Biomedical subjects
Publications and source records attributed to B Folkow.
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After a brief historic survey, sympathetic-neurogenic contributions to the multifactorial, polygenetically linked etiology of primary (essential) hypertension are outlined towards the background of experimental findings both in various rat models and in human subjects. It is emphasized how at least some variants of both human and rat primary hypertension show a genetically linked, central nervous system (CNS)-dependent increase of responsiveness to ordinary daily psychosocial stimuli. Such influences, conveyed by way of neurohormonal response patterns, seem to act in concert with cardiovascular structural adaptation, also sometimes genetically reinforced, so as to gradually elevate the pressure equilibrium until a state of "established" hypertension is reached. However, also in variants characterized by, eg, a genetically increased sensitivity to salt intake of renal or other origin, neurohormonal mechanisms seem to be involved early, though probably via other types of central mechanisms, thereby helping to convey the pressure-elevating influences of the altered salt-volume handling. Evidence is now at hand to indicate that these two "environmental factors," ie, excitatory psychosocial influences and increased salt intake, which at least partly operate via different genetic elements, are in fact closely intertwined, and even mutually reinforcing as to their actions. It is also briefly outlined how neurogenic contributions seem to vary in extent and type of impact, not only between different variants of hypertension but also along with the stage of disorder, probably being, in most cases, particularly important in the early stages.(ABSTRACT TRUNCATED AT 250 WORDS)
Electrophysiological, mechanical, dimensional and coronary flow characteristics were studied on papillary strips and on isolated hearts, from spontaneously hypertensive (SHR) and normotensive (WKY) rats respectively, which from 5 to 15 weeks of age had been on either 'low' (LNa, 0.5 mmol 100 g-1 food), control (CNa, 5) 'high' (HNa, 50) or 'very high' (vHNa, 120) sodium diets. With respect to cardiac electrophysiological characteristics, contractility, and maximal stroke volume capacity only minor, if any, differences were observed between the various Na diet groups, both in WKY and SHR. This is in accordance with our earlier findings concerning vascular smooth muscle, where a largely unchanged sensitivity and responsiveness to, for example, noradrenaline was noted. Further, only to the extent that the various Na diets had also caused changes in average blood pressure levels, adaptations of cardiac and coronary resistance vessel design were observed, in general agreement with our earlier findings in other preparations and experimental designs. The largely unaffected functional characteristics of cardiac as well as vascular effector cells, despite 240-fold long-term variations in sodium intake, are in sharp contrast to the marked changes that have been shown to affect the adrenergic nerves, as here chronic low-Na intakes cause reductions of transmitter release/impulse, and vice versa at high Na intakes. This latter type of change seems to be by far the most important functional deviation affecting cardiovascular control during long-term alterations of sodium intake, as it can markedly affect both cardiac and vascular influences on haemodynamics, even though the respective effector functions seem to be surprisingly little influenced directly.(ABSTRACT TRUNCATED AT 250 WORDS)
Various in-vitro studies have indicated a direct attenuating effect of sodium on the affinity of adrenergic alpha 2-receptors. It has been suggested that ingested sodium in this way might increase blood pressure by reducing the activity of central alpha 2-receptors and thereby increasing sympathetic discharge. However, such an effect of sodium would also impair the function of peripheral alpha 2-receptors. In the present study we have therefore investigated the effect of high sodium intake on the alpha 2-receptor-mediated inhibition of the vascular neurogenic response. Male Wistar rats were given 2% NaCl in their drinking water from 4 to 9 weeks of age. Another group receiving plain tap water served as controls. Segments of small branches from the mesenteric artery were mounted in a myograph. Responses to transmural nerve stimulation were determined before and after alpha 2-receptor blockade with either yohimbine or idazoxan. The response to a continuous nerve stimulation that elicited 30% of maximal contraction was increased 2-3 times after addition of either idazoxan (0.1 microM) or yohimbine (0.3 microM), with no significant difference between sodium-treated and control rats; if anything the enhancement was slightly greater in the sodium-treated group. Also, responses to intermittent burst stimulation were increased from 30 to about 80% of maximal response in both rat groups. The results thus indicate that high sodium intake does not affect the inhibitory influence of pre-junctional alpha 2-receptors on the vascular neurogenic response.
