Hypothesis: Reactive increases in plasma renin activity attenuate the fall in blood pressure caused by salt depletion and renin–angiotensin system inhibition

Abstract

There are inconsistencies in the effect of raising or lowering body salt on blood pressure (BP). We hypothesize that they are caused in part by differences in plasma renin activity (PRA). PRA changes reciprocally with body salt. PRA is the rate limiting step in the formation of the vasoconstrictor peptide angiotensin II (Ang II) in the circulation where it cleaves Ang I from plasma angiotensinogen, and then Ang I is rapidly converted to Ang II by angiotensin-converting enzyme in plasma and vascular endothelial cells. We hypothesize that PRA levels above 0.65 ng/ml/h lead to sufficient Ang II production to cause vasoconstriction, whereas lower levels do not. PRA is usually more than 0.65 in normotensives who are not on a high-salt diet; in them, the increase in PRA/Ang II vasoconstriction caused by reduction in body salt (low-salt diet, diuretic use) is large enough to prevent BP from falling. By contrast, a similar reduction in body salt lowers BP in the 30% of hypertensive patients with low baseline PRA (<0.65 ng/ml/h), because vasoconstriction does not increase in that range. A similar reduction in body salt also lowers BP in the 60% of hypertensive patients with baseline PRA between 0.65 and 4.5 ng/ml/h, but for a different reason; the rise in PRA and the increase in vasoconstriction is too small to prevent BP from falling. However, after body salt has been reduced enough to raise PRA above 4.5 ng/ml/h, further salt depletion increases PRA to a greater extent, and BP does not fall. Renin–angiotensin system (RAS) inhibitors leave a small amount of renin unblocked. In salt-depleted hypertensive patients, they also raise PRA enough to prevent BP from falling significantly. We propose that this PRA/Ang II vasoconstrictor effect related to reactive increases in PRA can prevent or attenuate the decrease in BP caused by excessive salt depletion, even during concurrent RAS inhibition. This phenomenon, if confirmed, could inform new strategies to optimize the treatment of hypertension, cardiovascular disease (CVD) and chronic kidney disease (CKD).

INTRODUCTION

There are inconsistencies in the effect of raising or lowering body salt on BP. An abnormally high dietary salt intake often raises BP [1,2], but neither an abnormally low dietary salt intake [3] nor diuretic abuse [4] consistently lower BP. It has been proposed that reactive increases in plasma renin activity (PRA) caused by reduction in body salt [5] or natriuretic drugs [6] attenuate the fall in BP. This is possible because plasma renin cleaves Ang I from plasma angiotensinogen, and then Ang I is rapidly converted to Ang II by angiotensin-converting enzyme in plasma and vascular endothelial cells. As renin is the rate-limiting step in the production of plasma Ang II, and Ang II is a potent vasoconstrictor peptide, reactive increases in PRA are likely to reduce the BP-lowering effect of reduction in body salt.

However, if a rise in PRA prevents sodium depletion from lowering BP, then concurrent administration of renin–angiotensin system (RAS) blockers should cause sustained hypotension. In fact, RAS blockade during sodium depletion can marginally lower BP [7], but it does not fall to hypotensive levels [8]. In this report, we propose that differences in reactive increases in PRA may be responsible for the differences in the BP response to a change in body salt and as a defense against hypotension in patients taking RAS inhibitors.

We hypothesize that reducing body salt does not lower BP in most normotensives because PRA rises enough to prevent it by increasing angiotensin II (Ang II) levels. Moreover, RAS inhibitors do not interfere with this response, because they block less than 90% of the effect of PRA while raising PRA enough for more than 10% that is not blocked to counteract the fall in the BP. Conversely, an increase in body salt often raises BP, because it lowers PRA into the range where it lacks a vasoconstrictor effect (<0.65 ng/ml/h) where its further suppression cannot counteract the rise in BP. Accordingly, high levels of body salt can raise BP, but neither excessive salt depletion nor RAS inhibition cause hypotension.

For this hypothesis to be valid, Ang II must cause a sustained rise in BP, renin must similarly raise BP, RAS inhibitors must not totally block the BP raising effect of Ang I (the precursor to Ang II) at the doses used clinically, reducing body salt must cause a larger reactive rise in PRA and lesser fall in BP in normotensives than hypertensive patients, and RAS inhibitors must raise PRA enough in salt-depleted patients to increase vasoconstriction.

DOES ANGIOTENSIN II CAUSE A LONG-TERM RISE IN BLOOD PRESSURE?

