The Renin–Angiotensin–Aldosterone System: A Personal Perspective and Festschrift for John H. Laragh, MD

John Laragh has been a great inspiration to me and many others in the field of hypertension research. His inquisitive mind, deep knowledge of physiology and medicine, and keen clinical insights led him to discoveries and innovation that were critical to our current understanding of the renin–angiotensin–aldosterone system (RAAS) and to the development of effective therapies for hypertension. I first met John in the 1970s during one of his visits to Mississippi, along with his research group, to meet with our Department of Physiology, led at that time by Arthur Guyton. My lab was engaged in basic research studies on the intrarenal actions of angiotensin II (Ang II) in regulating glomerular filtration rate, tubular reabsorption, and long-term control of blood pressure, and I was deeply impressed by the work of John and his colleagues at Cornell. Teprotide (SQ-20881), the peptide inhibitor of angiotensin-converting enzyme (ACE), and peptide antagonists of the ANG II type 1 receptor were just becoming available, and I was eager to use these compounds to investigate the intrarenal role of Ang II in long-term blood pressure regulation. One major reason for my interest was John’s previous studies that showed that low-dose Ang II infusions in humans had powerful effects on blood pressure that were not only sustained but also actually amplified during several days of infusion.1 The progressive hypertensive effect of Ang II was related to sodium balance and was even more impressive than that of aldosterone. The effects of Ang II contrasted with those of norepinephrine, which had progressively weaker blood pressure effects during several days of infusion and caused either natriuresis or no change in sodium balance.1 In a seminal series of studies in humans, John and his colleagues found that Ang II controls sodium balance and blood pressure not only through stimulation of aldosterone but also by direct actions on the kidneys. A paragraph in his 1965 paper in the Journal of Clinical Investigation1 was especially enlightening: Our data indicate that angiotensin is oriented to prevent sodium depletion or arterial hypotension. Loss of body sodium is associated with a tendency for a fall in arterial pressure; either may elicit the secretion of renin and the elaboration of angiotensin. Angiotensin then promotes salt retention both directly and by augmenting aldosterone secretion; as sodium stores increase pressure sensitivity to angiotensin rises, leading to blood pressure elevation. If blood pressure rises excessively “pressure natriuresis” occurs, returning the sodium stores and blood pressure toward normal. This analysis of the RAAS is as relevant today as it was in 1965. These and other studies by John and his colleagues stimulated my interest and influenced the direction of my early research.2 In the 1970s, John and his colleagues Hans Brunner and Haralambos (Harry) Gavras first demonstrated that antagonizing Ang II receptors with sarcosine1-alanine8-angiotensin II (saralasin) or blocking Ang II formation with teprotide lowered blood pressure in patients with essential hypertension.3,4 This groundbreaking work propelled the development of SQ-14225 (captopril), the first orally active ACE inhibitor, and was a major breakthrough in hypertension treatment. Gavras and Brunner,5 as well as John and his colleagues,6 independently demonstrated that ACE inhibition was effective in treating essential hypertension and set off a flurry of basic and clinical research using SQ-14225, including studies in our lab,7 that quickly led to widespread use of this new and highly effective approach to treating hypertension. Although John was at the forefront of treating hypertension with blockers of the RAAS in the 1970s, his major contributions to this area of research began much earlier, in the late 1950s, when he and his colleagues discovered that malignant hypertension was associated with excessive adrenal aldosterone secretion,8 a major breakthrough because no biochemical abnormality had previously been identified in this disease and no effective treatment was available. When he found that adrenalectomy was ineffective in returning blood pressure to normal in malignant hypertension, John surmised that these patients must have a circulating hormonal abnormality that was responsible for increased adrenal aldosterone secretion, hypertension, and vascular injury, the hallmarks of malignant hypertension. Because kidney damage is also rampant in malignant hypertension, John suspected that the missing hormone might be renin, which stimulated Ang II formation and aldosterone secretion.9 The timing was right for John to test this idea because Ciba Pharmaceuticals had synthesized Ang II and made it widely available and a sensitive double isotope assay for aldosterone had been developed by Jean Sealey.10 This led to studies in which Ang II was infused in humans and to groundbreaking work that demonstrated a major role for Ang II in regulating blood pressure and body sodium content.1 The next 40 years of John’s research resulted in a steady stream of basic and clinical research papers that provided impetus for the widespread use of 3 different drug types to block the RAAS. Today, these drugs—beta-blockers (to block renin release), ACE inhibitors (to block Ang II formation), and Ang II receptor blockers—are the cornerstone of antihypertensive treatment. A much longer review than this one would be required to adequately summarize John’s major research accomplishments, which anyone involved with the field of hypertension would easily recognize. After all, how many hypertension researchers have had their picture on the cover of Time magazine?11 On a personal level, I have always been deeply impressed with John’s powerful intellect and inquisitive mind. Almost every conversation that I have had with him quickly turns to science, including a wide range of topics related to basic renal and cardiovascular physiology, nephrology, and hypertension. When John founded the American Society of Hypertension in 1986 and invited me to become a founding member, I gladly accepted because I knew that the meetings and activities would include exciting science if he was involved. My first visit to his laboratory in 1988 was memorable. Within a couple of minutes after I began my lecture, he inquired, “Do you mind if we ask questions?” Although I planned for my presentation to be about 45 minutes, it lasted approximately 2 hours because of the questions and discussion that ensued. This was followed by dinner with John (preceded by a couple of martinis) and more discussion about the intrarenal actions of Ang II, macula densa feedback control of renal hemodynamics, nephron heterogeneity, basic cardiovascular and renal physiology, and a host of other topics. My most recent meeting with John in August 2013 was just as memorable; he still loves to talk about physiology and hypertension. Conversations with John Laragh are always exhilarating and informative (probably much more so for me than for him). The list of hypertension researchers who trained and published with John Laragh is impressive. I will not list them in this brief paper, but do encourage the reader to quickly scan the list of >600 publications on PubMed and see the many leaders in the fields of hypertension, cardiology, and nephrology who have benefited from his insights and critical thinking. When I asked Arthur Guyton, on the occasion of his retirement in 1989, to provide a list of the 3 most outstanding people in the field of cardiovascular physiology or hypertension to speak at a symposium in his honor, I was not surprised that John Laragh was his first choice. John’s pioneering research, his leadership and service to professional organizations, and his training of several generations of hypertension researchers are recognized by basic scientists and clinicians alike. His long list of prestigious awards from a wide range of international professional societies, including physiologists, nephrologists, cardiologists, hypertension specialists, and others, is truly impressive and richly deserved. John H. Laragh, MD, standing beside a picture of Robert Tigerstedt, who discovered renin in 1898. Laragh received the Robert Tigerstedt Award from the American Society of Hypertension in 1990. Thank you John for your innovative and truly pioneering research, for your leadership, and for the many wonderful conversations we have had over the years. I am delighted to see that your life work will be honored in this Festschrift.