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In this review we have analyzed the present knowledge about the differentiation and growth processes in vascular smooth muscle cells (SMC) in hypertension. The study of smooth muscle (SM) and nonmuscle (NM) myosin isoform expression has permitted us to identify a three-stage specific maturational pathway, namely, fetal, postnatal, and adult. In the renovascular (rabbit) and genetic (rat) models of hypertension, adaptive changes occurring in hypertensive vessels make SMC resemble those found in the early stages of development (smooth muscle plasticity). In fact, based on SM- and NM-myosin isoform distribution, postnatal-type SMC predominate in the arterial media during the early remodeling of the arterial wall that occurs in hypertension, whereas postnatal- and fetal-type SMC predominate in the intimal thickening. Locally produced or activated autocrine/paracrine factors, such as growth factors or cytokines, along with circulating hormones, seem to be involved in the growth response or changes in the differentiation pattern of SMC. Thus, these factors not only play a specific role in the regulation of blood pressure, but also are likely to be responsible for the remodeling of the arterial wall in hypertension.

It has recently been shown that ischemia in collateral-dependent myocardium may develop at a very variable threshold in anginal patients; accordingly, the aim of this study was to assess whether nifedipine and diltiazem can increase blood flow to collateralized myocardium in man. Nine patients with complete coronary occlusion filled by collaterals, with no other coronary stenosis, normal left ventricular function, and reproducibly positive exercise tests were studied. They underwent exercise tests off therapy and after acute randomized administration of nifedipine (10 mg sublingually), diltiazem (120 mg orally), and nitroglycerin (0.5 mg sublingually), the latter a drug known to increase blood flow to collateralized myocardium. Following nifedipine, time to 1 mm ST segment depression increased significantly (from 430 +/- 176 to 576 +/- 205 seconds, p0.01), while heart rate and rate-pressure product remained unchanged (115 +/- 16 vs 121 +/- 17 beats/min and 199 +/- 29 vs 204 +/- 44 beats/min.mm Hg.10(2), respectively, p = NS for both). Similarly, diltiazem significantly increased time to ischemic threshold from baseline to 638 +/- 125 seconds (p0.01), but did not change heart rate and rate-pressure product at 1 mm ST segment depression. Submaximal rate-pressure products were significantly lowered by both nifedipine and diltiazem. Nitroglycerin not only significantly improved time to ischemic threshold (from baseline to 666 +/- 76 seconds, p0.01), but also increased heart rate (from baseline to 137 +/- 16 beats/min, p0.01) and rate-pressure product (from baseline to 242 +/- 48 beats/min.mm Hg.10(2), p0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE: To investigate whether the hypotensive effects of angiotensin converting enzyme (ACE) inhibitors in comparison with those of calcium antagonist might be predicted by urinary kallikrein activity, a marker of the activity of the renal kallikrein-kinin system. DESIGN: Seventy-five essential hypertensive patients were randomly assigned to treatment with ACE inhibitors (enalapril or lisinopril 20 mg once a day) or with calcium antagonists (nifedipine 20 mg twice a day or lacidipine 4 mg once a day). Fifty-four had normal (NK) and 21 low (LK) kallikrein activity. Blood pressure was measured after 2 weeks, and 3 and 6 months. Patients whose diagnostic blood pressure, 2 weeks after the first dose, decreased by at least 15 mmHg or was < or = 90 mmHg were defined as responders. The others were defined as non-responders. In non-responders a second drug was added and the patients were not considered for further analysis. METHODS: Urinary kallikrein activity was determined by a spectrophotometric assay using a synthetic chromogenic substrate. RESULTS: After 2 weeks therapy with ACE inhibitors 88% of NK patients were responders, whereas in the LK subgroup 40% were responders, a significant difference between subgroups. For the patients treated with calcium antagonists, conversely, 59% of NK patients were responders in comparison with 82% of the LK subgroup, a significant difference between drug groups. After 3 and 6 months of treatment blood pressure was significantly lower in NK patients treated with ACE inhibitors and in LK patients treated with calcium antagonists. In the NK group on ACE inhibitors the mean arterial pressure after the first dose was significantly related to that observed after 6 months (n = 0.71, P < 0.01). CONCLUSIONS: Our data indicate that urinary kallikrein activity may represent an index to predict the chronic antihypertensive effect not only of ACE inhibition but also of calcium antagonism, and support the concept that the renal kallikrein-kinin system might play some contributory role in modulating the hypotensive action of ACE inhibitors.

