Hypertension's 3 Dilemmas and 3 Solutions: Pharmacology of the Kidney in Hypertension

Pettinger, William A. MD

Journal of Cardiovascular Pharmacology: March 2017 - Volume 69 - Issue 3 - p 129–139
doi: 10.1097/FJC.0000000000000458
Commentary

Abstract: The Hypertension Community has 3 conflicting dilemmas: a goal systolic pressure of 120 mm Hg or less (the SPRINT Trials), 40% of our 60,000,000 hypertensives still sustain blood pressures above 140/90 mm Hg, and our most potent antihypertensive drug minoxidil sits on the sidelines, imprisoned in the Food and Drug Administration's Black Box designation. My solutions to these dilemmas are: (1) review of the facts of our most potent antihypertensive drug minoxidil which is essentially free of toxicity, (2) treatment focus on the fundamental cause of high blood pressure, that is excess dietary sodium and, (3) prevention of, and/or reversal of, the fundamental mechanism of worsening hypertension, arteriolar hypertrophy.

Summary: The Hypertension Community has 3 conflicting dilemmas: a goal systolic pressure of 120 mm Hg or less (the SPRINT Trials), 40% of our 60,000,000 hypertensives still sustain blood pressures above 140/90 mm Hg, and our most potent antihypertensive drug minoxidil sits on the sidelines, imprisoned in the Food and Drug Administration's Black Box designation. My solutions to these dilemmas are: (1) review of the facts of our most potent antihypertensive drug minoxidil which is essentially free of toxicity, (2) treatment focus on the fundamental cause of high blood pressure (HBP) and excess dietary sodium and, (3) prevention of, and/or reversal of, the fundamental mechanism of worsening hypertension, arteriolar hypertrophy. My focus at UT Southwestern in Dallas was on extremely severely hypertensive patients with a quantifiable, measurable complication of HBP, progression of nephrosclerotic damage to kidneys. This model had the greatest likelihood of exposing fundamental disregulatory mechanisms in hypertensive patients (which it did) and the potential for study of the most relevant antihypertensive drug interactions to achieve optimal blood pressure control (which it did). By maintaining diastolic pressures at 80 mm Hg or less in the first National Institutes of Health–supported, long-term randomized clinical trial to save the kidneys, the bases for a fundamental blood pressure support mechanism (arteriolar hypertrophy) was illuminated but not fully described until now. This fundamental hypertensinogenic mechanism results from HBP but with time and severity, becomes its own raison d'être. I am now aged 84 years. As a result of a stroke 20 years ago, which caused permanent double vision, and because of poor blood pressure control with triple therapy, I started using minoxidil 5 mg/d along with atenolol and occasional furosemide. Now, along with some dietary salt restriction, my resting blood pressure is 110/65–125/75 and, despite >30 years history of HBP, I have no retinal arteriolar hypertrophy nor arcus senilis (Dr. Schwartz-U. of Miami) which is almost universally present at this age. Yes, prevention of, or reversal of, arteriolar hypertrophy should be a central focus of HBP treatment. I simply wish to share a bit of accumulated wisdom that might be of use to others.

Division of Clinical Pharmacology (Retired), University of Texas Southwestern Medical School (Retired), Bonita Springs, FL.

Reprints: William A. Pettinger, MD, Division of Clinical Pharmacology (Retired), University of Texas Southwestern Medical School (Retired), 27557 Shore Drive, Bonita Springs, FL 34134 (e-mail: billpettinger@mac.com).

See editorial: Editorial for “Hypertension's 3 Dilemmas and 3 Solutions: Pharmacology of the Kidney in Hypertension” by Edwin Kerry Jackson, Journal of Cardiovascular Pharmacology 2017;69:127–128.

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INTRODUCTION

Results of the recent SPRINT Trials1,2 demand that we and the Food and Drug Administration (FDA) reassess the clinical use of minoxidil (Loniten), our most potent antihypertensive drug. The goal systolic blood pressure in the SPRINT Trials in the strict control group was 120 mm Hg. Complications of high blood pressure (HBP) in this group were reduced except that renal function seemed to decline in the strict control group (discussed below with edema and the pseudo renal artery stenosis (PRAS) syndrome). An embarrassing fact to our hypertension community is that over 40% of hypertensives' blood pressure is sustained above 140/90 mm Hg in the United States of America.3 Even though minoxidil is virtually free of toxicity, the FDA has essentially shut down its use by a Black Box designation. This designation resulted from 2 side effects (cardiac symptoms and edema) that could have been, and should have been, controlled by companion drugs which, in fact, potentiate minoxidil's efficacy.

Chidsey's prophetic analysis4 in 1973 of minoxidil's role was ignored by the FDA and by the medical community. He noted that “minoxidil's extraordinary efficacy when combined with a diuretic and beta-receptor blocker, lack of tolerance for 2 years, and its paucity of side effects suggests that this agent may be of great value in the chronic therapy of hypertension.”

