The kidney blood pressure hormone, renin, was discovered, characterized and named in 1898 by Robert Tigerstedt, Professor of Physiology at the Karolinska Institute in Stockholm. Tigerstedt showed that minced saline extracts of rabbit kidneys, when injected into another rabbit promptly produced striking increases in blood pressure in the recipient rabbit. In this classic study, Tigerstedt also showed that this "renin" raised blood pressure entirely by constricting the muscular arterioles, while not affecting cardiac rate or output. He also described the enhanced and prolonged pressor response to renin in nephrectomized rabbits. He postulated a major role for kidney release of renin, for causing human hypertension. However, less meticulous European scientists failed to confirm his work, and renin fell into total disrepute and Tigerstedt continued his distinguished career without further studies of renin. In retrospect, the failures to confirm him were likely due to degradation on standing of the renin protein by proteolytic bactenia, so that only testing of freshly made renin was essential in the absence of refrigeration, sterile technique or antibiotics in that era.

In was not until 1934 that interest in renin was revived by a landmark experiment of another ingenious and meticulous scientist. Harry Goldblatt, a pathologist, working in Cleveland, observed that hypertensive patients at autopsy exhibit narrowing of their kidney arterioles. To mimic this, Goldblatt designed and surgically placed a partially occlusive clamp on one kidney artery of a dog kidney to reduce its blood supply. Amazingly, this produced chronic hypertension in his dogs, lasting for years, extremely similar to human hypertension. Goldblatt also showed that these dogs were releasing excess renin into the blood steam. He therefore proposed that excess kidney renin release is a major cause of human high blood pressure. His findings were readily and widely confirmed and extended by other scientists. However, renin again fell into disrepute as a relevant biologic substance when clinicians uniformly failed to relate the presence or absence of renin in the blood to the presence or absence of human hypertension. These latter findings were basically correct because we now know that there are two forms of human and animal hypertension, pathophysiologically described as the salt and renin forms that respectively have very low or high renin values. But, in the absence of this knowledge, the medical establishment concluded that the wide fluctuations in renin levels among hypertensive patients indicated that plasma renin levels could not have anything to do with what they incorrectly assumed must be due to a single homogenous pathophysiologic process, known as essential hypertension, and so "renin," once again, became a dead biological issue.

The Modern Renin System Story Begins

Renin release by the kidneys activates a major endocrine control system that simultaneously regulates ambient blood pressure levels and body sodium and potassium content

In 1948, John Laragh began his career as a physician and a scientist working under the guidance of his Chief, Robert F. Loeb, Chairman of the Department of Medicine at Columbia. Laragh worked in a small laboratory of Loeb's where for some time he insisted that Laragh perform all of his laboratory tests himself including the aldosterone assays and the electrolyte measurements. This included preparing the constant diets for his animal studies. It was not until 1959 that he was given biochemical and physiological assistance with the advent of Jean Sealey and Joan Banes.

Dr. Laragh's first research (1955-57) investigated the roles of dietary sodium and potassium and of the newly discovered adrenal cortical sodium retaining hormone, aldosterone, for causing edematous congestive cardiac failure. To this end, Dr. Laragh worked for several years with his colleague and close friend Stanley Ulick, to develop and perfect most precise but arduous double label H3-C14 assay for measuring endogenous adrenal cortical aldosterone secretion rates.

In this setting, armed with his precise aldosterone assay John Laragh's research with his early colleagues led to the following:

(1) In 1957, Laragh showed that adrenal cortical secretion of aldosterone, the newly discovered powerful renal sodium-retaining and kaliuretic hormone, was markedly increased in his patients with congestive heart failure and that it was the likely cause of their edematous condition. Moreover, he found that these high aldosterone secretion rates were further increased by feeding KCl, leading him to show in normal dogs that the plasma K+ level, (as driven by dietary K+ intakes) is, in fact, a potent direct and continuous stimulus for adrenal aldosterone secretion (JCI, 1957). These findings, in turn, led him to study the roles of dietary sodium and potassium and of aldosterone secretion in human hypertensive diseases in whom causal roles for aldosterone had been suspected.

