Nicorandil-induced changes in the distribution of cardiac output and coronary blood flow in pigs

Summary The present investigation was conducted to study systemic and regional haemodynamic effects of nicorandil, a potent coronary vasodilator, after intravenous or local intracoronary administration in anaesthetized or conscious pigs. Intravenous infusions of nicorandil for 10 min in both anaesthetized (15, 30, 75 and 150 g · kg^–1 · min^–1) and conscious (20, 40 and 80 g · kg^–1 · min^–1) pigs reduced arterial blood pressure, stroke volume, left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance, but increased heart rate and maxLVdP/dt. Since nicorandil decreased LVEDP at doses which did not affect arterial blood pressure, the drug may be considered as a more potent venodilator than arterial dilator. Nicorandil increased cardiac output only in conscious animals due to a more marked tachycardia (85% after 80 g · kg^–1 · min^–1) than in anaesthetized animals (30% after 75 g · kg^–1 · min^–1). The nicorandil-induced increase in heart rate and maxLVdP/dt, being substantially attenuated in conscious pigs after treatment with propranolol, can be ascribed to a reflex activation of the sympathetic nervous system following the fall in arterial pressure. Although cardiac output did not change in anaesthetized animals, intravenous infusions of nicorandil did cause a redistribution of blood flow in favour of organs such as the heart, adrenals, spleen, small intestine and brain at the expense of that to the stomach and kidneys; hepatic artery and skeletal muscle blood flow did not change. The increase in myocardial blood flow, primarily to the subepicardial layers, was associated with an enhancement in coronary venous oxygen content and was also noticed after intracoronary infusions of nicorandil (0.6, 1.5, 3 and 6 g · kg^–1 · min^–1). The above cardiovascular profile suggests a possible usefulness of nicorandil in angina pectoris as well as congestive heart failure. However, caution is needed because the strong hypotensive action and reflex-mediated tachycardia may under certain conditions aggravate myocardial ischaemia, particularly in the subendocardial layers. Send offprint requests to P. D. Verdouw     

The pharmacokinetics and haemodynamic effects of continuous nicorandil infusion in healthy volunteers

Summary We have studied the pharmacokinetics and haemodynamic effects of nicorandil after a 12-h infusion. Nicorandil is a mixed vasodilator combining the actions of a nitrate and a potassium channel opener.Nicorandil was infused for 12 h in 21 healthy volunteers at rates of 0.05, 0.10, and 0.20 g·kg^–1·min^–1 using a placebo controlled, crossover design. Systemic blood pressure, heart rate, electrocardiographic (ECG) intervals, and cardiac output (impedance cardiography) were measured supine and standing.Dose-related, steady-state plasma nicorandil concentrations occurred within 3 to 4 h. Nicorandil's pharmacokinetics were linear with dose.Four 0.20 g·kg^–1·min^–1 nicorandil infusions were terminated early primarily because of moderate or severe headaches. There were no safety concerns (ECG intervals, laboratory assays).Blood pressure fell versus placebo only in the standing position and heart rate increased slightly (not significant). That is, standing blood pressure in the 6 to 12 h interval fell from baseline 8.0*/6.8, 1.6/5.1, and 9.8*/7.9* mmHg (systolic/diastolic, *=P<0.05 versus placebo) at 0.05, 0.10, and 0.20 g·kg^–1·min^–1 respectively. Cardiac output increased slightly above placebo at lower doses. Haemodynamic changes correlated poorly with plasma nicorandil concentrations. Similar total doses were less well-tolerated when extended over 12 h. We saw no evidence of pharmacodynamic tolerance to nicorandil within 12 h.     

Steady-state concentrations of choline and acetylcholine in rat brain parts during a constant rate infusion of deuterated choline

Summary An intravenous infusion of deuterated choline at constant rate for 6 min (5 or 25 moles kg^–1 min^–1) significantly increases the concentration of choline in plasma, occipital cortex and striatum. Both 5 and 25 moles kg^–1 min^–1 increase the concentration of acetylcholine in cortex but only 25 moles kg^–1 min^–1 increases the acetylcholine content in striatum. In contrast, 1 mole kg^–1 min^–1 does not change the choline or acetylcholine content in cortex or striatum. A single pulse injection of choline (200 moles kg^–1) causes a significant increase in the concentration of choline in striatum 30 sec following injection. The choline content returns to normal values within 2 min. These studies show that when a pulse injection of a non-tracer dose of radioactive choline is used to measure brain acetylcholine turnover rate the maintenance of steady state must be verified within seconds after the pulse injection of radioactive choline. When constant infusion of deuterated choline is used to measure turnover rate of acetylcholine in the brain of rats, a dose of 1 mole kg^–1 min^–1 appears to be a maximal infusion rate.     

