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Our objective was to evaluate pretreatment predictors of longevity, particularly blood pressure, in a large cohort of hypertensive men. During 1974 to 1976, 10,367 male hypertensive veterans (47% black) were identified at screening and subsequently characterized in 32 special Veterans Administration (VA) hypertension clinics. Their mean age was 52 years and mean blood pressure (BP) 154/100 mm Hg. During an average of 21 years of follow-up, 61% died. Risk ratios for all-cause mortality as functions of BP and other risk factors are presented for each variable alone; for each variable controlling for age, race, and BP; and for a multivariate model. We observed that when the entire cohort was divided into deciles by systolic blood pressure (SBP) and by diastolic blood pressure (DBP), the risk ratios for 21-year mortality increased from lowest to highest decile by 178% for SBP and 16% for DBP. When the deciles were computed separately by age group, increases from lowest to highest decile for those less than 40 years of age were 138% for SBP and 263% for DBP. For those over 60 years, the increases were 154% and -10%, respectively. Although blacks were younger and had more severe diastolic hypertension than whites, the risk ratios were similar within each race group. Risk patterns for mean arterial pressure and pulse pressure resembled those for SBP but had smaller gradients. Survival curves for BP groups suggested constant mortality rates during follow-up. Other significant observations included decreasing mortality with increasing body mass index and increased mortality in the Stroke Belt. We concluded that pretreatment SBP strongly predicted all-cause mortality during 21-year follow-up. For the young, both SBP and DBP were strong predictors; for the elderly, only SBP was predictive.

1. The adult spontaneously hypertensive Lyon rats (LH strain) exhibited increased maximal epidermal growth factor (EGF) binding in freshly prepared kidney and aortic tissue membranes compared with age-matched normotensive (LN) or hypotensive (LL) strains. However, the binding affinity of the receptors to EGF was the same in all the three strains studied. These findings indicate an increased number of EGF receptors (EGFR) in the hypertensive LH strain. 2. Protein tyrosine kinase activity associated with the EGFR was also elevated in the LH strain compared with LN or LL strains, indicating that these receptors are functionally active. 3. There was a correlation between maximal EGF binding by aortic membranes and blood pressure in individual animals (r = 0.55; P < 0.001). 4. Taken together with previously reported similar findings in other models of genetic hypertension, the present results suggest a possible role for increased levels of EGFR in the development and maintenance of genetic hypertension.

Dahl salt sensitive rats (DS) developed severe hypertension on four weeks of high salt feeding while the Dahl salt resistant rats (DR) remained normotensive under the same conditions. The specific maximal binding of epidermal growth factor (EGF) in the freshly prepared kidney membranes of high salt fed DS rats was higher than those from DR rats (5.3 +/- 1.9 vs. 1.6 +/- 0.62 fmoles/mg protein, p<0.001). Scatchard analysis of EGF binding in the kidney showed one class of receptors in the DR (K(d) = 0.75 +/- 0.05 nM) as well as in the DS rats (K(d)=0.69 +/- 0.06 nM). The EGF binding in the aortic membranes of DS rats was also high compared to DR rats (24.98 +/- 5.52 vs. 13.20 +/- 4.10 fmoles/mg protein, p < 0.001). Scatchard analysis of EGF binding in the aorta showed one class of receptors in the DR aorta with a K(d) of 0.70 +/- 0.06 nM. On the other hand, in the DS rat aorta two classes of receptors, a high affinity form (K(d)=0.05 +/- 0.01 nM) and a low affinity form (K(d)=3.5 +/- 0.3 nM) were noted. The induction of a high affinity species of EGF receptors in the aorta, appears to be a mechanism unique to the salt fed DS rats.

There has been a continuing increase in the incidence of end-stage renal disease (ESRD) in the United States, including the fraction that has been attributed to hypertension. This study was done to seek relationships between ESRD and pretreatment clinical data and between ESRD and early treated blood pressure data in a population of hypertensive veterans. We identified a total of 5730 black and 6182 nonblack male veterans as hypertensive from 1974 through 1976 in 32 Veterans Administration Hypertension Screening and Treatment Program clinics. Their mean age was 52.5 +/- 10.2 years, and their mean pretreatment blood pressure was 154.3 +/- 19.0/100.8 +/- 9.8 mm Hg. During a minimum of 13.9 years of follow-up, 5337 (44.8%) of these patients died and 245 developed ESRD. For 1055 of these subjects, pretreatment systolic blood pressure (SBP) was greater than 180 mm Hg; 901 were diabetic; 1471 had a history of urinary tract problems; and 2358 of the 9644 who were treated had an early fall in SBP of more than 20 mm Hg. We used proportional hazards modeling to fit multivariate survival models to determine the effect of the available pretreatment data and early treated blood pressure levels on ESRD. This model demonstrated the independent increased risk of ESRD associated with being black or diabetic (risk ratio, 2.2 or 1.8), having a history of urinary tract problems (risk ratio, 2.2), or having high pretreatment SBP (for SBP 165 to 180 mm Hg, risk ratio was 2.8; for SBP > 180 mm Hg, risk ratio was 7.6).(ABSTRACT TRUNCATED AT 250 WORDS)

