Editorial for Hypertension's 3 Dilemmas & 3 Solutions: Pharmacology of the Kidney in Hypertension

Jackson, Edwin K. PhD

Journal of Cardiovascular Pharmacology: March 2017 - Volume 69 - Issue 3 - p 127–128
doi: 10.1097/FJC.0000000000000457

Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Reprints: Edwin K. Jackson, PhD, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 100 Technology Drive, Suite 514, Pittsburgh, PA 15219 (e-mail: edj@pitt.edu).

The author reports no conflicts of interest.

Article Outline

During my graduate studies (1976–1979) at the University of Texas Southwestern Medical School at Dallas, my academic home was the Division of Clinical Pharmacology. Dr William A. Pettinger established this Division and led a talented team of young investigators, including Dr William B. Campbell (my former thesis advisor and current Chairman of Pharmacology, Medical College of Wisconsin), Dr Robert M. Graham (current Executive Director of the Victor Chang Cardiac Research Institute, Sidney, Australia), and Dr D. Craig Brater (former Dean of the Indiana University School of Medicine). Dr Pettinger played a major role in our intellectual and career development by directing a vibrant Division, the raison d'être of which was to elucidate the basic and clinical pharmacology of antihypertensive drugs.

Dr Pettinger,1 who by the way was the founding editor-in-chief of the Journal of Cardiovascular Pharmacology, made seminal contributions to the field of cardiovascular pharmacology; not least of which was a landmark article in the New England Journal of Medicine that saved countless patients the horrible fate of bilateral nephrectomy for refractory hypertension. In an amazingly focused research program, he followed up on this remarkable contribution by pioneering the science of leveraging drug–drug interactions to enhance antihypertensive efficacy2–12; which should now be standard practice. In addition to his influential clinical contributions, Dr Pettinger13 made numerous basic discoveries including describing a functional basis for the classification of alpha-adrenergic receptors. Dr Pettinger's credentials included Distinguished Fellow of the: American College of Physicians; American College of Cardiology; American Society of Pharmacology and Experimental Therapeutics; American Society of Clinical Pharmacology and Therapeutics; and American Society of Clinical Investigation. At the age of 84, Dr Pettinger uses his laser-sharp mind to promote improved care of hypertensive patients by actively writing and speaking about high blood pressure to the lay public.

After publication of the Systolic Blood Pressure Intervention Trial (SPRINT),14 I urged Dr Pettinger to write a commentary addressing the challenges created by the SPRINT findings. I encouraged Dr Pettinger to write a commentary for three reasons. First, the work of Dr Pettinger et al15,16 in the 1980s and 1990s established a goal blood pressure very similar to SPRINT. After years of intensive—and expensive—research, heated discussion, and changing official recommendations, SPRINT has corroborated the conclusions reached by Dr Pettinger's research over 2 decades ago! Thus, his investigative approach is a paradigm for obtaining cost-effective insights. Second, although SPRINT clearly defines the need for better blood pressure control, SPRINT may achieve only a small fraction of its potential benefit because in many patients, lowering blood pressure to less than 120/80 mm Hg is problematic. In the 1970s, Dr Pettinger et al7 described the life-saving benefits of minoxidil. Then for reasons explained in his commentary, this drug fell from grace. Here, Dr Pettinger makes a strong case for his view that minoxidil should be used to control blood pressure in a wider spectrum of hypertensives. Third, Dr Pettinger is a forceful and frank critic of the USDA MDR for dietary sodium. Dr Pettinger's carefully conducted, low–sodium-intake studies in hypertensives established the safety and efficacy of very low-sodium diets. He reminds us that we should look to the jungles of South America and Papua, New Guinea to discover the true “normal” sodium intake and concludes that unless we correct the current sodium USDA MDR to safe levels, achieving the SPRINT blood pressure goals will remain elusive. Although some may take issue with Dr Pettinger's positions, all will benefit from reading his commentary17 entitled “Hypertension's 3 Dilemmas & 3 Solutions: Pharmacology of the Kidney in Hypertension.”

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1. Pettinger WA, Mitchell HC. Minoxidil—an alternative to nephrectomy for refractory hypertension. N Engl J Med. 1973;289:167–171.
2. Mitchell HC, Pettinger WA. The hypernoradrenergic state in vasodilator drug-treated hypertensive patients: effect of clonidine. J Cardiovasc Pharmacol. 1980;2:1–7.
3. Mitchell HC, Pettinger WA. Dose-response of clonidine on plasma catecholamines in the hypernoradrenergic state associated with vasodilator beta-blocker therapy. J Cardiovasc Pharmacol. 1981;3:647–654.
4. Mitchell HC, Pettinger WA. Clonidine and prazosin effects in hypernoradrenergic vasodilator-treated and beta-blocker-treated patients. Clin Pharmacol Ther. 1981;30:297–302.
5. Mitchell HC, Pettinger WA, Gianotti L, et al. Further studies on the hypernoradrenergic state of treated hypertensives: effect of captopril. Clin Exp Hypertens A. 1983;5:1611–1627.
6. Pettinger W, Sheppard H, Palkoski Z, et al. Angiotensin antagonism and antihypertensive activity of phosphodiesterase inhibiting agents. Life Sci. 1973;12:49–62.
7. Pettinger WA. Minoxidil and the treatment of severe hypertension. N Engl J Med. 1980;303:922–926.
8. Pettinger WA, Campbell WB, Keeton K. Adrenergic component of renin release induced by vasodilating antihypertensive drugs in the rat. Circ Res. 1973;33:82–86.
9. Pettinger WA, Keeton K. Altered renin release and propranolol potentiation of vasodilatory drug hypotension. J Clin Invest. 1975;55:236–243.
10. Pettinger WA, Mitchell HC. Renin release, saralasin and the vasodilator-beta-blocker drug interaction in man. N Engl J Med. 1975;292:1214–1217.
11. Pettinger WA, Mitchell HC. Additive effect of beta-adrenergic blockers in combination with vasodilators in lowering blood pressure. Aust N Z J Med. 1976;6(3 suppl l):76–82.
12. Pettinger WA, Mitchell HC, Gullner HG. Clonidine and the vasodilating beta blocker antihypertensive drug interaction. Clin Pharmacol Ther. 1977;22:164–171.
13. Berthelsen S, Pettinger WA. A functional basis for classification of alpha-adrenergic receptors. Life Sci. 1977;21:595–606.
14. The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–2116.
15. Pettinger WA, Lee HC, Reisch J, et al. Long-term improvement in renal function after short-term strict blood pressure control in hypertensive nephrosclerosis. Hypertension. 1989;13(6 pt 2):766–772.
16. Toto RD, Mitchell HC, Smith RD, et al. “Strict” blood pressure control and progression of renal disease in hypertensive nephrosclerosis. Kidney Int. 1995;48:851–859.
17. Pettinger WA. Hypertension's 3 dilemmas & 3 solutions: pharmacology of the kidney in hypertension. J Cardiovasc Pharmacol. 2016.
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