Biomedical subjects

M Nordlander

Publications and source records attributed to M Nordlander.

At least 55 records · Page 3Linked to original sources

PubMed1987

Felodipine sensitivity in vivo and in vitro of activation pathways in vascular smooth muscles.

Felodipine is a dihydropyridine calcium antagonist that exerts a markedly selective inhibition of the smooth muscle of arterial resistance vessels. In this paper, we report on the effects of felodipine on vascular smooth muscle in vivo and in vitro. Contractions in these effector cells are categorized according to means of activation, membrane events, and sensitivity to felodipine and are discussed in terms of four schematic "activation pathways." Stimulation of aortic smooth muscle by K+ or noradrenaline may be accounted for by separate pathways (I and IV) that might involve potential-operated and receptor-operated Ca2+ channels with high and low sensitivity to calcium antagonists. In the spike-generating vascular smooth muscle of the portal vein, both spontaneous myogenic activity and responses to adrenergic stimuli of physiological intensity are more adequately described in terms of an action potential-mediated pathway (II). This pathway is sensitive to felodipine in nanomolar concentrations irrespective of the primary means of stimulation. Basal tone and adrenergic responses of resistance vessels in vivo show similar sensitivity to felodipine, suggesting that they are also mediated by II or by a closely related pathway (III) involving graded changes in membrane potential rather than in action potentials. The latter activation pathways (II and III) are the ones relevant to the pharmacodynamic effects of felodipine for therapeutic purposes.

Action Potentials↗

PubMed1987

Effects of felodipine on local and neurogenic control of vascular resistance.

Arterial vascular resistance is established by myogenic mechanisms and is modulated both by local factors such as vasodilator metabolites and by remote controls of neurogenic and hormonal origin. This paper reports on the effects of felodipine and hydralazine on the myogenic tone and the neurogenic control of the vascular resistance of skeletal muscle. The vascular bed of the calf muscle of anesthetized cats was isolated and autoperfused at a constant flow. The sympathetic vasomotor nerves were activated by efferent stimulation of the lumbar sympathetic chain. Intraarterial infusion of felodipine and hydralazine reduced, in a dose-dependent manner, basal vascular resistance determined by myogenic factors and the vasoconstriction induced by nerve stimulation. After the infusion of felodipine, the vasoconstrictor responses to low, physiological rates of stimulation (0.5-4 Hz) were depressed to the same relative extent as resistance determined by myogenic factors, whereas the vasoconstrictor responses to supramaximal stimulation rates (16-32 Hz) were relatively more resistant. Felodipine had no effect on noradrenaline (NA) release during vasomotor nerve stimulation as determined by the NA venoarterial concentration difference. Hydralazine also reduced basal vascular resistance in a dose-dependent manner, but in contrast to felodipine, supramaximal doses of hydralazine totally abolished vasoconstrictor responses to supramaximal stimulation rates (32 Hz). It is concluded that felodipine reduces vascular resistance by a direct action on the contraction of vascular smooth muscle in the resistance vessels, as myogenic activity and physiological levels of neurogenic vasoconstriction are equally suppressed by felodipine. During supramaximal stimulation of vasomotor nerves, a separate activation pathway or more proximal vascular segments are likely to be engaged that are less sensitive to felodipine.

Animals↗

PubMed1987

Pharmacodynamic properties of felodipine.

This overview presents the pharmacodynamic properties of felodipine as studied in animal experiments with emphasis on results from our laboratory. Felodipine is 100-fold more potent in causing inhibition of spontaneously active vascular smooth muscle than myocardium in vitro. This vascular selectivity is significantly greater than that of nifedipine (potency ratio 15). Verapamil, D-600, La3+ and reduction of [Ca2+]o lack selectivity. The cellular mechanisms underlying this variable selectivity are not clear at present. In conscious spontaneously hypertensive rats (SHR), the plasma concentration required for 20% reduction of mean arterial pressure is approximately 10 nmol. Mean arterial pressure is lowered dose-dependently as a result of reduced peripheral vascular resistance accompanied by increased cardiac output due to transient tachycardia and increased stroke volume. There was rapid resetting of the baroreflex set point but unaltered sensitivity after felodipine and hydralazine in SHR. Therefore, the reflexogenic increase in heart rate and plasma renin activity subsided within 3 to 5 hours of continuous felodipine administration in SHR. In addition, there was a uniform dilatation of the peripheral vascular beds after felodipine administration. During long term treatment of SHR with felodipine, progression of left ventricular and vascular wall hypertrophy was prevented. Within the 'therapeutic dose range', the only primary effect observed in addition to arterial vasodilation is diuresis/natriuresis caused by a renal tubular action.

Antihypertensive Agents↗

PubMed1987

Baroreflex control of renin release in spontaneously hypertensive rats after administration of felodipine.

