Dietary sodium effects on cardiovascular and sympathetic neuroeffector functions as studied in various rat models.
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Animals↗
Biomedical subjects
B Folkow
Publications and source records attributed to B Folkow.
Behavioral mechanisms in hypertension.
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Animals↗
Extrinsic mechanisms of vascular growth.
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Animals↗
Cardiac dimensions in spontaneously hypertensive rats following different modes of blood pressure reduction by antihypertensive treatment.
The present study examined changes in left ventricular design in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats in response to different types of antihypertensive therapy. Blood pressure was reduced for 12 weeks by either peripheral vasodilators [hydralazine or felodipine (calcium antagonist)] or by sympatholytic drugs (alpha-methyldopa or metoprolol). End diastolic volumes (EDV) were obtained in vitro by determining the diastolic pressure-volume relationships of isolated perfused hearts, arrested in diastole by excluding calcium from the perfusate. Wall thickness (w) and internal radius (ri) were calculated from a ventricle considered as a spherical model. Compared with WKY, untreated SHR had elevated EDV and w. Vasodilator therapy, particularly felodipine, increased EDV but reduced w, while sympatholytic therapy with alpha-methyldopa reduced EDV in SHR. It is suggested that cardiac design is affected not only by the prevailing arterial pressure level which will affect w, but also by the haemodynamic situation. Vasodilators turn such a situation into one characterized by increased cardiac output and hence increased cardiac filling, whereas sympatholytic drugs by venodilatation will turn the haemodynamic situation towards a state characterized by reduced cardiac filling. Left ventricular EDV (ri) therefore seems to adapt to long-term filling conditions, while w adapts to bring w:ri ratio in balance with the pressure load.
Animals↗
The effects of varying sodium diets on haemodynamics and fluid balance in the spontaneously hypertensive rat.
Spontaneously hypertensive rats (SHR) were given either 'low' (LNa; 0.5 mmol Na 100 g-1 food), 'control' (CNa; 12 mmol) or 'very high' (vHNa; 120 mmol) sodium diets from 5 to 13-14 weeks of age, to explore how these 240-fold variations in Na intake affected body weight, cardiac, renal and adrenal weights, overall water-electrolyte equilibrium and haemodynamic balance during rest, mental stress and blood loss. Body growth was retarded both in vHNa and LNa SHR presumably reflecting disturbed appetite due to the greatly altered dietary Na contents. Compared with CNa SHR, both cardiac and renal weights 100 g-1 body wt were slightly increased in vHNa and decreased in LNa SHR, with opposite changes of adrenal weights. Total body water, haematocrit and plasma Na-K levels were largely equal in the three groups. Furthermore, cardiac output (CO), stroke volume (SV) and central blood volume (CBV) did not differ significantly between groups; if anything, CO and SV were higher and CBV lower in vHNa and LNa SHR than in CNa SHR. However, while mean arterial pressure (MAP) was only marginally elevated in vHNa compared with CNa SHR, both MAP and total peripheral resistance (TPR) were lowered about 15% in LNa SHR with signs of increased sympathetic activity to the heart also during rest. Despite an apparently normal volume and cardiac output balance in LNa SHR, the latter changes suggest a disturbed neuro-hormonal cardiovascular control.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cardiac design and pressure-volume characteristics of the left ventricle in normotensive (WKY) and hypertensive (SHR) rats after various dietary sodium treatments.