(2) Then in 1960, in research initiated by his initial studies of aldosterone secretion rates in human hypertension Dr. Laragh published four consecutive papers (JCI, Annals Int. Med., JAMA (2)) that put the discarded kidney enzyme, renin, on the biological map. In this work he demonstrated, before it had been shown in animals, that in fact, plasma renin-angiotensin levels were the initiator of a heretofore unknown endocrine servocontrol system, the renin-angiotensin-aldosterone system, which he postulated and subsequently proved, to be the major regulator, of both of our ambulatory blood pressure levels, via plasma renin-angiotensin servocontrol, and simultaneously, of our body Na+ and K+ content, via angiotensin regulated adrenal aldosterone release to cause renal Na retention and K+ loss.

At the same time, from these human studies, Laragh proposed and later proved that unabated, runaway kidney release of renin creates the very high plasma renin-angiotensin and aldosterone levels that cause the syndrome of rapidly fatal human malignant hypertension (MHT), i.e, severe hypertension, high aldosterone levels with hypokalemia, and prompt extensive vascular injury to the heart, brain, retina, and kidney vessels, that to induces fatal heart attack, or heart failure, or stroke, or kidney failure.

These Laragh discoveries were built on his immediately preceding research (JCI, 1960) showing that, contrary to claims of others, adrenal cortical secretion of aldosterone was normal in essential hypertension. However, in sharp contrast, all of his 14 patients with fatal malignant hypertension, exhibited massive oversecretion of aldosterone, consistently associated with hypokalemia and with bilateral adrenal hyperplasia at surgery (Annals Int. Med., 1960), indicating to Laragh that a stimulus other than plasma K+ must be involved in stimulating their adrenal cortical aldosterone oversecretion. But when total adrenalectomies failed to benefit them, Laragh reasoned that the entire MHT syndrome must all be due to a circulating pressor substance which (1) raises blood pressure, (2) markedly stimulates adrenal cortical aldosterone release to cause hypokalemia and (3) is also directly and diffusely vasculotoxic to heart, brain and kidney arteriolar vessels. He suspected a renal source for all of this i.e., renin, release from damaged kidneys. To test this, Laragh infused five different natural pressor substances, each in tiny amounts, into normal volunteers in 40 studies to show that only angiotensin, the unique pressor product of renin's enzymatic action in plasma, promptly, markedly, and consistently stimulated large increases in adrenal aldosterone secretion in 8 studies. (JAMA, 1960).

Thus, in the above 4 consecutive reports in major journals in 1960 Laragh discovered a major biologic role for plasma renin. It was the initiator of a kidney based hormonal servocontrol, the renin-angiotensin-aldosterone system which simultaneously co-regulates ambulatory blood pressures levels together with body Na+ and K+ content in all of us. From the same research, he simultaneously proposed that a gross derangement of this new renin system with very high plasma renin-angiotensin levels, created by unchecked kidney release of renin from damaged kidneys, causes the entire syndrome of human malignant hypertension, i.e.: its severe hypertension, its aldosterone excess with hypokalemia, and its severe heart, brain and kidney vasculitis leading rapidly to fatal heart attack, stroke, heart failure or kidney failure. These four reports published in 1960 in major journals abruptly launched a worldwide explosion in basic and clinical renin system research that continues today.

(3) Laragh then performed classic balance and clearance studies to define the workings of the new kidney based renin angiotensin aldosterone endocrine servocontrol, in which plasma renin, released by the kidneys, regulates ambulatory blood pressure (via plasma angiotensin release) and body sodium and potassium content (via angiotensin-induced adrenal aldosterone release), to promote renal Na+ retention and K+ loss in all of us. In this system, the kidney releases renin in response to the blood pressure falls of upright posture or exercise, or from dietary or alimentary sodium depletion, or from blood loss, to thereby co-maintain, via angiotensin release, normal ambulatory blood pressures levels, and via aldosterone release, Na+ and K+ homeostasis. In these ways, the renin system continuously sets normal ambulatory blood pressure levels to maintain blood flows, and tissue nutrition in all of us.

