Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial.

BACKGROUND: The randomized, phase III AVAPERL trial evaluated the safety and efficacy of bevacizumab maintenance with or without pemetrexed in nonsquamous nonsmall-cell lung cancer (nsNSCLC). Progression-free survival (PFS) was significantly prolonged with bevacizumab-pemetrexed, but overall survival (OS) data were immature. In this article, we report an independent, updated analysis of survival outcomes in AVAPERL. PATIENTS AND METHODS: Patients with advanced nsNSCLC received first-line bevacizumab (7.5 mg/kg), cisplatin (75 mg/m(2)), and pemetrexed (500 mg/m(2)) every 3 weeks (q3w) for four cycles. Nonprogressing patients were randomized to maintenance bevacizumab (7.5 mg/kg) or bevacizumab-pemetrexed (500 mg/m(2)) q3w until progression or consent withdrawal. The primary end point of the trial was PFS; in this independent OS analysis, participating study centers were contacted to collect survival data on patients still alive at the time of the first analysis. RESULTS: A total of 376 patients received induction treatment. Disease control was confirmed in 71.9% of patients; 253 patients were randomized to maintenance treatment with bevacizumab (n = 125) or bevacizumab-pemetrexed (n = 128). At a median follow-up of 14.8 months, patients allocated to bevacizumab-pemetrexed had significantly improved PFS versus those on bevacizumab when measured from randomization [7.4 versus 3.7 months, hazard ratio (HR), 0.57, 95% confidence interval (CI) 0.44-0.75); P < 0.0001]. OS events occurred in 58% of all patients. OS was numerically longer with bevacizumab-pemetrexed versus bevacizumab when measured from randomization [17.1 versus 13.2 months, HR 0.87 (0.63-1.21); P = 0.29]. Second-line therapy was administered in 77% and 70% of patients in the bevacizumab and bevacizumab-pemetrexed arms, respectively. No new adverse events were reported during this updated analysis. CONCLUSION: In an unselected population of nsNSCLC patients achieving disease control on platinum-based induction therapy, maintenance with bevacizumab-pemetrexed was associated with a nonsignificant increase in OS over bevacizumab alone.

Systemic inflammatory markers and psychophysical olfactory scores in coronavirus disease 2019 patients: is there any correlation?

OBJECTIVE: To analyse the correlations between olfactory psychophysical scores and the serum levels of D-dimer, C-reactive protein, ferritin, lactate dehydrogenase, procalcitonin and neutrophil-to-lymphocyte ratio in coronavirus disease 2019 patients. METHODS: Patients underwent psychophysical olfactory assessment with the Connecticut Chemosensory Clinical Research Center test, and determination of blood serum levels of the inflammatory markers D-dimer, C-reactive protein, ferritin, lactate dehydrogenase, procalcitonin and neutrophil-to-lymphocyte ratio within 10 days of the clinical onset of coronavirus disease 2019 and 60 days after. RESULTS: Seventy-seven patients were included in this study. D-dimer, procalcitonin, ferritin and neutrophil-to-lymphocyte ratio correlated significantly with severe coronavirus disease 2019. No significant correlations were found between baseline and 60-day Connecticut Chemosensory Clinical Research Center test scores and the inflammatory markers assessed. CONCLUSION: Olfactory disturbances appear to have little prognostic value in predicting the severity of coronavirus disease 2019 compared to D-dimer, ferritin, procalcitonin and neutrophil-to-lymphocyte ratio. The lack of correlation between the severity and duration of olfactory disturbances and serum levels of inflammatory markers seems to further suggest that the pathogenetic mechanisms underlying the loss of smell in coronavirus disease 2019 patients are related to local rather than systemic inflammatory factors.

T-DM1 versus pertuzumab, trastuzumab and a taxane as first-line therapy of early-relapsed HER2-positive metastatic breast cancer: an Italian multicenter observational study.

BACKGROUND: The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting. PATIENTS AND METHODS: We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian 'real-world' setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant. RESULTS: Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095). CONCLUSIONS: Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials.

Similarity between active and trypsin-activated inactive renin in dog plasma by means of renin inhibition: the dog as an animal model for studies of inactive renin.