Normotensive (WKY) and hypertensive rats (SHR) from 5 to 13-14 weeks of age were given 'low' (LNa; 0.5 mmol Na 100 g-1 food), 'control' (CNa; 5 or 12 mmol), 'high' (HNa; 50 mmol) and in SHR also 'medium low' (mLNa; 2 mmol) and 'very high' (vHNa; 120 mmol) sodium diets, to explore how such 240-fold variations in Na intake affect cardiac design. This was assessed in isolated perfused, temporarily-arrested hearts by recordings of left ventricular (LV) diastolic pressure-volume relationships (P/V), LV and RV weights, and by calculations of the ratio between LV wall thickness and internal radius (w/ri), after in vivo recordings of awake mean arterial pressure (MAP) and heart rate (HR). In WKY, where MAP was the same in all diet groups, the HNa group showed an increased w/ri due to a 20% reduction of LV diastolic volume, with signs of reduced wall compliance compared with CNa. The LNa WKY showed less marked changes in the same direction. In the SHR LNa group, where MAP was lowered about 20 mmHg, LV diastolic volume was reduced nearly 20% at a modest w/ri increase, while HNa and Cna SHR had equal MAP, LV weights, P/V and w/ri relationships. However, in vHNa SHR, where MAP was elevated about 25 mmHg, the LV showed a mainly eccentric hypertrophy with 15% increase of diastolic volume at a slight increase of w/ri. These differentiated, and in WKY and SHR partially differing structural cardiac adaptations consequent to changes in Na intake, can hardly be ascribed only to the respective pre- and afterload alterations, suggesting that also altered neuro-hormonal profiles may have contributed with 'trophic' influences.(ABSTRACT TRUNCATED AT 250 WORDS)
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The structural cardiovascular factor in primary hypertension--pressure dependence and genetic reinforcement.
Experimental results suggesting a genetic facilitation of cardiovascular structural adaptation in primary hypertension are surveyed. Most such studies have been performed on spontaneously hypertensive rats (SHR), a few on New Zealand genetically hypertensive (GH) and Dahl salt-sensitive (Dahl-S) rats, and primary human hypertension has also been explored. The evidence comes partly from various haemodynamic-morphometric analyses of the relationships between cardiovascular design and pressure level in vivo and partly from in vitro studies of SHR vascular smooth muscle in tissue culture. When combined, the experimental findings from the various approaches strongly suggest that genetic elements can so reinforce the normal process of structural cardiovascular adaptation in primary hypertension, that this factor becomes a primary element of great haemodynamic importance, particularly in SHR, probably in GH rats and perhaps in man, but hardly in Dahl-S rats. The overall support for this type of genetic reinforcement appears, in fact, to be stronger than for any other type of mechanism presently considered to be genetically linked to the induction of primary hypertension. This genetic structural endowment seems to be partly intrinsic in the muscle cells and partly the result of extrinsic 'trophic' effects, e.g. from catecholamines, consequent to a genetically based central accentuation of sympathetic activity, present in SHR and evidently often in man.
Adaptation, Biological↗
Sodium appetite and 24-hour variations in fluid balance, mean arterial pressure and heart rate in SHR and WKY on various sodium diets.
Young spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were compared with respect to firstly, sodium (Na) appetite during 'rest', mild social stress and adrenocorticotrophic hormone (ACTH) injections and secondly, 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, being 50% higher in SHR than in WKY (4-4.5 versus 2.5-3 mmol Na/100 g body weight per day), was modestly increased by both social stress and ACTH, more so in WKY. With regard to influences of the various Na diets, daytime resting MAP was modestly lowered in LNaSHR and slightly increased in vHNaSHR compared with CNaSHR, but about equal in all WKY groups. Food and water consumption was concentrated to the active night period, but even high Na water intakes caused no signs of sustained hypervolaemia, as intake bouts were eliminated by urine within 30-40 min in both SHR and WKY. However, the vHNa diet in particular in SHR increased drinking frequency; each drinking bout induced such rapid, 5-10 min long neurogenic MAP and HR increases that they could not be ascribed to blood volume expansion per se. The diurnal MAP-HR patterns in SHR therefore varied markedly with the Na diets, with a considerably raised average MAP in the vHNa group, even though resting daytime MAP was nearly the same as in CNaSHR.(ABSTRACT TRUNCATED AT 250 WORDS)
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Blood pressure and heart rate responses to mental stress in spontaneously hypertensive (SHB) and normotensive (WKY) rats on various sodium diets.