Our interest in minoxidil was precipitated by its historic role in arresting the tragic procedure of removing both kidneys of patients with refractory hypertension and advanced nephrosclerosis.5 It soon became apparent that far better blood pressure control was needed to “save-the-kidneys” and that more understanding of drug interactions with minoxidil and blood pressure support mechanisms might enable us to achieve better blood pressure control. These interactions extend to fascinating intrarenal mechanisms involving arteriolar hypertrophy, adrenoceptors (ARs), renin–angiotensin, and the increasingly recognized cause of reversible renal failure from drugs, the PRAS syndrome (PRASS).6 Interestingly, mechanisms of PRASS (to be discussed) were the cause of poor kidney outcomes in the SPRINT trial in the elderly2 in the strict blood pressure control group (37 events) versus the conventional (13 events) blood pressure control group. All other indices of outcomes were improved in the “Strict” (<120 mm Hg systolic pressure) control group.

Our early goal was to reduce diastolic blood pressure to <80 mm Hg (minoxidil was required in all patients) in the patients with most severely hypertensive nephrosclerosis before randomization into 2 groups. In one randomized group, we attempted to maintain diastolic pressures below 80 mm Hg, and in the other, to permit diastolic pressure to be maintained above 90 mm Hg by reducing drug dosages. Analogies to this strategy were subsequently applied in the 2 SPRINT Trial designs.1,2

The interactions reviewed herein relate to impressive activation of the sympathetic nervous system and renal retention of sodium leading to edema. Because of the power of the 4 mechanisms causing edema from minoxidil, emphasis is placed on restriction of dietary sodium by documenting the real minimum daily requirement (MDR) for sodium (<0.2 g/d).

When compared with most other antihypertensive drugs, minoxidil is unique in several ways:

1. Minoxidil dilates precapillary arterioles. Arteriolar hypertrophy (discussed later) results from HBP. Because of encroachment on the arteriolar lumen, it becomes a fundamental hypertensinogenic mechanism independent of the initiating cause.

2. Minoxidil is as an agonist drug. Receptor blockers or enzyme inhibitors suppress only the ambient level of activity of their specific blood pressure support mechanism, whereas an agonist has a full range of pharmacologic activity.

3. Minoxidil has a 3–4 days of duration of action. It binds strongly to its arteriolar site of action by a covalent (sulfydryl) linkage. Therefore, its pharmacologic effects are cumulative with constant daily dosing for up to a week at which time its efficacy reaches a plateau; once daily dosage should suffice. This pharmacologic property of minoxidil may be the determining factor of its greater efficacy in clinical use than the vasodilator hydralazine (Apresoline).

4. Minoxidil stimulates/maintains hair growth. This effect is highly variable from patient to patient and a mixed bag indeed. Because its site and mechanism of action is on vascular smooth muscle leading to increased blood flow, future minoxidil research should include diseases potentially related to ischemia. These include age-related hearing loss and penile erectile dysfunction for which use patents (not mine) are on file. If age-related dementias are due to ischemia, minoxidil might have efficacy therein as well.

Fortunately, we had a large coterie of severely hypertensive patients at Parkland Hospital in Dallas in whom we could do full dose–response curves (DRCs) of each of the types of antihypertensive drugs superimposed on 2 or 3 other drugs at fixed doses. We monitored indices of each blood pressure support mechanism including supine and standing serum renin activity (SRA) and plasma norepinephrine (NE) concentrations and vasoconstrictor effects using the selective antagonists P-113 (saralasin) for angiotensin (Ang II) and phentolamine or prazosin for NE. In some studies, we measured cardiac output, venous compliance, peripheral and pulmonary vascular resistance, and, of course, blood pressures with various drug combinations. Mechanistic studies of these interactions and blood pressure support mechanisms were also conducted in genetic hypertensive and normotensive animals and in isolated perfused rat kidneys.

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PHARMACOLOGY

My focus is on the mechanisms of side effects of minoxidil and control thereof by companion drugs with the goal of “opening the door” for physicians to take advantage of its unique efficacy. For traditional aspects of minoxidil pharmacology, see reviews.7–9

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1. Cardiac Reflex Effects

Minoxidil's antihypertensive site of action is arteriolar smooth muscle; active-agonist dilation at this site decreases peripheral resistance thereby lowering blood pressure. Lowering of blood pressure by any mechanism other than suppressing of, or blocking, sympathetic neuronal effects causes reflex activation of the sympathetic neural release of NE (Fig. 1) onto peripheral alpha-ARs and beta-ARs.