Several different investigators have reported increased stroke mortality in the southeastern United States, leading to the introduction of the term "Stroke Belt." The results presented here from the Veterans Administration Hypertension Screening and Treatment Program (HSTP) demonstrate an increased all-cause mortality among hypertensive patients seen in HSTP clinics in the southeastern United States when compared with similar patients from other HSTP clinics. Several different groupings of southeastern states were examined and compared with nine states west of the Mississippi River. A total of 11,936 male veterans, 5737 of whom were black, were identified as hypertensive during 1974-1976 in 32 HSTP clinics. Their mean age was 52.4 +/- 10.4 years, and their mean pretreatment blood pressure was 153.8 +/- 19.1/100.4 +/- 9.8 mm Hg. During a minimum of 13.9 years of follow-up, 5360 (44.9%) of these patients died. Proportional hazards modeling was used to fit a basic survival model with terms representing race, age, blood pressure, smoking, and obesity. Risk was increased with higher blood pressure, age, and smoking and with lower body mass index. For 6 HSTP clinics in an 11-state Stroke Belt (defined as states with stroke mortality > 10% above the United States average), the relative risk of death was 1.226 (95% confidence interval, 1.106-1.358) when compared with 9 states west of the Mississippi River. For two different groupings of southeastern states with 10 and 8 HSTP clinics the relative risk of death was 1.231 and 1.295.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: To seek regional differences within the USA in the 'all-cause mortality' of hypertensive men during the 14 years following institution of antihypertensive treatment, and to determine how other pretreatment data can be related to that all-cause mortality., Design: In the mid-1970s pretreatment clinical data were collected and computerized for 5698 hypertensive veterans. Deaths during the subsequent 14 years were obtained from the Veterans Administration Beneficiary Identification and Record Location System and the National Death Index. Relationships between pretreatment data and death were sought using chi 2- and z-tests for bivariate comparisons and logistic regression for multivariate analyses., Patients: Half of the 5698 previously untreated male hypertensive military veterans were Black. Their mean age was 52.3 years and mean pretreatment blood pressure was 160/104 mmHg. Additional pretreatment data included body mass index, cigarette and alcohol usage, age and self-reported comorbidities. These patients began antihypertensive treatment during 1974-1975 in 28 special Veterans Administration outpatient clinics throughout the USA., Results: During the 14 years after treatment began, 2283 of these patients (40%) died. Those from the southeastern USA, i.e. in the 'Stroke Belt', were 1.32-fold more likely to die than patients living elsewhere. Other pretreatment characteristics positively related to all-cause mortality included age, systolic blood pressure, cigarette and alcohol usage, and self-reported comorbidities. Race was unrelated to mortality., Conclusion: All-cause mortality was increased among hypertensive subjects from the southeastern USA. The reasons for this excess mortality remain unclear. Other pretreatment characteristics were also related to mortality, but race was not.

Inhibition of the renin-angiotensin system is being applied with considerable success to the treatment of hypertension and heart failure. Angiotensin-converting enzyme (ACE) inhibitors are the only currently available agents that can achieve this objective. In general, the major therapeutic effects of these agents in the treatment of mild to moderate hypertension or of heart failure are exerted on the vascular tissue through inhibition of the renin-angiotensin system and, secondarily, of the sympathetic nervous system. When cardiovascular functional reserve is diminished and autoregulation of regional and systemic blood flow is strained, however, ACE inhibitors may affect other organ functions (heart, kidneys, and possibly brain), hormones other than the renin system, and local tissue humoral systems. The interrelations between the renin-angiotensin system and several other vasoactive systems--including circulating and locally generated tissue hormones and centrally acting neurohormonal factors--are complex and unclear. A better understanding of these mechanisms and interrelations would allow for a more rational therapeutic use of these agents. Unknown also are the clinical effects of prolonged ACE inhibition. Whether the use of ACE inhibitors can provide primary cardiorenal protection requires proof through definitive clinical trials.

This study examines the changes in the mRNA expression of epidermal growth factor (EGF), EGF receptor (EGFR), platelet derived growth factor (PDGF-B), and transforming growth factor beta (TGF-beta 1) before and after sustained pressor infusion of angiotensin II (Ang II) for 4 weeks. A threefold increase occurred in the levels of EGFR mRNA (17,240 +/- 827 vs 6403 +/- 1372 units, P less than 0.01) and TGF-beta 1 mRNA (1644 +/- 584 vs 475 +/- 30 units, P less than 0.01) only in the aorta and not in the heart and kidney tissues. This increase in both of the above mRNA transcripts highly correlated (r = 0.96 and 0.92, P less than 0.01) with the elevation of blood pressure. The specific binding of 125I-labeled EGF to aortic membranes also increased (11,429 +/- 728 vs 8630 +/- 420 cpm/mg protein, P less than 0.05) with a parallel increase in the protein tyrosine kinase activity of the membranes indicating that the enhanced EGFR mRNA expression resulted in increased activity of a functional receptor. No significant changes were observed in either EGF mRNA or PDGF-B mRNA levels. These findings suggest that EGFR and TGF-beta 1 participate in the long-term progressive pressor response to Ang II and thus potentially in the progression and the maintenance of chronic hypertension.

Structural changes in the cardiovascular musculature of the SHR during the development of hypertension appears to involve both prehypertensive hyperplastic cellular growth and hypertension induced cellular hypertrophy. The genetic factors determining these changes are not fully known, but may involve altered growth control. The role of genetic determination on the development of hypertension in the SHR was investigated by producing chimeric rats composed of a mixture of genetically homozygous SHR and normotensive cells. Preimplantation 8-cell embryos isolated from SHR and the normotensive NBR (NIH Black Wistar) rat strains were aggregated in vitro and cultured to the blastocyst stage before implantation into surrogate mothers. Chimeric rats born to the surrogate females were raised to 36-40 wks of age and the development of hypertension monitored by tail cuff pressure (BP). BP in the chimeras varied from 115 to 205 mm Hg (146 +/- 25). Heart weights were positively correlated with BP, r = 0.76, p less than 0.05, while only a marginal and non-significant correlation of aortic weight was found (r = 0.53). The renin-angiotensin system was normal in the chimeras. This model may prove useful in determining the extent of genetically mediated cellular events in the development of hypertrophy and hypertension in the SHR.