Normotensive (WKY) and hypertensive rats (SHR) were, from 5 to 12 weeks of age, given 'low' (LNa), 'control' and 'high' (HNa) Na diets (0.5, 5 and 50 mmol X 100 g-1 food, respectively, during weekly recordings of body weight, conscious indirect systolic blood pressure (SBP) and heart rate (HR). During the last week, mean arterial pressure (MAP) and HR responses to standardized stress stimuli (air jet) were recorded before and after sequential cardiac nerve blockade. While resting, SBP was about equal in all WKY groups, but it was significantly reduced in SHR-LNa (152 mmHg versus 174 and 178 mmHg in SHR controls and HNa; P less than 0.05). In both LNa groups HR was elevated nearly 25% compared with controls, being in SHR 513 versus 419 bpm (P less than 0.01) and in WKY 489 versus 393 bpm (P less than 0.01). Cardiac nerve blockade indicated that this HR elevation was about equally due to elevations of sympathetic activity and 'intrinsic' pacemaker activity. SHR-LNa also showed attenuated MAP elevations to acute mental stress. There were, however, no significant differences between groups concerning haematocrit or plasma Na-K levels. The results suggest that SHR have a greater salt requirement than WKY, as Na restriction to one-tenth of normal led to a considerable MAP reduction in SHR despite compensatory sympathetic activation, and also to attenuated pressor responses to mental stress. Further, the cardiovascular effects in SHR were much more extensive when on a low-Na diet than when Na intake was increased tenfold above normal.
Adrenergic alpha-Antagonists↗
Effects of ageing on cardiac performance and coronary flow in spontaneously hypertensive and normotensive rats.
The aim of the present study was to assess the influence of ageing on cardiac function and coronary flow in Wistar Kyoto normotensive rats (WKY, 16 and 78 weeks of age) and spontaneously hypertensive rats (SHR) of the same age. Cardiac function was determined on isolated hearts by means of an antegrade heart perfusion technique. Left atrial pressure and peak aortic pressure could be altered independently of each other. Recordings of cardiac output and coronary flow were then obtained at both normotensive and hypertensive levels of peak aortic pressures. Peak stroke volume (SV) was reduced with age in both WKY and SHR. Peak SV determined at normotensive pressure loads became diminished with age in WKY, while it at hypertensive pressure loads showed a small decline with age, since peak SV was low as early as 16 weeks of age. The age-dependent fall in cardiac performance was greater in SHR than in WKY, due to the enhanced peak SV in 16-week-old SHR at hypertensive pressure loads. Peak SV was markedly decreased at normotensive pressure levels in both 16- and 78-week-old SHR v. age-matched WKY. Coronary flow per unit tissue declined with age both in WKY and SHR. Coronary flow was also lower in SHR compared to age-matched WKY. With ageing this elevated performance was reduced down to the same level as in 78-week-old WKY. The age-related coronary flow reduction and the consistently reduced flow in SHR indicate a structural narrowing of the coronary vascular bed, particularly in SHR.
Aging↗
Structural adaptation of the rat left ventricle in response to changes in pressure and volume loads.
Female Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were used to explore the structural changes of cardiac dimensions in connection with a sustained hyperkinetic circulation, as induced by pregnancy or thyroxine administration. Cardiac design was assessed by recordings of the diastolic left ventricular pressure-volume relationships in isolated arrested hearts. Left ventricular weight: body weight and end-diastolic volume (EDV) for given end-diastolic pressures (EDP), were both increased about 50% in control SHR, with a marginal reduction of the wall:lumen ratio (w:ri) compared with control WKY. During the hyperkinetic circulatory states of pregnancy and hyperthyroidism, EDV was in WKY increased about 30% and 50%, respectively, with concomitant w:ri reductions. In SHR pregnancy did not significantly alter left ventricular dimensions, whereas EDV was increased by about 20% in hyperthyroid SHR. Thus, the rat left ventricle can, within 3 weeks, markedly alter not only the wall mass but also, and independently, the luminal design in response to different haemodynamic interventions. Early established SHR hypertension is characterized mainly by eccentric left ventricular hypertrophy, despite the elevated arterial pressure. Volume overloads in WKY due to pregnancy or hyperthyroidism can induce marked structural widening of the left ventricle. In SHR these structural luminal changes were only minor, perhaps because considerable eccentric hypertrophy is already present. Such a structural cardiac enlargement may allow delivery of an increased stroke volume for a given myocardial fibre shortening.