Objective: Angiotensinogen (AGT)-derived peptides, as angiotensin II, regulate renal biology and physiology. Two novel AGT gene promoter variants (G-175A and G-163A) influence AGT gene expression in adipocytes as recently published. Moreover, obesity has been consistently linked to renal cell cancer. In a small population of kidney cancer patients studied mainly to obtain visceral adipose tissue samples, we have found a very high prevalence of -175A and -163A AGT gene variants.The aim of the present study was to compare the frequencies of these alleles in populations with or without kidney cancer. Design and Method: Three populations differing in size and gender were studied: 1075 healthy men of the Olivetti Heart Study (OHS) from southern Italy, 91 obese females, and 35 consecutive patients (both males and females) with kidney cancer from center Italy. The allele frequencies of G-175A and G-163A were evaluated. The known -20A/C SNP was used as control AGT promoter SNP. Results: AGT -163A and -175A variants were significantly more common with a striking 8-fold (for tha -163A) to 26-fold (for the -175A) difference in kidney cancer patients than in OHS males (P = 0.001) or obese female subjects (P = 0.001). Indeed, comparing allele frequencies we found that the -163A allele was 2.9% in OHS, 3.3% in obese females and 24.3% in kidney cancer patients (P = 0.001). The frequency of -175A allele was 1.8% in OHS, 1.1% in obese female but a striking 37.1% in kidney cancer patients (P = 0.001). No differences were found comparing -163A and -175A frequencies of OHS and obese females despite the differences in gender and size of populations. In kidney cancer patients no allele frequencies differences were found comparing males (n = 26) and females (n = 9). No differences in A-20C allele frequencies were found among the three different populations. Conclusions: Two novel AGT gene promoter functional variants are dramatically more frequent among kidney cancer patients suggesting a link between these genetic markers and renal cancer maybe through altered AGT expression in adipose tissue.

OBJECTIVE To seek possible correlations between plasma atrial natriuretic factor (ANF) and left ventricular diastolic function (LVDF) in hypertensive patients. DESIGN Since LVDF abnormalities can be detected in patients with normal left ventricular mass, we studied a group of hypertensive patients without left ventricular hypertrophy. METHODS Untreated hypertensive patients (n = 23) and normotensive control subjects (n = 19) were studied. LVDF indices were obtained by M-mode and pulsed Doppler echocardiography. Blood samples for plasma ANF were taken in the recumbent position from subjects on normal-sodium intake. RESULTS Plasma ANF levels were significantly higher in hypertensive patients than in normotensive subjects. All indices for systolic function were normal in both normotensive subjects and hypertensive patients. Left atrial diameter was significantly higher for hypertensive patients than for normotensive subjects. Considering LVDF, all indices for ventricular filling were found to be altered, on average, in hypertensive patients, the only exception being peak early velocity. In addition, significant correlations were found between plasma ANF and the pulsed Doppler parameters of left ventricular filling, peak atrial velocity and the peak early:peak atrial velocity ratio. Overall correlations between plasma ANF and left atrial diameter, and between left atrial diameter and left ventricular mass index were also observed. CONCLUSIONS The high levels of plasma ANF observed in our hypertensive patients and their correlation with the LVDF indices (which mainly reflect the atrial contribution to ventricular filling) could be the result of an increased atrial stretch due to diastolic ventricular dysfunction. This may exist in hypertensive patients before the development of ventricular hypertrophy.

