BLOOD PRESSURE
1992; 1: 5-8
Some Reflections on Today’s Hypertension Research BJORN FOLKOW
Blood Press Downloaded from informahealthcare.com by University of Otago on 01/09/15 For personal use only.
From the Department of Physiology, University of Goteborg. Goteborg, Sweden
Asked “to add some words” to this BLOOD PRESSURE volume, the first one will be “Welcome” to this neophyte among journals devoted to hypertension. Research in this field has during the last few decades increased dramatically and, with that, the need of making the results rapidly and widely accessible for criticism and application. A major reason for this development is the fact that a rapidly growing fraction of the world population nowadays reaches an age where the harmful effects of increased blood pressure become serious not only for individuals but for society as well, Not seldom, however, the complaint can be heard that “too much is already getting published”-though mainly as a cry of despair, since it is well-nigh impossible to cope with the present deluge of news. T o this should be added that everything emerging from hypertension research is not always gold. It is, on the other hand, true that the chance to strike gold increases with the number, and efforts, of diggers; furthermore, that it can never be foreseen where, how and by whom real discoveries will emerge. In addition, as the history of science strikingly illustrates, apparently trivial findings have not seldom in the final end proven to be of great importance. So much about the justification of getting BLOOD PRESSURE launched and airborne. Concerning the choice of title-BLOOD PRESSURE-it appeals much, also to physiologists: Apart from striking the heart of the matter in hypertension research, it also provides room for the many factors which-at different levels of biological organisation-help to determine the driving force behind tissue blood supply. Like it cannot be foreseen from which individuals the best contributions to hypertension research will come, it can neither be predicted which lines of approach, or levels of biomedical research, will finally offer the best insight into this multifactorial disorder of regulation. I will take this opportunity to discuss some aspects of hypertension research that I have found particularly interesting, sometimes amusing and not seldom puzzling; one reason is that they exemplify how also scientists, and thereby science, are far from immune to the impact of fads and fashions which have so often dominated human endeavours throughout history. I first want to say a few words about comparative physiology, a lovely discipline where the strangest species are explored by more or less ‘odd’ biologists,
who often couldn’t care less about human affairs. However, more often than not this has led to discoveries of general biomedical importance, and not seldom with direct relevance for human disorders. Had, for example, hypertensiologists during the last 5-6 decades of intense studies on man, rats, dogs and rabbits paid some attention also to the up to 6 meter tall giraffe and its circulatory situation, the great hemodynamic importance of altered cardiovascular design even for hypertensive disorders had probably been understood much earlier [l, 21. It might then also have been realized that the level of arterial pressure is not onZy an affair for the kidneys, as is so often assumed. Certainly the brainmodest as it is in giraffes-must have a dominant say, simply because mean aortic pressure must in a mature giraffe bull be above 250 mmHg for the brain to receive any blood at all. The giraffe’s kidneys, placed at heart level, merely have to accept this CNS dominance and arrange their preglomerular resistance and glomerular filtration accordingly. Sure enough, the brain must have an important say in most species, and man is probably no exception as we insist on carrying our brain most of the day almost half a meter above heart level. This may be at least part of the reason why during sleep we allow for a blood pressure decline of 20-25 mmHg, only to force the brain towards morning events again to raise mean arterial pressure via neuro-hormonal signals, which then also give the kidneys a signal. Furthermore, how about the feet circulation in giraffes,with a driving pressure of some 250 mmHg, but with 1 transmural arterial pressures of 400-500 mmHg? This creature certainly needs a highly specialized geometric design of cardiovascular structures. This was, in fact, illustrated as early as in 1957 in a fascinating paper by Goetz & Keen [3], though this was apparently unknown to, or neglected by, most hypertensiologists. Here the law of Laplace must determine the regional relationships between pressure and structural wall/ lumen ratio for both heart and vessels, and the law of Poiseuille the relationships between driving pressure and the dimensions of the resistance vasculature. Functional influences of myogenic orland neurohormonal origin could not possibly alone handle such immense regional differences in transmural and driving pressures, and particularly not since they, when superimposed on a suitable structural framework, must allow
Blood Press Downloaded from informahealthcare.com by University of Otago on 01/09/15 For personal use only.
