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

Abstract

SUMMARY The Hypertension Community has three conflicting dilemmas, a goal systolic pressure of 120 mmHg or less (The SPRINT Trials), 40% of our 60,000,000 hypertensives still sustain blood pressures above 140/90 mmHg and our most potent antihypertensive drug minoxidil sits on the side-lines, imprisoned in the FDA’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, excess dietary sodium and, #3. Prevention of, and/or reversal of, the fundamental mechanism of worsening hypertension, arteriolar hypertrophy. My focus at U.T. Southwestern in Dallas was on extremely severely hypertensive patients with a quantifiable, measurable complication of high blood pressure, progression of nephrosclerotic damage to kidneys. This model had the greatest likelihood of exposing fundamental dis-regulatory 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 mmHg or less in the first NIH 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 84 years of age. 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/day along with atenolol and occasional furosemide. Now, along with some dietary salt restriction, my resting blood pressure is 110/65–125/75 and, in spite of > 30 year 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.

Adenosine Receptors Influence Hypertension in Dahl Salt-Sensitive Rats

“…Our motivation for examining the role of adenosine receptors in Dahl SS rats over a wide range of dietary salt levels (0.3%, 4%, and 8% salt diets) is that in humans there is a “dose-response” curve for dietary sodium intake versus arterial blood pressure that extends over a wide range (0.1 to 10 grams per day) of dietary sodium intake (see Figure 5 of article by Pettinger 59 ). The current study indicates that the protection against salt-diet induced hypertension afforded to females by knocking out A 1 or A 2B receptors is lost at very high levels (8%) of dietary salt.…”

α 2-Adrenoceptors: Challenges and Opportunities—Enlightenment from the Kidney

“…From a public health viewpoint, the causal role of altered α 2 -AR regulation in hypertension via retention of excess sodium appears very promising. Millions of people ingesting 20 times the real minimum daily requirement for sodium [33] have no hypertension which is obviously genetically determined; they are salt-resistant. A drug which would convert salt-sensitive hypertension to salt-resistance by interfering selectively with the α 2 -AR-sodium retaining mechanism could be paradigm shifting.…”

“…However, when the sympathetic nervous system is reflexly activated by peripheral acting antihypertensive drugs, β-adrenoceptor blockade of excess renin release is a powerful blood pressure lowering mechanism [26][27][28]. Extensive blood pressure lowering in severely hypertensive patients leads to passive tubular retention of sodium that can be overpowering leading to severe edema, even cardiac tamponade [32], details of which are described by Pettinger [33]. Moreover, severe preglomerular arteriolar hypertrophy coupled with the magnitude of blood pressure reduction decreases glomerular filtration rate causing uremia.…”

“…Moreover, severe preglomerular arteriolar hypertrophy coupled with the magnitude of blood pressure reduction decreases glomerular filtration rate causing uremia. is syndrome is known as the pseudorenal artery stenosis syndrome (PRASS) [33]. It is important because extremely elevated serum creatinine and urea in this syndrome could precipitate needless hemodialysis for the remainder of a patient's life.…”

“…medications, kidney function can be restored. It is of particular note that reversal of arteriolar hypertrophy should be a goal of hypertension treatment [33].…”