Differential effects of locally-applied capsaicin on distension-stimulated gastric acid secretion in the anesthetized rat

Summary The effects induced by the local administration of capsaicin on acid production have been investigated in the continuously perfused stomach of the anesthetized rat. Basal acid secretion was not influenced by 10 min intragastric perfusion with capsaicin (300 g min^–1). Acid responses elicited by distension of the stomach with increases in intragastric pressure of 5 and 10 cm H₂O were not modified after a 10 min intraluminal infusion with 80 or 300 g min^–1 of capsaicin. H⁺ output stimulated by higher intraluminal pressure (20 cm H₂O) were significantly decreased by intraluminal infusion of capsaicin (20, 80, 300 and 600 g min^–1). Acid responses to carbachol (4 g kg^–1, i.p.) were not influenced by intragastric (300 g min^–1), or systemic neonatal, treatment with capsaicin.Intraluminal infusion of the neurotoxin tetrodotoxin (0.12 g min^–1, 10 min) decreased acid responses to an increase in intragastric pressure of 20 cm H₂O but not those elicited by distention with a pressure of 10 cm H₂O. Neonatal systemic treatment (s. c.) with capsaicin or local gastric serosal application of either capsaicin or tetrodotoxin abolished acid responses to gastric distension (+ 20 cm H₂O). Capsaicin (80 g min^–1) and tetrodotoxin (0.12 g min^–1) infused concurrently into the lumen did not inhibit gastric acid secretion stimulated by an increase of 20 cm H₂O in intragastric pressure to any greater extent than did either drug given alone. The inhibition of acid secretion cannot be attributed to an increase in H⁺ loss, since intragastric infusion of capsaicin (300 g min^–1) did not cause any significant acid loss in rats pretreated with omeprazole and undergoing luminal perfusion with acid saline during gastric distension (+ 20 cm H₂O). Neither the intragastric perfusion nor the serosal application of capsaicin modified the H⁺ production induced by electrical stimulation of the vagus. This acid response was, however, abolished following 10 min intraluminal perfusion with tetrodotoxin (0.12 g min^–1).These observations confirm that capsaicin-sensitive sensory fibers located in the stomach wall mediate the acid secretory responses to intragastric distension. Such fibers are susceptible to the effects of capsaicin when administered systemically or through the gastric serosa, but only partially if capsaicin is infused intraluminally.Correspondence to: J. V. Esplugues     

Pharmacokinetics of exogenous adenosine in man after infusion

Summary The plasma kinetics of adenosine was investigated in healthy volunteers after a 1 minute infusion of 2.5, 5 and 10 mg (38, 79 and 148 g·kg^–1 respectively) and after infusion of 200 g·kg^–1 in 10 min followed by 400 g·kg^–1 in 10 min.As the dose in the 1 min infusion study was increased the mean CL of adenosine decreased (10.7, 4.70 and 4.14 l·min^–1, respectively), its mean half-life increased (0.91, 1.24 and 1.86 min, respectively), and the mean volume of distribution did not show any clear trend (8–13 l).After the 20 minute infusion the plasma level of adenosine reached a peak value comparable to that observed after infusion of 5 mg in 1 min (about 0.5 g·ml^–1), but the mean clearance and half-life were significantly different (12.1 l·min^–1 and 0.63 min respectively).In all the subjects the plasma concentration of adenosine had returned to the baseline value in 5–15 min after the end of the infusion.     

