal vasculature and to examine the theory of Jiménez Días on their stimulation in essential hypertension. Vascular sections obtained intraoperatively from 14 normotensive and 16 hypertensive patients undergoing corrective surgery, 68 umbilical cord blood vessels from parturient women, tissue samples from nine explanted hearts, and serum from anephric and healthy individuals were investigated. Ang I-forming angiotensinogenase activities were determined enzyme-kinetically by using Ang I radioimmunoassay and purified sheep or human angiotensinogens. Three nonrenin Ang I-forming angiotensinogenases (pH optima of 4.0, 5.1, and 6.1) were identified in extrarenal vasculature, in cardiac tissues, and in plasma. Highest specific activities of nonrenin Ang I-forming angiotensinogenase (in nanograms Ang I per gram times hour; mean +/- SD) were found in cardiac tissue (2,821 +/- 497, n = 9), followed by carotid artery intima (1,448 +/- 982, n = 10), arteries (1,307 +/- 736, n = 18), and umbilical cord arteries (135 +/- 55, n = 35). Extrarenal arterial Ang I-forming angiotensinogenases were linearly correlated with those of local angiotensin converting enzyme and plasma renin activity. In essential hypertension, extrarenal arterial Ang I-forming angiotensinogenases were scattered, but not generally stimulated. The data obtained indicate the existence of nonrenin Ang I-forming angiotensinogenases in human extrarenal vasculature, in kidney, and in plasma. The postulate of stimulation of extrarenal arterial Ang I-forming angiotensinogenases in essential hypertension cannot be supported. Similar to the classification of plasma renin activity, a classification of Ang I-forming angiotensinogenase activity is proposed, consisting of patients with essential hypertension divided into subgroups exhibiting high, normal, or low vascular Ang I-forming angiotensinogenase activities.

Effect of zinc depletion on angiotensin I-converting enzyme in arterial walls and plasma of the rat.

The effect of zinc depletion and of additional angiotensin I-converting enzyme (ACE) inhibitor treatment was studied on ACE in aortic and other tissues, in plasma and on systolic blood pressure of the rat. Zinc deprivation significantly reduced plasma zinc concentration, plasma and testicular ACE activities and blood pressure, but stimulated aortic ACE while lung values remained constant. Zinc deficiency combined with ACE inhibition further suppressed plasma ACE and stimulated the aortic enzyme earlier. Zinc repletion experiments (in vitro) suggest the existence of a feedback mechanism controlling ACE synthesis depending on plasma ACE activity.

Suppression of renin-angiotensin system in the heart of spontaneously hypertensive rats.

Renin-like enzyme and angiotensin converting enzyme (ACE) were identified and their specific activities measured in cardiac tissues of spontaneously hypertensive rats (SHR) and their Wistar-Kyoto (WKY) normotensive controls. In addition, the enzyme activities were determined following administration of hypotensive drugs. The pH optima of cardiac renin-like enzymes were identical with those in vascular walls, the specific activity being higher in the heart. Cardiac ACE revealed similarities with the venous wall enzyme. The highest specific cardiac renin-like activity was found in the septum and that of ACE in atria/auricles. Both enzyme values were lower in the hearts of SHR than in those of normotensive controls. Following nifedipine treatment, specific renin-like activities increased in all cardiac structures studied (P less than 0.01); with nitrendipine and muzolimine less pronounced elevations were obtained. Administration of these three hypotensive drugs resulted in a stimulation of ACE in all the cardiac structures except in atria/auricles, where their activities were lowered.

Effect of hypotensive agents on the renin-angiotensin system in vascular walls of spontaneously hypertensive rats.

Previous investigations have shown that the renin-angiotensin system (RAS) is activated in vascular walls of spontaneously hypertensive rats (SHR). The present study was undertaken to determine whether antihypertensive drugs attenuate this activation. Two calcium channel blockers, nifedipine and nitrendipine, and the diuretic muzolimine were applied to SHR for 2-4 weeks, and angiotensin (ANG) I-forming angiotensinogenase (AIFA) and ANG I converting enzyme (ACE) activities were determined. The values for both enzymes were elevated in arterial tissues of SHR (P less than 0.01), whereas in venous walls AIFA activity was decreased (P less than 0.01). All hypotensive drugs reduced arterial ACE activities in SHR (nifedipine and muzolimine: P less than 0.01; nitrendipine: P less than 0.05). Angiotensin I-forming angiotensinogenase activity was increased following treatment with nifedipine (P less than 0.01) but reduced by nitrendipine (P less than 0.05); with muzolimine, no significant alterations were observed. The results obtained indicate that in SHR, stimulation of vascular wall ACE is abolished following treatment with hypotensive agents, and the effect is independent of their mode of action. It is assumed that the activation of vascular ACE is not caused by, but rather a reaction to, elevated blood pressure.