When Ang II was first synthesized in the early 1960s, Ames et al.[9] obtained enough pure peptide for prolonged infusions in normotensive individuals. They examined its effect on BP, urinary sodium excretion and aldosterone secretion and compared it with norepinephrine, another vasoconstrictor agent. Figure 1 shows the effect of 11 days of infusion of Ang II in a normotensive subject studied under metabolic ward conditions. BP rose immediately, and net sodium balance increased during days 1–4. The protocol required BP to remain constant during the infusion; to achieve this, the rate of Ang II infused had to be reduced by more than 50% on the fourth, fifth and sixth days to avoid further increases in BP. Within 24 h of discontinuing the Ang II infusion, there was a net loss of body salt. By the second postinfusion day, BP had returned to baseline. Norepinephrine did not cause a sustained rise in BP, even when the rate of infusion was increased. Altogether, this indicates that Ang II (unlike norepinephrine) causes a sustained rise in BP and a net increase in body sodium.

FIGURE 1.

Eleven days infusion of angiotensin II into a normal subject under metabolic ward conditions. Redrawn from [9].

DO RENIN AND ANGIOTENSIN II CAUSE COMPARABLE INCREASES IN BLOOD PRESSURE?

When renin became available for infusion, it was not considered safe to infuse it into human subjects because of the risk of uncontrolled hypertension and its complications. Instead, renin and Ang II were infused separately into conscious rats at doses that raised plasma Ang II two-fold in both groups [10]. Renin and Ang II each caused an initial increase in mean arterial pressure (MAP) by about 25 mmHg and they each raised MAP further and to a similar degree 5–8 days later. The second phase of the BP rise did not occur with Ang II in the human subject illustrated in Fig. 1, because the protocol intentionally prevented further increases in BP. Together, these studies showed that a rise in PRA can cause a sustained increase in BP and they support the view that this rise is mediated by an increase in the vasoconstrictor effect of plasma Ang II and is sustained by a net increase in body salt.

DO LOW LEVELS OF PLASMA RENIN ACTIVITY HAVE A VASOCONSTRICTOR EFFECT?

PRA values differ with different assays. The results using our assay [11] are consistent with those reported in the United States by Quest and LabCorp. When plasma renin levels are low, the assay increases sensitivity by allowing plasma renin to generate Ang I in plasma at pH 5.7 and 37 ^oC from endogenous angiotensinogen, and then Ang I is measured. The PRA test incorporates the effect of differences in plasma angiotensinogen. The ‘normal range’ of PRA is not easy to define as dietary salt intake affects the PRA value. Based on early studies, we use 0.65–4.5 ng/ml/h. This is supported by data from normal subjects studied at the worksite in which median PRA quartiles were 0.57, 1.6, 2.6 and 4.7 ng/ml/h [12]. A newer automated Diasorin Liaison Direct assay measures plasma renin concentration (PRC). As angiotensinogen is fairly stable, the two assays are roughly comparable. The units are different – a PRA level of 1 ng/ml/h is roughly equivalent to a PRC of 10 μU/ml.

It is likely that very low PRA levels do not cause hemodynamically significant vasoconstriction. This is supported by data from hypertensive patients showing that blocking the effect of PRA with either a direct renin inhibitor or an ARB failed to lower BP in most patients with PRA levels less than 0.3 ng/ml/h (Fig. 2) using an assay that reports lower PRA values than ours because Ang I is generated at pH 7.4 [13] rather than 5.7 [11].

FIGURE 2.

Effect of 4 weeks of four different doses of the direct renin inhibitor aliskiren and one dose of the ARB losartan on (a) the change in the average day time SBP and (b) the change in PRA in individual low-renin hypertensive patients (left side; PRA ≤ 0.3 ng/ml/h) and individual medium-renin/high-renin hypertensive patients (right side; PRA > 0.3 ng/ml/h). Data above and below the dashed lines indicate at least 10 mmHg change in SBP. A, aliskiren; LOS, losartan; PRA, plasma renin activity. Redrawn from [14]. Reprinted from [15]. ARB, angiotensin receptor blocker; PRA, plasma renin activity.

DO ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS BLOCK THE BP RESPONSE TO ANGIOTENSIN I (THE INACTIVE PRECURSOR OF ANGIOTENSIN II)?