In order to seek possible relationships between renal kallikrein and atrial natriuretic factor (ANF), we measured urinary kallikrein (UK) and ANF in 84 normal subjects (NS) and in 104 uncomplicated essential hypertensives (HP). Atrial natriuretic factor was significantly higher in HP than in NS (38.5 +/- 1.3 vs 29.0 +/- 1.3 pg/mL, P less than .01), whereas UK was significantly lower in HP than in NS (11.1 +/- 0.9 v 15.3 +/- 0.6 nkatal/24 h, P less than .01). Calculating the 95% of the percentile distribution of the single values of UK in the group of NS we were able to show that 24 out of 104 HP had a UK which fell below the lowest limit (4.5 nkat/24 h) of the normal range. We therefore divided our HP into two subgroups: patients with normal kallikrein excretion (NK) (n = 80; mean UK 13.8 +/- 0.8 nkat/24 h) and patients with low kallikrein excretion (LK) (n = 24; mean UK 2.3 +/- 0.3 nkat/24 h). Normal kallikrein patients had a mean plasma ANF value of 31.9 +/- 1.2 pg/mL which was almost superimposable to that found in NS; on the contrary, the mean plasma level of ANF in LK patients (50.7 +/- 2.2 pg/mL) was significantly higher than that measured in NK patients and in NS (P less than .01 v NK patients and NS, respectively). Since a low urinary kallikrein excretion may represent a marker of an impaired production of renal kallikrein, the high levels of ANF found in the LK subgroup could be the result of a compensatory response of the atrium attempting to maintain sodium and volume homeostasis.

We studied two groups of hypertensive patients in order to ascertain whether the acute natriuretic effect of nifedipine is mediated by humoral factors such as renal kallikrein or atrial natriuretic factor (ANF). First, 17 patients with mild to moderate essential hypertension maintained on a 130-mmol/day diet, received either nifedipine (10 mg orally) or placebo during a 6-h infusion of the kallikrein inhibitor aprotinin (2 x 10(6) KIU) or saline as control. Aprotinin, while significantly reducing urinary kallikrein activity, did not interfere with the acute effects of nifedipine on blood pressure, heart rate, urinary volume, urinary Na+ and creatinine clearance. In another group of eight patients on a constant daily Na+ intake of 130 mmol and in the supine position, placebo or nifedipine (10 mg sublingually) were administered, and blood pressure, heart rate, plasma renin activity, plasma aldosterone and plasma ANF, urinary Na+, urine volume and creatinine clearance, were monitored for 2 h. While placebo did not induce changes in any of the above parameters, nifedipine administration induced a significant decrease in blood pressure and increase in urinary Na+, urine volume and creatinine clearance, and a significant rise in ANF levels, from 19.4 +/- 2.8 pg/ml to a maximum of 23.9 +/- 2.5 and 24.1 +/- 2.2 pg/ml (P less than 0.05) at 60 and 90 min, respectively. In conclusion, our data do not support a role for renal kallikrein as a humoral mediator of the natriuretic effect of calcium antagonists, but do not exclude the possibility that ANF might participate in the nifedipine-induced increase in sodium and water excretion.

Intracellular Ca2+ influx is an essential step in insulin (I) release. Calcium antagonists are reported to reduce I release in vitro and in patients with impaired glucose tolerance (IGT) during acute administration. Their effects during long-term therapy are still controversial. To evaluate the effects of chronic verapamil (V) and nifedipine (N) on carbohydrate metabolism, 12 hypertensive patients (WHO II; aged 37-64 years) with IGT underwent intravenous glucose tolerance tests (IVGTT) (0.33 g/kg body weight in 3 min), arginine (A) infusion (30 g/30 min), and hypoglycemic stress (regular insulin 0.15 U/kg body weight) during which blood levels of glucose (G), I, growth hormone (GH), glucagon (IRG), and cortisol (C) were measured. The patients were then randomized to V (120 mg b.i.d.) or N (20 mg b.i.d.) treatment and, 1 month later, both IVGTT and A infusion were repeated. Hormone determinations were performed by the radioimmunoassay (RIA) and G by the enzymatic method. The patients were maintained on their usual diet for the duration of the study. The rate of decline of G during IVGTT was expressed as Conard's K coefficient (K; normal values greater than 1.3). I and GH during IVGTT were evaluated as the differences between basal and peak values. I, IRG, and GH during A infusion were analyzed as incremental areas. Our results show that neither V nor N impaired carbohydrate metabolism in hypertensive patients with IGT.