Renin-angiotensin system responses of acute graded hemorrhage in dogs.

The effect of acute hemorrhage on hemodynamics and the renin-angiotensin system (RAS) was studied in eight anesthetized dogs. Stepwise blood loss to 17 +/- 6.2 ml/kg within 9 to 33 min decreased cardiac output (CO) to 42.8% of control. Mean arterial blood pressure was decreased to 35%, peripheral vascular resistance (PVR) was 1.58-fold increased, plasma renin activity (PRA) and plasma renin concentration (PRC) were increased 3.6-fold and 4.3-fold, respectively, angiotensin I (A I) concentration in plasma was 3.7-fold increased, angiotensin II (A II) was 3.8-fold increased, and A I-degrading enzyme was strongly decreased. Angiotensinogen, A I-converting enzyme, and A II-degrading enzyme activities into blood circulation were not significantly changed. The minimal blood loss to activate the RAS was 3 ml/kg. The rate of plasma active renin (PRA and PRC) increase depended on the velocity of blood withdrawn. PRA was correlated inversely to CO. PVR correlated linearly to increased plasma angiotensin concentrations. The experiments conducted demonstrate the high sensitivity and prompt activation of RAS to blood loss and suggest that RAS is involved in the regulating mechanisms of hemodynamics during acute graded hemorrhage. The stimulation of RAS supports survival of grave blood loss.

The effect of zinc in vivo and in vitro on the activities of angiotensin converting enzyme and kininase-I in the plasma of rats.

Two groups of rats were pair fed, for 18 days, diets containing either 2.6 (Zn deficient) or 100 mg Zn/kg (control diet). Plasma was assayed spectrophotometrically for the activity of kininase-I and angiotensin converting enzyme (ACE) in the presence of varying concentrations of added Zn2+. Zinc deficient rats had only 76% of the activity of both kininase-I and ACE compared with zinc supplemented control rats. There was a significant linear relationship between enzyme activity and concentration of zinc in plasma for both enzymes. When zinc was added to the enzyme incubation mixture for zinc deficient rats, the activity of ACE increased by 73% and that of kininase-I by 33%. This Zn2+-stimulated increase in enzyme activity was negatively correlated with the in vivo concentration of zinc in plasma, and a plateau in enzyme activity was seen at concentrations of plasma zinc that were commensurate with normal zinc status (over 14 mumol/1). The results demonstrate that the activities of both kininase-I and ACE are dependent on the concentration of zinc in vivo and in vitro, and suggest that information concerning the concentration of zinc in plasma and assay solutions be a prerequisite solutions be a prerequisite for the use of these enzymes in the clinical diagnosis of disease states. The results also showed that the activity of ACE and kininase-I in plasma could be used for the biochemical diagnosis of a suboptimal zinc status.

Evidence for a potent angiotensin I degrading enzyme different from angiotensin I converting enzyme in rat vascular tissues.

There are indications for the existence of an intrinsic renin angiotensin system in vascular walls, which is assumed to participate in blood pressure regulation and in pathogenesis of arterial hypertension. It was evaluated if and to what extent the decapeptide angiotensin (A) I, one of the natural substrates of A I converting enzyme (ACE), is degraded by other peptidases than ACE in rat vascular tissues. A I and A II degradation was studied in arterial and venous vascular wall extracts. The activities ranged between 0.068 +/- 0.025 U and 0.044 +/- 0.025 U. The enzymes involved were biochemically characterized by determination of isoelectric points (pI), pH optima, molecular weights and by investigation of their inhibition behavior in vitro. One potent A I degrading enzyme (AIDE) was identified with pI between 3.6 and 3.9, and pH optimum at 7.75. In vitro studies revealed that AIDE activity was not blocked by the specific ACE inhibitors MK 421 or MK 422 (both 11 nMol/ml). The molecular weight of AIDE ranged between 440,000 and 457,000. The results indicate that AIDE is not identical to ACE (pI 4.2-5.0; pH optimum 8.3). AIDE was also observed in aortic smooth muscle cells cultured in vitro. AIDE decreased following bilateral nephrectomy or administration of aldosterone combined with sodium chloride loading, whereas it was elevated in spontaneously hypertensive rats (Okamoto strain). Since AIDE metabolizes A I, one of the substrates of ACE, it may indirectly affect A II formation and bradykinin inactivation as well.