Nimodipine has no beneficial effect on neurological outcome in a cardiopulmonary arrest model in the rat

Summary Brain damage after resuscitation from cardiac arrest is believed to be related to calcium influx in ischaemic neurons and to postischaemic calcium-dependent vasospasm. We therefore evaluated the potentially protective effects of the calcium-entry blocker nimodipine in a cardiopulmonary arrest model in the rat.Male Wistar rats were anaesthetized with ketamine (group I) or hexobarbital (group II) and subjected to a KCl-induced cardiac arrest during 7 min (group I) or 12 min (group II). Five minutes after resuscitation, the rats were treated intravenously in a randomized and blind fashion. Group I received either saline or 1 g · kg^–1 · min ^–1 or 5 g · kg^–1 · min^–1 of nimodipine and group II either saline or 1 g · kg^–1 · min^–1 of nimodipine. Survival, occurrence of seizures and neurological status were assessed daily during 7 days after resuscitation. On day 7, the brains of the surviving rats were perfusion-fixed and a histopathological evaluation of the hippocampus was performed.Nimodipine, in the doses tested, had no beneficial influence on the 7 day survival rate, nor on the occurrence of seizures and the neurological and histopathological scores in the rats surviving after 7 days. With the highest dose of nimodipine, there was even a trend towards a decrease of the survival rate, probably related to the drug's hypotensive effect. Therefore, our data do not show a protective effect of nimodipine after cardiac arrest.Research Assistant, National Fund for Scientific Research, BelgiumSend offprint requests to W. A. Buylaert at the above address     

Inhibitory effects of apomorphine and pergolide on neurogenic vasoconstriction in the hindquarters of the rat

Summary The effects of locally administered apomorphine and pergolide were studied in the isolated autoperfused hindquarters of the rat, in an attempt to assess the possible role of presynaptic dopamine receptors at the level in the hypotensive effect of these dopamine agonists.Local infusion of apomorphine (1g·kg^–1·min^–1 for 5 min) or pergolide (1g·kg^–1·min^–1 for 5 min) [into the hindquarters] did not alter perfusion pressure per se, but reduced the pressor response to electrical stimulation of the lumbar sympathetic chains for the whole frequency range used during a cumulative frequency-response curve (0.25–16 Hz, 1 ms, supramaximal voltage). Apomorphine and pergolide reduced the pressor response elicited by 4 Hz electrical stimulation (applied until maximum response was reached) to 54.8±7.1% and 53.9±1.7% respectively, but they did not modify similar increases of perfusion pressure produced by locally administered noradrenaline.The inhibition by apomorphine and pergolide of the 4 Hz stimulation-evoked pressor response was completely antagonized by local administration of the dopamine antagonist haloperidol (1g·kg^–1), but was not influenced by the ₂-antagonist rauwolscine (100g·kg^–1). This dose of rauwolscine antagonized the inhibitory effect of the ₂-agonist UK-14,304, which was not influenced by haloperidol.Local administration of rauwolscine increased the pressor response to stimulation at 4 Hz by 37.4–46.2%. In contrast, local administration of haloperidol did not influence the 4 Hz stimulation-evoked pressor response.These results indicate that dopamine receptors are pressent on the sympathetic innervation of the vascular bed in the rat hindquarters but do not provide evidence for a physiological role of these receptors in modulating peripheral sympathetic neurotransmission. Stimulation of these receptors, leading to a decrease of noradrenaline release and thus of vasomotor tone, might—at least in part—explain the blood pressure lowering effects of intravenous apomorphine and pergolide in the rat.     

Biphasic dose-response relationship observed with Bay k 8644 on atrioventricular nodal conduction inhibited by verapamil

Summary The effects of a calcium channel blocker, verapamil, on the atrioventricular (AV) node, are antagonized by calcium, intravenously infused, so long as plasma calcium concentration does not reach 5.0 or 5.5 mmol . 1^–1, as previously shown. Beyond this, the antagonistic effects decrease progressively, so that there is a bellshaped relationship between dose (or concentration) and response. The purpose of the present experiments has been to investigate a possible similar dose-response curve with a calcium channel activator, Bay k 8644. The study was carried out in anaesthetized, atropinized dogs, with cardiac pacing. The His bundle potentials were recorded by endocavitary electrodes and the AV nodal effective refractory period was measured by the extrastimulus method. Verapamil impaired AV nodal conduction and additional infusion of Bay k 8644 at a rate of 1 g · kg^–1 · min^–1 partly antagonized this effect. Increasing the infusion rate of Bay k 8644 to 5 g kg^–1 · min^–1 did not further increase but reduced the antagonism. In other experiments where infusion of calcium had partly antagonized the effect of verapamil, Bay k 8644 infused after cessation of calcium infusion did not further antagonize the effect of verapamil which even became again increasingly marked. Consequently, in the AV node depressed by a calcium channel blocker, Bay k 8644 gives rise to a bell-shaped dose-response relationship of its verapamilantagonistic action and the reversal of this action by high doses of Bay k 8644 can be observed after both administration of either calcium or Bay k 8644 in moderate doses. Send offprint requests to J. Lang at the above address     