(4) To prove his proposal that unabated excesses of plasma renin-angiotensin cause malignant hypertension Dr. Laragh first needed to demonstrate the presence in his MHT patients of high plasma renin levels as compared to normal people, or to other hypertensives. For this with Jean Sealey, they developed a very sensitive renin assay capable of discriminating with certainty those with very low renin values in the 10-12M range from those that are medium or high, to thereby define the low point below which renin support of blood pressure is fully replaced by a salt-volume excess. This renin assay was perfected by Dr. Jean Sealey over a seven year period. With this firmly in hand, Laragh knew he also needed to find ways to block circulating plasma renin activity with drugs which could lower or block circulating renin or angiotensin levels to determine whether blood pressure would fall and more especially could the malignant syndrome be arrested or corrected? To launch his proposed antirenin system drug strategy, he introduced and characterized three pharmacologic probes, each of which block the plasma renin system hormonal cascade at three different biochemical sites: (1) propranolol, a beta receptor blocker to block kidney beta receptor activate renin release to reduce plasma levels by 75 percent (NEJM,1972, Am . J. Cardiol. 1973), (2) the intravenous octapeptide, saralasin, the first angiotensin II receptor blocker, (ARB) Circ Res., 1974, A. J .Med., 1976, and (3) intravenous nonapeptide, teprotide from venom, the first angiotensin converting enzyme inhibitor (CEI) NEJM 1974,1977,AJM, 1976.

(5) For proof of his concept of MHT, Laragh then showed that each of his three anti-renin system R drug types, when given alone, promptly and strikingly arrested human MHT, including its signs of retinal, heart, brain, kidney and peripheral vascular injury, e.g., retinopathy, heart attack, stroke and heart and kidney failure, with the therapeutic benefits of each drug in MHT resembling those of a total nephrectomy. Then, with the advent of the first of many orally active analogs of intravenous teprotide, captopril, he was able to verify the longterm persistence of the original dramatic effects of his antirenin system pharmacologic probes in patients with malignant or high renin essential hypertensions (Case et al, Circ. 1981) in whom the persisting benefits of captopril were similar to those originally produced either by oral propranolol (NEJM 1972; Am J Cardiol. 1973) or by intravenous teprotide or saralasin (see refs in preceding section 4).

Thus, the high plasma renin, angiotensin, and aldosterone levels that Laragh found in patients with the syndrome of MHT fulfilled all of Robert Koch's postulates for causation because (1) the presence of excess renin-angiotensin-aldosterone levels in the blood was closely associated with the occurrence and progression of the syndrome (2) reducing or blocking this plasma renin activity with any one of his three anti-renin drugs types, or removing it by bilateral nephrectomy, produced prompt dramatic and similar corrections of the syndrome, including its hyperaldosteronism and hypokalemia along with physical signs of healing or arrest of vascular injury to brain, heart and kidneys, and (3) moreover, the MHT syndrome could be reproduced in humans by (1) an abrupt renal artery graft closure, or (2) by the rebound hyperreninemia upon abrupt cessation of saralasin infusions, or (3) by injections of renin or angiotensin in hypertensive animal models.

(6) With this incontrovertible template for the endocrine causation of malignant hypertension and of its fatal vasculitis, in hand, Laragh then investigated whether the milder increases in plasma renin angiotensin occurring in 70% of essential hypertension might sustain their hypertension too, and in them might, albeit more gradually, become vasculotoxic, leading to later occurrence of fatal heart attack, stroke or kidney failure. Finally, to focus the specificity relevance of these findings, he needed to also demonstrate a lack of renin causation of similar high blood pressure levels in the 30 percent of patients who have low renin essential hypertension.

To address these questions, Laragh with Dr. David Case used an ingenious pharmaceutical strategy to determine whether the milder plasma renin excesses that occur in medium and high renin essential hypertensions actually account for their hypertension: Thus, in that 70 percent of 425 untreated patients who had medium or high renin essential hypertension (PRA > 0.65), they showed that the immediate depressor responses to each one of his 3 different anti-renin system drugs (see refs section 4) were always closely related to the height of the baseline pretreatment ambulatory plasma renin level. These data thereby indicated that the height of the ambulatory baseline plasma renin level was in fact accounting for all or part of the existing hypertension in the first place, because the higher the antecedent baseline endogenous renin levels, the greater were the prompt drops in blood pressure induced by giving the anti-renin drug and vice versa. (see refs section 4).