The baroreflex control of heart rate will be rapidly reset to operate at a lower pressure level after blood pressure reduction by felodipine. The present study investigates whether the baroreflex control of renin release in spontaneously hypertensive rats (SHR) will also be reset after prolonged felodipine administration. Conscious SHR, fitted with catheters in the tail artery and vein, were given felodipine intravenously for 5 hours. The initial reflexogenic elevation in plasma renin activity and heart rate caused by felodipine-induced blood pressure reduction were successively normalised with time. Heart rate returned to pre-drug values after 3 hours and plasma renin activity after 5 hours of stable blood pressure reduction. This indicates rapid resetting of baroreflex control of both cardiac and renal function after blood pressure reduction by felodipine.

Animals↗

PubMed1987

Baroreflex control of heart rate and renin release in SHR following administration of felodipine, an antihypertensive Ca2+ antagonist.

Baroreflex control of renin release following acute and prolonged blood pressure reduction by felodipine administration was investigated in conscious spontaneously hypertensive rats (SHR) fitted with arterial and venous catheters. Basal values of mean arterial pressure (MAP), heart rate (HR), and plasma renin activity (PRA) were obtained in SHR and in SHR given felodipine for 2 weeks (SHRF). In SHRFMAP was reduced by 12% (p less than 0.01) versus SHR, but PRA and HR were similar. Acute i.v. infusion of felodipine, during 5 h, maintained MAP reduction by 40%. Initially, HR increased 29 +/- 3% but returned to predrug levels after 3 h. PRA increased from 1.4 +/- 0.5 to 6.5 +/- 1.0 ng/ml/h. After 5 h PRA had reached low levels equal to those in SHR given placebo instead of felodipine. In SHR pretreated with metoprolol neither HR nor PRA increased following felodipine, an indication that the observed changes were neurogenically determined. This suggests that baroreflex control of cardiac and renal function resets within 3-5 h following blood pressure reduction by felodipine.

Animals↗

PubMed1987

Myocardial and vascular structural adaptation to chronic pressure overload.

Left ventricular (LV) function and end-diastolic dimensions were determined during antegrade and retrograde perfusions, respectively. Isolated hearts from spontaneously hypertensive rats (SHRs) and renal hypertensive rats and SHRs to which either feldopine, nifedipine, alpha-methyldopa, or a combination of felodipine and metoprolol was administered were used. Maximal cardiac function [cardiac output x (aortic pressure - left atrial pressure)] was elevated in SHRs, but depressed in those with renal hypertension. The diastolic pressure-volume relationships revealed eccentric rather than concentric LV hypertrophy in the SHRs. Renal hypertension in SHRs caused concentric LV hypertrophy. Antihypertensive therapy with calcium antagonists (but not with alpha-methyldopa) caused reduction of LV wall thickness, but increased LV end-diastolic volume (EDV). In SHRs, coronary flow was reduced at any given level of aortic pressure. At low aortic pressures (and hence, limited coronary perfusion), cardiac function was attenuated in SHRs. This reduction could be reversed by administration of antihypertensive therapy. These results suggest an improvement in maximal stroke work in SHRs as a result of eccentric hypertrophy which allows increased stroke volume for a given degree of myocardial shortening. Structural coronary vascular changes, which can be reversed by antihypertensive therapy, can limit coronary perfusion--and hence, cardiac performance--at low aortic pressures in SHRs. Maintenance of maximal cardiac function in treated SHRs, despite a reduction in LV wall thickness, may be due to an increase in LV end-diastolic volume.

Animals↗

PubMed1986

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↗

PubMed1986

Influence of long-term antihypertensive therapy on cardiac function, coronary flow and myocardial oxygen consumption in spontaneously hypertensive rats.

The relationships between cardiac performance, coronary flow, coronary vascular resistance at maximal vasodilatation and myocardial oxygen consumption were determined in isolated hearts from spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY) and from SHR given metoprolol (beta 1-selective blocker) and felodipine (selective calcium antagonist) for 35 weeks. A working heart perfusion system was used. An oxygen electrode allowed continuous measurement of oxygen tension in the venous coronary effluent. Blood pressure was reduced close to normal levels in treated SHR. Treatment also caused a substantial reduction of left ventricular weight. In both treated and untreated SHR, maximal cardiac performance, expressed as peak stroke volume, was enhanced above that of WKY at high perfusion pressures, while performance at low perfusion pressures was clearly reduced in the former groups. At a given workload, myocardial oxygen consumption (mmol O2/min per g) was reduced in both groups of SHR. This suggests a physiological structural adaptation to an elevated cardiac load in hypertension, where more myofibrils contribute to produce a given amount of work and therefore less oxygen is consumed per unit muscle mass. Coronary flow was reduced at any given perfusion pressure and oxygen extraction was increased in untreated SHR versus WKY. By causing regression of hypertensive structural vascular changes, treatment markedly increased coronary flow and correspondingly decreased oxygen extraction. Thus, by enhancing the myocardial nutritional supply with antihypertensive treatment, the reduced cardiac function at low perfusion pressure in untreated SHR was almost normalized.

Animals↗

PubMed1986

Peripheral haemodynamics after surgical reversal of two-kidney, one clip renal hypertension in rats.