The effects of ethanol and lead,alone and in combination,on the severity of arrhythmias induced by coronary artery occlusion,and by noradrenaline,in anaesthetised rats

The aim of this study was to investigate whether chronic (3 or 10 months) administration, via the dinking water, of lead (25 ppm) and/or ethanol (25% v/v) altered the susceptibility of the heart to arrhythmias induced either by coronary artery occlusion or noradrenaline infusion in pentobarbitone-anaesthetised male Sprague-Dawley rats. The cardiac effects of acute intravenous infusions of ethanol (17, 33 and 66 mg kg^–1 min^–1) were also measured. Chronic exposure to ethanol and/or lead in the drinking water had no marked effect on the severity of arrhythmias occurring within the initial 30 min of coronary artery occlusion. In control rats and in those administered ethanol and/or lead for 10 months, noradrenaline (16 g kg^–1 min^–1 given IV 1 h post-occlusion for a 15-min period) induced a similar number of ectopic beats during the infusion period, although these arrhythmias persisted beyond the infusion period in treated animals only. There was a significant accummulation of lead in the bone but not in the blood of lead-treated rats. Blood ethanol concentrations varied considerably between animals, ranging from 0 to 319 mg%. Ethanol (66 mg kg^–1 min^–1) given acutely and yielding a blood concentration of 174 mg % had a slight antiarrhythmic effect in this model.     

Plasma insulin during physiological and pathophysiological changes in atrial natriuretic factor

Summary Changes in plasma insulin in response to a physiological or pathophysiological elevation in circulating atrial natriuretic factor (ANF) have been investigated.Plasma insulin, glucose, immunoreactive (ir) ANF, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), absolute and fractional excretion of sodium (FENa), have been measured in 14 volunteers before and during infusion of low doses of ANF or vehicle (V). Each subject received single-blind in a randomized sequence at 2 week-intervals: V alone, or ANF 4, 8 and 16 ng·kg^–1·min^–1, indused over 90 min.Plasma irANF was increased 2.5- to 11-fold during the ANF infusion as compared to the test with the vehicle. Plasma insulin did not change during V administration (baseline vs V: 22 vs 21 U·ml^–1) and was unchanged during ANF at 4, 8 and 16 ng·kg^–1·min^–1 (19, 19, 21 U·ml^–1, respectively). Blood pressure, ERPF and GFR were not affected, and diuresis, FENa and urinary Na excretion were increased significantly and dose-dependently during ANF, but not V infusion. Compared to baseline, ANF 4, 8 and 16 ng·kg^–1·min^–1 increased urinary Na excretion by 147, 241 and 446 mol·min^–1, respectively.The findings indicate that, in normal humans, an acute increase in irANF within or slightly above the physiological range, which modified natriuresis and diuresis, did not alter circulating plasma insulin.The work was supported in part by the Swiss National Science Foundation     

α-Adrenoceptor-mediated inhibitory effect of the sympathetic nervous system on the isoprenaline-induced increase in plasma renin concentration

Summary The importance of the sympatho-adrenal system for the isoprenaline-induced increase in plasma renin concentration was investigated in conscious rats. Ganglionic blockade by trimethidinium (10 mg kg^–1) increased the dose-dependent elevation of plasma renin concentration induced by isoprenaline (0.03–0.48 g kg^–1 min^–1). Also treatment of the rats with guanethidine (6 mg kg^–1) or reserpine (2.5 mg kg^–1, given 16 and 7 h prior to the experiments) further increased the effect of isoprenaline (0.5 g kg^–1 min^–1) on plasma renin concentration. Unilateral renal denervation combined with contralateral nephrectomy doubled the effect of the -sympathomimetic amine on renin release. The -adrenoceptor antagonist phenoxybenzamine (3 mg kg^–1) also enhanced the effect of isoprenaline on this parameter.It is concluded that apart from a stimulation of renin release via -adrenoceptors the sympathetic nervous system may inhibit renin release via stimulation of -adrenoceptors.Supported by DFG Me 541/1Partial preliminary communication: Meyer et al. (1976)     