6
B. Folkow
for constriction-dilatation adjustments of a range similar to that in other species. Moreover, how about pressure and cardiovascular design in the giraffe baby which, after floating weightlessly in the womb, is delivered from 3 meters’ height by the standing mother, and thereafter must soon put a 2-meter body in the erect position with the brain placed a good meter above heart level? How is cardiovascular design and function programmed to handle such dramatic changes in hydrostatic forces, and how do they change along with additional growth? Last, but certainly not least, how can heart and vessels handle these regionally enormous loads during a giraffe life span of some 40-50 years (in zoos, where lions cannot provide a shortcut) with apparently little damage, while in man and most other species heart and vessels suffer badly already at some 25% pressure elevation beyond our modest 90- 100 mmHg? Why, incidentally, have our rabbit friends almost a 20 mmHg lower pressure than man, while still smaller rats which are little troubled by hydrostatic pressure differences have, if anything, slightly higher MAP levels than man? And why do rabbits often shown cardiovascular deterioration upon so modest pressure elevations that they hardly surpass what is normal for rats or man? In the unlikely case that man could incorporate those particular parts of the giraffe genome (preferentially not the others) which make cardiovascular tissues fairly immune to high load, then hypertension might have been considered to be about as harmless as long feet or large ears. Here molecular biology could have its day by revealing these particular secrets. In fact, heart and vessels in some human beings seem to endure quite high pressures fairly well over decades, while in others even modest pressure elevations seem to invite to trouble, a circumstance which might reflect similar genetic differences also inbetween human subjects, though of a less striking dignity than between giraffes and man. To this comes the highly interesting operations of the barostat mechanisms when for instance giraffes drink and must place the brain well below heart level, when presumably the carotid baroreceptors must work intensely to keep the pressure load on brain arteries reflexly within limits. In other words, these creatures offer a series of interesting challenges also to hypertensiologists, though unfortunately they are difficult to house, far from easy to handle and also forbiddingly expensive. There are several other aspects of hypertension research where in my view the balance of interest, and with that research engagements, has been somewhat unidirectional. For example, why was the great importance of brain influences on circulatory events 14, 51 for long so relatively little considered when it comes to primary hypertension, while papers dealing with the
supposed role of for instance the renin-angiotensin system could fill libraries? After all, the brain can via its limbic-hypothalamic regions take command over essentially all nervous and hormonal links involved in cardiovascular control, which includes the kidneys and the renin-angiotensin system [4, 51. As already mentioned, the important central nervous influence on cardiovascular affairs should be obvious from the very diurnal pressure differences in our sleep and wakefulness. Furthermore, the brain can by means of these links powerfully overrule the bulbospinal reflex control, as well as the autoregulatory adjustments of heart and vessels, by superimposing on both a variety of differentiated reaction patterns. Several of these limbic-hypothalamic response patterns, designed millions of years ago to handle the environmental challenges of a primitive huntergatherer existence, are nowadays mainly activated by a variety of ‘brave-new-world’ psychosocial stimuli. Thus, particularly in susceptible individuals even modest fits of anger, irritation, thrill or enjoyment can raise blood pressure by 15-20% or more, and for many this may occur frequently over long periods. It would therefore indeed be strange if such events left cardiovascular structures entirely unaffected, particularly in genetically predisposed subjects [l, 2, 4, 51. It should then be emphasized that several of the involved transmitters and hormones exert longterm trophic influences on heart and vessels, thus facilitating the development of a gradual structural upward resetting of the cardiovascular system which characterizes established primary hypertension [l , 2, 61. Sceptics doubting the longterm importance of such intermittent pressure and growth-promoting effects on cardiovascular design should perhaps consider how their own skeletal muscle system responds to changes in load: It is well known that intermittent physical training soon leads to muscle hypertrophy, largely proportioned to the extent, duration and frequency of the imposed load. Moreover, the doping abuses in modern athletics emphasize the trophic importance of several hormones for these growth processes. Finally, it is also obvious how genetics determine the basic design of the locomotor system as well as its responsiveness to training, as is reflected by leptosomic versus athletic body builds and what happens when they are exposed to changes in activity. Why should the cardiovascular system be principally different in these respects? Nevertheless, the longterm importance of the psychosocial environment for the gradual development of primary hypertension has often been relatively disregarded, while the assumed harmful effects of another ‘environmental’ factor, i.e. the level of salt intake, has intensely engaged hypertensiologists for almost a cen-
Blood Press Downloaded from informahealthcare.com by University of Otago on 01/09/15 For personal use only.