Aortic vascular smooth muscle cells isolated from spontaneously hypertensive rats (SHR) replicate in vitro nearly twice as fast as cells isolated from several normotensive control strains of rats. Serum-derived peptide growth factors are known to stimulate cells to enter the DNA synthetic phase of the cell cycle and subsequent mitosis. We have examined the effect of several peptide growth factors to stimulate [3H]thymidine incorporation into DNA in smooth muscle cells isolated from adult (24 wk, hypertensive) SHR and age matched normotensive NIH Black Wistar (NBR) control rats. Our results indicate that the response of the SHR cells to epidermal growth factor (EGF) is selectively enhanced compared to the control NBR cells. PDGF also stimulated DNA synthesis but no significant difference between SHR and NBR was observed. Nerve growth factor and endothelial derived growth factor were not mitotic on either cell line. Additionally, we have found that SHR cells, isolated from young early hypertensive weanling animals before a significant elevation in pressure has occurred, divide at the same rate as adult SHR cells normotensive strains. These results are consistent with the view that genetic changes affecting the cellular response to EGF may influence the development of early hypertensive hyperplasia in the SHR which in concert with other factors aggravates the later development of hypertension.

Two studies of the responses to clonidine as the sole antihypertensive drug in the treatment of mild-to-moderate hypertension are reported. In the first, 11 patients with mild hypertension were treated with 0.1 mg clonidine twice daily for eight weeks. Those patients with "low renin" hypertension (n = 7) were noted to show an increase in plasma renin activity; the patients with "normal renin" hypertension (n = 4) tended to show a decrease. Both groups had a similar decrease in blood pressure. The changes in renin activity correlated significantly (p less than 0.01) with the small changes in endogenous creatinine clearance (r = 0.84). In the second study, 16 patients with mild-to-moderate essential hypertension were treated for three months with 0.2 mg clonidine three times daily. Blood pressure decreased from 167 +/- 4/105 +/- 2 to 140 +/- 3/90 +/- 2 mm Hg (p less than 0.01). Blood pressure changes correlated with decreases in plasma catecholamines (r = 0.61, p less than 0.001) and heart rate (r = 0.78, p less than 0.001). No significant changes in cardiac output, blood volume, renal blood flow, or glomerular filtration rate were noted. Clonidine is an effective and safe therapy when used as the sole medication in treating mild-to-moderate hypertension.

The interaction of the prostaglandin and renin-angiotensin systems on blood pressure and renal function was studied in conscious rabbits following mild (6 ml/kg) or moderate (15 ml/kg) hemorrhage. One hour following the injection of the prostaglandin synthetase inhibitor indomethacin (Indo) plasma renin activity (PRA) was significantly lower than the values in control animals. Two hours following hemorrhage, the increase in PRA was very similar in the Indo and control animals. Renal plasma flow (RPF) was not affected by Indo. Glomerular filtration rate (GFR) was significantly lower in the Indo group following moderate hemorrhage. Interruption of the renin-angiotensin system with the converting enzyme inhibitor (CEI), captopril, resulted in similar hypotensive responses in the Indo and non-Indo groups. The marked PRA increase induced by this agent also was not influenced by Indo. The CEI increased RPF and decreased renal vascular resistance (RVR) in the mild hemorrhage animals. However, in the moderate hemorrhage group the RPF changes were variable and RVR tended to increase, especially in the Indo group. GFR fell significantly following captopril in both Indo and non-Indo animals after moderate hemorrhage. The results indicate that prostaglandin inhibition lowers basal PRA levels but that the renin response to hemorrhage and captopril are not prevented. Indo also did not alter the hypotensive response to CEI, suggesting that prostaglandins do not play a major role in this effect. The magnitude of the hemorrhagic stress influences the renal responses to inhibition of the prostaglandin or renin-angiotensin systems in the conscious rabbit.

Plasma levels of active and inactive renin were measured in the rat following manipulation of renin release. In the anesthetized rat intravenous captopril or sodium nitroprusside resulted in elevation of active renin only. Neither active nor inactive renin were altered following ether anesthesia of 2 hour bilaterally nephrectomized animals. Elevated levels of active and total renin were observed in anesthetized Wistar rats that had received oral captopril for a 6 week period. Renin substrate was decreased suggesting that blood angiotensin II exerts a tonic influence on renin substrate. In sodium deplete SHR, sacrificed by decapitation, chronic captopril resulted in a significant increase of both the active and inactive form of the enzyme concomitant with blood pressure reduction. The present data further confirm the independent control of active and inactive renin in the rat.

Renin angiotensin system parameters and blood pressure (B.P.) were followed monthly in patients with essential hypertension on metolazone, 5 mg daily for three months and with added propranolol, 40 to 160 mg, for the subsequent three months. On metolazone alone at three months, sitting B.P. declined from 166/108 +/- 14/11 mm Hg to 145/98 +/- 14/9 mm Hg (P less than 0.005). Plasma renin activity (PRA) increased from 3.9 +/- ng/ml/hr to 10.4 +/- 8.6 ng/ml/hr (P less than 0.005); plasma angiotensinogen did not change. Venous blood angiotensin I and II levels (pg/ml) rose initially but returned toward control values. A significant decline in plasma renin substrate reactivity (PRSr) in index occurred. Propranolol addition caused further lowering of only systolic B.P. and predominantly in the standing position, more marked at one month (40 mg) than at three months (160 mg). No significant further changes were observed in any of the measured parameters of renin angiotensin system, except for a rise in PRSr index concomitant with B.P. elevation at three months. Metolazone-induced changes in B.P. showed significant correlations at three months with changes in PRSr index. It is concluded that during chronic metolazone administration, the overall activity of the renin angiotensin system was diminished or unchanged. Propranolol did not inhibit metolazone stimulated PRA but did cause further decline in B.P. in the first two months, unrelated to renin angiotensin system.