Dopamine pharmacokinetics in critically ill newborn infants

Summary Dopamine is frequently used in critically ill newborn infants for treatment of shock and cardiac failure, but its pharmacokinetics has not been evaluated using a specific analytical method. Steady-state arterial plasma concentrations of dopamine were measured in 11 seriously ill infants receiving dopamine infusion, 5–20 g · kg^–1 · min^–1, for presumed or proven sepsis and hypotensive shock.Steady-state concentrations of dopamine ranged from 0.013–0.3 g/ml. Total body clearance averaged 115 ml · kg^–1 · min^–1. The apparent volume of distribution and elimination half life averaged 1.8 1 · kg^–1 and 6.9 min, respectively.No relationship was observed between dopamine pharmacokinetics and gestational age, postnatal age or birthweight. Substantial interindividual variation was seen in dopamine pharmacokinetics in seriously ill infants, and plasma concentrations could not be predicted accurately from its infusion rate.Marked variation in clearance explains in part, the wide dose requirements of dopamine needed to elicit clinical response in critically ill newborn infants.VBM was a Fellow at Ohio State University and Children's Hospital at the time of study and is now at the Department of Pharmacy Services and College of Pharmacy, University of Michigan, Ann Arbor, MI, USA     

Low-dose Iloprost infusion improves insulin action and non-oxidative glucose metabolism in hypertensive patients

Fourteen hypertensive (174.3/98.3 mmHg) non-diabetic patients were given a euglyceamic glucose clamp along with infusion of 0.9% NaCl and the prostacyclin (PGI₂) analogue Iloporst (0.7 ng · kg · min^–1). Substrate oxidation was also determined by indirect calorimetry. Over the last 60 min of the clamp, Iloprost vs saline improved whole body glucose disposal (WBGD) (35 vs 28.3 mol · kg^–1 LBM) and non-oxidative glucose metabolism (24.7 vs 18.1 mol · kg^–1 LBM · min^–1). Iloprost delivery was associated with a significant decrease in membrane microviscosity (0.253 vs 0.205), but did not affect arterial blood pressure and heart rate. In nine patients, skeletal muscle blood flow (SMBF) and insulin-stimulated glucose uptake (GU) were also studied. At the end of the study, despite a similar SMBF (37 vs 38 ml · min^–1 · kg^–1), GU (0.55 vs 0.46 mmol · 1^–1) was significantly increased by Iloprost infusion. Percentage decrease in membrane microviscosity was correlated with percentage increase in WBGD (r=0.65) and non-oxidative glucose metabolism (r=0.68). In conclusion, low-dose Iloprost infusion improves insulin action and non-oxidative glucose metabolism in hypertensive patients.     

Atrial natriuretic factor and autonomic nervous system function in man

Summary To delineate a possible interaction of atrial natriuretic peptide ANF-(99–126) with autonomic nervous system function in humans, a spectrum of indices were assessed in 10 healthy young men during a 90 min iv administration of a) synthetic ANF-(99–126) 50 g bolus followed by 0.025 g·kg^–1·min^–1, b) the potent vasodilator sodium nitroprusside (SNP) 0.35 g·kg^–1·min^–1, or c) vehicle 0.9% NaCl 40 ml and 20% albumin 5 ml, in random sequence.Plasma immunoreactive ANF (irANF) rose from 32 to 1700 pg·ml^–1 during the ANF-(99–126) infusion and was stable during SNP or vehicle. Infusion of ANF-(99–126) and SNP, but not vehicle, decreased diastolic blood pressure (BP) on average by –9 and –7.5%, respectively; systolic BP was largely unchanged. Heart rate (HR, +15 and 12%) or plasma norepinephrine (NE) rose similarly during ANF-(99–126) and SNP infusions, and the systolic BP response to orthostasis was similar (–18 mm Hg). The following autonomic indices did not differ significantly after the 3 infusions: responses of HR and NE to orthrostasis; reflex bradycardic response to phenylephrine (PE)-induced rise in systolic BP (+20 mm Hg); responses of BP to hyperventilation, PE, or 3 min of sustained handgrip; and beat-to-beat variation (R-R interval) during deep breathing. The immediate orthostatic HR response (30/15 R-R interval ratio) fell similarly during infusion of ANF-(99–126) or nitroprusside.The findings indicate that in healthy men the function of the autonomic nervous system is not notably impaired by high circulating ANF levels. ANF-(99–126) infused in moderate dosage seems to lower BP largely by non-autonomic mechanisms.The study was supported in part by the Swiss National Science Foundation     

