Abstracts

Abstract

Special LectureBackstage History of Hypertension Research. Kikuo Arakawa. Kawanami Hospital, Fukuoka, Japan.Half a century has past since I became a physician in 1954, during which hypertension research has advanced dramatically, and I have witnessed it including the backstage. I meant first to become a surgeon, but nephritis after tonsillitis that I suffered changed my mind, and I took a postgraduate course of biochemistry where I learned peptide chemistry. I experienced many surprises, one of which was finding a mistake by Nobelist Emil Fisher. No one trusted me, and I was abused until it was also pointed out by an American in JACS. These happenings made me wish to work in a more open world and in a more medical peptide field such as angiotensin.I joined Page's group at the Cleveland Clinic; he was one of the discoverers of angiotensin. However, his description in 1940 was wrong in two areas. One was the description that serum renin activator made renin active, which he corrected in 1943 according to a simultaneous discovery by Braun-Menendez's finding. The other was that he claimed to have obtained it in “crystalline” form, which he never corrected. It was so crude a preparation that no one would have been able to crystallize it. Even those purely isolated angiotensins from horse (Skeggs et al.) and ox (Peart et al.) 15 years later have never been crystallized, nor was human angiotensin that I isolated another 10 years later.When Skeggs et al. clarified the whole biochemical pathway of renin-angiotensin system (RAS) in 1956, they predicted three possible approaches for developing antihypertensives: the renin inhibitor, ACE inhibitor (ACE-I), and angiotensin receptor blocker (ARB). Of them, natural ACE-I teprotide has been found from snake venom that was, in turn, minimized in size into the first nonpeptide ACE-I captopril by Ondetti et al.ARB was first developed by Bumpus' group at the Cleveland Clinic in 1960. To begin with, they elucidated the relationship between the structure and biological activity of angiotensin II (AII). Based on this, they made the first peptide ARB, [Ala8]-AII in 1970. Pals et al. modified it three years later and made [Sar1]-[Ala8]-AII or sar-ala-sin, without referring [Ala8]-AII, giving an impression that saralasin was the first peptide ARB.The peptide ARB must be made as a small nonpeptide molecule for oral administration. Two approaches were taken: minimization of the octapeptide, which was tried only up to a hexapeptide ARB; modification of the smallest essential part for the biological activity of AII molecule until enough antagonistic action would appear. The latter approach was first followed by Furukawa et al. in 1980 (CV2961), but they dropped it, regrettably, despite my enthusiastic advice to proceed further on that track. Instead, the Dupon group picked it up, added biphenyltetrazole, and made the first nonpeptide ARB, losartan.The thought that the RAS is responsible for essential hypertension, at least in part, has made people assume that AII is not working in essential hypotension. We, however, found the opposite, which made me think that easy leakage of Na causes essential hypotension and the retention causes essential hypertension.