Hasler et al.[16] tested the BP response to a single injection of Ang I in normotensive men previously treated for 8 days with either an ACEI (lisinopril) or an ARB (olmesartan) or both (Fig. 3). Four hours after the last dose of the ACEI or ARB, between 10 and 15% of the rise in BP remained intact. The combination of ACEI and ARB left 8% intact. There was no apparent difference between the effects of ACEIs and ARBs on Ang I-mediated increases in BP. If we assume that the clinically used doses of RAS inhibitors leave approximately 13% of the vasoconstrictor effect of Ang I intact, and if we accept that PRA normally has no vasoconstrictor effect below 0.65 ng/ml/h, then the lowest PRA level likely to have an effect on BP during RAS inhibition is approximately 4.5 ng/ml/hr (= 0.65/0.13). In sum, ACEIs and ARBs incompletely block the vasoconstrictor effect of PRA. Consequently, if PRA were to rise seven-fold during RAS inhibition, its blocking effect would be completely eliminated.

FIGURE 3.

Percentage of SBP response to angiotensin I that remained 4 h after the last dose of 8 days of renin–angiotensin system inhibition with either 20 mg lisinopril or three different doses of olmesartan or both [16].

WHAT IS THE RELATIONSHIP BETWEEN BODY SALT AND PLASMA RENIN ACTIVITY?

Figure 4 illustrates the reciprocal relationship between PRA and the 24 h urinary sodium excretion (and urinary aldosterone excretion) in young normotensives [17]. The mechanism underlying this relationship was studied over many years. Metabolic balance studies showed that a change in salt intake causes a proportional change in urinary sodium excretion and body salt [18]. Sophisticated animal studies showed that a change in body salt alters the sodium chloride load passing the juxtaglomerular region of each nephron, and this is detected by macula densa cells, which signal for a reciprocal change in renin secretion [19]. This mechanism tightly links the normal changes in sodium balance that occur during variations in salt intake to distal renal sodium delivery and reciprocal changes in PRA.

FIGURE 4.

Left side: relationship of noon ambulatory plasma renin activity to concurrent daily urinary sodium excretion in normal subjects. (Multiply PRA by 0.65 ng/ml/h to conform to current reference standards.) Right side: relationship of 24 h urinary aldosterone excretion to the concurrent urinary sodium excretion. Reprinted from [17]. PRA, plasma renin activity.

However, the data in Fig. 4 also show that when sodium excretion is high, there is only a weak reciprocal relationship between PRA (and aldosterone) and urinary salt excretion, but when sodium excretion is low, there is a strong reciprocal relationship. Thus, a low PRA level in a patient indicates a high level of body salt, but it does not indicate how high, whereas a high PRA level is a good indicator of the degree to which body salt is low.

Normotensives and hypertensive patients have a 10-fold range of baseline PRA. In large studies, quartiles of PRA were found to be 0.57, 1.6, 2.6 and 4.7 ng/ml/h in normotensives [14,20] (perhaps indicating a wide range of body salt), and they shifted lower in untreated hypertensive patients to 0.29, 0.96, 1.9 and 4.0 ng/ml/h [21] (perhaps indicating higher levels of body salt than normotensives). Treated hypertensive patients were found to have both abnormally low and abnormally high PRA quartiles: 0.20, 0.81, 2.1 and 7.8 ng/ml/h [22] (perhaps indicating high levels of body salt in some, but low levels of body salt in others).

ARE THERE DIFFERENCES BETWEEN NORMOTENSIVES AND HYPERTENSIVE PATIENTS IN THE MAGNITUDE OF THE REACTIVE RISE IN PLASMA RENIN ACTIVITY AND THE BLOOD PRESSURE RESPONSE TO SALT DEPLETION OR RENIN–ANGIOTENSIN SYSTEM INHIBITION?

To address these questions, we explored reported studies in normotensives [3,5,7,16,23–27] and hypertensive patients [5,24,28–34] in which either body salt was moderately reduced, or a RAS inhibitor was added, BP was measured, and PRA was measured using a method similar to that used in our laboratory [11] so that we could compare the absolute PRA levels.