Investigations of components of the renin-angiotensin system in rat vascular tissue.

Investigations were performed on components of the renin-angiotensin system (RAS) in homogenate extracts of vascular tissue and aortic smooth muscle cells cultivated in vitro. Determinations of isoelectric points and pH optima indicated the existence in aortic homogenate extracts of two local angiotensin I (AI)-forming enzymes (AIFE) that were different from those of plasma, renal cortex, veins, and aortic smooth muscle cells. The pH optima for AI-converting enzyme (ACE) from vascular tissues, aortic smooth muscle cells, and plasma were in the same range (pH 8.0-8.5), and in agreement with those measured previously in other tissues. In contrast, in vitro studies with the ACE inhibitors MK-421 and MK-422 and measurement of isoelectric points suggested that aortic ACE was different from the plasma enzyme. AIFE and ACE activities were found to be elevated in spontaneously hypertensive rats (SHR). The biochemical characteristics of the enzymes investigated in the vascular tissue of SHR were not different from those of the normotensive controls. AI- and AII-degrading enzymes were found both in aortic tissue and in aortic smooth muscle cells. One potent AI-degrading enzyme different from ACE was observed in aortic tissue. A high ratio of AI/AII immunoreactivities in arterial walls suggests the availability of renin substrate, and that AI-degrading enzymes are the rate-limiting enzymes for AII formation. The results further support the concept of an intrinsic vascular RAS.

Angiotensin I converting enzyme in the ejaculate of fertile and infertile men.

ACE has been measured in the seminal plasma of fertile and infertile men according to the method of Cushman and Cheung. High enzyme activity was found in fertile subjects which did not significantly differ from those with oligozoospermia and those with the Sertoli cell-only syndrome. Enzyme activity was significantly lower after vasectomy. The data suggest a higher enzyme/sperm cell ratio in oligozoospermia. Considerable enzyme activity in obstructive azoospermia can be attributed to enzyme formation within either the prostate or the seminal vesicles.

The effect of age, mating and vasoligature on angiotensin I converting enzyme in rat testis and epididymis.

Angiotensin I converting enzyme was measured in testis, different sections of epididymis and vas deferens of rats with the analytical method of Piquilloud et al. In tissue specimens without a prior washout of seminal fluid the highest enzyme activity was found in the testis. The enzyme activity fell significantly towards the end of the excurrent ducts, suggesting that the enzyme is synthesized in the Sertoli cells of the testis, undergoes exocrine secretion and is partially inhibited during passage through the epididymis. This was supported by additional analyses of seminal fluid from rete testis and vas deferens. According to data obtained from various age groups, sexual stimulation due to mating and bilateral vasoligature, enzyme synthesis in the testis and enzyme inhibition in the epididymis seem to be under simultaneous (androgenic) control. Though the highest specific enzyme activity in the rat is located in the gonads, CE's enzyme substrate and the anatomical structures on which its reaction product is effective are not yet apparent.

Tubular signal for the renin activity in the juxtaglomerular apparatus.

To investigate the effect of ionic composition of the tubular fluid in the macula densa segment upon the JGA renin activity, the macula densa segment was perfused with different solutions and the renin activity in the attached juxtaglomerular apparatus was measured. Increasing the sodium chloride concentration at the macula densa by perfusion with Ringer's solution or saline increased the JGA renin activity. An activation of JGA renin activity did not occur when amiloride was added to the saline or when the animals were pretreated by a high-salt diet. Perfusing the macula densa segment with a sodium-chloride-free solution, with sodium- or chloride-substituted solutions, or with mock early distal fluid, did not affect the JGA renin activity. These data are in accord with the proposition that in the tubuloglomerular feedback mechanism the renin-angiotensin salt diet. Perfusing the macula densa segment with a sodium-chloride-free solution, with sodium- or chloride-substituted solutions, or with mock early distal fluid, did not affect the JGA renin activity. These data are in accord with the proposition that in the tubuloglomerular feedback mechanism the renin-angiotensin salt diet. Perfusing the macula densa segment with a sodium-chloride-free solution, with sodium- or chloride-substituted solutions, or with mock early distal fluid, did not affect the JGA renin activity. These data are in accord with the proposition that in the tubuloglomerular feedback mechanism the renin-angiotensin system in the juxtaglomerular apparatus acts as a local, humoral mediator between the signal perceived at the macula densa and the hemodynamic response at the glomerulus. The mediation by the renin-angiotensin system, which is influenced by the sodium chloride balance, allows the sensitivity of this control of GFR to be adjusted in a homeostatically appropriate manner.