(7) Moreover, Dr. Laragh showed that the reciprocal converses were also true: Accordingly, in those 30% of essential hypertension with low renin values (PRA<0.65) who had similar or higher blood pressures, their high blood pressure levels were unresponsive to each of his three anti-renin system R drugs, but were promptly correctable instead by the natriuretic antivolume V drugs, i.e., diuretics, spironolactone, CCBs or alpha blockers. These latter patients instead have "wet" sodium-volume V essential hypertension with little or no renin involvement, and so are also much less prone to fatal cardiac renal and cerebral vasculotoxic sequelae (see section 8 below).

As described already (see section 4) early in their research Laragh's group had defined the specific anti-renin anti-hypertensive actions first of beta blockers and then of teprotide, the original snake venom nonapeptide CEI, in malignant and in essential hypertension (Gavras 1974; NEJM, Case 1976 Am. J. Med. [2] and 1977 NEJM) and finally of saralasin the original octapeptide angiotensin receptor blocker (ARB) Lancet 1973, Circ. Res. 1974, Am. J. med. 1976, 1977. Their research with teprotide preceded and led industry to develop many orally active analogs of teprotide, beginning with the syntheses of captopril by Squibb (Ondetti et al, Science 1977) and enalapril and lisinopril by Merck (Patchett et al, Nature 1980). Both papers cited the Gavras, Laragh, New Engl. J. Med. 1974 original research work with teprotide from venom as the reason for their work to create the first oral analogs of teprotide, i.e. captopril, and enalapril and lisinopril. These pharmaceutical achievements launched a worldwide explosion in orally active CEI drug usage, to quickly make CEI's a revolutionary new corrective treatment for the more severe renin-mediated forms of essential hypertension, and, of equal relevance and impact, for the prevention or arrest of their related renin-mediated fatal cardiovascular sequelae, (heart attack, heart failure, kidney failure, stroke) as originally defined and predicted by the Laragh template of the fatal vascular injury in MHT, caused by excess plasma renin-angiotensin levels. The effectiveness of these three anti-renin system R drug strategies introduced and defined by Dr. Laragh's group was further enriched and conceptually verified again in 1988, (Timmermans et al 1988) with the advent of losartan, the first of many orally active, saralasin-like specific angiotensin II type-1 receptor blockers (ARB) e.g. irbesartan, valsartan, candesartan, olmesartan. These ARB's produce clinical benefits virtually identical to those of CEI inhibitors; with both being highly selective for correction of the renin-mediated forms of hypertension.

(8) In parallel clinical research, in two major 8 year clinical trials of hypertensive patients, Dr. Laragh with his colleagues, revealed and characterized a close association between the height of the entry ambulatory plasma renin level and the later development of heart attacks or strokes, thereby again implicating direct plasma angiotensin vasculotoxicity in their causation (Brunner, NEJM 1972 and Alderman, NEJM 1991). In the latter study the Alderman group showed that the milder elevations in plasma renin-angiotensin that sustain medium and high renin essential hypertension (see section 6 above) were similarly highly associated with subsequent, albeit more gradually developing, vasculotoxic sequelae (heart attack and stroke), than what occurs more rapidly in malignant hypertension. Furthermore, in both of these trials, the converses strengthened the renin theory, because no heart attacks or strokes occurred in 300 consecutive, equally hypertensive low renin patients. This relative lack of cardiovascular damage in low renin patients sharply focuses the specificity of the close relationships between both the presence and the height of the renin level and later occurrences of heart attack or stroke. Moreover, in two genetic hypertensive animal models, Laragh showed that either administration of K+ to reduce plasma renin activity levels, or of losartan to specifically block angiotensin II type 1 receptors, strikingly arrests progression of vascular injury in the heart, brain and kidneys, even when the blood pressures were not reduced (Hypertension 1990, J. Hypertension 1992,1993). In sum, these human and animal studies provided parallel lines of evidence confirming the potency and specificity of plasma renin-angiotensin-mediated vasculotoxicity for inducing fatal heart attack, heart failure, stroke, or kidney failure.