Failure to control this reflex activation (Fig. 2) or its effects, especially with higher doses of minoxidil, causes increased heart rate, myocardial contractility, arrhythmias, and even myocardial infarction. Failure of physicians to control this minoxidil-induced reflex activation contributed to the FDA's Black Box designation, thereby restricting and limiting minoxidil usage to drug-resistant hypertension and scaring physicians away from its use because of potential litigation.

Plasma concentrations of NE with various antihypertensive drug combinations are shown in Figure 1. Hypertensives tended to have slightly (not statistically significant) higher plasma NE levels, and there was a gradation throughout more severely hypertensive patients as a function of the requirement for more powerful drug combinations. High plasma NE concentrations were reversed by clonidine or methyldopa which lower blood pressure by their site of action on10 alpha2-ARs in the cardiovascular control center in the brain.11

Veins are like a sewer for disposal of NE released from sympathetic nerve endings, so its concentration in venous blood is an index of sympathetic neuronal activity. Circulating levels of NE are normally below the level for vasoconstriction. However, the circulating levels (Fig. 1) with higher doses of minoxidil are in the range of circulating NE concentrations in pheochromocytoma. Interestingly, the effects of excess NE released from sympathetic nerve terminals directly onto receptors (ie, because of reflex activation) contrast remarkably from effects of high circulating NE levels from pheochromocytoma, a concept deserving further comment in a discussion of minoxidil edema and effects of clonidine (see 2. Minoxidil Edema) on the edema.

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Hydralazine (Apresoline) and Reflex Cardiac Stimulation

Hydralazine, like minoxidil, is an agonist vasodilator but is also an angiotensin receptor blocker (ARB).12 In the model (ganglionic blockaded anesthetized rat) in which this property was discovered, vasodilators shifted angiotensin and NE DRCs to the right equally, except for hydralazine. Hydralazine shifted the DRC for angiotensin much further to the right than NE and therefore is also a selective ARB. The shift of DRCs by 40+ vasodilators correlated quantitatively with antihypertensive activity in genetic hypertensive and deoxycorticosterone acetate-sodium hypertensive rats.12 Interestingly, the enzyme inhibiting capacity of phosphodiesterase inhibitors (caffeine, theophylline, and 20 other unnamed drugs) were directly proportional to their antihypertensive and vasodilating potencies,12 thus linking causality of these 3 properties.

Because of this combined pharmacologic property (ARB plus vasodilator), hydralazine caused cardiac arrhythmias and infarctions in the emergency room of Parkland Hospital when hydralazine was administered intravenously for extreme blood pressure elevation. Consequently, we abandoned its use in this manner. Alternatively, orally administered minoxidil has been used for rapid control of extreme elevations of blood pressure,13,14 and I have used it this way as well. Alpert and Bauer13 started with a 20 mg dose of minoxidil superimposed on a beta-blocker and furosemide and added 5–20 mg 4 hours later, if necessary. One could start with 5–10 mg initially (after a beta-blocker) and add to the dose at 3–4 hours intervals with careful monitoring. Importantly, it is simpler and easier to use than nitroprusside or even diazoxide. However, if heart failure–pulmonary edema is present, nitroprusside infusion is preferable because of venodilation and reduction of venous return by this drug, thereby reducing cardiac workload.

Even with the combination of pharmacologic effects, hydralazine is less potent as a blood pressure lowering agent than minoxidil, as first noted by Chidsey4 and in our own experience. Keep in mind, however, that hydralazine was a major component of the drug combination used in the transformative VA Cooperative Studies coordinated by Fries,15,16 so this drug clearly has efficacy in controlling blood pressure and preventing complications. Note the expression of Fries' wisdom of the use of reserpine (site of action is in the central nervous system like for clonidine and methyldopa) in Figure 2. Hydralazine causes headaches and occasional lupus erythematosus at doses of 200 mg/d and higher.

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2. Minoxidil Edema

Four physiologic mechanisms contribute to edema from minoxidil, each of which is dependent on excess dietary sodium. The mechanisms are as follows:

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1. Capillary Leakage

A function of precapillary arterioles is to prevent excess blood flow into capillaries when blood pressure is temporarily increased. Long-standing HBP from any cause leads to hypertrophy of this circular smooth muscle (Fig. 3), encroachment on the lumen, and increased passive resistance to blood flow. Therefore, arteriolar hypertrophy becomes a fundamental mechanism of sustaining HBP per se. Arteriolar dilation, especially with minoxidil, increases blood flow into capillaries thereby increasing their transmural pressure gradient which shifts water into extracellular spaces thereby contributing to edema formation, which is highly variable among patients.

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2. Reduced Glomerular Filtration Pressure

Because salt excretion is partially pressure dependent as described by Guyton,17 the extraordinary lowering of blood pressure capacity of minoxidil (combined with other drugs) increases passive (independent of aldosterone) renal retention of sodium and water thereby contributing to edema.