A method for trypsin-activation of dog plasma inactive renin is described. Liquid phase trypsin (final concentration 6.7 mg/ml) was used and the reaction was stopped after 2 min at 4 degrees C by soybean trypsin inhibitor (13 mg/ml). Renin was measured as angiotensin I (Ang I) generation in trypsin-treated and untreated plasma using the antibody-trapping method, in the presence of excess ox renin substrate. The renin-like activity after trypsin was indeed due to renin, since Ang I generation in dog plasma before and after trypsin treatment was completely inhibited by H-77 at 10(-6) mol/l, and the two IC50 values were very similar (2.7 +/- 0.7 and 2.9 +/- 0.7 at 10(-8) mol/l, respectively). Dog plasma inactive renin was effectively separated from active renin by chromatography on Affigel Blue. Like human prorenin, dog plasma inactive renin rose in response to sodium depletion (furosemide 5 mg/kg, i.v.) followed by a low-salt diet (1 mmol Na+/day) for 4 days, (from 29.6 +/- 8 to 162 +/- 22 microU/ml; P less than 0.01, n = 10). Active renin also increased as expected. Intravenous captopril (6 mg/kg per h), for 3 h, led to a sharp increase in dog plasma active renin (from 53 +/- 8 to 360 +/- 60 microU/ml; P less than 0.01, n = 6), whereas inactive renin remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation of human prorenin by lipidic constituents of the cell membrane.

Activation of semipurified human kidney prorenin was found to occur in vitro in presence of a mixture of lipids that mimics the composition of the inner human cell membrane. The lipid-dependent activation was indeed only partial (38 +/- 4%) when compared to that obtained by trypsin in liquid phase (100 micrograms/mL) used as a control of maximal activation (100%) under our experimental conditions (semipurified human kidney prorenin in presence of semipurified human plasma renin substrate at a concentration of 1400 ng/mL, at pH 7.2). The phenomenon was time-dependent up to 60 min whereas the angiotensin I generated after 120 min was virtually the same as that generated after 60 min thus indicating a possible reversible activation of human prorenin. We speculate that prorenin may be reversibly activated by contact with the lipidic portion of the cell membrane either inside or outside the cells thus allowing a limited angiotensin II-generating cascade at a local site initiated by prorenin independently from the presence of active renin.

Correlates of atrial natriuretic factor in chronic renal failure.

Plasma atrial natriuretic factor (ANF), blood pressure, age, plasma renin activity and creatinine were measured in 50 normal volunteers, 141 essential hypertensives, 35 patients with chronic renal failure who had never been dialysed and 27 patients with end-stage renal failure on constant haemodialysis. Plasma ANF was correlated positively with age in the normal group (r = 0.52, P less than 0.01) and with blood pressure in the essential hypertensives (r = 0.50, P less than 0.001), and negatively with renin in the normal and end-stage renal failure patients (r = -0.47, r = -0.34; P less than 0.01, P less than 0.05, respectively). When patients without left ventricular hypertrophy were matched for age and blood pressure, plasma ANF was significantly different between the essential hypertensives and the normal and end-stage renal failure patients (16 +/- 1, 38 +/- 6 and 148 +/- 24 pmol/l, respectively; P less than 0.001). Cardiac factors are therefore not the only determinant of circulating plasma ANF in humans with chronic renal failure.

Circulating prorenin and renin in response to intravenous adrenocorticotrophic hormone in essential hypertension.

Plasma prorenin and renin changes after a bolus injection of 25 U intravenous adrenocorticotrophic hormone (ACTH, synacthen) were studied in seven untreated uncomplicated essential hypertensives over a period of 24 h. Plasma prorenin did not change significantly during the study, whereas renin after 24 h was higher than at baseline (4.3 +/- 0.6 versus 2.3 +/- 0.9 ng angiotensin I (Ang I)/ml per h, P less than 0.01). We conclude that endogenous glucocorticoid stimulation induced by exogenous ACTH and ACTH itself seem to induce a secondary or tertiary rather than a primary effect on the human renin gene.

Plasma clearance and effects of alpha-hANP infused in patients with end-stage renal failure.