(9) Altogether, by calling on this body of research Dr. Laragh conceived and built his two component volume-vasoconstriction analytic model in which all forms of human hypertension are visualized as composing a spectrum, of salt-volume- plasma renin level interactions, operating according to Dr. Laragh's modification of the Poisieulle equation [BP=CO X TPR] which states that all normotension as well as all hypertension must be sustained by the product of the (body sodium-volume content V) multiplied by the (plasma renin-angiotensin levels) (Am. J. Med., 1973, Fed Proc 1982). Malignant hypertension, with very high plasma renin levels and low body sodium content is the "dry" high renin R polar extreme of this spectrum. It expresses ischemic, renin-mediated vicious vascular disease of heart, brain and kidney vessels. By contrast, at the other polar extreme, adenomatous primary aldosteronism expresses "wet" hypertension with massive body sodium-volume V excesses which markedly suppress renin levels to zero. In contrast to malignant hypertension, these equally hypertensive but "wet" salty patients generally exhibit comparatively superior blood flows and less or no vascular injury. Altogether then, the entire pathophysiologic spectrum, of human hypertension, is sustained by a range of abnormally high (plasma renin level)X(body sodium content) products that sustain either pure renin, pure salt, or a mixed renin and salt type of hypertension and within which the height of the renin level (PRA >0.65) directly indicates the degree of plasma renin causation and the potential for angiotensin vasculotoxic injury, whereas the lowness of the renin (PRA <0.65) indicates instead the strength of the sodium-volume V factor in the hypertension equation. Dr. Laragh's research with Dr. Sealey, (J. Hypertens. 1988) further indicated that these abnormal volume-vasoconstriction (body sodium X plasma renin level) products in hypertensive patients are sustained by nephron heterogeneity arising from the intermingled presence of minor subpopulations of afferently narrowed, ischemic, renin hypersecreting and sodium retaining nephrons, whose fixed renin hypersecretion cannot be turned off by salt loading so that net total kidney renin secretion can overtly exceed the "normal" renal renin production, even after full sodium-volume induced suppression of renin secretion is induced in the neighboring compensatory hyperfiltering normal nephrons (Sealey, J. Hyper 1988).

(10) Dr. Laragh and Dr. Jon Blumenfeld applied this vasoconstriction-volume model to clinical practice using office-based initial and follow-up ambulatory plasma renin testing to define the presence and degree of the initial V or R factor in individual patients. The renin test proved useful whether or not patients were receiving antihypertensive drugs, thereby enabling physicians to correctly guide primary or follow-up drug therapies based on the strength of the ambient renin R or the sodium volume V factor involved in the (sodium-volume)x(renin) hypertension equation. Corrective addition or subtractions of drugs guided by renin testing in treatment-failure patients already taking one or more anti-hypertensive drugs also led to full correction with one or at most two drugs. Thus, diastolic pressures <90 in 87 percent were achieved by using only 1.3 drugs per patient, in which most were fully corrected by longterm monotherapy (Blumenfeld, Am. J. Hypertens. 1998) a considerable improvement over the dismal worldwide treatment results reported from using empiric or government guidelines (ALLHAT 2002) in which 2-4 drugs were required for antihypertensive therapy in 62% of patients to correct hypertension in only 67%.

