Biomedical subjects
Publications and source records attributed to H Nilsson.
The development of new vasoactive drugs has increased the possibilities to treat patients with digital vasospasm, known as Raynaud's phenomenon. The purpose of this paper is to give a review of recent clinical trials and also a short review of the pathophysiological reasons for each type of pharmacological treatment.
A combined morphological and physiological analysis of the properties of the adrenergic vasoconstrictor innervation was carried out in the splanchnic vasculature in the rat. Three generations of vessels were studied: (1) the abdominal aorta and the caval vein; (2) the superior mesenteric artery and vein; (3) 200 microns branches of the superior mesenteric artery and their parallelling veins. The adrenergic innervation was visualized by the Hillarp-Falck fluorescence technique, and by the immunohistochemical localization of immunoreactivity to tyrosine hydroxylase and dopamine-beta-hydroxylase. Determination of responses to applied noradrenaline, to transmural nerve stimulation and to direct activation of the muscle was made on ring preparations mounted in a myograph. All vessels were found to be innervated at the adventitio-medial border by noradrenergic nerves with varying density; the small arteries had the highest nerve density, the abdominal aorta was least innervated. When related to the maximal isometric response to applied noradrenaline, the maximal neurogenic response parallelled the density of the adrenergic innervation. Variations in frequency for half-maximal response among the vessels could not, however, be ascribed to innervation properties only. The constriction under isotonic conditions amounted to 20% of the initial circumference in the aorta, and to 30% in the small arteries and veins. The relation between response to applied noradrenaline and to nerve stimulation was similar for isometric and isotonic responses. In the smaller veins, a beta-receptor-mediated decline in the response to applied noradrenaline was seen. This decline was much less pronounced in neurogenic responses. The results indicate a gradation from proximal to peripheral arteries towards denser innervation and greater neurogenic responses. On the venous side only minor differences were found.
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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Local effects of enflurane on intestinal vascular resistance were studied in vivo in cats. A jejunal segment was prepared and perfused at constant flow with blood from the femoral arteries. The intestine was either: (1) left with intact sympathetic innervation, (2) denervated and exposed to electrical post-ganglionic vasoconstrictor nerve stimulation, or (3) excluded from neurogenic remote control by post-ganglionic denervation. Enflurane dissolved in lipid and intra-arterially administered to the jejunal segment in doses comparable to those clinically encountered, decreased intestinal vascular resistance in relation to the intra-arterial concentration of the drug. The vasodilator response was, at the highest enflurane doses studied (blood concentration: 400 and 800 mg X 1(-1], most pronounced in the intestine with intact sympathetic innervation. Otherwise, no differences were observed in vasodilator responses between the three different investigated modes of neurogenic influence on the intestine. In vitro enflurane (-in-lipid) did not affect the vasoconstrictor response to electrical field stimulation in the rat mesenteric arterioles. Enflurane, however, dose-dependently reduced spontaneous contractile activity in the rat portal veins.
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.
Contractile responses to electrical field stimulation of excised small mesenteric arteries and veins of the rat were compared when stimuli were delivered in irregular bursts or at regular intervals. Spontaneously occurring skin vasoconstrictor impulses in a few-unit median nerve recording in man were stored on tape and used to trigger a stimulator. Two irregular stimulation sequences at average frequencies of 1.6 and 1.8 Hz, respectively, were used. In the arteries, average contractile responses were significantly greater at an irregular than at an even stimulation frequency, but in the veins, similar degrees of contraction were obtained with the two modes of stimulation. The frequency-response relationships to continuous regular stimulation showed the artery to respond less than the vein at low frequencies. This apparently explains the differences in behaviour between the vessels to irregular stimulation. The results show that not only the number of impulses, but also their pattern of occurrence, may influence the degree of vasoconstriction. Thus, the normal irregular sympathetic discharge pattern in itself has a bearing on the physiology of neuro-effector control mechanisms.
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.
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.
The effects of distension on the sensitivity to noradrenaline and potassium were assessed in ring preparations of 200 micron branches from the superior mesenteric artery of the rat. In response to noradrenaline, maximal tension development occurred at smaller luminal diameters than with potassium activation. The sensitivity to noradrenaline increased with increasing distension whereas potassium sensitivity remained largely unchanged. A distension-dependent increase in noradrenaline sensitivity was observed also in vessels depolarized with high-potassium solution. The role of the distension-dependent sensitivity to noradrenaline for isotonic contractions was also studied. Upon activation with applied noradrenaline, submaximal isotonic responses were somewhat smaller than isometric responses at the same dose. This may be ascribed to a reduction in sensitivity during the isotonic contraction. Upon neurogenic activation, no difference between isotonic and isometric responses was found. The results show that distension increases noradrenaline sensitivity in resistance vessels in vitro, but that the consequences for their function as neuroeffectors may be small.
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.