Adaptation, Physiological↗
Interaction between prejunctional alpha 2-receptors and neuronal transmitter reuptake in small mesenteric arteries from the rat.
The role of the prejunctional alpha 2-receptors for the response to vaso-constrictor nerve stimulation has been examined before and after inhibition of neuronal transmitter reuptake in mesenteric resistance vessels from the rat. Small arteries (diameter about 200 micron) feeding the jejunum were mounted in a myograph for recording of their isometric wall tension during transmural field stimulation of the intramural nerves. Blockade of prejunctional alpha 2-receptors with 0.01 microM idazoxan (RX 781094) caused a marginal potentiation of the neurogenic response when neuronal reuptake was left intact. Also, inhibition of reuptake alone with 3 microM cocaine had little effect on the response. However, when both alpha 2-receptors and reuptake had been inhibited, a strong enhancement of the neurogenic vasoconstriction was observed. Similar findings were made when yohimbine and LU 3-010 instead were used for alpha 2-blockade and reuptake inhibition, respectively. The results thus indicate that in these resistance arteries the effector response is normally influenced by the combined activity of alpha 2-receptors and uptake, and that failure of one mechanism increases the activity of the other, so as to maintain a largely constant effector response.
Adrenergic alpha-Agonists↗
Effects of high and low sodium diets on the resistance vessels and their adrenergic vasoconstrictor fibre control in normotensive (WKY) and hypertensive (SHR) rats.
As part of our studies in normotensive (WKY) and hypertensive (SHR) rats concerning the cardiovascular effects of 240-fold variations in sodium (Na) intake, the present experiments explore how vascular design, smooth-muscle sensitivity to noradrenaline and adrenergic vasoconstrictor fibre function are affected. In vitro comparisons were performed on pair-perfused hindquarter vascular beds and on paired small mesenteric arteries (diameter 150-200 micron), using a two-vessel Mulvany-Halpern myograph. Preparations were taken from WKY and SHR which between 5 and 12-13 weeks of age were on 'low' (LNa, 0.5), 'control' (CNa, 5), 'high' (HNa, 50) or 'very high' (vHNa, 120 mmol Na 100 g-1 food) sodium diets. Structural vascular adaptation occurred only when arterial pressure was altered (only in LNa SHR). In both preparations smooth-muscle sensitivity and dose-response curves to noradrenaline remained unaffected by the Na diets. However, in both LNa groups the frequency-response curves to vasoconstrictor fibre stimulation in the small arteries were displaced to the right of the CNa one, with generally attenuated responses, while the curves of particularly the vHNa arteries were displaced to the left, with enhanced responses. Inhibition of NaKATPase by ouabain particularly enhanced the neurogenic responses, but to similar extents in all Na groups. Thus, low sodium intake apparently reduces the transmitter release/impulse in adrenergic neurons, while it increases the transmitter stores. High sodium intake has the opposite effects. These adaptations of adrenergic neuronal function may be one of the most important long-term consequences of altered sodium intake.
Adrenergic Fibers↗
Evaluation of the 'stretched pore phenomenon' in isolated rat hindquarters.
In order to study the changes in capillary permeability occurring upon marked elevations in microvascular pressure, capillary filtration coefficient (CFC) and diffusion capacity (PS) for Cr-EDTA were repeatedly measured 'on-line' before and after brief periods (3 min) of large venous pressure (PV) elevations in maximally vasodilated perfused rat hindquarters. First at PV's greater than or equal to 55 mmHg, increases in CFC and Ps-Cr-EDTA were observed immediately after the pressure elevations. While the CFC increases were then always pronounced (up to 4-to 5-fold), the concomitant increases in Ps-Cr-EDTA were small (at most 30-40%). For PV greater than or equal to 55 mmHg there was a rough proportionality between PV and CFC. While PS for Cr-EDTA showed little reversibility with time upon PV normalization, CFC was usually almost completely reversed after 10-20 min. The mentioned CFC and PS increases at PV's greater than or equal to 55 mmHg were quantitatively similar to those induced by histamine-type mediators in the same preparation. It is concluded that capillary hydraulic conductivity can increase markedly but reversibly upon large PV elevations, and that this is mainly due to forceful opening of ordinarily closed 'large pores' in the microvascular membrane, rather than being caused by lesional rifts in the endothelium.