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3. Renal Nerve–Released NE

This mechanism for minoxidil-induced edema is due to increased sympathetic nerve release of NE directly onto alpha1-ARs in the kidney which causes sodium retention.18–20 This mechanism of sodium–water retention predominates over the high circulating NE levels (as in pheochromocytoma [see below]) which suppress release of NE through the inhibitory action of presynaptic alpha2-ARs.10

Interestingly, vasopressin also has a direct renal effect of retaining sodium in addition to its water-retaining action.21 Because we did not study any vasopressin antagonists or blood levels of this peptide, we cannot exclude an important salt- and water-retaining role of vasopressin in minoxidil edema. Interestingly, excess antidiuretic hormone (vasopressin) secretion syndrome in myxedema is associated with low serum sodium (even less than 105 meq/L)22 which seems inconsistent with a direct renal effect of sodium retention by this hormone. However, mineralocorticoids potentiate vasopressin's effects on salt and water retention. Thus, the volume expansion mechanism suppressing aldosterone secretion seems to be absolute in continuing urinary sodium excretion (despite serum sodium concentrations as low as 100 meq/L) in the syndrome of inappropriate secretion of antidiuretic hormone.22

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4. Beta-Adrenoceptor–Mediated Renin Release

Finally, sympathetic nerve activation stimulates renin release by a beta-ARs23,24 on the juxtaglomerular apparatus, leading to angiotensin formation, and synthesis, and release of aldosterone, the sodium-retaining hormone. This minoxidil-augmented renin release is largely inhibited by beta-blockers, a major blood pressure–lowering mechanism in this antihypertensive drug combination in man and animals.23,24

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Contrasting Effects on Edema of High Sympathetic Nerve–released NE Versus High Circulating NE as in Pheochromocytoma

Minoxidil-induced sympathetic nerve–released NE onto renal tubules induces reabsorption of sodium-causing edema (see 3. Renal Nerve–Released NE). Alternatively, high circulating levels of NE from pheochromocytoma have 2 opposite effects on salt and water excretion. One is to constrict veins which forces stored blood to the heart and, by the Starling mechanism, propels the excess blood to the kidney and forces salt and water excretion.17 The second mechanism of high circulating NE in pheochromocytoma to increase salt and water excretion is to activate presynaptic alpha2-ARs which inhibit sympathetic neuronal release of NE10 on renal tubules and thereby to reduce sodium retention. Intravascular volume depletion by these 2 mechanisms in pheochromocytoma can be so severe that patients may even fall from the sitting position because of orthostatic hypotension. Alternatively, orthostatic hypotension is absent with minoxidil because of this drug's 4 cumulative mechanisms (see 2. Minoxidil Edema) causing renal retention of salt and water resulting in volume expansion.

Why not just use the alpha1-AR antagonist prazosin to prevent minoxidil's reflex–mediated salt-retention edema (see 3. Renal Nerve–Released NE)? What a fine idea! However, after 3 days of prazosin administration, alpha2-ARs multiply, move into the postsynaptic site on renal tubules, and mediate nerve-stimulated salt and water retention,25 the otherwise exclusive domain of alpha1-ARs. A similar multiplication of alpha2-ARs with prazosin and substitution for alpha2-ARs on veins may explain temporary (2–3 days) orthostatic hypotension with alpha1ABs and very short-term benefits in congestive heart failure.26 I do not know whether some degree of tolerance (to relief of urethral obstruction) occurs when alpha1-AR antagonist are used to relieve urethral obstruction from prostatic hypertrophy.

Failure of physicians to optimally combine counteracting drugs with minoxidil to control effects of the reflex activation caused cardiac stimulation and edema. On the flip side of this issue is the occasional patient with poor cardiac conduction as in the “sick-sinus-syndrome”. In some patients with this syndrome, I have used minoxidil in lower doses (ie, 10 mg) without a beta-blocker to enhance conduction through activation of beta-ARs in the heart. Such use of minoxidil is possible because of its constant, long duration of increased sympathetic neuronal release of NE for which tolerance does not develop. This mechanism substituted for having pacemakers installed in some of my patients.

Cause and effect relationships of antihypertensive drug interactions (Fig. 2) were confirmed using selective blockers (prazosin, saralasin, and propranolol) of each receptor type. Beta-blockers, such as propranolol or atenolol, when added to minoxidil, lowers blood pressure impressively by inhibiting the exaggerated renin release.23,24 The renin–angiotensin limb in Figure 2 can become a critical support mechanism when minoxidil is used alone27 as shown in Figure 4. Without a beta-blockers such as propranolol, SRA is high and infusion of the ARB saralasin can cause extreme lowering28 of blood pressure (Fig. 4).

Because converting enzyme inhibitors such as captopril, ARBs, or inhibitors of the renin enzyme have similar anti-angiotensin profiles,27 these drugs should be used very carefully with a vasodilator.