Rejections on hypertension research tury [7, 81. Thus it may in a way have come as an anticlimax when a recent world-wide study of over 10,000 people suggested that mean arterial pressure differs by 1 mmHg at the most over an intake range from some 50 mM up to 150-200 mM Na per day [9, 101. However, such ‘either-or’ attitudes4ertainly not uncommon in research debates-nearly always tend to end up in a biological ‘both-and’ solution, because the ‘psycho-social’and the ‘salt’ factors prove to be closely intertwined concerning their functional effects and are then in some respects even mutually reinforcing [7, 101. My long interest in such interactions between combined genetic-environmental excitatory influences and the rapidly induced structural response to such stimuli-and particularly since this invites to positivefeedback effects at the resistance level [ 1,2]-has led to the fact that I nowadays find it more mysterious that 85-90% of populations manage to remain normotensive for a lifetime than the fact that 10-15% gradually develop hypertension. This points to some as yet neglected but potentially powerful negative-feedback mechanisms which must also be more resistant to, for instance, structural upward resettings than is the case with most reflex barostat mechanisms and the renal barostat function. This has increasingly turned my interest towards the renomedullary hormonal depressor system, pioneered by Eric Muirhead [ 113. More than 3 decades ago he realized that reduced activity of physiological depressor systems could be as important in hypertension as increased engagement of ‘pressor’ mechanisms. This potentially very powerful depressor system combines in a unique way direct vasodilator actions with inhibition of sympathetic activity and renal natriuretic effects [ 1 1, 121. For decades, however, the Muirhead group was almost alone in pursuing such lines of thought and biological actions, and it may be questioned why. One important reason may simply be the fact that the powerful renomedullary depressor system has also its efficient physiological negative feedbacks. Thus, it is reciprocally suppressed by sympathetic activation and by angiotensin. Now, mostly in experiments on anesthetized or awake animals, the sympathetic and renin-angiotensin activities are more or less enhanced. Thereby their suppression of the renomedullary system hinders Medullipin release and the system will remain masked. Incidentally, several of the ‘unexplained’ beneficial actions of e.g. p-receptor blockers or ACE-blockers during hypertension treatment might be due to their suppression of this sympathetic-angiotensin inhibitory influence, causing a ‘des-inhibitory’ release of the humoral renomedullary depressor effects. In any case, a wider interest in dilator influences in
7
general, and also in hypertension research, was in a way aroused first when Robert Furchgott (1982) showed to an astonished scientific community that also endothelial cells release powerful vasodilator factors which, among other things, help to relax their smooth muscle neighbours [13]. This finding started a hectic hunt for both endothelial pressor and depressor influences, as well as explorations whether a failure of inhibitory endothelial mechanisms might contribute to raise systemic resistance also in primary hypertension. Thus, at long last studies of physiological depressor mechanisms have become highest fashion-but should have been so decades ago when the early studies of Muirhead paved the way. These examples may illustrate how scientists, and thereby research, on and off can be carried away by the very human faiblesse for fads and fashions, and how such influences have also affected hypertension research. Obviously, this multifactorial disorder of regulation involves virtually all levels of biological organisation-ranging from the highest brain centres, via the levels of bulbospinal reflex control and organsystem autoregulatory regulation, down to the cellularsubcellular and molecular levels. Among these no-one is likely to offer the whole solution, and no-one can replace the others. For example, a genetic-molecular change, affecting cells in general, may well have quite opposite effects on for instance vascular smooth muscle cells and on CNS centres for cardiovascular control, with unpredictable net effects on blood pressure. Therefore, all the mentioned levels of biological control must be taken into account in judging overall circulatory effects when the complexities of primary hypertension are considered. This leads me to some final considerations concerning molecular biology, where certainly great breakthroughs have occurred which in all likelihood will hold also for hypertension research. However. again the human tendency to be carried away by new and glorious trends calls for a word of caution since the present enthusiasm for molecular biology has not seldom led to dangerous neglect of the other-in the final end+qually important levels of bio-medical research-even affecting the policy of scientific support in some countries. On a less dramatic level, the following sequence appeared, for example, in a recent, per se interesting “NATURE” article [I41 illustrating how the virtues of the molecular approach to the author seemed to be way above the supposedly ‘descriptive’ studies so far carried out at higher levels of biological organisation with respect to primary hypertension: . . .Until recently, much of the research on hypertension has consisted of descriptive studies of the “
8
B. Folkow
Blood Press Downloaded from informahealthcare.com by University of Otago on 01/09/15 For personal use only.