The effects and clearance of synthetic atrial natriuretic peptide (alpha-hANP) were investigated in eight patients with end-stage renal failure and six normal volunteers. ANP or vehicle was infused for 1 h at 10 pmol.kg-1.min-1 in random order on two separate occasions. During ANP infusions in end-stage renal patients, microhematocrit rose by 9.8 +/- 2% (P less than 0.005, n = 8), from base-line values of 0.24 +/- 0.02. Serum protein and albumin rose consistently. In contrast, during placebo infusions, no significant changes were seen. Blood pressure, heart rate, plasma renin concentration, serum creatinine, and electrolytes did not change significantly during either study phase. In end-stage renal failure patients, metabolic clearance rate of infused ANP was 1.04 +/- 0.095 l/min and its plasma half-life was 4 min 34 s. In normal volunteers, metabolic clearance rate was 2.6 l/min and its plasma half-life 3 min 30 s. The data suggest that ANP promotes contraction of plasma volume via a mechanism independent of renal function and also indicate that the kidney is not the only organ involved in the ANP metabolism.

Effect of a kinin antagonist on renal function and haemodynamics during alterations in sodium balance in conscious normotensive rats.

1. To evaluate whether sodium intake can modulate the action of endogenous kinins on renal function and haemodynamics, a receptor antagonist of bradykinin was infused in conscious normotensive rats maintained on either a normal or a low sodium diet. 2. The antagonist inhibited the hypotensive effect of exogenously administered bradykinin. It did not change the vasodepressor effect of acetylcholine, dopamine or prostaglandin E2. 3. The antagonist did not affect mean blood pressure, glomerular filtration rate, renal blood flow or urinary sodium excretion, in rats on sodium restriction. It did not change mean blood pressure, glomerular filtration rate or urinary sodium excretion, but decreased renal blood flow, in rats on a normal sodium intake. 4. The kallikrein-kinin system has a role in the regulation of renal blood flow in rats on a normal sodium diet.

Different sensitivity to hydrochlorothiazide and to potassium-canrenoate among essential hypertensive patients.

We compared the response of blood pressure (BP) to either K-Canrenoate (K-Can) or hydrochlorothiazide (HCTZ) in 26 mild-to-moderate essential hypertensives in a double-blind, cross-over design over 2 months each. The dose was 12.5 mg o.d. for HCTZ and 50 mg o.d. for K-Can: dosing was doubled after 1 month if seated diastolic BP was > or = 95 mmHg. Eight pts were "selective responder" to the lowest dose of HCTZ (HCTZ-R), and 6 to K-Can (K-Can-R). Seven pts had their high blood pressure controlled by the highest dose of both drugs and 4 were insensitive to both. One pt dropped out during HCTZ for low plasma K+, and 3 during K-Can (nausea and dizziness: 2 pts; plasma creatinine rise: 1 pt). All these side effects were reverted after drug withdrawal. HCTZ-R and K-Can-R differed for PRA (1.4 +/- 0.6 vs 0.8 +/- 0.4 Ang I ng/ml/h, p < 0.05) and Na-K-Cl cotransport (230 +/- 39 vs 372 +/- 24 mumolNa/L RBC/h, p < 0.01). Our data suggest the existence of a subgroup of essential hypertensives surprisingly insensitive to HCTZ, characterized by a "low" PRA and by a Na(+)-K(+)-Cl- cotransport higher than the HCTZ-R. Their selective response to K-Can suggest a peculiar pathogenetic mechanism underlying their high blood pressure.

Effect of angiotensin converting enzyme inhibition on the menstrual cycle of hypertensive women.

Angiotensin II was reported to play a key role in ovulation in rats and it seems also to be involved in the regulation of LH release. Thus, we studied the effect of chronic ACE inhibition on the menstrual cycle, measuring daily plasma estradiol, progesterone, LH and FSH, and renin and prorenin before and during the third month of treatment with enalapril (10 mg b.i.d.) in 10 mild essential hypertensive women. Blood pressure was normalized by treatment. The cyclical changes of steroids and gonadotrophins were unaffected in their temporal relationships and in the magnitude of their variation during the experimental cycle compared with the basal cycle. A synchronization of plasma prorenin with the other hormones was seen both before, as previously reported, and during enalapril treatment. Our data show that peripheral blockade of angiotensin I conversion does not affect the pituitary guidance of the ovarian hormonal response or the ovarian prorenin release during the menstrual cycle. Our data are in agreement with the hypothesis that circulating angiotensin II does not play a key role in the human fertility process and that hydrophilic ACE inhibitors can be safely used in the treatment of hypertensive women of reproductive age.

Effects of nitrendipine on blood pressure, renin-angiotensin system, and kidney function in essential hypertension.