Role of nitric oxide formation in the regulation of haemodynamics and the release of noradrenaline and adrenaline

Summary This study in the anaesthetized rabbit aimed at determining the role of nitric oxide (NO), the putative endothelium-derived relaxing factor, in the regulation of haemodynamics and the release into plasma of noradrenaline and adrenaline. Specific inhibition of NO formation was achieved by i.v. bolus injection of l-N^G-monomethyl-arginine (l-NMMA; 3–100 mg kg^–1). Phenylephrine was infused i.v. at constant rates (2.5–20 g kg^–1 min^–1) in order to assess baroreflex-mediated changes in release due to direct peripheral vasoconstriction. Rates of noradrenaline and adrenaline release into plasma were determined by the radio-tracer technique. l-NMMA, but not d-NMMA, dose-dependently increased mean arterial pressure and total peripheral vasular resistance, whereas both heart rate and cardiac output decreased concomitantly. The corresponding ED₅₀ values for l-NMMA ranged from 11.2 to 18.5 mg kg^–1. Inhibition of NO formation by l-NMMA as well as phenylephrine infusion caused decreases in the plasma clearance of noradrenaline and adrenaline which were correlated with the drug-induced decreases in cardiac output. Both l-NMMA and phenylephrine reduced the rate of noradrenaline release into plasma as they increased total peripheral resistance. Moreover, the curvilinear relationship between these two parameters obtained for l-NMMA was virtually identical to that produced by phenylephrine, indicating that the reduction in noradrenaline release by l-NMMA is mediated solely by the baroreflex. From the l-NMMA-induced maximum inhibition of noradrenaline release, it is concluded that the counter-regulation against peripheral vasodilation by NO accounts for 69% of basal noradrenaline release. The baroreflex-sensitive component of noradrenaline release, as determined by the maximum inhibition of release induced by phenylephrine, amounted to 83% of basal release. l-NMMA also reduced the release into plasma of adrenaline; the maximum inhibition of release was 52%. However, when related to total peripheral resistance, this inhibition of adrenaline release was more pronounced than that induced by phenylephrine, suggesting that the formation of endogenous NO facilitates the release of adrenaline.This study was supported by the Deutsche Forschungsgemeinschaft (Gr 490/5-3). A preliminary account of the present results was presented to the German Pharmacological Society (Halbrügge and Lütsch 1991) Send offprint requests to T. Halbrügge at the above address     

Simvastatin reduces plasma lipid levels and improves insulin action in elderly,non-insulin dependent diabetics

Summary Twelve elderly non-insulin dependent diabetic patients took part in a double-blind, cross-over, randomized study comparing simvastatin 30 mg/day and placebo. Each treatment period lasted 3 weeks and was separated by a 3 week wash-out period. At the end of each treatment period all subjects underwent in randomized order an oral glucose tolerance test (OGTT; 75 g) and an euglycaemic hyperinsulinaemic (50 mU/kg·h) glucose clamp.Simvastatin compared to placebo significantly reduced plasma total cholesterol (7.9 vs 5.3 mmol·l^–1), LDL-cholesterol (7.2 vs 4.3 mmol·l^–1), triglycerides (2.9 vs 2.1 mmol·l^–1), free fatty acids (1106 vs 818 mmol^–1) and glucose (7.4 vs 6.6 mmol·l^–1) levels.After simvastatin, and in the last 60 min of the glucose clamp, there was an improvement in the action of insulin as demonstrated by stronger inhibition of hepatic glucose output (2.7 vs 5.2 mol·kg^–1·min^–1) and stimulation both of the glucose disappearance rate (26.3 vs 19.5 mol·kg^–1·min^–1) and glucose metabolic clearance rate (4.3 vs 3.6 ml·kg^–1·min^–1).The changes in glucose turnover parameters were significantly correlated with basal plasma free fatty acids and were independent of plasma glucoregulatory hormones. In conclusion, simvastatin seems to exert beneficial effects both on lipid and glucose metabolism.     