Heavy reversible proteinuria induced by antihypertensive treatment with low doses of captopril has recently been reported by our group in psoriatic patients. To ascertain whether an increased permeability of the glomerular basal membrane of psoriatics can lead to an enhanced urinary excretion of albumin independently from the presence or absence of coexisting diabetes or hypertension, the latter parameter was measured in 39 patients affected by diffuse psoriasis. A high prevalence of microalbuminuria was observed in diabetic and hypertensive psoriatics. Moreover, a direct correlation was found between the diastolic blood pressure (BP) values and the urinary excretion of albumin in the entire group of psoriatics, thus suggesting systemic hypertension as one of the factors responsible for proteinuria in these patients. However, more than 50% of normotensive psoriatics showed an enhanced excretion of albumin. Since microalbuminuria has been indicated as a reliable index to predict the development of renal impairment, the finding of an enhanced albumin loss in psoriatics represents a further risk factor in these patients, who are particularly susceptible to experience cardiovascular complications.

Since hypertension is an important risk factor of cardiovascular morbidity and mortality that can be at least in part decreased by pharmacologic reduction in elevated blood pressure, it is necessary that an antihypertensive agent be effective, but at the same time well tolerated and, according to some recent hypotheses, have no deleterious effect on serum electrolyte levels, as well as lipoprotein and glucose tolerance. However, due to different cultural and social backgrounds, lifestyles, and so on, the tolerability may differ from one population to another and the conclusions drawn from a population cannot be extrapolated to people of other countries. For these reasons, the well-being of patients, as well as the tolerability of indapamide, a non-thiazide diuretic, have been investigated in patients with hypertension of mild and moderate degree from different parts of Italy with a satisfactory blood-pressure response to this drug (−22.8 ± 0.6/−17.1 ± 0.5 mm Hg). Simultaneous to the significant blood-pressure reduction, the only significant change among the metabolic effects was a slight reduction in plasma potassium levels (−0.37 ± 0.03 meq/liter). The tolerability was, on the whole, very good with a tendency toward an improvement of well-being in patients, the majority of whom were already asymptomatic before starting the treatment.

The following methodological aspects of the use of trypsin as activator of inactive renin in human plasma have been studied: a) the effect of SBTI on renin activity and angiotensin; b) the reaction velocity of trypsin on inactive renin; c) the optimum trypsin concentration; d) the ability of human plasma to neutralize exogenous trypsin. Our results show that: 1) Some commercially available SBTI may exert an angiotensinase-like effect which can be abolished by PMSF. 2) At 4 degrees C activation of inactive renin reached a maximum within the first two minutes then no further activation could be demonstrated. 3) Trypsin 2 mg/ml yielded more inactive renin than trypsin 1 or 0.5 mg/ml. A higher concentration (3 mg/ml) gave substantially equivalent activation as (with) trypsin 2 mg/ml whereas when using a still higher concentration (4 mg/ml) a degradation of the renin system components could be noted. 4) Endogenous trypsin inhibitors can eventually inactivate exogenous trypsin up to 3 mg/ml. About 20% of renin is destroyed by trypsin 4 mg/ml within 2 min at 4 degrees C while an additional 40% is lost during the incubation at 37 degrees C if no SBTI is added.

To investigate the role of Angiotensin II in the release of ACTH, the response of adrenocorticotrophic hormone to hypoglycaemia was studied before and during treatment with an angiotensin converting enzyme inhibitor, enalapril, in 15 male patients with essential hypertension. Plasma levels of ACTH were measured before and 60, 90 and 120 min after an i.v. bolus of normal saline, as placebo, and, 3 days later, after an i.v. bolus of regular insulin (0.15 U/Kg b.w.). Enalapril treatment was then started and both placebo and hypoglycaemic tests were repeated 15 days thereafter. No changes in ACTH plasma levels were observed after acute normal saline either before or during enalapril treatment. On the contrary, hypoglycaemia induced a sharp increase of ACTH before enalapril (from 19.5 +/- 4.1 to 74.4 +/- 13.0 pg/ml, p less than 0.01 60 min after insulin) but not during ACE inhibition (from 26.1 +/- 6.2 to 34.6 +/- 5.9 pg/ml, NS, at min 60 of the study). The present data confirm our previous observation on the reduction of the hypoglycaemic-induced ACTH release during ACE inhibition with captopril and support the hypothesis that circulating Ang II may exert a facilitating role on adrenocorticotrophic hormone release.