The effects of nitrendipine (10 mg b.i.d.) on blood pressure, renin-angiotensin-aldosterone system, and kidney function (by means of glomerular and tubular function) were studied in comparison to captopril (50 mg b.i.d.) and to nitrendipine (10 mg q.d.) + captopril (25 mg b.i.d.) in 30 untreated essential mild-to-moderate hypertensives. The blood pressure lowering effect was similar with either regimen. Nitrendipine showed an acute and chronic natriuretic effect not accompanied by modifications of kidney function. All regimens were well tolerated by the patients without any appreciable side effects over the 4-week study period.

Low-dose infusion of atrial natriuretic factor in mild essential hypertension.

Intra-arterial blood pressure, cardiac output, heart rate, right heart indexes, urinary electrolytes, and urinary volume were monitored in eight patients with untreated (WHO Class I) essential hypertension. The patients were given synthetic atrial natriuretic factor (ANF) (99-126 alpha-hANP) at 1 and 2 pmol/kg/min in series (phases 1 and 2, 2 hours each dose) or vehicle (hemaccel) in random order on two separate occasions while on their usual diet. Arterial plasma ANF levels increased significantly from basal and time-matched placebo values from 25 +/- 2 and 28 +/- 3 pmol/l to 50 +/- 4 and 83 +/- 9 pmol/l at the end of phases 1 and 2, respectively (p less than 0.001). After 30 minutes during phase 2, systolic blood pressure decreased significantly by 20 +/- 4 mm Hg (p less than 0.001) from basal and time-matched placebo values and remained significantly reduced (-17 +/- 4 mm Hg, p less than 0.001) by the end of the recovery period (2 hours after infusions were completed). Pulmonary systolic blood pressure decreased by 5 +/- 1 mm Hg (phase 2, p less than 0.05). Cardiac output decreased by 0.5 +/- 0.1 l/min below baseline at the end of phase 2 of ANF infusion, whereas it increased significantly (p less than 0.02) by 0.6 +/- 0.1 l/min during vehicle infusion. Systemic diastolic, pulmonary diastolic, right atrial, and wedge pressures were not significantly changed during ANF or vehicle infusions, nor were pulmonary vascular resistance or heart rate altered. Systemic vascular resistance did not change significantly during both infusions, whereas during recovery, systemic vascular resistance decreased significantly after ANF infusion was discontinued (p less than 0.05). Microhematocrit levels increased dose dependently during ANF. The maximum increase was observed at the end of phase 2 (+4.7 +/- 1.7%), whereas the microhematocrit level decreased to -2.4 +/- 0.6% with vehicle (p less than 0.001) at the end of phase 2. Urinary sodium excretion increased significantly (p less than 0.02) by the end of phase 2 under ANF infusion (+38 +/- 15%), whereas it decreased (-10 +/- 6%) under placebo infusion by the end of phase 2. Urinary magnesium excretion was significantly increased during ANF infusion from phase 1 (p less than 0.02), whereas urinary potassium levels, calcium levels, creatinine levels, volume, and glomerular filtration rate did not differ significantly between the two infusions. Plasma renin, angiotensin II, aldosterone, and catecholamine concentrations did not change significantly during ANF or vehicle infusions.(ABSTRACT TRUNCATED AT 400 WORDS)

[Erythrocyte cation transport in arterial hypertension: interrelation with the renin-angiotensin-aldosterone system and the atrial natriuretic factor]. / I trasporti cationici eritrocitari nell ipertensione arteriosa: interrelazioni con il sistema renina-angiotensina-aldosterone ed il fattore atriale natriuretico.

Red cell membrane Na(+)-K+ transport systems, renin-angiotensin-aldosterone system (RAAS) and atrial natriuretic factor (ANF) were studied in a group of 50 mild essential hypertensive patients (n = 25 for each group) age, sex and blood pressure matched. Na(+)-K+ ATPase and intracellular Na+ (Na+ i) were significantly different between the two groups (p less than 0.01). A slight difference was also seen for the Na(+)-K+ cotransport (p less than 0.05) as a likely consequence of the differences in the methodology of Na+ charge to study its efflux from the red cells in vitro. A negative correlation (r = -0.47, p less than 0.01) was observed between ANF and Na(+)-K+ cotransport suggesting an interrelationship of the two systems in the homeostasis in body fluid and electrolytes.