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Edema and the MDR for Sodium

Excess dietary sodium is a prerequisite for edema from minoxidil and is the cause of HBP in the vast majority of hypertensive patients. So how much sodium do we really need, or “What is the Real MDR for sodium?”

Here are 2 scientific fact bases for the MDR of sodium:

1. Millions of people with dietary sodium intake of <9 meq/d (0.2 g) have neither HBP nor its complications and do not even have obesity or diabetes.29,30 Their blood pressure does not even increase with age, and their exercise tolerance is excellent. I constructed a pseudo DRC by combining blood pressure as a function of dietary sodium intake from the Intersalt studies29,30 and the salt-blood pressure study of Mente et al31 in Figure 5. The Mente Study also indicated a quantitative relationship between salt intake and blood pressure but over a narrow and very high range of salt intake. Clearly, the MDR for sodium is <0.2 g/d.

2. I personally conducted studies in hypertensive patients ingesting diets containing 9 meq/d of sodium (0.207 g) in National Institutes of Health (NIH)-supported Clinical Research Centers at the University of Texas Southwestern Medical School in Dallas, at Vanderbilt in Nashville, TN and at NIH's Clinical Center in Bethesda, MD. Note the placement on the DRC of 0.207 g sodium/d.

Blood pressure was reduced in every patient by reducing sodium intake for 2 weeks but none to the level associated with the same salt intake for people shown in Figure 5; why not? I suspect that failure to lower blood pressure over a short time interval (2 weeks) of lowered salt intake was due to residual arteriolar hypertrophy (Fig. 3) in my patients that had resulted from long-standing HBP. Clearly the MDR for sodium is <0.2 g/d, and political pressure should be put on the United States Department of Agriculture (USDA) to reduce this toxic addictive poison (kills more people than opiates, car accidents, and terrorists' guns combined) on food labels in our grocery stores. I suspect that there would be no minoxidil-edema if salt intake were reduced to 0.2 g/d of sodium. Reduction even to 1.0 g/d might eliminate most of the diuretic requirement in the vasodilator–beta-blocker drug combination.

Dr. Frieden's recent Viewpoint Title in JAMA32 “Sodium Reduction-Saving Lives by Putting Choice Into Consumers' Hands” is incisive except for 2 issues: (1) He fails to demand of the USDA to use a scientific basis for labeling of foods with the real MDR for sodium of <0.2 g/d and (2) a recommendation for ready availability at low cost of urine sodium and creatinine measurements for people who really care about preventing a stroke and other HBP complications. Now few are aware of their sodium intake relative to the 0.2 g/d value in Figure 5. Measurements of urine sodium-creatinine are analogous to monitoring of blood pressure with a cuff for hypertensives or blood sugar for diabetics.

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High Pulmonary Vascular Resistance and Minoxidil

Pulmonary vascular resistance and pressure increases in proportion to peripheral vascular resistance33,34 and hypertension. Thus, the isolated reports of high pulmonary vascular resistance associated with minoxidil are due to the preminoxidil status. In fact, minoxidil blunts pulmonary hypertension from hypoxia.35

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Minoxidil and Saving the Kidneys in Refractory Hypertension

To the reader it may seem ironic that a stroke and its sequelae were a cause of my writing of this update on minoxidil. JP's average blood pressure for 3 years in the outpatient clinic of Parkland Hospital had been 239/139, and it had destroyed 90% of his kidney function. He fit the policy at that time5 of removing both kidneys to save his life. However, in the admitting office, he had a stroke with coma and was no longer a candidate for hemodialysis so was admitted for stabilization and transfer to a nursing home to die. I happened to be his attending physician and had just received the research drug minoxidil from Upjohn. After 3 days of minoxidil, his blood pressure was normal, and in 2 weeks, he walked out of the hospital with a cane and 2 months later returned to work.

One year later, we had accumulated similar experiences (minus the stroke) in 11 patients and published “Minoxidil, an Alternative to Nephrectomy For Refractory Hypertension”5 because of which this horrendous procedure was soon abandoned. Instead of cardiac problems, JP.'s huge cardiac hypertrophy had been reduced to normal voltage on his electrocardiogram, and he had had no arrhythmias. His kidney function had improved by >50% from his remaining 10%, and it seemed that this huge problem of severe hypertension nephrosclerosis was solved.

But not quite! One to 2 years later, several of the patients' kidney function were deteriorating. Fortunately, Mitch and Walser36 had published a straight line of decay of kidney function (Fig. 6) in patients like JP, which predicted the date for beginning hemodialysis in individual patients to within a few months; what a tragic, depressing perspective! JP's decay of renal function shown in Figure 7 before minoxidil fit perfectly with Mitch and Walser's observations. Unfortunately, another straight line of decay (Fig. 7), albeit at a slower rate, predicted that he would require hemodialysis in 6–7 years which actually occurred. Because his blood pressures were in the 145/95 range, we suspected that further lowering of blood pressure might reduce the downward slope of his decay curve. Nevertheless, the capacity of good blood pressure control to change the slope of the Mitch–Walser curve was very encouraging.