The aim of this study has been to see whether acute variations in the proportions of circulating active and inactive renin in normal subjects were related to concurrent changes in the excretion of urinary kallikrein. Hydrochlorothiazide (50 mg/day) was given to 6 normal volunteers for 6 days; another group of 6 normal subjects received spironolactone (300 mg/day) for 6 days whereas synthetic aldosterone (0.5 mg/day) was administered i.m. for three days to 3 normal subjects. Both diuretics induced a sharp rise in active and total renin and a significant transient decrease in inactive renin so that the active: total renin proportion significantly increased. Urinary kallikrein excretion did not significantly change in either group. Parenteral administration of aldosterone induced a striking fall in all renin components without changing the proportions of active and inactive renin whereas urinary kallikrein excretion increased. These results indicate that changes in active: total renin proportions can occur without parallel variations in urinary kallikrein excretion. The latter cannot be used, therefore, as a reliable index of the possible role of renal kallikrein as activator in-vivo of inactive renin in man.

A retrospective analysis of renal vein renin results has been done in 96 patients with renal artery stenosis and hypertension studied in two Italian centers (Sassari and Pisa) with respect to the outcome of either surgery or percutaneous transluminal angioplasty (PTA). In all patients the renal vein renin ratio and the V-A/A ratios for the affected and unaffected kidney were calculated. Each patient underwent surgery (75) of PTA (21): 71 subjects were cured, 17 improved whereas the arterial pressure did not vary after revascularisation procedure in 8 patients. In the Pisa series all 54 patients showed a lateralisation with contralateral renin suppression and 95% of them benefitted from surgery. In the Sassari series 42 patients were submitted to PTA or surgery, not only on the basis of a positive renal vein renin study but taking into account a complete clinical evaluation: 8 of them were cured or improved in spite of negative renal vein renin criteria. In the two series, the better predictive index appeared to be the suppression of the renin secretion from the contralateral kidney while the high/low renin ratio showed a consistent amount of false-positive and false-negative results. Our retrospective study demonstrates that the renal vein test in hypertensive patients with renal artery stenosis is highly predictive of the curability of the disease, particularly when contralateral suppression of renin secretion is present. On the other hand, since patients with negative renin indexes can also take benefit from surgery of PTA, the renin parameters cannot be adopted as the sole criterion in making the decision to operate.

Conflicting data concerning the presence of enhanced serum angiotensin-converting enzyme (SACE) activity in psoriasis are reported in the literature. In order to verify whether this abnormality is a typical pattern of psoriasis, SACE levels were determined in 27 psoriatics as well as in 18 healthy subjects and in 30 patients with essential hypertension. We found that SACE levels were normal in patients affected by psoriasis independently of the presence or the absence of abnormalities in carbohydrate metabolism. Furthermore, SACE levels were not related to the severity of the skin lesions. We conclude that an elevated SACE activity is not a typical pattern of psoriasis, whereas, when present in a psoriatic, it might suggest the possibility of a coexisting unknown systemic sarcoidosis.

Thirty-one essential hypertensives with normal or low PRA were evaluated before and after a single oral dose (50 mg) of captopril. A significant fall both in systolic and diastolic blood pressure (BP) was obtained in the subgroup of patients who were classified as "normal kallikrein hypertensives", while no significant change in BP was observed in "low kallikrein hypertensives". Furthermore the mean percentage fall in mean BP, throughout the 2 hours following captopril administration, was significantly related to the basal value of urinary kallikrein excretion (r = 0.47 p less than 0.05) in the entire group of patients. Our results suggest that a blunted activity of the kallikrein system might be responsible for failure of captopril in lowering BP in patients in whom the renin-angiotensin system is not pathogenetically implicated.