The rate of angiotensin generation with added renin in plasma from patients with benign essential hypertension has been shown to be higher than in plasma from norm ensive controls. An index of the angiotensin generation rate in relation to to al plasma renin substrate (PRS-r index) has been defined which allows for screening for "activated" plasma. In hypertensive subjects, this index was shown to be higher than that of the normotensive subjects (61 plus or minus 2.4 SE, and 45 plus or minus 5 SE). The index did not correlate with the absolute levels of blood pressure, 24-hour sodium excretion, or plasma renin activity in hypertensive subjects either during the control period or during acute alterations of blood pressure, but was shown to respond in a parallel fashion with chronically induced changes in blood pressure and circulating levels of angiotensin I. By the use of an isolated system of human renin and homologous renin substrate, we have demonstrated that plasma from hypertensive subjects contains a modifier of the renin reaction which increases both V-max and Km of the system, behaving as an uncompetitive activator. No significant change was noted with the addition of normal plasma to the same isolated system.

The effects of acute (single-dose) and chronic (26-day) therapy with nitrendipine on renal function were evaluated in 10 patients with mild to moderate hypertension. The patients were studied during three phases: for one week while on a constant diet containing 100 mEq of sodium and 80 mEq of potassium daily and receiving placebo, after administration of a single 20-mg oral dose of nitrendipine, and during one week of treatment with nitrendipine at 10 mg twice daily. After two weeks of outpatient treatment at 10 or 20 mg twice daily, the patients were readmitted and reevaluated while on controlled diets. Isotopic determinations of glomerular filtration rate, effective renal blood flow, blood volume, and cardiac output were made during each phase, and free water clearance and osmolar clearance following a water load were measured; during the periods of hospitalization, 24-hour urinary creatinine and electrolyte excretion were assessed. A significant decrease in blood pressure occurred during both the acute and chronic phases as compared with the placebo phase. During the first week of treatment with nitrendipine, a significant increase in urinary sodium excretion over control values was observed, with a mean deficit of 148 +/- 7 mEq (p less than 0.001); a mean weight loss of 1.0 +/- 0.1 kg during this period was also significant (p less than 0.05). No substantial changes in glomerular filtration rate, renal blood flow, blood volume, cardiac output, plasma renin activity, and levels of plasma catecholamines or urinary aldosterone from control values were noted during either the acute or chronic phases.(ABSTRACT TRUNCATED AT 250 WORDS)

The rate of recovery of the renin-angiotensin-aldosterone axis after stopping diuretic administration was examined in 18 male patients with essential hypertension. Upright plasma renin activity (PRA) and plasma aldosterone (PA) were measured during sodium restriction (10 mEq sodium intake), after three days of furosemide administration (40 mg BID po) and for five days following cessation of the diuretic. After diuretic administration, the mean PRA level (8.2 +/- 1.7 ng/ml/hr) was significantly elevated compared to the level on low sodium diet (4.2 +/- 0.5 ng/ml/hr). However, the major finding was that PRA levels continued to increase significantly compared to levels during diuresis on days 1 (11.3 +/- 1.7 ng/ml/hr) and 2 (10.8 +/- 1.5 ng/ml/hr) of the postdiuretic period. Mean PA values paralleled PRA responses in the study. Infusion of normal saline on postdiuretic day 1 failed to suppress PRA to levels seen in subjects not receiving diuretics. The postdiuretic period was accompanied by increased urinary sodium reabsorption and decreased urinary potassium excretion and by significant decreases in creatinine, PAH and free water clearance. The mechanism of this sustained renin response several days after cessation of diuretic therapy may be best explained by a prolonged action of furosemide or by partial ongoing volume depletion with reduced sodium load to the distal nephron. Since all patients demonstrated a marked and consistent PRA response after diuretic withdrawal, this time period represents a potent stimulatory challenge for monitering renin responses.

Sixteen patients with uncomplicated essential hypertension were treated with 0.2 mg of clonidine three times daily as the sole antihypertensive drug. Blood pressure decreased from 167 +/- 4/105 +/- 2 to 139 +/- 3/89 +/- 2 mm Hg (mean +/- standard error of the mean) after 1 week (p less than 0.001) and remained at 140 +/- 3/90 +/- 2 mm Hg after 3 months of therapy. There were no significant changes in cardiac output, blood volume, renal blood flow or glomerular filtration rate during clonidine therapy. Clonidine significantly decreased plasma catecholamines and there was a linear correlation between the change in blood pressure and decreases in plasma catecholamine concentration (r = 0.61, p less than 0.001). There was also a significant correlation between the decreases in heart rate and blood pressure (r = 0.78, p less than 0.001). It is concluded that clonidine can be used effectively and safely as the sole agent in the treatment of mild to moderate hypertension.

Ten male patients with essential hypertension were studied on a constant diet (100 mEq of sodium daily) while on placebo, immediately following a 20-mg oral dose of nitrendipine, and during 1 week of nitrendipine therapy (10 mg twice daily). After 2 weeks of outpatient follow-up on 20-40 mg nitrendipine daily, the patients were readmitted and restudied with the same protocol. Glomerular filtration rate, effective renal blood flow, blood volume, and cardiac output were determined isotopically. Free water clearance and osmolar clearance following a water load were also measured. Twenty-four-hour urinary creatinine and electrolyte excretion were measured during the hospitalization periods. Blood pressure decreased significantly during the acute and chronic periods when compared to placebo. During the first 7 days of nitrendipine treatment, urinary sodium excretion increased significantly from control, and a mean deficit of 148 +/- 7 mEq (p less than 0.001) was calculated. There was a mean weight loss of 1.0 +/- 0.1 kg (p less than 0.05) after a week of treatment. Glomerular filtration rate, renal blood flow, blood volume, cardiac output, plasma renin activity, plasma catecholamines, and urinary aldosterone remained unchanged from control in both the acute and chronic periods. Compared to the placebo period, free water clearance (1.8 +/- 0.6 versus 2.9 +/- 0.5 ml/min; p less than 0.05) and osmolar clearance (1.9 +/- 0.3 versus 2.9 +/- 0.5 ml/min; p less than 0.05) increased significantly in the chronic period. The natriuresis and diuresis associated with nitrendipine therapy without any changes in renal function may represent a direct renal tubular effect of the drug.