In fact, another patient had 3 slopes of decay of renal function. The first was rapid decay of renal function; the second with the triple combination of minoxidil, propranolol, and diuretic; and the third with an increased dose of minoxidil to 60 mg/d plus clonidine (Fig. 8). The latter combination controlled blood pressure in the range of 120/70 mm Hg, and renal function was sustained for 14 years at which time I lost contact with CW.

The stage was set to pursue every aspect of interactions of antihypertensive drugs with each blood pressure support mechanism, one of which is shown in Figure 9. The informative DRC for clonidine suppression of plasma NE,37 blood pressure, and plasma renin activity (Fig. 10) emphasizes the role of the DRC as the pharmacologist's sword. Would not the world be better if each physician could draw the DRC for every drug she/he prescribes? Or, if definitive DRCs were required before sale of all dietary supplements?

Maximum lowering of blood pressure and of the high plasma NE concentrations occurred at or below 0.4 mg/d of clonidine. Higher doses of clonidine produced no additional lowering of plasma NE or blood pressure; in fact, blood pressure tended to increase. Also, higher doses are associated with increased withdrawal symptoms and very HBP with discontinuation of this drug. Consequently, I recommend 0.2 mg of clonidine at night (enhances sleep) and 0.1 mg in the morning; I add another 0.1 mg at noon but only if it is really necessary.

Not only did clonidine lower blood pressure further but seemed to cause diuresis.38 This effect is expected because of suppression of high reflex-induced NE release directly onto renal alpha1-ARs which, in turn, cause renal retention of sodium and water.19,20 Theoretically, there are 2 sites of clonidine suppression of NE release: one is in the cardiovascular control center in the brain, which suppresses peripheral sympathetic nerve activity and the other is on the sympathetic nerve terminal through activation of alpha2-ARs suppressive to NE release.10 The resulting diuresis is sufficient to increase SRA38 even though alpha2-ARs are inhibitory to renin release.

Now if all of these interactions seem a bit complicated, just place yourself in CW's position or that of his wife, a cardiologist. She grasped the significance of the decay curves shown in Figure 8 for CW and Figure 7 for JP so was motivated to take any measures to save his kidneys. Most importantly, keep in mind the potential for improvement (reduced need for drugs) if diastolic blood pressure is maintained below 80 mm Hg for 2–6 months,38 which improvement seems due to reversal of arteriolar hypertrophy.

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The First NIH-supported Randomized Trial Attempting to Save Kidneys

The design of the study38 is shown in Figure 11. Eighty-seven nondiabetic severely hypertensive patients with advanced nephrosclerosis qualified for the study.39 To qualify, they had to have severe refractory hypertension requiring minoxidil to control (hence the focus on minoxidil), to have lost more than half of their kidney function, and to be sufficiently responsible and compliant to sustain diastolic blood pressure control at <80 mm Hg for 2–6 months before randomization. Ten percent of the original group had failed to sustain diastolic pressures below 80 mm Hg so were not randomized but continued to be followed in the study. In 1 randomized group (1/2), diastolic pressures were permitted to rise above 90 mm Hg by reducing medication dosage. In the group randomized to lower blood pressures, we attempted to maintain diastolic pressures below 80 mm Hg. Diastolic pressure was selected because of less variability than that in systolic blood pressure.

Our NIH-supported, randomized, long-term clinical trial achieved the following:

1. As a result of 2–6 months of blood pressure control at <80 mm Hg in both patient groups, kidney function improved for 3 years. Antihypertensive drug requirement was remarkably reduced in both groups.38 My opinion is that this quality of blood pressure control for this time interval caused reversal of arteriolar hypertrophy. This result contrasted with Mitch and Walser's conclusion that, “renal disease progression once established progresses irrevocably”36 in such patients.

2. Simultaneous studies40 reversed the concept that hyperfiltration is the mechanism for progressive loss of kidney function studied in rats.41,42 Minoxidil-induced hyperfiltration in patients with hypertensive nephrosclerosis while simultaneously improving kidney function over a 3-year period. Thus, hyperfiltration cannot be a major mechanism of destroying kidney function in our patients as suggested by studies in rats.41,42 Minoxidil-induced hyperfiltration may, in fact, explain why hemodialysis may be discontinued in some minoxidil-treated patients43 and should be systematically studied for delay of, or reducing, hemodialysis.