biochemical and physiological phenomena that accompany high blood pressure. The current reports, together with those by Rapp et al. and Mullins et al. on the role of the renin gene in experimental models of high blood pressure, signal the beginning of a new era in which the pathogenesis of hypertension may finally be unravelled with modern molecular genetic techniques. . .” Admittedly a word or caution was added but, in a way, attitudes like these carry some resemblance to the remark of an old brick producer joining a tourist trip to Rome. When faced by the magnificent beauty and immense vault dimensions of Michelangelo’s St. Peter’s Cathedral he mumbled “Trivialities compared with production of building stones”. Another rough parallel: An airborne Jumbojet is something infinitely more than the sum of per se perfect myriads of components from which it is constructed. These, after all, remain ‘a heap of sophisticated junk’, until assembled, trimmed, tested and made airborne, which calls for an entirely different set of experts in aerodynamics, feedback systems, combustion energetics, etc., plus come competent pilots at the helm. Obviously, hypertension research also for the future needs the close cooperation of experts at all the mentioned levels of biological organisation where, of course, molecular biologists are bound to make very important contributions. I am also confident that BLOOD PRESSURE will attract both readers and writers from a wide range of experts in hypertension research, and I wish the new journal a happy start and a successful future. REFERENCES 1. Folkow B. Physiological aspects of primary hyperten-
sion. Physiol Rev 1982; 62: 347-504. 2. Folkow B. Giraffes rats, and man-what is the importance of the ‘structural factor’ in normo- and hypertensive states? Clin Exp Pharmacol Physiol 1991; 18: 3-11.
3. Goetz RH, Keen EN. Some aspects of the cardiovascular system in the giraffe. Angiology 1957; 8: 542-64. 4. Folkow B. Psychosocial and central nervous influences in primary hypertension. Circulation 1987,76(Suppl I): 1019. 5 . Henry JP, Grim CE. Psychosocial mechanisms of primary hypertension. J Hypertension 1990; 8: 783-93. 6. Lever AF. Editorial review. Slow pressor mechanisms in hypertension: A role for hypertrophy of resistance vessels? J Hypertension 1986; 4: 515-24. 7. Folkow B, Ely DL. Editorial review. Dietary sodium effects on cardiovascular and sympathetic neuroeffector functions as studied in various rat models. J Hypertension 1987; 5 : 383-95. 8. Simpson FO. Blood pressure and sodium intake. In Laragh, J.H, Brenner B.M, eds. Hypertension: pathophysiology, diagnosis and management. New York: Raven 1990: 205-15. 9. Special Issue. Intersalt J Hum Hypertens 1989; 3: 279407. 10. Folkow B. Salt and hypertension. NIPS 1990; 5: 220-4. 1 . Muirhead EE, Pitcock JA. Editorial review. The renal antihypertensive hormone. Hypertension 1985; 3: 1-8. 2. Karlstrom G, Folkow B, Gothberg G. The humoral renal antihypertensive system: Nervous and hemodynamic effects in normotensive and unclipped renal hypertensive rats. Am J Med Sci 1988; 295: 258-62. 3. Furchgott RF. The 1989 Ulf von Euler Lecture. Studies on endothelium-dependent vasodilatation and the endothelium-derived relaxing factor. Acta Physiol Scand 1989; 139: 257-70. 14. Kurtz T. An ACE for hypertension. Nature 1991; 353: 499.
