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.     

Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection

The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg^–1 or 8 mg·kg^–1 was administered in a suspension; five children received 2 mg·kg^–1 and four 8 mg·kg^–1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg^–1, the C_max, AUC (0–), and t_1/2 ranged from 2.3–4.4 g·ml^–1, 84.9–136 g·h·ml^–1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg^–1 the C_max, AUC (0–), and t_1/2 ranged from 5.4–12.1 g·ml^–1, 330–684 gh·ml^–1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.     

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.     

Salivary nystatin concentrations after administration of an osmotic controlled release tablet and a pastille

Mucosal oral therapeutic system (MOTS) is a controlled-release osmotic system for oral cavity therapy. MOTS (nystatin) is designed to deliver approximately 200,000 units of nystatin over several hours. A crossover study was conducted in five healthy volunteers to evaluate the amount of nystatin released (based on residual drug content) when the system is held in the mouth for 30 min, 1 h, and 2 h, and to compare these concentrations with those achieved with a Mycostatin (nystatin) pastille.An average of 37% of the nystatin content was released intra-orally from MOTS during 2 h in the mouth, which was very similar to the percentage delivered in vitro. Mean salivary drug concentrations were as follows: 279 g·ml^–1 at 30 min; 654 g·ml^–1 after 1 h; and 532 g·ml^–1 at 2 h. These concentrations consistently exceeded those produced by the pastille at the same time points. Fifteen minutes after placement of the pastille in the mouth (i.e., immediately after its dissolution) mean nystatin concentrations reached 746 g·ml^–1 but fell rapidly to 13.2 g·ml^–1 at 30 min, 7.2 g·ml^–1 at 1 h, and 5.6 g·ml^–1 at 2 h.The study demonstrates that MOTS maintains high salivary nystatin concentrations throughout a 2 h dosing interval.     

The pharmacokinetics of theβ 2-adrenoceptor agonist fenoterol in healthy women

Summary We have studied the pharmacokinetics of fenoterol in healthy women during and after a 3 h intravenous infusion of different doses within the therapeutic range for tocolysis (0.5 g·min^–1, 1.0 g·min^–1, and 2.0 g·min^–1). A specific and sensitive radioimmuno-assay was used for the determination of fenoterol. For compartmental analysis the plasma concentration time data were fitted with the TOPFIT program, assuming two exponentials.The total clearance of fenoterol increased with dose (1299 ml·min^–1 at 0.5 g·min^–1, 1483 ml·min^–1 at 1.0 g·min^–1, and 1924 ml·min^–1 at 2.0 g·min^–1), as did the apparent volume of distribution (from 491 at the lowest to 851 at the highest dose).In contrast, the apparent half-lives were not dose-dependent, with t_{1/2· 1} 4.8 min and t_{1/2· 2} 52 min.This paper is dedicated to Prof. Dr. Ellen Weber, Heidelberg, FRG     

The penetration of ciprofloxacin into bronchial mucosa,lung parenchyma,and pleural tissue after intravenous administration

Summary We have studied the concentrations of ciprofloxacin in serum, bronchial mucosa, lung parenchyma, and pleural tissue after a single intravenous dose of 200 mg in 20 patients subjected to lung surgery.The concentrations of ciprofloxacin in the tissues exceeded that in the serum by 3-fold to 7-fold: serum 0.6 g·ml^–1, bronchial mucosa 1.9 g·g^–1 lung parenchyma 3.4 g·g^–, and pleural tissue 1.7 g·g^–1.The achievable concentrations of ciprofloxacin in the tissues of the lower respiratory tract are above the MICs for most lung pathogens.     

Lack of accumulation of midazolam in plasma and lipoprotein fractions during intravenous lipid infusions in patients on artificial respiration