Forty-eight elderly patients with uncomplicated mild essential hypertension entered two drug regimens. In group 1, clonidine monotherapy (n = 15), clonidine was titrated to achieve goal blood pressure (less than 90 mm Hg diastolic) in dosages of 0.05 mg twice daily to 0.2 mg three times daily. Blood pressure decreased without major side effects (p less than 0.001). Three patients required small doses of diuretic after six months of clonidine monotherapy. In group 2, step-care therapy (n = 33), clonidine was added to chlorthalidone, 25 mg daily, for three weeks. Eight patients achieved the goal blood pressure with chlorthalidone, 25 required clonidine (0.1 mg to 0.3 mg twice daily) to achieve blood pressure control. Side effects of clonidine did not require discontinuation of therapy. Retrospective analysis of up to 2 1/2 years of clonidine plus diuretic (n = 51) showed a similar blood pressure reduction. Clonidine can be used effectively with or without a diuretic in the elderly hypertensive.

Three distinct molecular weight species of active renin, with apparent molecular weights of more than 150,000, 65,000, and 43,000 are present in the plasma of conscious rats. After acute in vivo renin stimulation (ether anesthesia and hemorrhage), however, only the low molecular weight form could be detected. If, on the other hand, when diabutal was given and the duration of anesthesia was extended to 1 h to allow the active plasma renin level to return toward control, two species of renin were observed (greater than 150,000 and 43,000). Acid dialysis (pH 3.3) of normal plasma resulted in a significant increase in renin concentration, confirming the presence of an inactive renin (prorenin) in this species. Acid dialysis was shown to induce a decrease in the relative proportion of the high molecular weight form of the enzyme (greater than 150,000), with a concomitant increase in the 43,000 molecular weight species. Dialysis to pH 1.5 of plasma from 30-h nephrectomized rats to inactivate renin and destroy renin substrate resulted in the generation of an acid-stable factor which, when added to normal rat plasma, caused renin activation at pH 7.4. This renin- and renin substrate-free dialysate (pH 1.5) did not, however, alter the rate of angiotensin I generation when added to plasma samples devoid of inactive renin. Activation of renin in normal plasma could also be induced at pH 7.4 by the addition of plasma from nephrectomized rats which had previously been dialyzed to pH 3.3. These results indicate that the activation of renin by acid dialysis is not directly mediated by acid conditions and confirm the existence of an endogenous plasma factor which, after acid dialysis, is capable of converting inactive to active renin.

In a nineteen-year-old male in whom severe and protracted hypertension developed after a successful renal transplantation, the removal of the diseased kidneys resulted in restoration of normal blood pressure. Prenephrectomy blood samples obtained from the venous drainage of all three renal veins demonstrated no evidence for excessive renin secretion, nor was a significant difference in renin activity found between any two kidneys. It is postulated that the patient may be a clinical variant of the experimental form of renal hypertension with normoreninemia. Alternatively, the remnant kidneys may be implicated to produce a nonrenin pressor substance.

To determine whether vaginal administration of conjugated equine estrogens (VCE) could provide physiological replacement while avoiding effects on hepatic function, as occurs with oral administration, a study was conducted in which 20 postmenopausal women were evaluated before and after the vaginal administration of CE. The dosages studied were 0.3, 0.625, 1.25, and 2.5 mg/day for 4 weeks. Twenty premenopausal women were also studied, and their values were presumed to reflect normal physiological function. The findings in the postmenopausal women were compared with previously reported results obtained in a similar group of subjects given oral CE (OCE). Vaginal cytology returned to premenopausal values with 0.3 mg VCE. This response was similar to that exerted with 1.25 mg OCE. Stepwise increases in circulating estrone and estradiol occurred with increasing dosages. The 2.5-mg dosage of VCE raised estrone levels to values similar to those in premenopausal women in the late follicular phase, and estradiol concentrations were similar to early follicular phase concentrations. Limited or no responses of the systemic markers of estrogen action occurred with all doses of VCE. Small decreases in LH and FSH levels occurred, but no dosage significantly reduced the level of either gonadotropin. Although the urinary calcium to creatinine ratio was significantly reduced by the two largest dosages of VCE, the effect of the 2.5-mg dosage was less than that observed with 0.625 mg OCE, the lowest dosage that protects against osteoporosis. Hepatic protein synthesis was significantly increased only by the higher dosages tested. No dosage had a significant effect on circulating levels of triglycerides or total or fractionated cholesterol levels. These data suggest that the vaginal administration of CE exerts mainly a local effect, with limited or no measurable changes in systemic markers of the action of estrogen.

The oral dose metabolism of dilazep dihydrochloride [tetrahydro-1H-1,4-diazepine-1,4(5H)-dipropanol 3,4,5-trimethoxybenzoate] was examined in six hypertensive patients receiving a single oral dose of 600 mg of dilazep (3-3.8 mg/kg BW). Blood was collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after administration of the dose and urine was collected for three time intervals of 0-4 h, 4-10 h, and 10-24 h. Dilazep concentrations in blood and urine were determined by high-performance liquid chromatography. Dilazep decayed monoexponentially with a mean elimination rate constant of 0.27 +/- 0.13 h-1 and a mean half-life of 3.04 +/- 1.34 h. The mean tmax of absorption was 1.40 +/- 0.82 h. With maximally tolerated chronic doses, the steady-state concentration measured at 1 week was 25.6 ng/mL in a patient receiving 300 mg daily (100 mg TID) for 3 weeks, and dilazep concentration increased with the dose in others for up to a 600-mg dose daily. Dilazep did not produce any significant changes in heart rate and blood pressure after a single oral dose or during chronic dosing. There was no correlation between blood dilazep levels and the changes in heart rate and blood pressure. In three additional patients, oral dilazep dihydrochloride titrated gradually to maximally tolerated doses (900 mg daily) failed to produce significant effects on biochemical and neurohumoral measurements, and hemodynamic parameters as well as ventricular functional indices measured by radionucleide methods. Oral dilazep administration in maximally tolerated doses is devoid of effects on blood pressure and cardiac hemodynamic function.