Address for correspondence: Professor Bjorn Folkow Department of Physiology University of Gothenburg P.O. Box 33031 S-400 33 Gothenburg Sweden
1992; 1: 5-8
Some Reflections on Today’s Hypertension Research BJORN FOLKOW
Blood Press Downloaded from informahealthcare.com by University of Otago on 01/09/15 For personal use only.
From the Department of Physiology, University of Goteborg. Goteborg, Sweden
Asked “to add some words” to this BLOOD PRESSURE volume, the first one will be “Welcome” to this neophyte among journals devoted to hypertension. Research in this field has during the last few decades increased dramatically and, with that, the need of making the results rapidly and widely accessible for criticism and application. A major reason for this development is the fact that a rapidly growing fraction of the world population nowadays reaches an age where the harmful effects of increased blood pressure become serious not only for individuals but for society as well, Not seldom, however, the complaint can be heard that “too much is already getting published”-though mainly as a cry of despair, since it is well-nigh impossible to cope with the present deluge of news. T o this should be added that everything emerging from hypertension research is not always gold. It is, on the other hand, true that the chance to strike gold increases with the number, and efforts, of diggers; furthermore, that it can never be foreseen where, how and by whom real discoveries will emerge. In addition, as the history of science strikingly illustrates, apparently trivial findings have not seldom in the final end proven to be of great importance. So much about the justification of getting BLOOD PRESSURE launched and airborne. Concerning the choice of title-BLOOD PRESSURE-it appeals much, also to physiologists: Apart from striking the heart of the matter in hypertension research, it also provides room for the many factors which-at different levels of biological organisation-help to determine the driving force behind tissue blood supply. Like it cannot be foreseen from which individuals the best contributions to hypertension research will come, it can neither be predicted which lines of approach, or levels of biomedical research, will finally offer the best insight into this multifactorial disorder of regulation. I will take this opportunity to discuss some aspects of hypertension research that I have found particularly interesting, sometimes amusing and not seldom puzzling; one reason is that they exemplify how also scientists, and thereby science, are far from immune to the impact of fads and fashions which have so often dominated human endeavours throughout history. I first want to say a few words about comparative physiology, a lovely discipline where the strangest species are explored by more or less ‘odd’ biologists,
who often couldn’t care less about human affairs. However, more often than not this has led to discoveries of general biomedical importance, and not seldom with direct relevance for human disorders. Had, for example, hypertensiologists during the last 5-6 decades of intense studies on man, rats, dogs and rabbits paid some attention also to the up to 6 meter tall giraffe and its circulatory situation, the great hemodynamic importance of altered cardiovascular design even for hypertensive disorders had probably been understood much earlier [l, 21. It might then also have been realized that the level of arterial pressure is not onZy an affair for the kidneys, as is so often assumed. Certainly the brainmodest as it is in giraffes-must have a dominant say, simply because mean aortic pressure must in a mature giraffe bull be above 250 mmHg for the brain to receive any blood at all. The giraffe’s kidneys, placed at heart level, merely have to accept this CNS dominance and arrange their preglomerular resistance and glomerular filtration accordingly. Sure enough, the brain must have an important say in most species, and man is probably no exception as we insist on carrying our brain most of the day almost half a meter above heart level. This may be at least part of the reason why during sleep we allow for a blood pressure decline of 20-25 mmHg, only to force the brain towards morning events again to raise mean arterial pressure via neuro-hormonal signals, which then also give the kidneys a signal. Furthermore, how about the feet circulation in giraffes,with a driving pressure of some 250 mmHg, but with 1 transmural arterial pressures of 400-500 mmHg? This creature certainly needs a highly specialized geometric design of cardiovascular structures. This was, in fact, illustrated as early as in 1957 in a fascinating paper by Goetz & Keen [3], though this was apparently unknown to, or neglected by, most hypertensiologists. Here the law of Laplace must determine the regional relationships between pressure and structural wall/ lumen ratio for both heart and vessels, and the law of Poiseuille the relationships between driving pressure and the dimensions of the resistance vasculature. Functional influences of myogenic orland neurohormonal origin could not possibly alone handle such immense regional differences in transmural and driving pressures, and particularly not since they, when superimposed on a suitable structural framework, must allow
Blood Press Downloaded from informahealthcare.com by University of Otago on 01/09/15 For personal use only.