3. Discovery and understanding of the mechanism of the PRASS originally described for minoxidil6 but was subsequently found to be related to severe reversible loss of renal function with other antihypertensive drugs43,44 (see below).

4. Final results of the hypertension nephrosclerosis trial were reported by Toto et al.39 Mean diastolic blood pressure in the strict group was 81 ± 1 and in the conventional group 87 ± 1 mm Hg. The mean slopes of decay of renal function in both groups were not significantly different from 0. However, by combining results in all patients, there was a slight but significant decline of renal function. Although it is not possible to identify a specific goal diastolic pressure, I recommend 2–6 months of blood pressure control at or <80 mm Hg by whatever drug combination is required. For long-term maintenance, try to keep resting diastolic pressure <83 mm Hg and the lower the better without hypotensive symptoms. Reduction of dietary salt intake to <1.0 g/d will help greatly.

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PRASS and Arteriolar Hypertrophy

PRASS was first described in minoxidil-treated patients6 because it was the only antihypertensive drug sufficiently effective to control HBP in refractory patients.5 Reduction of systemic arterial pressure by minoxidil (plus companion drugs) along with extreme narrowing of arteriolar lumen due to hypertrophy reduced filtration pressure in the glomerulus to such an extent that little filtration occurred. Also, this reduced pressure triggered huge rates of renin release, but the perfusion pressure was so low that even angiotensin constriction of the efferent arteriole was unable to maintain filtration, as in unilateral renal artery stenosis as previously discussed. Thus, the syndrome consists of reversible very high concentrations of serum creatinine and urea (nearly to uremic levels), high SRA, and edema with weight gain.

Two of these abnormalities, increased renin release and increased tubular reabsorption of sodium and water, occur in unilateral renal artery stenosis, but functioning of the opposite kidney compensates for the increased reabsorption, so split function studies are required to demonstrate this altered function. However, in bilateral renal artery stenosis, excess tubular reabsorption is so severe that patients present with extreme HBP and acute heart failure with pulmonary edema. The PRASS is therefore like bilateral renal artery stenosis and, in fact, stenosis is bilateral because it involves all precapillary arterioles in both kidneys.

Some of these functional abnormalities also occur with angiotensin converting enzyme inhibitors (ACEI) because of the following paradigm. Renin is released from the juxtaglomerular apparatus located on the afferent arteriole into the glomerular capillaries heavily laden with converting enzyme which forms Ang II. Ang II constricts the efferent arteriole which increases feedback pressure to the glomerulus and maintains filtration despite decreased filtration pressure from artery stenosis. In normal circumstances, renin–angiotensin concentration is low, so ACEI does not decrease glomerular filtration rate normally. However, decreases of glomerular filtration pressure increase renin release to such an extent that glomerular filtration depends, at least in part, on Ang II constriction of the efferent arteriole. This phenomenon explains the worst outcome, apparent renal failure, in the strict control group of the SPRINT Trial in the elderly.2 Diuretics and ACEI potentiate the PRASS dysfunctions.45

There are several other important aspects of arteriolar hypertrophy. A major function of precapillary arterioles is to prevent excess flow of blood into capillaries during temporary increases in blood pressure. Excess flow into capillaries increases transmural pressure in thin capillary walls forcing water and salt into extracellular spaces and edema. An anatomic feature of arterioles (Fig. 3) includes a fixed-dimension fibrous outer layer, a circular muscle, and a thin inner lining which extends into and, in fact, comprises the capillary wall. This thin lining is the site of exchange of oxygen, carbon dioxide, sugar, creatine-creatinine, and urea in all tissues. Capillaries in the glomerulus of the kidney constitute the filtering mechanism, the first step in urine formation. Malignant hypertension occurs when the onset of extreme elevation of blood pressure occurs rapidly, before sufficient smooth muscle hypertrophy develops to prevent the excess blood flow into capillaries.

Arteriolar hypertrophy was first demonstrated in the hindlimb arterioles of dogs (circa 1948) that were made hypertensive by renal artery constriction. The hypertrophy was prevented by partial constriction of 1 femoral artery, thereby reducing perfusion pressure of that hindlimb. This paradigm may explain why blood pressure in my patients on short-term (2–3 weeks) restricted salt intake (0.207 g sodium) failed to decrease to the levels existing in people whose salt intake had been limited throughout their life span.30,31 It would be anticipated that reversal of the hypertrophic smooth muscle encroachment on the lumen of arterioles caused by chronic hypertension would require significant time to reverse.