Effect of endothelin on regional hemodynamics and renal function in awake normotensive rats.

The effects of endothelin on regional hemodynamics and renal function were studied in awake normotensive rats. Intravenous injection of endothelin (700 pmol/kg) transiently lowered mean blood pressure (from 108 +/- 2 to 84 +/- 2 mm Hg, p less than 0.01), due to a reduction in total vascular resistance (38 +/- 1%, p less than 0.01), and increased stroke volume (29 +/- 5%, p less than 0.01) and heart rate (from 399 +/- 18 to 447 +/- 18 bpm, p less than 0.05); mesenteric and renal blood flow was reduced (37 +/- 13, p less than 0.05 and 63 +/- 5%, p less than 0.01), whereas carotid blood flow was increased (78 +/- 5%, p less than 0.01). This effect was followed by long-lasting hypertension due to increased total vascular resistance (112 +/- 19%, p less than 0.01); stroke volume, mesenteric, and renal blood flow were reduced (34 +/- 5, 41 +/- 4, and 58 +/- 4%, respectively, p less than 0.05) and carotid blood flow returned to basal levels. Bilateral nephrectomy enhanced the initial hypotensive effect. Pretreatment with nifedipine blocked the hypertensive effect, whereas bilateral nephrectomy did not. A subpressor dose of endothelin (70 pmol/kg) had no effect on stroke volume, mesenteric blood flow, glomerular filtration rate, and plasma renin activity; carotid blood flow was transiently increased (48 +/- 16%, p less than 0.05), then returned to basal levels; renal blood flow decreased (22 +/- 6 and 15 +/- 4% at 30 s and 10 min, respectively p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelin-1-induced renal vasoconstriction is blunted by enalaprilat and enhanced by EDRF antagonist in awake normotensive rats.

We attempt to elucidate the putative indirect mechanisms by which endothelin-1 affects mean blood pressure and renal blood flow in normotensive awake rats. Endothelin-1 (700 pg/kg, i.v.) induced a short-lasting decrease followed by a prolonged increase in mean blood pressure (from 113 +/- 4 to 92 +/- 4 mmHg at 30 sec, 132 +/- 7 mmHg at 10 min, and 129 +/- 6 mmHg at 30 min, p less than 0.01), and caused a profound and long-lasting fall in renal blood flow as measured by Doppler flowmeter technique (from 2.87 +/- 0.29 to 1.40 +/- 0.37 kHz at 30 sec, 1.77 +/- 0.32 kHz at 10 min and 2.10 +/- 0.45 kHz at 30 min, p less than 0.01). Neither the receptor antagonist of bradykinin D-Arg0-Hyp3-Thi5,8-DPhe7-bradykinin (30 micrograms/kg/min, i.v.) nor the antagonist of angiotensin II Sar1, Thr8-angiotensin II (4 micrograms/kg/min, i.v.) altered the changes in mean blood pressure and renal blood flow induced by endothelin-1. The antagonist of EDRF synthesis, NG-monomethyl-L-arginine (100 micrograms/kg/min, i.v.) enhanced the endothelin-1-induced increase in mean blood pressure (endothelin-1: 20 +/- 2 mmHg vs endothelin-1 + EDRF antagonist: 39 +/- 3 mmHg at 10 min, p less than 0.01) and decrease in renal blodo flow (endothelin-1: -40 +/- 4% vs endothelin-1 + EDRF antagonist: -73 +/- 3% at 10 min, p less than 0.01).2+ mediated by the blockade of angiotensin II formation.

Efficacy of nifedipine to prevent systemic and renal vasoconstrictor effects of endothelin.