This paper surveys the early studies and ideas that led to the development of the Bayliss theory in 1902 of a pressure-dependent myogenic tone in the systemic resistance vessels; this important concept was not experimentally verified until about 50 years later. Studies of the complex interactions between this 'active' intrinsic vascular tone, 'passive' wall distensibility and tissue-produced vasodilator factors gradually led to a better understanding of local circulatory control. Precapillary smooth muscles seem to function almost like 'stretch (and/or tension?) receptors with built-in contractility', where transmural pressure serves as a limited positive feedback and tissue vasodilator factors as a potentially powerful negative feedback. Together, these positive and negative feedback factors automatically adjust blood supply to local tissue needs and also protect the capillary exchange section from undue pressure increases thanks to the ensuing 'functional autoregulation'. Observations in these early studies also led to experimental analyses of what was later called 'structural autoregulation', as a long-term analogue to 'functional autoregulation'. 'Structural autoregulation' is the rapid morphological adaptation of the precapillary resistance vessels in hypertension whereby, by a structurally based inner radius reduction and hypertrophic wall (media) thickening, systemic resistance becomes reset upwards for functional operation at a higher pressure level. Like 'functional autoregulation', 'structural autoregulation' is essentially a local vascular response to pressure changes. Finally, myogenic activity, functional and structural autoregulation may have important cellular mechanisms in common, while 'extrinsic' influences, from nexa-connected endothelial cells and neurohormonal mechanisms for example, are likely to act as important modulators of intrinsic smooth muscle activities.
Experiments are surveyed, suggesting that rats (WKY and SHR) have a very wide 'safety range' concerning salt intake with respect to cardiovascular homeostasis. Further, they are able to maintain their 'resting' volume and circulatory equilibria remarkably well over a 240-fold range of intakes, at least when young. The major longterm functional consequences of low and high intake were noted concerning sympathetic nervous control, chronic low Na intake leading to reduction of the transmitter release per impulse, and vice versa at high intakes. Otherwise blood volume, exchangeable sodium, cardiac and vascular muscle functions remained largely unchanged during rest, but the altered capacity of sympathetic control made the low Na rats dangerously vulnerable to e.g. fluid losses. In these respects SHR were, if anything, worse off than WKY. If allowed to choose their Na intake, the rats put themselves at an intake 30-50 times above that on which they can barely manage, and SHR on an even higher level than WKY. Some comparisons to man's situation are made, adjusting for differences in body size and metabolic rate. Such data suggest that human Na intakes in western societies are in fact similar to those instinctively chosen by e.g. sheep or rats, when on free access to salt. Some aspects of the assumed relationships between Na intake and primary hypertension, are also discussed. At least in the SHR variant of primary hypertension high salt intake is evidently of fairly subordinate pathogenetic importance, as seems to be the case also in the great majority of human subjects, to judge from recent epidemiological studies.
A series of studies of the humoral renal antihypertensive system in normotensive and 2K 1C-renal antihypertensive rats is outlined. The rapid structural upward resetting of the cardiovascular system in renal hypertensive rats was associated with a structural downward resetting in the vasculature of the hypotensive clipped kidney. Unclipping of this kidney caused a pronounced release of renomedullary depressor agents, explaining the rapid normalization of pressure seen after unclipping. This normalization of pressure masks a state of pronounced functional hypotension in a structurally still hypertensive cardiovascular system, characterized by marked splanchnic vasodilatation and a lack of neurogenic counter-regulation. Only when this state has lasted long enough to normalize the structural upward resettings, characteristic of hypertension does the cardiovascular system return to normal. Further, cross-circulation techniques have shown that the humoral antihypertensive agents suppress tonic sympathetic activity, thereby inhibiting normal reflex counter-regulation of their vasodilator effects. Presumably this occurs via both vagal cardiac afferents and central actions. Further, behavior and awareness become depressed during intense and prolonged renomedullary release. Finally, experiments for which a normotensive kidney is cross-circulated from a normotensive rat suggest that the humoral renomedullary antihypertensive system has its threshold of release set so low as to contribute to normal blood pressure regulation, presumably in reciprocal balance with the renocortical renin-angiotensin system. Stepwise pressure elevations increasingly enhance release of the depressor agents from the cross-perfused kidney.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of renal artery clipping was tested in three groups of male Sprague-Dawley rats: (1) 30 control animals, (2) 30 hypophysectomized animals, and (3) 30 hypophysectomized animals treated with growth hormone and thyroxine. Fifteen rats in each group were clipped and 15 acted as controls. In the first group clipping raised arterial pressure and plasma renin activity. Thirty-five days after clipping, pair-perfused hindquarter preparations at maximal dilation and maximal pressor response were both increased, reflecting, respectively, decreased lumen diameters and increased media thickness in the resistance vessels. Clipping also increased left ventricular weight. Hypophysectomy eliminated the weight gain, and the maximal pressor response and maximal dilation were lower than in the control and treated groups. Hypophysectomy also considerably reduced the rise in blood pressure on clipping and, even more so, the associated structural cardiovascular changes. Replacement therapy with growth hormone and thyroxine almost restored the weight gain and also the structural responses of the heart and vessels to clipping. We conclude that pituitary hormones play an important, probably permissive, part in the development of normal vessel structure and in the adaptation of cardiovascular structure to chronic hypertension.