(11) Confirmations: (from outside the field of clinical hypertension), Dr. Laragh's conception that plasma renin-angiotensin II levels are directly vasculotoxic has gained impressive independent support from the many large clinical trials in the related fields of cardiology and nephrology in which long-term usage of the various anti-renin system R drug therapies were evaluated. Thus, in studies of over 120,000 post acute heart attack (MI) patients, whenever either a beta blocker or a CEI or both is added to the regimen, mortality and reinfarction rates are promptly, persistently and significantly reduced, survival is prolonged and LV remodeling and CHF are prevented or arrested (eg. BHAT, SOLVD, SAVE, GISSI-3 and ISIS-4). Moreover, in the CONSENSUS TRIAL of heart failure patients, the striking benefits of the CEI, enalapril to reduce morbidity and prolong survival were entirely confined to those patients whose entry plasma angiotensin levels were above the median. Actually in the half of patients whose plasma angiotensin levels were below the median, (i.e., low renin patients) enalapril functioned only as a placebo, producing no reduction in fatal endpoints or improved survival, nicely verifying in heart failure patients the same two final pathogenic the determinants i.e, sodium-volume V factor and/or the plasma renin R factor in causation, correctable in turn only by explicit individualized primary antisalt or antirenin therapies respectively. The more recent HOPE trial (NEJM 2000) is also consistent with the view that coronary and other vascular events are uniquely prevented by CEI treatment even when blood pressure is not reduced, and the LIFE trial using instead the ARB, losartan, produced striking stroke and heart attack reductions in both hypertensive and diabetic patients.

Similarly, in two large nephrology trials, CEI therapy strikingly arrested progression of small vessel renal disease in both diabetic (Lewis, NEJM; 1993) or non-diabetic patients (Maschio, NEJM; 1996). Altogether, these large clinical trials in cardiology and nephrology, patients, which show unique benefits for the anti-renin system drug therapies, strongly implicate endogenous plasma renin-angiotensin levels in pathogenesis of vascular injury. Moreover, all of the above clinical results are similar to the dramatic benefits for antihypertensive R drug therapy originally described by Dr. Laragh's group for producing arrest of cerebral, coronary and renal vascular injury in human malignant hypertension and most essential hypertension and resembling in turn, angiotensin receptor blocker induced the arrest of vascular injury to heart, brain and kidney vessels in genetic hypertensive SHRsp and Dahl-S malignant hypertension animal models (1992, 1993).

Summary

John Laragh, and his colleagues, in four papers published in 1960, discovered and defined the circulating renin system (i.e., the renin-angiotensin-aldosterone hormonal control system) as a major endocrine servocontrol that continuously co-regulates ambulatory blood pressure levels and body sodium and potassium content in all of us. At the same time, he proposed, and later proved, that high plasma renin-angiotensin levels cause and sustain the high blood pressure of malignant hypertension (MHT) and of medium and high renin essential hypertensions (EHT) in whom, their very high, or mildly elevated plasma renin excesses, respectively, are closely associated with immediate (MHT) or more delayed (EHT) occurrences of the plasma renin-angiotensin induced fatal vasculotoxic sequelae, i.e., heart attack, heart failure, stroke, or kidney failure, all of which, the high blood pressure, the high aldosterone and low K+ and the arteriolar vasculotoxic injury to heart, brain and kidney vessels can be explicitly prevented or arrested by antirenin R drug therapy in these R patients, or by a total nephrectomy. Understanding this MHT pathophysiologic template enabled Dr. Laragh and his group to develop a whole new understanding of the basic determinants of all hypertensions and its relevance for applying physiologically correct drug therapies.

Dr. Laragh with Joan Banes and with Dr. Jean Sealey introduced ambulatory plasma renin activity (PRA) testing to assess and correctly treat either the sodium-volume V factor (PRA <0.65) of low renin salt-volume V hypertensions or the plasma renin-angiotensin vasoconstrictor R factor (PRA >0.65) of R hypertensions. They showed how to reduce or block the R factor in R patients by giving one of three specific anti-renin system R drug types that Laragh had introduced and defined to block the circulating renin system at three different molecular sites, (1) a beta blocker, propranolol, to reduce kidney, beta receptor governed renin release, (2) the original venom i.v. nonapeptide converting enzyme inhibitor teprotide, (CEI) and (3) the first i.v. octapeptide angiotensin antagonist, saralasin, (ARB). This work, by defining three different antirenin system R drug prototypes and demonstrates their extremely similar antihypertensive effectiveness in patients, according to the height of the baseline renin level in each patient, launched the clinical field of antirenin system R drugs and soon led industry to develop many orally active analog of teprotide CEIs and later ARBs, which, together with the beta blockers, have revolutionized the drug treatment of a common plasma renin-mediated types of essential hypertension per se while having an equally powerful impact for preventing or arresting its accompanying fatal renin-angiotensin-mediated vasculotoxic events, heart attack, heart failure, stroke and kidney failure.