Juxtaglomerular angiotensin II formation.

Previous studies have indicated the existence of an unknown AII-forming enzyme (AFE) in the glomerular region. This investigation was undertaken to characterize this enzyme further and to elucidate its possible physiologic role. AFE activity was found in cortical tissue and in microdissected superficial and juxtamedullary glomeruli but not in renal medulla. It could be blocked by the converting enzyme (CE) inhibitors SQ 20881 (133.5 micrograms/ml; 70%), SQ 14225 (20 ng/ml; 80%), and DFP (20 micrograms/ml; 80%). In contrast to AI CE, AFE was neither blocked by EDTA nor stimulated by sodium chloride. In a further study, AFE activity and AII immunoreactivity were measured simultaneously in different renal structures and in plasma under control conditions and following water deprivation. Highest AII immunoreactivity was demonstrated in microdissected glomeruli (about 10 ng/g; N = 11) and lower amounts in cortical tissue (2.83 +/- 0.72 ng/g; N = 12), avascular cortical tissue (1.80 +/- 1.08 ng/g; N = 3), outer medulla (1.52 +/- 0.33 ng/g; N = 12), inner medulla (0.72 +/- 0.17 ng/g; N = 2), and in plasma (0.212 +/- 0.066 ng/ml; N = 12). Water deprivation had no measurable effect on AFE activity; but AII immunoreactivity increased significantly in all samples. This indicates that, in spite of the extremely high juxtaglomerular renin activity, AFE cannot be regarded as the limiting enzyme for local AII formation under the conditions investigated.

Angiotensin I converting enzyme in rat testis, epididymis and vas deferens under different conditions.

Angiotensin I converting enzyme (ACE) was found in the testis, epididymis and vas deferens of rats. In tissue specimens without a prior washout of seminal fluid the highest specific ACE activity was measured in the testis. The enzyme activity was significantly lower towards the end of the excurrent ducts, suggesting that the enzyme is synthesized in the testis and secreted into the seminal fluid there. An ACE inhibiting substance may be secreted by the epididymal epithelium. Enzyme synthesis and enzyme inhibition are probably under simultaneous endocrine control. In-vitro inhibition, pH- and temperature-dependence of gonadal ACE correspond with that of lung and blood plasma. However, the physiological function of the enzyme on sperm motility and fertility remains unsolved.

Plasma renin activity and cardiovascular changes in patients with chronic bladder distension.

Arterial plasma renin activity, arterial blood pressure, heart rate and respiratory frequency were measured in 10 patients with chronically distended bladder due to benign prostatic hyperplasia before and after bladder drainage. After suprapubical bladder puncture there was a decrease in all the values. Similar changes were also found in 3 patients with artificially induced acute bladder distension, who did not suffer from infravesical obstruction. A significant correlation was found between the changes of the arterial pressure and arterial plasma renin activity. It is therefore suggested that the renin-angiotensin system might be involved in patients with bladder distension.

Elevated angiotensin-I-converting enzyme (ACE) in patients with essential hypertension.

We investigated the alteration of the ACE in different parts of the circulation in 21 patients with essential hypertension, who suffered from angina pectoris attacks. Blood samples were taken during diagnostic cardiac catheterisation. The ACE was fluorimetrically measured and compared to 48 normotensive patients. In 11 patients the Plasma Renin Activity (PRA) was additionally determined by means of bioassay. The ACE was significantly (p less than 0.001) elevated in all investigated regions but a different distribution was not observed. We found a positive correlation between the ACE from the left ventricle and the systolic, mean arterial and diastolic blood pressure. Furthermore, we observed a negative correlation between ACE and PRA. No relationship could be calculated between ACE and electrolytes, creatinine or haemodynamic parameters. Our results indicate that the ACE may contribute to the pathogenesis of so-called essential hypertension.