To examine the effects of exogenous growth hormone on the cardiovascular system and sodium metabolism, ovine growth hormone was given daily to female rats for 5 weeks. Growth hormone resulted in a significant increase in body mass compared with controls. However, blood pressure in the treated rats was not significantly different from that in controls. Following treatment, the baseline resistances and pressor responses of the isolated mesenteric beds did not differ between the two groups. In addition, exchangeable sodium, erythrocytic intracellular sodium and transmembrane sodium efflux rate constants were not altered significantly by growth hormone treatment. The failure to observe cardiovascular or sodium effects of growth hormone despite significant potentiation of growth is, at present, unexplained.
The physiology of the emotional response patterns to "stressful" psychosocial stimuli is surveyed. These limbic-hypothalamic patterns are basically designed to protect the individual and species from adverse environmental influences in primitive life. Their expressions always form a triad, with a situation-specific "somatomotor"-behavioural link, a "visceromotor"-autonomic and a hormonal link, the latter two adjusting inner organs, metabolism, water-salt balance, etc., to provide optimal support to the behavioural expression. Because of their uniformity throughout species, animal experiments have greatly contributed to our understanding of how these responses may also importantly contribute to common disorders in modern society, at least when intensely and/or commonly evoked. Thanks to our more advanced neocortex, man differs here from animals mainly in two ways. First, we learn to cope with some environmental stimuli and thus delimit undue emotional engagements; second, when once elicited we can often suppress the behavioural link, when this is socially appropriate. As we cannot suppress the autonomic-hormonal links, however, they then occur more or less "in vain", and such socially enforced dissociations of per se normal response patterns may not in the long run be healthy. Finally, the better known among these differentiated responses are briefly outlined, with particular emphasis on the potentially most important ones, the "defence reaction" and the "defeat reaction".
Isolated kidneys taken from normotensive Wistar-Kyoto rats were cross-perfused extracorporeally by normotensive strain-matched donor rats. The extracorporeal perfusion circuit was arranged so that the perfusion pressure to the normotensive recipient kidney could be varied from 90 to 200 mm Hg without any change in total flow through this circuit. This setup avoided hemodynamic or mechanical interferences with reflexogenic circulatory control in the normotensive donor rat when the recipient kidney was manipulated. Diuresis and natriuresis were measured in the normotensive donor rat and the normotensive recipient kidney. A few minutes after normotensive recipient kidney perfusion pressure had been raised, mean arterial pressure (MAP) and heart rate started to decline rapidly in the normotensive donor rat, and circulatory collapse ensued within 15 to 100 minutes. During the control period at 90 mm Hg normotensive recipient kidney perfusion pressure, urinary flow, MAP and heart rate were stable in the normotensive donor rat and the normotensive recipient kidney. When perfusion pressure was raised to 200 mm Hg in the recipient kidney, the urinary flow in the donor rat increased 62% on average in the first 10 minutes over values recorded before the pressure rise (p less than 0.05) while MAP simultaneously fell by 16% and HR remained unchanged. During the subsequent period, the urinary flow of the donor rat declined together with MAP and heart rate. In the extracorporeally high-pressure perfused recipient kidneys, an eightfold to ninefold increase in diuresis and natriuresis occurred during the first 45 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)
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Like tissues in other parts of the body, those of the heart and blood vessels can rapidly adapt their design. The principles of these differentiated structural changes in response to altered functional demands will be outlined in this report. With respect to arterial resistance vessels in hypertension, any sustained arterial pressure elevation leads to wall (w) hypertrophy, whereas the average inner radius (ri) decreases. The reverse occurs at sustained pressure reductions, and this process is aptly termed "structural autoregulation." By means of this structural autoregulation, wall tension per unit layer (T) remains largely constant when pressure (P) increases (decreases), according to Laplace's law: T = P X r/w. Furthermore, this structural w/ri increase, because it is a local vascular response although it is often considerably modified by neurohormonal "trophic" influences, results in a geometrically based vascular hyperreactivity affecting the systemic precapillary resistance vessels, whereas the structural ri reduction leads to an upward resetting of systemic resistance to flow which is present even at maximal vasodilation (Rmin). Because of this "structural amplifier" principle, an increased systemic resistance can be maintained even at normal vascular smooth muscle activity, and smooth muscle activations may then lead to exaggerated resistance elevations. Thus, a most important positive-feedback interaction is created between even mild functional "pressor" influences, if adequately sustained, and this normal process of structural adaptation. This positive-feedback interaction therefore gradually tends to accentuate the latter element until it entirely dominates the hemodynamics of established hypertension. As the process is induced early and established rapidly, and in primary hypertension often even seems to be genetically reinforced in various ways, it becomes of utmost pathogenetic significance. With respect to the aorta-large conduit arteries, their "Windkessel function" becomes reduced by the same process of adaptive wall thickening. This increases the pulse amplitude and thereby accentuates the systolic afterload of the left heart, the load of which is raised also because of the upward structural resetting of systemic precapillary resistance. Furthermore, the same type of structural adaptation also contributes to the upward resetting of the cardiac, arterial, and renal "barostat" mechanisms, as cardiac and arterial walls become thicker and stiffer, whereas renal preglomerular resistance vessels participate in the upward structural autoregulation.(ABSTRACT TRUNCATED AT 400 WORDS)