In general, we found that the size of the reactive rise in PRA was proportional to the baseline PRA. Nonetheless, normotensives appeared to have a larger reactive rise in PRA than hypertensive patients (Fig. 5) and a smaller fall in MAP in response to salt depletion and RAS inhibition. Thus, during salt depletion, PRA rose from 1.5 to 6.1 ng/ml/h in normotensives and from 1.0 to 3.1 in hypertensive patients; MAP fell by 0 mmHg in normotensives and 8 mmHg in hypertensive patients. Similarly, RAS inhibition raised PRA from 1.5 to 11 ng/ml/h in normotensives and from 0.7 to 3.0 ng/ml/hr in hypertensive patients; MAP fell by 4 mmHg in normotensives and by 10 mmHg in hypertensive patients. There was almost no overlap in the final PRA level or in the fall in MAP between normotensives and hypertensive patients. On the other hand, salt depletion and RAS inhibition caused similar reactive increases in PRA. These data need to be confirmed in prospective studies, but they do support the view that PRA rises high enough during reduction in body salt to totally prevent BP from falling in normotensives, but it does not rise high enough in hypertensive patients to prevent BP from falling. These data also support the view that PRA rises high enough during RAS inhibition to prevent all but a small fall in BP in normotensives, but it does not rise high enough to prevent BP from falling in hypertensive patients.

FIGURE 5.

Left hand side: effect of moderate reduction in body salt on plasma renin activity and the change in mean arterial pressure in six reports of cohorts of normotensive subjects [3,5,23–26] and eight reports of cohorts of untreated hypertensive patients [5,24,28–31]. Right hand side: effect of renin–angiotensin system inhibition (RASi) on PRA and the change in MAP in seven studies of three cohorts of normotensive subjects [7,16,27] and six studies of six cohorts of untreated hypertensive patients [32–34]. For comparative purposes and where necessary, MAP was calculated from systolic and diastolic pressure and PRA levels were normalized to current reference standards. MAP, mean arterial pressure; PRA, plasma renin activity.

It is of interest that RAS inhibition raised PRA above 4.5 ng/ml/h in most normotensives but not in most hypertensive patients and caused smaller reductions in MAP in the normotensives despite their slightly higher baseline PRA. This is consistent with the hypothesis that RAS inhibitors do not totally block the vasoconstrictor effect of PRA above 4.5 ng/ml/h and raise PRA above this in normotensives.

DOES BLOOD PRESSURE FALL IN NORMOTENSIVES DURING MORE SEVERE SALT DEPLETION?

Posternak et al.[3] moderately salt-depleted four normotensives during 6 days of a low-salt diet (10 mmol/day) group A, Table 1, and more severely salt depleted five other normotensives by adding a diuretic during the low-salt diet (group B). In group B, supine PRA rose from 0.8 to 23 ng/ml/h and upright PRA rose from 4.7 to 31 ng/ml/h, but MAP did not fall in either supine (+9 mmHg) or upright (+ 5 mmHg) positions. In fact, mean MAP appeared to rise modestly. Therefore, severe salt depletion raised PRA so high that the salt depletion failed to lower BP.

TABLE 1.

Effect of sodium depletion on MAP and PRA in normotensive individuals

	Posture	MAP Med Na (mmHg)	MAP Lo Na (mmHg)	Delta MAP Med/Lo (mmHg)
Group A	Supine	81	85	+4
Group A	Upright	85	88	+3
Group B	Supine	78	87	+9
Group B	Upright	80	87	+5

		PRA Med Na (ng/ml/h)	PRA Lo Na (ng/ml/h)
Group A	Supine	0.9	3.2
Group A	Upright	1.9	6.2
Group B	Supine	0.8	23
Group B	Upright	4.7	31

Group A: moderate salt depletion: normotensive subjects were placed on a Na diet of 10 mmol/day for 6 days (Lo Na), and then 100 mmol/day for 6 days (Med Na). Group B: severe salt depletion: group B received the same dietary protocol as group A but also received a diuretic on 1 or 2 days of the 10 mmol/day Na diet [3]. MAP, mean arterial pressure; PRA, plasma renin activity.

DOES BLOOD PRESSURE FALL IN HYPERTENSIVE PATIENTS DURING MORE SEVERE SALT DEPLETION?

We carried out a study in which 3 weeks each of different degrees of salt depletion were achieved in 12 hypertensive patients over 18 weeks (Table 2) [35]. The data were analyzed separately for the six patients with low baseline PRA (<0.65 ng/ml/h) and the six with medium baseline PRA (0.65 ng/ml/h). The highest salt intake was 250 mmol/day and the most severe degree of salt depletion was achieved with the combination of a low salt diet (35 mmol/day) plus a diuretic. In the low-renin hypertensive patients, PRA rose from 0.10 to 4.0 ng/ml/h and MAP fell by 23 mmHg between the extremes of body salt. In the medium-renin hypertensive patients, the same extremes of body salt raised PRA from 1.2 to 11.4 ng/ml/h and MAP fell by only 12 mmHg. In fact, MAP had fallen by 12 mmHg during a lesser degree of salt depletion (100 mmol/day plus diuretic) when PRA rose to only 5.9 ng/ml/h, and no further fall in MAP occurred during the greatest decrement in body salt that coincided with a very large rise in PRA from 5.9 to 11.4 ng/ml/h.