Acute haemodynamic and neurohumoral effects of intravenous nisoldipine in patients with severe congestive heart failure

Summary Twenty patients (5 females, 15 males) with severe heart failure (NYHA IV), due to coronary artery disease in 14, and congestive cardiomyopathy in 6, received an intravenous bolus of the calcium blocker nisoldipine 0.2 mg followed by a continous infusion of 0.2 g · kg^–1 · min^–1. Haemodynamic measurements were performed at baseline and after 30 min.The mean arterial pressure fell from 91 to 73 mm Hg, pulmonary capillary wedge pressure from 31 to 26 mm Hg and systemic vascular resistance from 1695 to 1040 dyn · s · cm^–5.The cardiac index (2.2 to 2.71 · min^–1 · m^–2, and stroke volume index (25 to 33 ml · m^–2) were markedly increased. There was no reflex tachycardia as the heart rate dropped from 92 to 85 beats · min^–1. Plasma renin activity and norepinephrine concentration did not change significantly.The findings indicate that nisoldipine acts as a strong vasodilator and that it has a beneficial acute haemodynamic effect in patients with severe left heart failure irrespective of its aetiology.     

Dopamine-induced diuresis in the cat without changes in renal hemodynamics

Summary The effects of intravenous (i.v.) and intraarterial (i.a.) injection and infusion of dopamine (DA) on renal hemodynamics, regional sympathetic activity and kidney function were investigated in anaesthetized cats. In response to the i.v. bolus injection of DA (25 g/kg), mean arterial blood pressure (MABP) was increased by 19.7%, renal blood flow (RBF) by 16.6%, and regional sympathetic discharges were inhibited. The principal effect of i.a. bolus injection of DA into the renal artery was vasoconstriction. Vasodilation was observed neither after lower doses of DA nor after pretreatment with phenoxybenzamine.During continuous i.v. infusion of 10 g DA kg^–1 min^–1 MABP, RBF, renal sympathetic discharges and glomerular filtration rate (GFR) did not change, whereas urine volume was increased by 120.5%, sodium excretion by 99.7%, chloride excretion by 143.2%, and potassium excretion by 31.9%. Urine osmolality was decreased and osmolal clearance increased. Raising the DA dose to 25 g kg^–1 min^–1 resulted in a fall of GFR, but the diuretic response was not significantly different from that of the low dose. Bulbocapnine (6 mg/kg i.v.) antagonized the DA-induced diuresis.In conclusion, the diuretic effect of DA in the cat is not dependent on a change in RBF, GFR or renal sympathetic activity. This suggests that a tubular site of action is primarily responsible for DA diuresis.     

Parallel increases in noradrenaline reuptake and release into plasma during activation of the sympathetic nervous system in rabbits