1. Plasma samples from 31 normal subjects were treated (at 4°C, pH 7.0, for 2 min) with different concentrations of trypsin (500, 1000, 2000, 3000 and 4000 μg/ml) in order to assess which concentration yielded the maximum activation of inactive renin. 2. Endogenous antitryptic activity was also measured in all samples; the mean value ± sd (in μg of trypsin inhibited by 1 ml of plasma) was 953 ± 550 μg/ml (range 34–1800 μg/ml). 3. In the entire group of subjects the values of trypsin-activated renin measured with trypsin at 2000 μg/ml were significantly higher than those obtained with lower or higher trypsin concentrations. 4. With subjects divided into subgroups according to their endogenous anti-tryptic activity, the maximum yield of activation was reached with trypsin at 2000 μg/ml. 5. No significant correlations were found between single values of active, inactive or trypsin-activated renin and the corresponding levels of endogenous anti-tryptic activity. However, a weak but significant correlation (r = 0.39, P < 0.05) was found between single values of anti-tryptic activity and the corresponding percentage of activation of inactive renin. 6. Thus the maximum activation of inactive renin at 4°C for 2 min is obtained with trypsin at 2000 μg/ml independently of the corresponding endogenous anti-tryptic activity. It is not excluded that the content of protease inhibitors in human plasma might affect the proportion in vivo of circulating active and inactive renin.

To see whether the acute natriuretic effect of nifedipine is accompanied by changes in atrial natriuretic peptide levels, a group of eight hypertensive patients were studied. After at least a week of constant sodium intake, placebo or nifedipine (10 mg s.I.) were administered and blood pressure, heart rate, plasma renin activity, plasma aldosterone and atrial natriuretic peptide plasma levels, urinary sodium, urinary volume and creatinine clearance were monitored for 2 hours. While placebo did not induce changes in any of the above parameters, nifedipine administration was followed by a significant decrease in blood pressure and an increase in urinary sodium, urinary volume and creatinine clearance; these changes were accompanied by a significant rise in atrial natriuretic peptide levels from 19.4 +/- 2.8 pg/ml to a maximum of 23.9 +/- 2.5 pg/ml and 24.1 +/- 2.2 pg/ml (P less than 0.05) at 60 and 90 minutes, respectively. In conclusion, our data do not rule out the possibility that atrial natriuretic peptide participates in the nifedipine-induced increase in sodium and water excretion.

The antihypertensive efficacy of ACE inhibitors depends in theory from the blockade of the angiotensin II formation but also from the inhibition of kinin breakdown. To test whether a blunted activity of the kallikrein-kinin system might account for the failure of ACE inhibitors in lowering BP in patients in whom the renin-angiotensin system is not enhanced, thirty-one essential hypertensives with normal or low PRA were evaluated before and after a single oral dose (50 mg) of captopril. A significant fall both in systolic and diastolic blood pressure (BP) was obtained in the subgroup of patients who were classified as "normal kallikrein hypertensives" according to whether their pretreatment urinary kallikrein excretion was within the normal range, while no significant change in BP was observed in "low kallikrein hypertensives". Furthermore the mean percentage fall in mean BP, throughout the 2 hours following captopril administration, was significantly related to the basal value of urinary kallikrein excretion (r = 0.47, p less than 0.05) in the entire group of patients. Our results suggest that a blunted activity of the kallikrein system might be responsible for failure of captopril in lowering BP in patients in whom the renin-angiotensin system is not pathogenetically implicated.

The direct measurement of active renin with monoclonal antibodies (IRMA) in plasma from hypertensive patients was compared with the traditional PRA method. Two monoclonal antibodies were used: 3E8 and 4G1. The first was coupled to magnetizable beads and was used to trap both active and inactive renin from plasma. The second antibody, 4G1, was iodinated and used to detect active renin trapped by 3E8. The correlation coefficient between the two methods was very high (r = 0.98, p less than 0.001) in plasma samples whose PRA values were higher than 2 ng/ml/h; in low renin samples (PRA lower than 2 ng/ml/h) no significant correlation was found (r = 0.12 n.s.). When PRA and IRMA were performed before and after trypsin activation of inactive renin, the percentage of inactive over total renin was 86.8% and 84% as calculated with PRA and IRMA respectively. The direct monoclonal antibodies method for measuring active renin can be usefully adopted, in conjunction with the traditional PRA procedure, in studying both clinical and pathophysiological aspects of the renin-angiotensin system.