TABLE 2.

Effect of gradual reduction in body salt with three different dietary Na intakes with or without placebo in six untreated hypertensive patients with baseline plasma renin activity less than 0.65 ng/ml/h (low-renin hypertension) and in six with baseline plasma renin activity greater than 0.65 ng/ml/h (medium renin hypertension)

	Salt Depletion Index	PRA (ng/ml/h)	MAP (mmHg)	Urine aldo (μg/day)	Serum K (mmol/l)
Low renin hypertension (N = 6)
250 mmol/day Na + placebo	0	0.10	126	9.0	4.6
100 mmol/day Na + placebo	−1	0.16	123	9.5	4.3
35 mmol/day + placebo	−2	1.5	113	14	4.6
250 mmol/day + diuretic	−2	0.85	112	6.5	4.3
100 mmol/day Na+ diuretic	−3	1.3	109	11	3.9
35 mmol/day Na + diuretic	−4	4.0	103	16	3.7
		+3.9	−23	+7
Medium renin hypertension (N = 6)
250 mmol/day Na + placebo	0	1.2	117	4.5	4.3
100 mmol/day Na + placebo	−1	2.0	109	11	4.3
35 mmol/day + placebo	−2	3.4	109	17	4.4
250 mmol/day + diuretic	−2	3.3	112	7.0	3.9
100 mmol/day Na+ diuretic	−3	5.9	105	14	3.6
35 mmol/day Na + diuretic	−4	11.4	105	39	3.7
		+10.2	−12	+34

The Salt Depletion Index roughly describes the estimated loss of body salt. More negative number indicates greater salt loss Aldo, aldosterone.

Bold font indicates change in parameter between Salt Depletion Index 0 to −4.

Hypertensive patients differed from each other in the degree to which salt depletion lowered BP before PRA rose to 4.5 ng/ml/h and BP stopped falling. MAP fell twice as much in low renin as in medium renin hypertensive patients.

SUMMARY

We found that the magnitude of the rise in PRA caused by salt depletion or RAS inhibition was proportional to the initial PRA level; the reactive rise in PRA was larger in normotensives than hypertensive patients; when reduction in body salt caused a small rise in PRA, RAS inhibition had the same effect; the larger reactive increase in PRA was associated with a smaller fall in BP (in fact, no fall in BP with salt depletion in normotensives and only a small fall in BP with RAS inhibition); when hypertensive patients were depleted of enough salt to raise their PRA to 4.5 ng/ml/h, their BP did not fall further with greater salt loss in association with a larger reactive rise in PRA; and hypertensive patients with low baseline PRA could be depleted of more salt than those with medium baseline PRA before their PRA rose to 4.5 ng/ml/h and BP stopped falling, whereas even moderate salt depletion usually raised PRA above 4.5 ng/ml/h in normotensives with PRA greater than 0.65 ng/ml/h, and their BP did not fall.

HYPOTHESIS

There are inconsistencies in the effect of raising or lowering body salt on BP. We hypothesize that they are caused by differences in the vasoconstrictor effect of PRA and in the size of reactive changes in PRA. PRA causes vasoconstriction via Ang II but only above 0.65 ng/ml/h (or above 4.5 ng/ml/h during RAS inhibition). Moreover, reactive increases in PRA are larger in normotensives than in untreated hypertensive patients but become larger in excessively salt-depleted hypertensive patients. This means that changes in body salt do not affect BP in normotensives with PRA above 0.65 ng/ml/h, because reactive changes in PRA prevent it, but they do affect BP when PRA is suppressed below 0.65 ng/ml/h (or below 4.5 during RAS inhibition). Hypertensive patients respond differently. Baseline PRA is less than 0.65 ng/ml/h in about 30%, and their BP rises and falls with body salt until reduction in body salt raises PRA to 4.5 ng/ml/h. Baseline PRA is between 0.65 and 4.5 ng/ml/h in about 60% of hypertensive patients and their BP also rises and falls with body salt, but the change is less because small reactive changes in PRA modulate the fall in BP but do not prevent BP from falling. However, when body salt is reduced enough in hypertensive patients for PRA to rise to 4.5 ng/ml/h, reactive increases in PRA become large enough to prevent any further change in BP. Moreover, when PRA is above 4.5 ng/ml/h, the effect of PRA is only partially blocked by RAS inhibitors, and they induce a larger reactive rise in PRA. Therefore, after PRA rises to 4.5 ng/ml/h, further salt depletion and RAS inhibition have almost no BP-lowering effect. This hypothesis has implications for the treatment of hypertension, resistant hypertension, cardiovascular and renal disease.