The changes in peripheral haemodynamics and regional resistances were studied during the rapid fall in mean arterial pressure (MAP) after surgical reversal of two-kidney, one clip renal hypertension in rats (RHR). The controls used were sham-declipped RHR and normotensive control rats (NCR). During the 2 h following renal artery declipping or sham-operation, MAP and heart rate (HR) were followed continuously. Finally, the regional blood flows in the kidneys, small intestine and skeletal muscle were determined by the microsphere technique. Declipping caused MAP to fall from 167 +/- 5 to 108 +/- 5 mmHg (n = 10) with a concomitant fall in HR from 424 +/- 11 to 363 +/- 14 beats/min (P less than 0.01). The calculated vascular resistances fell in the intestinal and declipped renal vascular beds by 50-60% compared with sham-operated rats (P less than 0.01). However, vascular resistances remained unchanged in skeletal muscle and in the untouched kidney. This indicates that the reduction in flow resistance varies in the different vascular beds, presumably reflecting a mixture of suppressed sympathetic activity and direct vasodilatory actions induced by mechanisms activated upon reversal of two-kidney, one clip renal hypertension by renal artery declipping.

Animals↗

PubMed1986

Structural and functional adaptations within the myocardium and coronary vessels after antihypertensive therapy in spontaneously hypertensive rats.

The relationships between cardiac performance, coronary flow, minimal coronary vascular resistance and myocardial oxygen consumption (MVO2) were explored in isolated hearts from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) and in hearts from SHR given a combination of metoprolol and felodipine (selective calcium antagonist) for 35 weeks. Antihypertensive therapy markedly reduced arterial pressure and caused a substantial regression of left ventricular hypertrophy. An antegrade working-heart perfusion system was used, allowing measurements of stroke volume, coronary flow and MVO2 at varying pre- and afterloads. In untreated SHR cardiac function was reduced at low and enhanced at high perfusion pressure compared with WKY. Minimal coronary vascular resistance, which was greatly increased in SHR, was significantly reduced by treatment, allowing higher coronary flow for any given perfusion pressure and consequently a lower degree of oxygen extraction. In addition, at a given workload, MVO2 was reduced in both untreated and treated SHR. These results stress the importance of having adequate coronary perfusion within a hypertensive structurally redesigned coronary vascular bed in order to maintain cardiac performance. With antihypertensive therapy in SHR, an improved coronary flow capacity was created due to regression of the hypertensive vascular changes.

Animals↗

PubMed1985

Renal and cardiovascular effects of acute and chronic administration of felodipine to SHR.

Renal function and salt and water turnover were studied in SHR during acute and chronic administration of felodipine, which is an efficient antihypertensive vasodilating Ca2+ antagonist. In conscious SHR acute administration of felodipine in hypotensive doses increased renal sympathetic nerve activity but caused renal vasodilation, increases in GFR and a 2-3 fold increase in urinary flow rate and sodium excretion. The fraction of filtered sodium excreted (FENa) was approximately doubled. The diuretic and natriuretic effects of felodipine are therefore suggested to be due to a direct inhibitory action on the renal tubular cells, resulting in reduced sodium reabsorption. Nifedipine also induced diuresis and natriuresis in this system, while minoxidil reduced water and sodium excretion. Throughout 6 months of felodipine treatment, the mean arterial pressure (MAP), remained 25-20 per cent reduced. Felodipine in combination with metoprolol reduced MAP 25-30 per cent and also caused regression of left ventricular hypertrophy, while felodipine alone prevented its further progression. Also during chronic administration, felodipine induced diuresis but had no effect on plasma volume and on sodium or potassium excretion in SHR. It is concluded that in SHR felodipine induces diuresis; on acute treatment this is secondary to reduced tubular sodium reabsorption, although during chronic treatment the sodium loss is compensated for while the diuresis remains. Thus, the cardiovascular and renal effects of Ca2+ antagonists like felodipine differ substantially from those of other potent antihypertensive vasodilators e.g. minoxidil.

Animals↗

PubMed1985

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↗

PubMed1985

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↗

PubMed1985

Haemodynamic effects of short and long term administration of felodipine in spontaneously hypertensive rats.

Short term administration of felodipine to spontaneously hypertensive rats reduced mean arterial pressure, due to peripheral vasodilatation. This vasodilatation is generalised, since blood flow, determined by the microsphere technique, is maintained or increased in most vascular beds despite substantial mean arterial blood pressure reduction. The resistance and mean arterial blood pressure reduction after felodipine was counterbalanced by an increase in cardiac output. In short term therapy, cardiac output increased because of an increase in both heart rate and stroke volume. Following long term administration of felodipine cardiac output remained elevated owing to an increase in stroke volume. The lack of tachycardia during long term felodipine administration was shown to be due to a rapid resetting of the baroreflex control of heart rate. The marked increase in stroke volume after long term administration is suggested to be due to regression of left ventricular hypertrophy and structural rebuilding of the heart towards that characteristic of the well-trained athlete. Thus, the haemodynamic pattern induced by short term felodipine administration, and probably also other antihypertensive drugs, will become modified by neurogenic and structural adaptations upon prolonged administration.

Animals↗

PubMed1978