Plasma renin activity (PRA) of patients with Parkinson's disease was measured in recumbency, upright position, and after frusemide administration. The results show that the renin responses to both stimuli are significantly reduced as compared with those obtained in a group of normal subjects, while recumbent PRA levels of Parkinsonism patients are not significantly lower than those found in recumbent normal subjects. Levodopa treatment, alone or in combination with two different dopa-decarboxylase inhibitors, benserazide and carbidopa, does not modify the renin response to posture or to frusemide. Although the reduced activity of the renin-angiotensin system can play some role in the genesis of orthostatic hypotensive episodes encountered in patients with Parkinsonism, the greater incidence of orthostatis hypotension in patients treated with levodopa seems to be unrelated to any effect of this drug on the renin release.

Diuretics have a number of well known adverse effects such as hyperglycaemia (or reduced carbohydrate tolerance), hyperlipidemia, hyperuricemia and hypokaliemia (1,2,3). The latter seems to mediate, at least in part, the negative effects on carbohydrate methabolism through a reduction of insulin release (4). The aim of our study has been to compare the antihypertensive and metabolic effects of a thiazide diuretic alone, thiobutizide, versus a combination of thiobutizide plus a potassium sparing agent, potassium canrenoate.

In 25 hypertensive patients (15 with renal artery stenosis and 10 with essential hypertension), captopril, in a single 12.5 mg dose, caused a prompt decrease in arterial pressure without changing the heart rate. Plasma active and trypsin-activated renin significantly increases, whereas inactive renin and plasma aldosterone decreased. The plasma active/inactive renin ratio was also increased, suggesting that captopril, together with a release of active renin, may induce an in vivo activation of inactive renin. No correlations were found between blood pressure changes and both pretreatment and captopril-induced variations of active, inactive and trypsin-activated renin or the active/inactive ratio. However, the percent decrease in mean arterial pressure was significantly related to the increase in the active/inactive renin ratio in a group of patients whose blood pressure was brought to normal (r = -0.78; p less than 0.001). This finding suggests the possibility that vasodilating substances, in addition to inhibiting angiotensin II formation, might play some role both in exerting a full effect of captopril on blood pressure and in triggering the in vivo mechanisms of inactive renin activation.

The experimental conditions of trypsin activation of inactive renin in rat plasma have been studied. Our results showed that the pH optimum of trypsin-activated renin is 6.2, the same as that of rat plasma active renin. Trypsin concentration and incubation time might also interfere with the activation process. Trypsin concentration below 2 mg/ml cannot activate inactive renin. Trypsin at a concentration of 6 mg/ml for 1 min. can cleave dialyzable fragments from renin substrate which can generate Angiotensin I at 37 degrees C with a pH optimum of 5.3 but which do not affect Angiotensin generation at pH 6.2. Longer incubations (more than 2 min.), on the contrary, can produce a cleavage at 4 degrees C of Angiotensin I containing fragments directly from renin substrate strongly interfering with measurements of renin activity at pH 6.2. Trypsin concentrations lower than endogenous rat plasma anti-trypsin activity do not activate inactive renin. Much higher concentrations of trypsin, however, are needed to obtain optimum activation of inactive renin. In average, 40% of the total circulating renin in rat plasma can be activated by trypsin.

Despite their vasodilating action, calcium antagonists increase renal sodium excretion. To ascertain whether renal kallikrein plays a role in the renal effects of calcium antagonists, nifedipine (N) (10 mg orally) or placebo (P) was given to 17 male patients with mild to moderate essential hypertension during a 6-h infusion of either saline (S) or aprotinin (A) (2 X 10(6) KIU in 200 ml of saline). Blood pressure (BP) and heart rate (HR) were measured every 10 min, and blood samples were taken at -10, 0, 30, 60, 120, 240, 360 min for plasma renin activity (PRA), creatinine, and osmolarity determinations. Urinary kallikrein, aldosterone, creatinine, and electrolytes were measured in 6-h urine collections. The acute administration of N induced a significant systolic BP (SBP) and diastolic (DBP) fall and a transient PRA increase that peaked at 30 min and were not modified by A infusion. Urinary volume (+47%), Na+ (+54%) and Cl- (+58%) excretion were significantly enhanced by N. There were less pronounced and statistically not significant increases in urinary excretion of Ca2+ (+38%) and K+ (+29%). Infusion of A did not interfere with the natriuretic effect of N. Our data do not support the hypothesis that the kallikrein-kinin system plays an important role in mediating the renal effects of nifedipine in humans.