1. In rats, intra-arterial metoclopramide, a dopamine antagonist, resulted in an elevation of plasma aldosterone at 5 min and plasma renin activity at 10 min and peak aldosterone and renin responses at 10 and 30 min respectively. 2. Pre-administration of L-dopa blunted and delayed aldosterone and renin responses to metoclopramide, indicating that metoclopramide-induced plasma aldosterone and plasma renin activity increments are mediated by a direct effect of blockade of dopamine receptors rather than other effects of this drug. 3. Pre-administration of angiotensin converting enzyme inhibitor, captopril (SQ 14 225) and the angiotensin II antagonist, saralasin, as well as bilateral nephrectomy did not significantly affect the aldosterone response to metoclopramide, Thus dopaminergic modulation of aldosterone secretion occurs independently of alterations in the renin-angiotensin system. 4. Modulating effects of dopamine on plasma aldosterone are probably mediated by direct effects as well as by interaction with other factors influencing aldosterone secretion at the adrenal zona glomerulosa.

To determine which dosage of estrogen might provide physiologic replacement while minimizing adverse effects, 20 postmenopausal women were studied before and after oral administration of ethinyl estradiol. Twenty premenopausal women studied in the early and late follicular phases of the menstrual cycle were presumed to reflect normal physiologic function. Variable responses of the different biochemical and biologic markers to the actions of ethinyl estradiol were observed. Liver protein synthesis was the most sensitive measure of the action of ethinyl estradiol. In comparing the relative potencies of ethinyl estradiol with previously reported results observed with the usage of conjugated equine estrogens, the actions of 10 micrograms ethinyl estradiol were approximately equivalent to the biologic effects of 1.25 mg conjugated estrogens. The results suggest that ethinyl estradiol is far more potent than previously believed and that the daily administration of 10 micrograms, a dose lower than currently available commercial preparations, may be adequate for relief of symptoms of vaginal atrophy and may provide protection from the occurrence of osteoporotic fractures.

The levels of active, inactive, and total renin (trypsin treatment) were measured in rat plasma before and after in vivo stimulation or suppression of active plasma renin. Stimulation of active renin was accompanied by either an increase (low sodium diet), no change (pentobarbital anesthesia plus hemorrhage), or fall (pentobarbital anesthesia) in the plasma levels of inactive renin, while suppression of active renin was accompanied by a fall (high sodium diet) or mild but nonsignificant increases (clonidine or saline infusion) of the inactive enzyme. These results suggest the possible independence of in vivo regulation of active and inactive renin in the rat. Trypsin activation of plasma fractions obtained by isoeletric focusing indicated a minimum of three activable forms of inactive renin (pH 4.4, 4.6, 4.8). Inactive enzymes could not be completely separated from active renins by this technique. Isoelectric focusing indicated a similar lowering of the isoelectric points of the five detectable active renins of rat plasma following in vivo stimulation of the renin system (ether anesthesia plus hemorrhage) or trypsin treatment of normal rat plasma before fractionation. These results indicate that similar renins are activated both in vivo and in vitro. Although trypsin is not the physiological activator of renin, a similar enzymatic cleavage resulting in activation appears to occur in vivo.

1. Plasma renin activity and circulating amounts of blood angiotensin II were measured in twenty-six patients with uncomplicated essential hypertension. 2. Measurements were made during a control period and at 1, 4, 9 and 14 weeks of diuretic treatment with metolazone or hydrochlorothiazide. 3. Linear regression analysis indicated a progressive change in the relation of plasma renin activity and blood angiotensin II. 4. During chronic diuretic therapy (beyond 14 weeks) blood angiotensin II had stabilized to low and relatively fixed values across a wide range of plasma renin activities.

Aortic vascular smooth muscle cells isolated from spontaneously hypertensive rats (SHR) grow nearly twice as fast in vitro as cells isolated from several normotensive control strains of rats. We have previously shown that DNA synthesis in SHR cells from both young and adult animals in response to epidermal growth factor is selectively enhanced compared with normotensive controls, suggesting that epidermal growth factor may be at least partly responsible for the enhanced growth rate. To determine whether the enhanced DNA synthesis in response to epidermal growth factor in SHR cells is mediated via an enhanced epidermal growth factor receptor tyrosine kinase, we measured thymidine incorporation in epidermal growth factor-stimulated vascular smooth muscle cells in the presence of the highly specific tyrosine kinase inhibitor genistein. The 50% inhibitory dose (IC50) of genistein was higher for the SHR vascular smooth muscle cells than for the normotensive Wistar rat (NBR; National Institutes of Health Black rat). This suggests that the increased DNA synthesis in response to epidermal growth factor in SHR cells is a result of higher receptor tyrosine kinase activity initiating further intracellular signals.

Renin substrate was characterized in incubation medium of isolated hepatocytes, plasma, and brain extracts of the rat by isoelectric focusing and polyacrylamide gel electrophoresis. The isoelectric focusing (IEF) profile of renin substrate released into incubation medium of rat hepatocytes demonstrated two peaks with isoelectric points (pI) of 4.1 (minor peak) and 4.6 (major peak). Extracts of normal rat brain also showed two forms (pI 4.6 major form, and pI 5.1 minor form). In contrast, normal rat plasma contained a single broad peak of substrate with pI 4.5. On polyacrylamide gel electrophoresis (PAGE), the hepatocytes medium and brain extracts contained forms of substrate with reduced mobility as compared to the plasma form. Intraperitoneal injection of 17 beta estradiol (1 mg) or bilateral nephrectomy significantly elevated renin substrate levels in plasma and increased its release from hepatocytes, however, no change in the IEF or PAGE profiles was evident. There was no remarkable change of substrate concentration in the brain following these treatments. Molecular weights of renin substrate were 60,000-65,000 from all preparations. It remains to be established whether the different forms of renin substrate from hepatocytes represent precursor forms of circulating plasma substrate. The presence of distinct forms of brain renin substrate and the lack of an increase in brain renin substrate following nephrectomy or estrogen treatment suggest local synthesis and support the postulate of an independent renin-angiotensin system in the central nervous system.