A systematic comparison of neurogenic responses from consecutive sections of the cardiovascular system has not yet been performed under the well-defined conditions that an in-vitro system can offer. The present investigation aimed at analysing the neuroeffector properties of different isolated vessels, mounted in a myograph, where isotonic and isometric responses to transmural nerve stimulation could be determined. The vessels investigated were the abdominal aorta and caval vein, the superior mesenteric artery and vein, and 200-micron arteries and corresponding veins from the mesenteric arcades, the latter representing true resistance and capacitance vessels, respectively. Further, the vascular adrenergic innervation was visualized by Hillarp-Falck's formaldehyde fluorescence technique as well as immunohistochemical methods. In all vessels the innervation was confined to the adventitio-medial border. The responses to single neurogenic impulses differed markedly between the vessels, being distinct and rapid in the small, slow in the intermediate vessels, and absent in the aorta and the caval vein. This was in contrast to the responses to direct electrical activation of the muscle, which were quite rapid in all vessels. The organisation of the neuromuscular transmission thus has a marked influence on the effector response. The maximal neurogenic responses parallelled the innervation density, being greatest in the small arteries and least in the abdominal aorta. The frequency for half-maximal response appeared to depend also on other factors, such as velocity of contraction and relaxation of the smooth muscle. Of the small vessels, the veins were relatively more activated by low frequencies. Stimulation with an irregular impulse pattern, derived from human sympathetic nerve discharge, had greater effects than the corresponding constant-frequency stimulation on the resistance arteries; the small veins responded equally to either pattern. This difference could be related to the observed frequency-response relations around the average frequency used. The effects of inhibition of neuronal amine uptake on neurogenic responses and on responses to exogenous noradrenaline differed considerably, particularly in the resistance arteries. Here the magnitude of the neurogenic responses were hardly affected by this inhibition, whereas responses to exogenous noradrenaline were strongly enhanced. On its own, blockade of prejunctional adrenergic alpha 2-receptors had little effect on either response, but blocking both alpha 2-receptors and reuptake clearly potentiated the neurogenic responses.(ABSTRACT TRUNCATED AT 400 WORDS)
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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.
Eight patients with vasospastic disease of the digital arteries were treated with the calcium-entry blocker nifedipine (capsules), 10 mg t.i.d. and 20 mg t.i.d. The degree of cold-induced digital vasospasm after local cooling of the finger to 15 and 10 degrees C, measured by strain-gauge technique, was significantly decreased by nifedipine. The degree of reduction was dose-dependent. All patients improved symptomatically. The side-effects of the drug were minor but became more prominent when the dose was increased. We conclude that nifedipine is a useful agent in the treatment of digital vasospastic disease.
Isometric responses to nerve stimulation and to applied noradrenaline were compared in isolated ring preparations of three consecutive types of rat arteries, viz. the aorta, the superior mesenteric artery and 200-micron branches of the latter. Intramural nerves were activated by graded electrical field stimulation; obtained responses were blocked by tetrodotoxin, phentolamine or prazosin. Also direct muscle activation could be accomplished, using impulses of long duration. In the aorta responses to nerve stimulation were sluggish, could reach only 30-40% of the maximal noradrenaline response and single impulses were ineffective. In the small resistance arteries, neurogenic responses matched the maximal noradrenaline responses and distinct, rapid contractions occurred to single nerve impulses. The superior mesenteric artery was intermediate in these respects. By contrast, on direct muscle activation all vessels responded to single impulses with rapid contractions that differed little in velocity. Pharmacological inhibition of transmitter reuptake increased noradrenaline sensitivity most in the small arteries, but nerve responses were most enhanced in the superior mesenteric artery. These regional differences, probably reflecting decreasing neuromuscular distance with decreasing vessel size, imply that generalizations concerning the relation between responses to nerve stimulation and to exogenous noradrenaline cannot be made from one vascular model only.
Five current lines of cardiovascular studies in rats are outlined, mainly dealing with some functional and structural relationships of particular relevance for hypertension and ordinary aging: 1. Characteristics of the smooth muscles and their neurogenic control in 'Windkessel' arteries, conduit arteries, precapillary resistance vessels and venous capacitance vessels from normotensive rats (WKY) with comparisons to rats with primary hypertension (SHR). 2. Different types of structural renovascular adaptation, comparing aging with advancing SHR hypertension, with 'high-pressure' and 'low-pressure' kidneys in one-clip, two-kidney renal hypertension, and with hypertrophied kidneys in uni-nephrectomized normotensive rats. 3. Relationships between 'structural autoregulation', wall distensibility, vascular reactivity and smooth muscle sensitivity in SHR and WKY hindquarter resistance vessels along with aging. 4. Relationships between wall thickness, luminal dimension and contractility in left ventricles from SHR and WKY during aging, and when one-clip, two-kidney hypertension is superimposed. 5. Interference with the capacity of the neurohormonal mechanisms counteracting blood loss in rats when on chronic low-salt diet.
The authors have previously shown that vasoconstrictor nerve responses of mesenteric small arteries from spontaneously hypertensive rats (SHR) are increased compared with normotensive rats. In this paper, whether this is due to differences in the degree of negative feedback of the transmitter on its own release is investigated. Small (i.d. 200 microns) arteries from the mesenteric arcades of SHR and normotensive control rats (NCR) were mounted in a Mulvany-Halpern myograph. In both SHR and NCR, nerve stimulation and applied noradrenaline elicited maximal contractions of similar magnitude, although SHR vessels were somewhat stronger and more responsive to nerve stimulation. Blocking alpha 2-receptors with 10 nM RX 781094 reduced the frequency for half-maximal activation to 84% and 80%, respectively, but did not eliminate the difference between the strains. Presynaptic alpha 2-receptors thus do not seem to cause the enhanced vasoconstrictor responses in SHR vessels.