Summary Rates of noradrenaline reuptake and spillover into plasma were examined in conscious rabbits before and during activation of the sympathetic nervous system to determine whether neuronal reuptake varies disproportionately or in parallel with increases in noradrenaline release. The sympathetic nervous system was stimulated by nitroprusside-induced hypotension, 2-deoxyglucoseinduced glucopenia or intravenous infusion of isoprenaline before and after administration of desipramine to block neuronal uptake. Spillover of noradrenaline into plasma was estimated from the dilution of intravenously infused 3H-noradrenaline with endogenous plasma noradrenaline. The amount of dihydroxyphenylglycol (DHPG) in plasma that was derived from metabolism of recaptured noradrenaline, together with the desipramine-induced decreases in clearance from plasma of ³H-noradrenaline and appearance in plasma of ³H-DHPG, were used to estimate the rate of neuronal reuptake of noradrenaline.The mean (± SEM) resting noradrenaline reuptake rate (n = 28) was 0.62 ± 0.04 nmol kg^–1 min^–1, 5-fold greater than the rate of its spillover into plasma (0.12 ± 0.02 nmol kg^–1 min^–1). Intravenous infusion of nitroprusside at 3 rates titrated to cause graded increases in heart rate caused 74%, 129% and 240% increases in noradrenaline spillover into plasma and 66%, 104% and 198% increases in noradrenaline reuptake. At 15–30 min after intravenous injection of 2-deoxyglucose (500 mg/kg) there was a 106% increase in noradrenaline spillover and a 93% increase in noradrenaline reuptake. Infusion of isoprenaline (0.25 g kg^–1 min^–) caused a 102% increase in noradrenaline spillover and a 130% increase in noradrenaline reuptake. The proportionally similar increases in noradrenaline reuptake and spillover into plasma during activation of noradrenaline release from sympathetic nerves indicated that the efficacy of neuronal reuptake — the percentage of released noradrenaline that is recaptured — is unaltered by short-term increases in the amount of neurotransmitter liberated into the synaptic cleft. Send offprint requests to G. Eisenhofer at the above address     

5-Hydroxytryptamine-induced increase in left ventricular dP/dtmax does not suggest the presence of ventricular 5-HT4 receptors in the pig

Summary Although 5-hydroxytryptamine (5-HT) increases porcine atrial force and rate via 5-HT₄ receptors, its effect on left ventricular contractility is not known. Therefore, using the maximum rate of rise of left ventricular pressure (LVdP/dt_max) as an index of cardiac contractility, we have attempted to analyze the possible role of ventricular 5-HT₄ receptors in the anaesthetized pig. The full agonists at 5-HT₄ receptors, 5-HT and 5-methoxytryptamine (each 3, 10 and 30 g · kg^–1), and the -adrenoceptor agonist, isoprenaline (0.01, 0.03 and 0.1 g · kg^–1), increased heart rate, LVdP/dt_max and cardiac output. For a given degree of tachycardia, the increase in LVdP/dt_max by isoprenaline was substantially more than that observed with either 5-HT or 5-methoxytryptamine. The 5-HT₄ receptor partial agonist, renzapride (3, 10, 30, 100 and 300 g · kg^–1), also increased heart rate and LVdP/dt_max dose-dependently. When the heart was paced at 150 beats · min^–1, increases in LVdP/dt_max as well as cardiac output (except with the highest doses) by 5-HT, 5-methoxytryptamine and isoprenaline were clearly attenuated. However, the magnitude of attenuation of LVdP/dt_max responses by cardiac pacing was more marked in the case of 5-HT and 5-methoxytryptamine than with isoprenaline.The effects of renzapride (300 g · kg^–1) and tropisetron (0.3 and 3 mg · kg^–1) on increases in heart rate and LVdP/dt_max by 5-HT, 5-methoxytryptamine and isoprenaline were also studied. In the absence of atrial pacing, both renzapride and tropisetron (3 mg · kg^–1) effectively antagonized the responses to 5-HT and 5-methoxytryptamine; except for some decrease in the LVdP/dt_max response by tropisetron, the effect of isoprenaline remained essentially unchanged after the antagonists. During atrial pacing, renzapride significantly antagonized the responses to the first two doses of 5-HT, but the responses to the highest 5-HT dose and to 5-methoxytryptamine remained unaffected. Though, particularly after its higher dose, tropisetron reduced the responses to 5-HT and 5-methoxytryptamine, isoprenaline responses were also affected.The above results show that a significant part of the increase in LVdP/dt_max by 5-HT receptor agonists in the anaesthetized pig is a consequence of tachycardia elicited by these compounds via 5-HT₄ receptors. Since the increase in LVdP/dt_max, compared to tachycardia, was much less with 5-HT and 5-methoxytryptamine than with isoprenaline, and since the antagonism by renzapride and tropisetron against 5-HT and 5-methoxytryptamine during atrial pacing was relatively weaker and/or unspecific, it appears unlikely that the increase in LVdP/dt_max, during atria] pacing is mediated by ventricular 5-HT₄ receptors. This view is substantiated by our recent in vitro experiments where 5-HT (0.01 to 100 mol/l) failed to significantly increase contractions of porcine left ventricular trabeculae.Correspondence to P. R. Saxena at the above address