We have previously reported on the differences in physical and chemical characteristics between the high-molecular weight renin substrate (HMS greater than 150,000 daltons) and the normal substrate (NMS = 60,000). In this study, the kinetic constants were determined in both HMS and NMS which were prepared by gel exclusion chromatography from the plasma of pregnant women at term. Renin substrate (angiotensinogen) levels were expressed by radioimmunoassay of angiotensin I after incubation of samples with added semi-purified human kidney renin in the presence of angiotensinase inhibitors. The kinetic constants (Km and Vmax) were determined by the method of Line-weaver-Burk plots and also the method of Wilkinson. The Km for the HMS was 1.79 micrograms angiotensin 1 equivalents ( AIeq )/ml and the Vmax = 41.2 ngAIeq /ml/h, and the Km for the NMS was 3.52 micrograms AIeq /ml and the Vmax = 138 ng/ml/h. When adding small amounts of the HMS to the NMS, the production of angiotensin I was found to increase more than that in the NMS alone. It was also observed that the renin substrate reactivities of the plasma of pregnant women, which contained small amounts of the HMS, were higher than that found in the plasma of normotensive women not taking oral contraceptives. It is suggested that the existence of small amounts of the HMS may therefore contribute to the elevation in blood pressure under the influence of estrogens.

The effect of metoclopramide, a procainamide derivative with dopamine antagonistic properties, and L-dopa on plasma renin activity (PRA) was studied in adult rats. Following an intravenous bolus of metoclopramide (200 microgram/kg) to the American Wistar rat there was a significant (p less than 0.05) elevation in PRA at 10 min and a maximum response at 30 min. There was a significant depression (p less than 0.05) in PRA at 15 through 40 min following an intravenous bolus of L-dopa (30 mg/kg). Pre-administration of L-dopa delayed and blunted the PRA response to metoclopramide. However, the PRA response to this dopamine antagonist was not altered by beta blockade with propranolol and alpha blockade with phentolamine. Administration of metoclopramide resulted in considerably greater (p less than 0.01) PRA responses in spontaneously hypertensive rats than in Wistar Kyoto (WKY) normotensive controls. Administration of L-dopa resulted in similar suppression of PRA in the two groups. These results indicate that there is a dopaminergic inhibitory control mechanism for renin secretion. Dopaminergic control of renin release appears to be altered in the spontaneously hypertensive rat.

Plasma renin activity (PRA) was measured during the administration of clonidine (0.1 mg twice daily) to 11 patients with essential hypertension. After eigth weeks a trend toward an increase in PRA was noted. This increase was significant in "low renin" subjects (less than 1 ng Al/ml/hr, n = 7) in whom PRA (ng/ml/hr +/- SEM) rose from a control value of 0.7 +/- 0.1 to 2.0 +/- 1.1 at one week, 5.6 +/- 2.1 at four weeks, and 4.4 +/- 1.0 at eight weeks (p less than 0.05). In contrast, in a small group of "normal renin" patients (n = 4), PRA did not change significantly but tended to decrease on clonidine therapy from 9.2 +/- 3.4 at control to 3.3 +/- 2.0 at one week, 3.4 +/- 0.6 at four weeks, and 4.7 +/- 1.7 ng Al/ml/hr at eight weeks. Plasma renin substrate and serum and urinary electrolytes did not change significantly in either group and blood pressure reduction was comparable in the two groups. A strong negative correlation (r = -0.84, p less than 0.001) was found between changes in creatinine clearance and changes in PRA. Previous studies have implicated alpha-adrenergic receptors as the site of clonidine actions on blood pressure and renin release. The observed renin stimulation during chronic administration of clonidine to "low renin" patients with essential hypertension may imply an altered intrarenal alpha-receptor function in "low renin" essential hypertension.

To evaluate the role of the renin-angiotensin system and sodium depletion in the hypotensive response to 1-sarcosine-8-alanine-angiotensin II (saralasin), 15 male patients with essential hypertension were studied on a diet containing 120 mEq of sodium and 100 mEq of potassium per day. After a 5-day control period, all subjects had a mild pressor response to the saralasin infusion (p less than 0.01). After 5 days of the diuretic metolazone (5 mg/day), eight of the 15 patients had a vasodepressor response; these responders had a significantly greater increase in plasma renin activity and angiotensin II concentrations than did the non-responders. Sodium deficit differed markedly (p less than 0.001) between the two groups (361 +/- 121 mEq (SD) vs 52 +/- 26 mEq sodium, respectively). The addition of spironolactone (400 mg/day) for 5 days resulted in saralasin responsiveness in all but two patients, both of whom had small sodium deficits. Thus, variability in the natriuretic response to diuretics may affect saralasin testing and limit its clinical utility.

The individual components of the renin-angiotensin system has been identified in numerous tissues. In this study we have examined whether a functional renin-angiotensin system is operative in several hog tissues including brain, aorta, and liver. The contribution of tissue renin substrate to the rate of local angiotensin generation was also assessed. Electrophoretic differences in plasma and tissue renin substrates, indicating structural differences, were employed as an index of independence of the tissue system from that of the peripheral circulation. Our results indicate that all tissues studied had the potential to locally generate angiotensin and that renin substrate limited to rate of the renin reaction in these tissues. Electrophoretic parameters, polyacrylamide gel electrophoresis, and isoelectric focusing suggest that the tissue renin systems are of local origin. The potential magnitude of local angiotensin production is such that tissue renin-angiotensin systems may significantly contribute to the control and regulation of blood pressure and other regulatory mechanisms influenced by angiotensin.