One might argue that emphasis on arteriolar hypertrophy and its potential reversal is inappropriate in an update of minoxidil. However, this concept is useful in explaining improvement of renal function after only 2–6 months of antihypertensive therapy noted above.38

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MINOXIDIL-HAIR GROWTH-ROGAINE

Increased hair growth is highly variable with minoxidil administration. Two women aged 20 and 24 years were so offended by body hair growth that they said that they would rather die, so stopped taking minoxidil; within 6 months, both were dead. Twin brothers age 59 years, had black hair growth over their bodies which was reminiscent of the appearance of bears; both had hair growth in their ear canals which required trimming. Two women noted lengthening and thickening of eye lashes requiring trimming to prevent scratching on their eye glasses. Two patients had roughening of facial features but preferred having blood pressure controlled with minoxidil, the only drug effective enough to do so. In most patients, increased hair growth was not a problem and was, in fact, a beneficial side effect, especially in men.

Topically applied minoxidil has to be absorbed through the skin, circulated to the hair follicles, and only then does it produce hair growth. It is much easier to take a 5-mg tablet of minoxidil, but the oral form is included in the Black Box designation by the FDA; how unfortunate because the off-patent pill is so inexpensive.

The DRC for minoxidil-induced hair growth is unknown. However, from my own experience and observations, I suspect that the maximum induction of hair growth occurs with 5–10 mg/d. Interestingly, the DRC for increased renal blood flow is biphasic with higher doses (30–40 mg/d) actually decreasing renal blood flow.46 Possibly, the lowered systemic blood pressure plus renal vasoconstrictor effects of angiotensin plus NE could reduce renal blood flow at higher doses. Whether a similar peak skin blood flow at 5–10 mg/d occurs is unknown.

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CONCLUSIONS

1. Reversal of arteriolar hypertrophy by controlling diastolic pressure <80 mm Hg for 2–6 months in our minoxidil trial seems to be a fundamental determinant of conserving kidney function in high-risk patients with nephrosclerosis. Whether minoxidil may play a unique role in remodeling of arterioles should be thoroughly investigated.47

2. Arteriolar hypertrophy is closely linked to the PRASS, the cause of reversible major loss of kidney function due to blood pressure reduction by minoxidil and by anti-renin–angiotensin agents.

3. Edema from minoxidil is caused by at least 4 mechanisms, each of which is dependent on dietary sodium in excess of the real MDR for sodium. Thus, the USDA must resort to fact-based science as reviewed herein, instead of profit-driven industries for MDR for sodium labeling on food items in our grocery stores.

4. Because excess dietary sodium is the basic cause of the vast majority of HBP and minoxidil edema is dependent on it, hypertensive patients should be “let-out-of-the-dark” concerning dietary intake of sodium. As with blood sugar for diabetics and blood pressure cuffs for hypertensives, they should have ready access to inexpensive measurements of urinary excretion of sodium and creatinine for monitoring of dietary sodium.

5. Minoxidil is underutilized48 because of the FDA's Black Box designation which should be eliminated and appropriate recommendations for its optimal use should be inserted into the package insert.

6. Excellent control of moderate hypertension can be achieved or augmented using doses of 5–10 mg/d of minoxidil with a beta-blocker, and with long-term use, the need for the beta-blocker may not even be required. Because of erratic HBP control with triple therapy and permanent diplopia from a small stroke 20 years ago, I have personally used minoxidil 5 mg/d plus 25 mg of atenolol each morning. If I exercise or do manual work in the afternoon, I take another 25 mg of atenolol. On the occasion that I dine at a restaurant, I use furosemide 20 mg the subsequent morning. My personal experience is a motive for writing this article. My resting blood pressures run from 115/65 to 130/75.

7. Minoxidil is valuable in hypertensive patients on hemodialysis because of cardiovascular stability, and, in fact, urine output and renal function can improve sufficiently with minoxidil to discontinue hemodialysis in some patients.

8. Use-patents for minoxidil are on file (not mine) for prevention of age-related hearing loss (ie, restoration of tiny hair cells on the cochlea which are lost with age-related hearing loss) and for restoration or maintenance of penile erection in patients with long-standing hypertension. Interestingly, patients in our long-term minoxidil project noted restoration of penile erection; whether it was due to improved general health or a specific benefit of minoxidil is unknown. Those were pre-Viagra days, so we were not specifically monitoring this issue.

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ACKNOWLEDGMENTS

Dr. Helen Mitchell (deceased) monitored patients, maintained records, and contributed to each article. The $100,000,000.00/yr tax base from Dallas County for care of indigent patients at Parkland Hospital provided the unique opportunity for Dr. Mitchell and me to: (1) accumulate the relatively homogeneous group of patients with severely hypertensive nephrosclerosis for the controlled randomized study and (2) pursue the multiple projects of drug interactions which permitted far better control of blood pressure than ever achieved in our patient population. This review describes the first NIH-supported, randomized, long-term clinical trial attempting to establish a goal blood pressure for preventing HBP complications. A subsequent multicenter clinical trial organized and funded by NIH ($65,000,000) had no chance of success because of results of our trial; we reduced the rate of loss of renal function to “not-different-from-0”.

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