6
B. Folkow
for constriction-dilatation adjustments of a range similar to that in other species. Moreover, how about pressure and cardiovascular design in the giraffe baby which, after floating weightlessly in the womb, is delivered from 3 meters’ height by the standing mother, and thereafter must soon put a 2-meter body in the erect position with the brain placed a good meter above heart level? How is cardiovascular design and function programmed to handle such dramatic changes in hydrostatic forces, and how do they change along with additional growth? Last, but certainly not least, how can heart and vessels handle these regionally enormous loads during a giraffe life span of some 40-50 years (in zoos, where lions cannot provide a shortcut) with apparently little damage, while in man and most other species heart and vessels suffer badly already at some 25% pressure elevation beyond our modest 90- 100 mmHg? Why, incidentally, have our rabbit friends almost a 20 mmHg lower pressure than man, while still smaller rats which are little troubled by hydrostatic pressure differences have, if anything, slightly higher MAP levels than man? And why do rabbits often shown cardiovascular deterioration upon so modest pressure elevations that they hardly surpass what is normal for rats or man? In the unlikely case that man could incorporate those particular parts of the giraffe genome (preferentially not the others) which make cardiovascular tissues fairly immune to high load, then hypertension might have been considered to be about as harmless as long feet or large ears. Here molecular biology could have its day by revealing these particular secrets. In fact, heart and vessels in some human beings seem to endure quite high pressures fairly well over decades, while in others even modest pressure elevations seem to invite to trouble, a circumstance which might reflect similar genetic differences also inbetween human subjects, though of a less striking dignity than between giraffes and man. To this comes the highly interesting operations of the barostat mechanisms when for instance giraffes drink and must place the brain well below heart level, when presumably the carotid baroreceptors must work intensely to keep the pressure load on brain arteries reflexly within limits. In other words, these creatures offer a series of interesting challenges also to hypertensiologists, though unfortunately they are difficult to house, far from easy to handle and also forbiddingly expensive. There are several other aspects of hypertension research where in my view the balance of interest, and with that research engagements, has been somewhat unidirectional. For example, why was the great importance of brain influences on circulatory events 14, 51 for long so relatively little considered when it comes to primary hypertension, while papers dealing with the
supposed role of for instance the renin-angiotensin system could fill libraries? After all, the brain can via its limbic-hypothalamic regions take command over essentially all nervous and hormonal links involved in cardiovascular control, which includes the kidneys and the renin-angiotensin system [4, 51. As already mentioned, the important central nervous influence on cardiovascular affairs should be obvious from the very diurnal pressure differences in our sleep and wakefulness. Furthermore, the brain can by means of these links powerfully overrule the bulbospinal reflex control, as well as the autoregulatory adjustments of heart and vessels, by superimposing on both a variety of differentiated reaction patterns. Several of these limbic-hypothalamic response patterns, designed millions of years ago to handle the environmental challenges of a primitive huntergatherer existence, are nowadays mainly activated by a variety of ‘brave-new-world’ psychosocial stimuli. Thus, particularly in susceptible individuals even modest fits of anger, irritation, thrill or enjoyment can raise blood pressure by 15-20% or more, and for many this may occur frequently over long periods. It would therefore indeed be strange if such events left cardiovascular structures entirely unaffected, particularly in genetically predisposed subjects [l, 2, 4, 51. It should then be emphasized that several of the involved transmitters and hormones exert longterm trophic influences on heart and vessels, thus facilitating the development of a gradual structural upward resetting of the cardiovascular system which characterizes established primary hypertension [l , 2, 61. Sceptics doubting the longterm importance of such intermittent pressure and growth-promoting effects on cardiovascular design should perhaps consider how their own skeletal muscle system responds to changes in load: It is well known that intermittent physical training soon leads to muscle hypertrophy, largely proportioned to the extent, duration and frequency of the imposed load. Moreover, the doping abuses in modern athletics emphasize the trophic importance of several hormones for these growth processes. Finally, it is also obvious how genetics determine the basic design of the locomotor system as well as its responsiveness to training, as is reflected by leptosomic versus athletic body builds and what happens when they are exposed to changes in activity. Why should the cardiovascular system be principally different in these respects? Nevertheless, the longterm importance of the psychosocial environment for the gradual development of primary hypertension has often been relatively disregarded, while the assumed harmful effects of another ‘environmental’ factor, i.e. the level of salt intake, has intensely engaged hypertensiologists for almost a cen-
Blood Press Downloaded from informahealthcare.com by University of Otago on 01/09/15 For personal use only.