We have produced monoclonal antibodies to a highly purified pig (P) angiotensinogen preparation and characterized their ability to bind [125]I-P- angiotensinogen. Lymphocytes of RBF/Dn mice immunized with P-angiotensinogen were fused with FOX-NY myeloma cells and clones were isolated by binding to [125]I-P-angiotensinogen and by an immunodot blot assay. Three of 16 clones which recognized P-angiotensinogen were characterized. Isolated monoclonal antibodies bound only 10-15% of the total [125]I-P-angiotensinogen; however, the bound counts could be displaced with unlabelled P-angiotensinogen. None of the monoclonals inhibited the cleavage of P-angiotensinogen by homologous renin, nor did they bind to the NH-terminal angiotensin I (ANG I) peptide. Little or no binding was detected to angiotensinogens in human, monkey, rat, rabbit, sheep or bovine serum. Mixtures of the clones and analysis of the immune complexes by PAGE indicated that different binding sites on different P-angiotensinogen were detected by some of the monoclonals, while the same or competing sites were recognized by others. No combination of clones tested significantly increased the amount of P-angiotensinogen bound. We interpret these findings to indicate that monoclonal antibodies to 'purified' pig P-angiotensinogen recognize species-specific minor epitope subsets of the protein, but not antigenic determinants common to all.

The phenomenon of plasma renin activattion by acid dialysis and preincubation with trypsin was studied in normal human plasma. Activation of plasma renin by exposure to pH 3.3 was shown to require at least one dialysis step and could be inhibited by the presence of Trasylol, indicating the involvement of a protease in acid activation. Amniotic fluid exposed to pH 1.5 to destroy renin and renin substrate was also found to contain an enzyme capable of activating plasma renin. The Michaelis-Menten constant Km and the molecular weight of activated "renin" were found to be similar to those of normal plasma renin. Inactive renins or renin-like enzymes were partially purified from plasma by affinity chromatography on concanavalin A, precipitation with (NH4)2SO4 and isoelectric focusing. Trypsin and acid exposure gave similar results with regard to the activation of this zymogen, suggesting that trypsin and acid dialysis may increase plasma renin activity by the same mechanism.

Prevalence of "higher than normal" blood pressures in a community is inversely related to the magnitude of the elevation; the milder grades of elevation are far more prevalent. A multifactorially inherited tendency to develop hypertension is modulated by multiple environmental influences. Autonomic nervous and behavioral factors plausibly appear to contribute to the initiating mechanisms of hypertension; the associated hemodynamic changes and the resulting cardiovascular structural changes interact to perpetuate the process. The complex interaction of hypertension and atherosclerosis is further complicated by direct as well as secondary effects of antihypertensive drugs on atherogenesis. Attributable cardiovascular risk is generally proportional to the degree of hypertension across the entire range of elevated blood pressure; this kind of relationship holds also for normal versus subnormal blood pressure values. Pharmacologic lowering of blood pressure, however, does not confer proportional benefit. Thus, such lowering of blood pressure to normotensive levels does not reduce the risk level to that in the normotensive population. Therapeutic outcome is influenced by the interaction of blood pressure lowering, type of antihypertensive agents used, existing risk factors, and target organ damage. Benefits of lowering blood pressure in established mild hypertension (diastolic blood pressure greater than 95 mm Hg) are confirmed. Drug treatment of patients with lower diastolic blood pressure or with isolated elevations of systolic blood pressures continues to be controversial as does the choice of initial therapeutic agent(s). The large-scale experience of clinical trials encompassing the long-term risks and benefits of the drug treatment of mild hypertension is limited to the use of diuretics and adrenergic beta blockers. A variety of new and promising therapeutic agents for use as alternate choices for initial therapy needs to undergo comparative evaluation.

When plasma from normal and hypertensive human subjects is incubated at pH 7.4 in the absence of angiotensinase inhibitors, a significant decline of active plasma renin occurs. The fall of active renin was more pronounced in the plasma from normotensive controls and was accompanied by a fall of total renin without change of inactive renin. In hypertensive subjects total renin levels (trypsin treatment) did not change. The fall of active renin in plasma from hypertensive subjects was due therefore to its in vitro conversion to an inactive form of renin which could be reactivated by trypsin. If reversible inactivation of active plasma renin occurs in vivo, inactivated active renin may contribute to a portion of the plasma pool of inactive renin. This form of inactive renin which may be activable in vivo would not therefore represent a renin precursor or "prorenin" of renal origin.

Human des-angiotensin I renin substrate, a cleavage product of the renin reaction, was generated in plasma and from semipurified renin substrate by exhaustive incubation with renin and was quantitated by a direct RIA. An increase in the Michaelis-Menten constant of the renin-substrate reaction, from 2000 to 5000 ng angiotensin I equivalents of renin substrate/ml, with no change in maximal velocity was observed upon addition of this semipurified protein to plasma. It is suggested that this phenomenon of competitive inhibition of the renin reaction by des-angiotensin I renin substrate accounts for discrepancies in the determination of renin substrate concentration and possibly has physiological significance for feedback inhibition of angiotensin I generation.

Inhibitors of the renin-angiotensin system, which are promising therapeutic agents with few side effects, have measurably improved the management of many patients with primary or secondary hypertension and those with heart failure. This paper briefly reviews the emerging evidence for the potential risk associated with long-term inhibition of the renin system. The current lack of methodology for quantification of renin-angiotensin inhibition in various tissues, however, precludes firm conclusions. Preliminary evidence suggests that in functional terms, a downregulation of the renin-angiotensin system, if therapeutically successful, is safer than aggressive and longer-lasting inhibition. It has been questioned whether antihypertensive therapy 'normalizes' the structural cardiovascular changes and whether interference with the initial adaptive phase may prove detrimental. However, no specific role for renin inhibition, apart from the antihypertensive effect, has yet been defined.