Relationships between renal kallikrein and plasma atrial natriuretic factor were investigated by measuring urinary kallikrein excretion (by spectrophotometric assay) and plasma atrial natriuretic factor (by radio-immunoassay after extraction from plasma) in 84 normal subjects and in 104 essential hypertensives with a normal renal function. The atrial natriuretic factor was significantly higher in the essential hypertensives than in the normal subjects (38.5 +/- 1.3 versus 29.0 +/- 1.3 pg/ml, P less than 0.01), whereas urinary kallikrein excretion was significantly lower in the hypertensives than in the normal subjects (11.1 +/- 0.9 versus 15.3 +/- 0.6 nkat/24 h, P less than 0.01). Taking the 95% confidence limits of urinary kallikrein excretion in the normal subjects (from 4.5 to 29.9 nkat/24 h), we divided our essential hypertensives into two subgroups, patients with a normal kallikrein excretion (n = 80; mean urinary kallikrein excretion 13.8 +/- 0.8 nkat/24 h) and patients with a low kallikrein excretion (n = 24; mean urinary kallikrein excretion 2.3 +/- 0.3 nkat/24 h) The patients with a normal kallikrein excretion had a mean plasma atrial natriuretic factor value of 31.9 +/- 1.2 pg/ml, which was similar to that found in normal subjects. In contrast, the mean plasma level of atrial natriuretic factor in the patients with a low kallikrein excretion (50.7 +/- 2.2 pg/ml) was significantly higher than that measured in the patients with a normal kallikrein excretion and in the normal subjects (P less than 0.01 versus patients with normal kallikrein excretion and normal subjects, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

1. Activation of inactive renin in rat plasma has been studied with different trypsin concentrations and incubation times at pH 6.2 and 4°C. 2. Trypsin concentrations below 2 mg/ml, lower than endogenous rat plasma anti-trypsin activity, do not activate inactive renin, whereas maximal activation is obtained with trypsin at 6 mg/ml for 1 min at 4°C, pH 6.2. 3. Under these conditions trypsin can cleave dialysable fragments from renin substrate. ANG I can be generated at 37°C with a pH optimum of 5.3. Nevertheless, the ANG I formation at pH 6.2 was totally unaffected. 4. Incubations longer than 2 min with trypsin at 6 mg/ml can induce a direct cleavage of dialysable ANG I-containing fragments strongly interfering with the measurements of renin activity at pH 6.2. 5. On average 40% of the total renin measured in plasma of normotensive WK rats is in the inactive form, although a wide range of variation is observed.

We have previously reported on a high prevalence of high renin essential hypertension in psoriasis. Since angiotensin-converting enzyme (ACE) was also reported to be increased in some psoriatics, we found it rational to treat 10 patients with hypertension and diffuse psoriasis with captopril at a dose of 25 mg t.i.d. Five patients had high PRA levels and in 1 of them serum ACE was also increased. Serum creatinine, BUN and urinalysis were normal in all of them. SPB fell from 163 +/- 3 to 138 +/- 3 and DBP from 107 +/- 3 to 86 +/- 2 mm Hg after 1 month of captopril treatment. A surprising clinical improvement of the cutaneous lesions occurred in 3 patients previously resistant to every local or systemic treatment. Unfortunately, however, 3 patients developed heavy proteinuria (greater than 2 g/day) which disappeared after captopril discontinuation. The unexpected incidence of reversible proteinuria induced by low doses of captopril in our patients recommends a careful monitoring of the renal function every time this drug is employed in the treatment of hypertension in a psoriatic.

The Authors investigated anterior pituitary function in hypertensive patients in basal conditions and following a 15-day course of treatment with Captopril, a drug which blocks the generation of Angiotensin II (Angio II). No differences were observed for any of the pituitary hormones except ACTH, whose response to hypoglycemia was significantly blunted by the pharmacological treatment. A possible role of Angio. II in modulating some aspects of pituitary function is proposed.