The physiology of renin secretion in essential hypertension. Estimation of renin secretion rate and renal plasma flow from peripheral and renal vein renin levels

From renin measurements made in blood collected simultaneously from renal veins, aorta and vena cava, an equation was developed for estimating renin secretion rates in patients with three renin subtypes of essential hypertension. From these data a second equation was derived for estimating differential renal plasma flow in patients with unequal kidney perfusion. The latter equation achieves maximum precision when there is no renin secretion from one side.Plasma renin activity was identical in blood collected from the aorta or the vena cava. It was also similar, but higher, in blood collected from either right or left renal veins. The ratio of renin from the two renal veins, an expression of the variability in renal vein renin measurements in essential hypertension, was 1.5 or less in 87 per cent of patients and less than 1.63 in 95 per cent.Renal vein renin content remained proportional to arterial renin over the range of peripheral renin levels found in essential hypertension, so that renal vein renin concentration from each kidney was consistently 124 per cent of arterial renin. The constancy of this relationship complements previous observations indicating that the metabolic clearance rate of renin is proportional to arterial renin levels. The observed equality of renin values between renal veins suggests that differential renal plasma flow is fairly equal and constant in patients with essential hypertension. Moreover, since renal plasma flow from each kidney is inversely related to the increment in renal vein renin concentration relative to arterial renin input [(V-A)/A], differential changes in (V-A)/A can be used to identify differential changes in renal plasma flow.These derived interrelationships are relevant to an analysis of renovascular hypertension since, with this approach, reductions in renal plasma flow can be estimated using only renal vein and arterial renin measurements and adequacy of sampling can be assessed from the sum of (V-A)/A from each kidney.There was no measurable difference in plasma renin substrate in the three renin subgroups of patients with essential hypertension so that observed differences in plasma renin activity levels appear entirely due to differences in renal renin secretion. Under conditions of this study renal renin secretion per minute was 144 times the arterial renin level.     

The role of renal kallikrein and prostaglandin in the control of renin release

Renal prostaglandins and kallikrein are considered to play an important role in the control of renin release. Recently, we have shown that aprotinin, a kallikrein inhibitor, inhibits the stimulation of plasma renin activity (PRA) by either furosemide or a low sodium diet. However, the mechanisms of action of kallikrein are unknown. Since kallikrein may stimulate bradykinin and prostaglandin production, the present study examines the relationship of renal kallikrein and renal prostaglandins in the control of renin release. Furosemide and a low sodium diet stimulated PRA, urinary kallikrein excretion and urinary prostaglandin E2 excretion. Aprotinin and indomethacin inhibited both furosemide and low sodium diet stimulation of PRA. When maximum doses of both aprotinin and indomethacin were given, PRA was more strongly suppressed than by indomethacin alone. The stimulation of urinary kallikrein excretion by furosemide and by a low sodium diet was not inhibited by indomethacin. These results suggest that both renal kallikrein and prostaglandins play an important role in the control of renin release under sodium depletion. Renal kallikrein may also have a direct action on the kidney to release renin.     

Effect of renin inhibitor, ES-8891, on renal renin secretion and storage in the marmoset: comparison with captopril.

We investigated the effects of the human renin inhibitor, ES-8891, and captopril on renal renin secretion and storage in the marmoset. Either ES-8891 (30 mg/kg) or captopril (2 mg/kg) was given orally twice a day for 1 week to conscious, sodium-depleted marmosets (n = 6 for each group). The ES-8891-treated group displayed a significant reduction in mean arterial pressure (MAP), plasma renin activity (PRA) and plasma immunoreactive renin (PIR) compared with the control group. Kidney renin content was significantly increased compared with the control group and enlarged renin granules containing heterogenous internum were observed in juxtaglomerular cells after treatment with ES-8891. Treatment with captopril significantly increased PRA and PIR compared with the control day as well as increasing kidney renin content and the number of renin granules with crystalline content in juxtaglomerular cells compared with the control group. These results suggest that ES-8891 inhibits both PRA and renin secretion from the kidney, resulting in an increase in renal renin storage.     

Evidence that the beta-adrenergic system and prostaglandins stimulate renin release through different mechanisms

In normal man, converting enzyme inhibition (CEI) acutely increases plasma active renin and decreases plasma inactive renin. This reciprocal relationship suggests that conversion of inactive to active renin may be important in the acute response to stimulation of renin secretion. To determine whether the beta-adrenergic system or prostaglandins (PGs) participate in the acute effect of CEI on renin, we administered captopril (50 mg) alone and with either propranolol (P; 80 mg) or a PG cyclooxygenase inhibitor [PI; indomethacin (50 mg) or ibuprofen (800 mg)] to normal subjects ingesting a 25 meq/day Na diet. Supine blood pressure fell by 12 +/- 2 (+/- SE) mm Hg with CEI alone, 10 +/- 1 mm Hg with CEI plus P, and 7 +/- 1 mm Hg with CEI plus PI. Active renin rose 8-fold (P less than 0.01), with a peak at 1-2 h, after CEI and 3-fold (P less than 0.02) in response to CEI plus P or CEI plus PI. P did not block the fall in acid-activated inactive renin compared to CEI alone. The nadir of the inactive renin response to both CEI or CEI plus P occurred at 1-2 h. PI, however, prevented the fall in inactive renin. To extend this observation, we compared the effects of infusion of a vasodilator PG (PGA1; 0.6 micrograms/kg X min) and a pure beta-agonist (isoproterenol; 0.3 micrograms/kg X min). PGA1 increased active renin 2.5-fold and decreased inactive renin by 80% (both P less than 0.02), while isoproterenol increased active renin 4.1-fold, but did not significantly change inactive renin. These data suggest that the beta-adrenergic system and PGs at least acutely stimulate renin production at different steps of its biosynthesis or secretion.     