Altogether, this Laragh research by describing the roles of excess plasma renin angiotensin levels for causing and sustaining major common hypertensive disorders and also causing their related angiotensin-mediated fatal vasculotoxic sequelae heart attack, or stroke or heart or kidney failure. Thus, two explicit effects of increased kidney renin release are (1) a blood pressure rise and (2) vasculotoxic arteriolar injury as induced by an overactive or dysregulated endocrine control system, have forever changed perceptions about the causation of hypertensive cardiovascular disorders in general while introducing new potentials targets for explicit primary and follow-up drug treatments targeted in each patient to correct either the salt-volume or the renin form of hypertension as revealed by initial and follow-up ambulatory plasma renin testing in either untreated patients or in unresponsive treated patients already receiving multiple drugs.

This research in turn has created as yet unexplored, but huge new opportunities for using routine renin testing to apply explicitly targeted corrective drug treatments on a broad scale, not just to correct each hypertensive patient, but also to prevent or arrest the fatal renin-mediated cardiovasculotoxic sequelae of R patients while treating V patients correctly instead with a primary V drug, to thereby extend useful life for millions of cardiovascular patients, many of whom can be controlled by a single correct drug type daily for life.

This opportunity to change hypertension analysis and treatment strategies is propitious because nationwide efforts to reduce the huge burden of cardiovascular mortality and morbidity continue to be far from optimal. Thus, heart attack rates may have stopped declining and stroke rates actually have been rising in the U.S over the past 10 years. These results are partly explained by the continued failure to improve BP correction rates despite the introduction of many new and potent antihypertensive drugs. These poor results are also surely due to the failure of government guidelines (JNC7) and of its companion huge clinical trial (ALLHAT) to recognize either the very existence of the V and R patient types or of the selective V and R specific hypertension drug types, while instead continuing to advise a diuretic first for all strategy supplemented by unselective and indiscriminate additions of more and more drugs for the treatment failures without any plan for subtraction of unneeded drugs.

The resulting poor drug treatment outcomes may also be explained by the statistically valid, but weak impact of the huge use of effective anticholesterol drugs and low-fat diets on heart attack and stroke rates, as indicated by results from many 5 year trials in which giving cholesterol lowering drugs lowered cholesterol but protected only a very few from a heart attack, and provided no 5 year benefits i.e., no reduction in heart attacks or strokes and thus no chance of benefit for over 90% of the trial participants. In short, despite all of the above well intentioned efforts, hypertension continues to be very poorly controlled, and heart attack rates are not falling, and stroke rates are rising in the USA. Altogether these failed experiences indicate a real need for a conceptually superior, and rational biochemically based hypertension treatment system, to really control hypertension the needs for which have never before been so clearly defined.

We now stand on a platform of opportunity created by the Laragh definition of a two component sodium or plasma renin causation model that works interactively to support all normotension and hypertension. We know that low renin salt hypertension is sodium-volume V excess mediated, and so is correctable by a natriuretic anti-volume V drug type and we also know that plasma renin-angiotensin mediated R excesses in humans and in animals, causes and sustain not only R hypertensions but also can directly cause their attendant fatal coronary, cerebral or renal vessel angiotensin induced vasculotoxic consequences, i.e., heart attack, heart failure, stroke, kidney failure, all of which are preventable or arrestable by applying explicit renin test-guided primary antisodium V drug treatment for V patients and instead primary antirenin R drug treatment for R patients. Thus, the goal of reaching a new level of health care to extend useful life for millions of patients is now within our grasp. Moreover, the data indicate that longterm correction for most patients can be achieved by monotherapy, using either a single correct anti-volume V or antirenin R drug type for life. In this context, other European countries, in writing their own guidelines, are now departing from their previous concordance with the US advice (JNC7) of simply and unselectively adding drug upon drug hoping to subdue blood pressure (JNC7). Most encouraging of all is the fact that the UK Hypertension Society Guidelines (2004 Journal of Human Hypertension) have abandoned the US system altogether to now recommend instead a plasma renin based model, similar to the Laragh Method, for analyzing and treating all hypertension.