We investigated whether systemic and renal vasoconstriction induced by porcine endothelin (endothelin 1) is prevented by nifedipine in awake normotensive rats. Endothelin (0.07-1.4 nmol/kg iv) induced a long-lasting increase in mean blood pressure (MBP) and a decrease in renal blood flow (RBF). Maximal decrease in RBF was 25 +/- 7% (0.07 nmol/kg), 40 +/- 2 (0.35), 67 +/- 5 (0.70), and 74 +/- 8 (1.4). Hemodynamic parameters were back to base line within 35 +/- 5 min (0.07 nmol/kg), 43 +/- 6 (0.35), 60 +/- 4 (0.70), and 81 +/- 7 (1.4). Intravenous bolus injection of either angiotensin II (ANG II, 0.006-0.024 nmol/kg) or norepinephrine (0.40-1.60 nmol/kg) caused a dose-related short-lasting increase in MBP and a decrease in RBF. Endothelin was less potent than ANG II (1:3.42) and more potent than norepinephrine (1:0.015) as a renal vasoconstrictor. Nifedipine (1 mg/kg ip) was equally effective in preventing the increase in MBP caused by endothelin, norepinephrine, or ANG II. It exerted a weaker protection on the renal hemodynamic response to endothelin compared with the inhibition of the other two vasoconstrictors. Thus the regression line representing the relationship between endothelin-induced changes in MBP and RBF was steeper in rats given nifedipine (slope: vehicle, -1.33; nifedipine, -5.50; P less than 0.05). These studies suggest that nifedipine can partially prevent systemic and renal vasoconstriction caused by exogenously administered endothelin in awake normotensive rats.

Prorenin is present in human red blood cells.

We looked for the presence of prorenin in erythrocytes from normal subjects (n = 8), hypertensive patients (n = 8), and pregnant women (n = 8). Angiotensin I generation was measured at 37 degrees C, pH 5.7, in the presence of homologous substrate (1400 ng/mL) before and after trypsin activation (100 micrograms/mL) in (A) haemolyzed erythrocytes, (B) supernatants of haemolyzed erythrocytes, and (C) in the sixth washing of erythrocytes diluted 1:1 with a 0.1 M Tris buffer containing 0.5% bovine serum albumin and protease inhibitors. Haemolyzed erythrocytes generated angiotensin I only after trypsin treatment, and the rate of generation was the same (A) before and (B) after centrifugation at 20,000g, indicating the absence of prorenin bound to the cell membranes. When aliquots of the last washing of erythrocytes (C) were tested for angiotensin I generation before and after trypsin, they did not generate angiotensin I, indicating that residual prorenin from the plasma was no longer present in our preparation. Angiotensin I generation by trypsin-treated A and B was completely abolished by preincubation with anti-renin serum. The level of prorenin was not significantly different in the erythrocytes from normal, hypertensive, and pregnant subjects (68 +/- 10, 58 +/- 7 and 107 +/- 17 pg angiotensin I.mL-1.h-1, ns) in spite of their very different plasma levels (21 +/- 2.5, 17 +/- 2.4 and 110 +/- 12 ng angiotensin I.mL-1.h-1, p less than 0.01 for pregnant women compared with both normal and hypertensive subjects). Our data show that prorenin is present in human erythrocytes in fairly constant and clearly detectable amounts, thus suggesting a possible intracellular role for it.

[Effect of chronic enalapril treatment on prorenin, renin and sex hormones during the menstrual cycle in patients with essential hypertension]. / Effetti del trattamento cronico con enalapril su prorenina, renina ed ormoni sessuali durante il ciclo mestruale in pazienti ipertese essenziali.

Since angiotensin II seems to be involved in the process of ovulation we studied the effect of chronic enalapril on plasma prorenin, renin, estradiol, progesterone, LH and FSH during the menstrual cycle in ten essential hypertensive women. Our data show that peripheral blockade of A I conversion does not affect the pituitary guidance and the ovarian hormonal response of the menstrual cycle and, we can speculate, that it does not interfere with the process of ovulation.

[Protective effect of a calcium antagonist against renal vasoconstriction induced by endothelin in the normotensive rat]. / Effetto protettivo di un calcio-antagonista nei confronti della vasocostrizione renale indotta dall'endotelina nel ratto normoteso.

We studied the effect of nifedipine, a dihydropyridine calcium antagonist, on the hemodynamic changes induced by endothelin, in awake normotensive rats. Endothelin (0.07-1.40 nmol/kg, e.v.) caused an initial hypotensive effect, followed by long lasting hypertension. Renal blood flow was reduced immediately and still remained below basal levels, at 30 minutes after endothelin injection. Nifedipine (1 mg/kg, i.p.) significantly prevented the effect of endothelin on mean blood pressure and induced a right-ward shift in the dose response curve of renal hemodynamic changes induced by endothelin. We conclude that treatment with calcium antagonist could be very useful in all those conditions in which systemic and regional vasocostriction is provoked by endothelin.