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Vascular changes in hypertension. Therapeutic implications.
A review of the general nature of cardiovascular structural adaptation and how this per se normal process becomes of key haemodynamic importance for the development of primary hypertension, particularly with respect to the gradual elevation of systemic precapillary resistance is presented. Because of the structural 'upward resetting' of the haemodynamic equilibrium, antihypertensive therapy in reality faces a far more formidable task in chronic hypertension than merely 'normalising' a supposedly raised vascular smooth muscle activity or/and cardiac output. Rather, it must bring about sub-normal activity levels to normalise the arterial pressure level, and only when such a pressure lowering has been sustained enough to allow for structural regression towards normal dimensions is a true normalisation achieved. However, the process of structural regression takes time and is complicated by the fact that the often long duration of the high-pressure state has led to structural changes which can be quite difficult to reverse. Finally, physiological-haemodynamic reasons are discussed which direct pharmacological interferences preferentially towards the pronounced myogenic activity of the precapillary resistance vessels, which both in normo- and hypertension is by far the most dominating element behind resting smooth muscle activity in these vessels and is, moreover, especially dependent on influx of external calcium ions. As the raised precapillary resistance (by means of 'structural autoregulation') represents the key element behind the pressure rise in established hypertension, such a pharmacological interference is directed towards the proper haemodynamic site and would not directly interfere with the neurohormonal integrative control of the circulation.
Adaptation, Physiological↗
Neurogenic responses in resistance vessels: roles of alpha 1- and alpha 2-adrenoceptors, transmitter reuptake, ouabain, and plasma factors.
Experiments on the vasoconstrictor fiber control of isolated spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) resistance vessels, which is throughout more efficient in SHR, suggest that the presynaptic alpha 2-negative feedback mechanism and the reuptake pump are largely complementary in adjusting the effective transmitter concentrations in these narrow junctions, and first when both are blocked a marked leftward displacement of the nervous frequency-response curve ensues. Also, ouabain causes a marked leftward displacement of the frequency response curve in a way which suggests a considerable increase of transmitter release/impulse. Finally, normal rat plasma contains agent(s) which, even in very low concentrations, seems to cause a strong ouabain-like effect on the neurogenic responses. However, these various interferences with the neurogenic vascular effects influence SHR and WKY to largely equal extents, implying that the more efficient nervous control in SHR vessels is not merely due to an altered balance of the ordinary local mechanisms that influence the adrenergic transmitter release.
Animals↗
Effects of varying salt diets and of ouabain on cardiovascular neuroeffector characteristics and on myogenic resistance vessel activity in SHR and WKY.
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Animals↗
How do changes in diameter at the precapillary level affect cardiovascular function?
A survey is given of the various high-pressure precapillary vascular sections and of how they affect local and overall cardiovascular functions, with special emphasis put on the important "precapillary resistance vessels." The complex interactions between hemodynamic effects dependent on (a) vessel design, (b) transmural pressure, (c) "passive" wall distensibility, and (d) "active" smooth muscle responses are outlined in principle and experimentally illustrated with respect to systemic resistance control. Particular attention is devoted to the influence of the sympathetic vasoconstrictor fibers on precapillary vascular functions, concerning aspects such as speed, precision, range, and differentiation of the neurogenic effects, because these fibers represent the most powerful and widespread of the vascular control mechanisms involved in cardiovascular homeostasis. How these fibers in well-innervated vascular circuits can command up to the maximum contractile capacity of both the precapillary resistance and postcapillary capacitance vessels is illustrated, as well as the way in which these sets of vessels respond to even single nerve impulses with twitchlike, rapid contractions.
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