IMPLICATIONS

Resistant hypertension

This hypothesis points to two possible types of resistant hypertension. In one type, PRA remains low during treatment with a natriuretic drug, because there remains an excess of body salt. In the second type, the PRA level is above 4.5 ng/ml/h. BP can be lowered in the first type by increasing the number or dose(s) of natriuretic drugs until PRA rises to 4.5 ng/ml/h, where the increased Ang II-mediated vasoconstriction limits the antihypertensive efficacy of additional natriuresis. In the second type, BP may be lowered by reducing the number or dose of natriuretic drug(s) to reduce the high PRA levels to below 4.5 ng/ml/h, where its effect can be blocked sufficiently by a RAS inhibitor.

Cardiovascular disease

Hypertension is a leading risk factor for cardiovascular disease, and patients with cardiovascular disease have a wide range of on-treatment PRA levels. Thus, in the HOPE trial of patients with cardiovascular disease (CVD), PRA quintiles were 0.29, 0.83, 1.4, 2.3 and 5.9 ng/ml/h when the RAS inhibitor was added [36]. In four reports of patients with CVD, cardiovascular mortality was found to be higher in patients with the highest on-treatment PRA levels despite treatment with a RAS inhibitor [12]. We found evidence that these high PRA levels were likely caused by excessive salt depletion. Mineralocorticoid receptor antagonists (MRAs) [37] and inhibitors of SGLT2 are being increasingly used in the treatment of cardiovascular disease [38]. As blocking the effect of aldosterone with MRAs reduces distal sodium reabsorption, and SGLT2 inhibitors reduce proximal sodium reabsorption [39], the drugs, particularly when used in combination therapy, have the potential to cause sodium depletion and raise PRA to the point where the renin system is incompletely blocked by ACEIs, ARBs and direct renin inhibitors, thereby attenuating or negating the beneficial effects of RAS inhibition [12].

Chronic kidney disease

Changes in PRA determine plasma Ang II levels. Ang II preferentially constricts efferent arterioles over afferent arterioles thereby raising glomerular filtration pressure, which contributes to progressive glomerulosclerosis [40]. RAS inhibitors slow the progression of CKD, at least partly by decreasing glomerular filtration pressure. Accordingly, conditions such as excessive salt depletion that raise PRA into the range where it is only partially blocked by the RAS inhibitor may reduce the beneficial effects of RAS blockade. SGLT2 inhibitors can reduce the rate of progression of some chronic kidney diseases [41]. Although they reduce proximal sodium reabsorption [39] and have the potential to cause sodium loss, their long-term effect on PRA has not been established in CKD. However, if the hypothesis presented here is correct, then SGLT2 inhibitors when used in combination with other natriuretic drugs may raise PRA in some patients into the range where it is only partially blocked by the RAS inhibitor. Our current analysis suggests that this might be avoided by titrating natriuretic drugs to maintain PRA below 4.5 ng/ml/h and thereby retain the efficacy of RAS inhibition [42].

CONCLUSION

Reactive changes in PRA in response to changes in body salt and RAS inhibition can explain the observations that natriuretic drugs and RAS inhibitors lower BP in hypertensive patients but do not cause hypotension in normotensives, addition of a natriuretic drug lowers BP in some but not all patients with resistant hypertension, and patients with cardiovascular disease with the highest PRA levels are at greater risk of complications despite concurrent RAS inhibition.

ACKNOWLEDGEMENTS

Our thanks to our late mentor Dr John H. Laragh for his description of the volume–vasoconstriction relationship between body salt, plasma renin, and BP, to Dr Curt D. Furberg for his recognition of the usefulness of the plasma renin test in the treatment of hypertension, to Dr Michael H. Alderman for his studies of plasma renin in normotensives and hypertensive patients and their relationship to myocardial infarction, to Dr John E. Hall for his insights into renal physiology and the relationship of Ang II to glomerular filtration, to Dr Theodore W. Kurtz for his insights into the relationship between BP and high levels of body salt, and to Dr Hillel Cohen for his inputs into statistical analysis.

Conflicts of interest

There are no conflicts of interest.