Rejections on hypertension research tury [7, 81. Thus it may in a way have come as an anticlimax when a recent world-wide study of over 10,000 people suggested that mean arterial pressure differs by 1 mmHg at the most over an intake range from some 50 mM up to 150-200 mM Na per day [9, 101. However, such ‘either-or’ attitudes4ertainly not uncommon in research debates-nearly always tend to end up in a biological ‘both-and’ solution, because the ‘psycho-social’and the ‘salt’ factors prove to be closely intertwined concerning their functional effects and are then in some respects even mutually reinforcing [7, 101. My long interest in such interactions between combined genetic-environmental excitatory influences and the rapidly induced structural response to such stimuli-and particularly since this invites to positivefeedback effects at the resistance level [ 1,2]-has led to the fact that I nowadays find it more mysterious that 85-90% of populations manage to remain normotensive for a lifetime than the fact that 10-15% gradually develop hypertension. This points to some as yet neglected but potentially powerful negative-feedback mechanisms which must also be more resistant to, for instance, structural upward resettings than is the case with most reflex barostat mechanisms and the renal barostat function. This has increasingly turned my interest towards the renomedullary hormonal depressor system, pioneered by Eric Muirhead [ 113. More than 3 decades ago he realized that reduced activity of physiological depressor systems could be as important in hypertension as increased engagement of ‘pressor’ mechanisms. This potentially very powerful depressor system combines in a unique way direct vasodilator actions with inhibition of sympathetic activity and renal natriuretic effects [ 1 1, 121. For decades, however, the Muirhead group was almost alone in pursuing such lines of thought and biological actions, and it may be questioned why. One important reason may simply be the fact that the powerful renomedullary depressor system has also its efficient physiological negative feedbacks. Thus, it is reciprocally suppressed by sympathetic activation and by angiotensin. Now, mostly in experiments on anesthetized or awake animals, the sympathetic and renin-angiotensin activities are more or less enhanced. Thereby their suppression of the renomedullary system hinders Medullipin release and the system will remain masked. Incidentally, several of the ‘unexplained’ beneficial actions of e.g. p-receptor blockers or ACE-blockers during hypertension treatment might be due to their suppression of this sympathetic-angiotensin inhibitory influence, causing a ‘des-inhibitory’ release of the humoral renomedullary depressor effects. In any case, a wider interest in dilator influences in
7
general, and also in hypertension research, was in a way aroused first when Robert Furchgott (1982) showed to an astonished scientific community that also endothelial cells release powerful vasodilator factors which, among other things, help to relax their smooth muscle neighbours [13]. This finding started a hectic hunt for both endothelial pressor and depressor influences, as well as explorations whether a failure of inhibitory endothelial mechanisms might contribute to raise systemic resistance also in primary hypertension. Thus, at long last studies of physiological depressor mechanisms have become highest fashion-but should have been so decades ago when the early studies of Muirhead paved the way. These examples may illustrate how scientists, and thereby research, on and off can be carried away by the very human faiblesse for fads and fashions, and how such influences have also affected hypertension research. Obviously, this multifactorial disorder of regulation involves virtually all levels of biological organisation-ranging from the highest brain centres, via the levels of bulbospinal reflex control and organsystem autoregulatory regulation, down to the cellularsubcellular and molecular levels. Among these no-one is likely to offer the whole solution, and no-one can replace the others. For example, a genetic-molecular change, affecting cells in general, may well have quite opposite effects on for instance vascular smooth muscle cells and on CNS centres for cardiovascular control, with unpredictable net effects on blood pressure. Therefore, all the mentioned levels of biological control must be taken into account in judging overall circulatory effects when the complexities of primary hypertension are considered. This leads me to some final considerations concerning molecular biology, where certainly great breakthroughs have occurred which in all likelihood will hold also for hypertension research. However. again the human tendency to be carried away by new and glorious trends calls for a word of caution since the present enthusiasm for molecular biology has not seldom led to dangerous neglect of the other-in the final end+qually important levels of bio-medical research-even affecting the policy of scientific support in some countries. On a less dramatic level, the following sequence appeared, for example, in a recent, per se interesting “NATURE” article [I41 illustrating how the virtues of the molecular approach to the author seemed to be way above the supposedly ‘descriptive’ studies so far carried out at higher levels of biological organisation with respect to primary hypertension: . . .Until recently, much of the research on hypertension has consisted of descriptive studies of the “
8
B. Folkow
Blood Press Downloaded from informahealthcare.com by University of Otago on 01/09/15 For personal use only.