Young SHR and WKY rats were compared, first, concerning sodium (Na) appetite during 'rest', mild social stress and ACTH injections, second, concerning the diurnal patterns of water intake, urine output, mean arterial pressure (MAP) and heart rate (HR) while on various Na diets: 0.5 mmol Na(LNa), 5 or 12-13 mmol Na (CNa), 50 (HNa) or 120 mmol Na (vHNa) per 100 g food. Sodium appetite and water intake were about 50% higher in SHR than in WKY (4-4.5 vs 2.5-3 mmol Na per 100 g body wt day-1). It was modestly increased by both social stress and ACTH, and more so in WKY, thereby approaching that in SHR. Concerning the various Na diets and their influences, daytime resting MAP was modestly lowered in LNaSHR and slightly increased in vHNaSHR compared with CNaSHR but largely equal in all WKY groups. Food-water consumption was concentrated to the active night period, but even high Na-water intakes caused no signs of sustained hypervolaemia, because each intake bout was in both SHR and WKY eliminated by urine within 30-40 min. However, particularly the vHNa diet in SHR also increased the frequency of drinking, and each bout caused transient, evidently neurogenic MAP and HR increases which occurred too rapidly to be consequences of blood volume expansion. As a result, the diurnal MAP-HR patterns in SHR varied markedly with the Na diets, in vHNa group resulting in considerably raised average diurnal MAP levels even though resting daytime MAP was here nearly the same as in CNaSHR. These findings illustrate how largely continuous diurnal recordings are needed to judge correctly the relationships between, for example, Na intake, volume equilibrium and MAP. Finally, the relevance of these results in rats for also judging the control of Na balance in man is discussed.
We have previously shown that, at least at frequencies of 4 Hz and above, a previous stimulation of the intramural vasoconstrictor nerves facilitates the subsequent response so that even maximal contractions can develop during periods of stimulation as short as a few seconds. In the present study the facilitating effect of a continuous nerve stimulation was quantitatively tested on 'single-twitch' responses to individual nerve impulses. Small arteries and veins (150-500 micron diameter) from rats were mounted in a myograph at known wall tension, and the intramural nerves were activated at frequencies between 0.1 and 32 Hz. After a period of continuous stimulation the single-twitch responses could be amplified 10-20 times, depending on frequency and duration of the continuous stimulation. No such amplification was observed after application of exogenous noradrenaline. The results therefore reflect a prejunctional frequency-dependent potentiating mechanism which can strongly reinforce sympathetic neuroeffector control. Furthermore, combined with previous data concerning adrenergic transmitter release, the present results seem to be more compatible with the view that the quantum of transmitter released from each varicosity upon activation is less than an entire granule.
First, the multifactorial background of primary hypertension is outlined in principle, where particular attention is given to the early, sometimes even genetically reinforced structural "upward resetting" of the cardiovascular system, which soon dominates hemodynamics in both human and rat hypertension. On this basis, it is then discussed which modes of action that antihypertensive treatment could best achieve regression of the structural changes in heart and vessels. Since both the luminal and wall changes can be affected in a different manner, and since the growth processes may be reinforced by both genetic and neurohormonal "trophic" influences, there are potentially many ways by which regression could be accomplished via specific interferences, apart from the blood pressure lowering per se. As to the "hemodynamic profile" of drug interferences, reasons are given for an approach where a systemic resistance vessel dilatation is combined with a mild damping of the beta-adrenergic sympathetic drive on the heart.
A variety of "emotional" response patterns can be elicited at the limbic-hypothalamic level by challenging environmental stimuli, and such mechanisms may contribute to the multifactorial etiology of primary hypertension. The "defense reaction" is of particular interest because of its widespread neurohormonal excitatory influences and frequent, although mild, engagement in daily life events. Evidence is presented showing how common genetic variants of primary hypertension, both in man and spontaneously hypertensive rats, are characterized by a genetically linked central hyperreactivity to psychosocial stimuli. As a result, the previously mentioned central response pattern--with its differentiated excitatory and tropic effects that also involve salt-volume regulation--is more commonly elicited by even trivial environmental stimuli, therefore constituting an important triggering influence in these variants of primary hypertension. Also discussed is the potential genetic nature of this central hyperreactivity and, further, how it interacts with other genetic-environmental influences and with the early induction of structural cardiovascular adaptation, by which the entire system is gradually reset to operate at a raised pressure equilibrium.
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