The mechanism of the control of renin release by beta-adrenergic receptors

Recent reports suggest that prostaglandins play an important role in the beta-adrenergic receptor mechanism of renin release. However, the site of the action of prostaglandins has not yet been clarified. Superfusion of rabbit renal cortical slices was used to evaluate the beta-adrenergic receptor mechanism of renin release. Renin release was stimulated by isoproterenol, prostaglandin E2, and dibutyryl cyclic AMP. Renin release stimulated by isoproterenol was inhibited by propranolol, whereas renin release stimulated by prostaglandin E2 was not inhibited by propranolol. Isoproterenol stimulated prostaglandin E2 release as well as renin release, and indomethacin inhibited these effects of isoproterenol. Propranolol inhibited prostaglandin E2 release stimulated by isoproterenol. On the other hand, indomethacin did not affect renin release stimulated by prostaglandin E2 release. Dibutyryl cyclic AMP did not stimulate prostaglandin E2 release. Indomethacin did not affect renin release stimulated by dibutyryl cyclic AMP, however, it suppressed prostaglandin E2 release during the superfusion with dibutyryl cyclic AMP. Finally, isoproterenol and prostaglandin E2 stimulated cyclic AMP release. These data suggest that prostaglandins play an important role in the beta-adrenergic receptor mechanism of renin release and the site of the action of prostaglandins is between the beta-adrenergic receptor and cyclic AMP.     

Type 2 diabetes, obesity, and the renal response to blocking the renin system with irbesartan.

AIM: Our recent studies revealed a striking but variable enhancement of renal vasodilator responses to blockers of the renin-angiotensin system in subjects with diabetes mellitus, possibly reflecting the level of intrarenal activation of the renin-angiotensin system, and thus a risk of nephropathy. As obesity is a common finding in diabetic individuals, and obesity has been linked to an increase in plasma angiotensinogen levels, we enrolled diabetic subjects with a wide range of body mass index (BMI) for this study. METHODS: Twelve Type 2 diabetic subjects in balance on a low sodium diet participated after baseline renal plasma flow and glomerular filtration measurements were made. Each subject then received 150 mg irbesartan, and renal function was measured every 45 min for 4 h. RESULTS: The average vasodilator response to irbesartan was 174 +/- 33 ml/min. No correlation was found between renal plasma flow response to irbesartan and duration of diabetes, baseline glucose, or HbA1c level. BMI, our measure of obesity, was highly correlated to the renal response to irbesartan (r = 0.7; P = 0.01). CONCLUSIONS: Our findings suggest an important role for obesity in activating the intrarenal renin system, perhaps via production of angiotensinogen. BMI may be an indicator of risk of nephropathy.     

Short-term systemic hemodynamic adaptation to beta-adrenergic inhibition with atenolol in hypertensive patients

Early systemic hemodynamic adjustments to antihypertensive therapy with the cardioselective beta inhibitor, atenolol, were investigated in 12 hospitalized men, mean age 52 years, with uncomplicated mild-to-moderate essential hypertension. Twice daily measurements of cardiac output (CO) by CO2 rebreathing, blood pressure by cuff, and heart rate were performed in all subjects for 3 days before and 5 days after initiation of oral atenolol therapy (50 or 100 mg daily). Cardiac output by CO2 rebreathing was checked with dye dilution just before, and 4 hours and 4 days after the start of therapy. Plasma volume (radioiodinated albumin) was measured before therapy and on Day 5 of therapy. The CO results obtained with the two methods were not significantly different (r = 0.88, p less than 0.01, n = 12). A reduction in heart rate, 18 +/- 2 beats/min (mean +/- SE), occurred in all patients while taking atenolol. By 4 hours after the first dose of atenolol, CO fell from 5.49 +/- 0./30 to 4.24 +/- 0.21 liters/min (p less than 0.01), while the control mean arterial pressure (MAP) of 108 +/- 4 mm Hg was not significantly changed, 110 +/- 4 mm Hg. At 24 hours, CO returned near baseline (5.10 +/- 0.21 liters/min) but MAP was reduced (95 +/- 3 mm Hg, p less than 0.001) and remained so thereafter. CO remained at baseline at 48 hours (5.50 +/- 0.29 liters/min) but fell again (p less than 0.01) to 4.81 +/- 0.11 on Day 4 and to 4.68 +/- 0.25 liters/min on Day 5 of atenolol therapy. Plasma volume, 3110 +/- 100 ml before therapy, was reduced to 2850 +/- 100 by Day 5 of atenolol therapy (p less than 0.01). The findings indicate a delayed onset of the antihypertensive action of atenolol. The transient return to baseline of CO on Day 2 and 3 of atenolol therapy suggests a reverse autoregulatory adjustment to the initial fall in CO.