biochemical and physiological phenomena that accompany high blood pressure. The current reports, together with those by Rapp et al. and Mullins et al. on the role of the renin gene in experimental models of high blood pressure, signal the beginning of a new era in which the pathogenesis of hypertension may finally be unravelled with modern molecular genetic techniques. . .” Admittedly a word or caution was added but, in a way, attitudes like these carry some resemblance to the remark of an old brick producer joining a tourist trip to Rome. When faced by the magnificent beauty and immense vault dimensions of Michelangelo’s St. Peter’s Cathedral he mumbled “Trivialities compared with production of building stones”. Another rough parallel: An airborne Jumbojet is something infinitely more than the sum of per se perfect myriads of components from which it is constructed. These, after all, remain ‘a heap of sophisticated junk’, until assembled, trimmed, tested and made airborne, which calls for an entirely different set of experts in aerodynamics, feedback systems, combustion energetics, etc., plus come competent pilots at the helm. Obviously, hypertension research also for the future needs the close cooperation of experts at all the mentioned levels of biological organisation where, of course, molecular biologists are bound to make very important contributions. I am also confident that BLOOD PRESSURE will attract both readers and writers from a wide range of experts in hypertension research, and I wish the new journal a happy start and a successful future. REFERENCES 1. Folkow B. Physiological aspects of primary hyperten-
sion. Physiol Rev 1982; 62: 347-504. 2. Folkow B. Giraffes rats, and man-what is the importance of the ‘structural factor’ in normo- and hypertensive states? Clin Exp Pharmacol Physiol 1991; 18: 3-11.
3. Goetz RH, Keen EN. Some aspects of the cardiovascular system in the giraffe. Angiology 1957; 8: 542-64. 4. Folkow B. Psychosocial and central nervous influences in primary hypertension. Circulation 1987,76(Suppl I): 1019. 5 . Henry JP, Grim CE. Psychosocial mechanisms of primary hypertension. J Hypertension 1990; 8: 783-93. 6. Lever AF. Editorial review. Slow pressor mechanisms in hypertension: A role for hypertrophy of resistance vessels? J Hypertension 1986; 4: 515-24. 7. Folkow B, Ely DL. Editorial review. Dietary sodium effects on cardiovascular and sympathetic neuroeffector functions as studied in various rat models. J Hypertension 1987; 5 : 383-95. 8. Simpson FO. Blood pressure and sodium intake. In Laragh, J.H, Brenner B.M, eds. Hypertension: pathophysiology, diagnosis and management. New York: Raven 1990: 205-15. 9. Special Issue. Intersalt J Hum Hypertens 1989; 3: 279407. 10. Folkow B. Salt and hypertension. NIPS 1990; 5: 220-4. 1 . Muirhead EE, Pitcock JA. Editorial review. The renal antihypertensive hormone. Hypertension 1985; 3: 1-8. 2. Karlstrom G, Folkow B, Gothberg G. The humoral renal antihypertensive system: Nervous and hemodynamic effects in normotensive and unclipped renal hypertensive rats. Am J Med Sci 1988; 295: 258-62. 3. Furchgott RF. The 1989 Ulf von Euler Lecture. Studies on endothelium-dependent vasodilatation and the endothelium-derived relaxing factor. Acta Physiol Scand 1989; 139: 257-70. 14. Kurtz T. An ACE for hypertension. Nature 1991; 353: 499.
Address for correspondence: Professor Bjorn Folkow Department of Physiology University of Gothenburg P.O. Box 33031 S-400 33 Gothenburg Sweden