Summary Severely ill patients often require total parenteral nutrition including intravenous liqid emulsions concurrently administered with lipophilic drugs. Therefore we investigated whether therapeutic application of a mixed medium chain/long chain triglyceride infusion affects the disposition of midazolam necessary for sedation in patients on artificial respiration. The concentrations of midazolam were measured in unfractionated plasma, and in lipoprotein fractions isolated from ex vivo blood samples, including determination of triglycerides and cholesterol; the albumin level was also analysed.Midazolam in the VLDL fraction was only 0.246 g·ml^–1, whereas the total plasma concentration averaged 1.101 g·ml^–1, and the midazolam content of the LDL plus HDL fractions amounted to 1.771 g·ml^–1. Albumin in these lipoprotein fractions was just as unequally distributed. A lipid infusion resulted in a significant elevation of total triglycerides from 157 to 221 mg·dl^–1 and VLDL-triglycerides from 77 to 155 mg·dl^–1. The triglyceride content of the LDL plus HDL fraction rose from 102 to 139 mg·dl^–1. At the same time the midazolam concentration in unfractionated plasma and in the VLDL and the LDL + HDL fractions decreased to 0.899 g·ml^–1, 0.130 g·ml^–1, and 1.265 g·ml^–1, respectively. Cholesterol and albumin concentrations were not affected.The data show for the first time that a significant increase in plasma triglycerides during an intravenous lipid infusion does not result in accumulation of midazolam in lipoproteins, probably because albumin binding of the drug is very strong. The lack of midazolam trapping is important with respect to the safety of concurrent use of lipophilic drugs and intravenous lipid infusions.     

Increase in plasma ACTH after dopaminergic stimulation in rats

The effects of a dopaminergic agonist, apomorphine, and a dopaminergic antagonist, haloperidol, on plasma ACTH, and corticosterone levels were evaluated in adult male rats. Subcutaneous administration of apomorphine in the dose range of 50–500 g · kg^–1 significantly increased plasma corticosterone levels. Acute treatment with apomorphine (250 g · kg^–1) resulted in an elevation of plasma ACTH concentration, peak values being reached 15 min after the injection. The apomorphine-induced rise in plasma ACTH levels was completely inhibited by pretreatment with haloperidol (1 mg · kg^–1). A stimulatory role for dopamine receptors in the control of pituitary ACTH release in the rat is suggested.     

Behavioural responses to stereotactically controlled injections of monoamine neurotransmitters into the accumbens and caudate-putamen nuclei

Bilateral stereotactically-controlled injections of dopamine (5–50 g of the hydrochloride salt) into the nucleus accumbens of nialamide-pretreated rats induced a marked stimulation of exploratory and locomotor activity, accompanied by intense sniffing and rearing. Conversely, bilateral injection of dopamine (12.5–50 g of the hydrochloride salt) into the caudate-putamen induced intense stereotyped activity which was dose-related. Both responses were blocked by IP haloperidol.Bilateral injection of noradrenaline (50 g of the hydrochloride salt) into the accumbens nuclei did not produce any particular behavioural changes. The same injection into the caudate-putamen led to a moderate stimulation of stereotyped activity.Bilateral injection of 5-HT (50 g of the bimaleinate salt) into the accumbens nuclei induced a moderate locomotor activity with some hole-dipping activity and sniffing; these behaviours were incoordinated and indecisive. The same injections into the caudateputamen led to a moderate stimulation of locomotor activity and hole-dipping which was predominantly stereotyped in character; on visual observation no other striking abnormalities were noted.     

Short-term effects of herbicides on primary productivity of periphyton in lotic environments

Freshwater algae are quite sensitive to herbicides that enter running water ecosystems through direct application, aerial drift, and/or watershed run-off. However, due to a lack of suitable methodologies, few studies examine the effects of such contamination on naturally occurring attached algal communities under field conditions (i. e., exposure regimes using pulsed doses or brief episodes of peak concentrations to simulate surface run-off during storm events). This paper describes a method for determining the acute short-term effects of four herbicides (hexazinone, atrazine, tebuthiuron and metolachlor) on the net primary productivity (NPP) of periphytic algae in the field using a portable bankside incubator; NPP was measured by monitoring changes in oxygen production (mg O₂ per m²) upper surface of rock substrate per h and mg O₂ h per mg chlorophyll using the light-dark technique. All herbicides with photosynthetic inhibition as a mode of action significantly reduced NPP. The lowest observed effect concentrations (LOECs) for the herbicides were 43 g hexazinone l^–1, 109 g atrazine l^–1 and 137 g tebuthiuron l^–1. The no observed effect concentrations (NOECs) for these chemicals were <43 g hexazinone l^–1, 93 g atrazine l^–1 and 52 g tebuthiuron l^–1. Metolachlor did not significantly reduce NPP at the concentrations that were tested (range 19.6–274 g l^–1). However, community respiration (which included respiration by invertebrates) was significantly reduced at the highest metolachlor concentration (274 g l^–1). Community respiration was not significantly affected by any concentration of the other three herbicides used.     

The sympathetic axons innervating the sinus node of the rabbit possess presynaptic opioid к- but not μ- or δ-receptors

Summary The postganglionic sympathic nerves of rabbit isolated hearts were stimulated with pulses delivered at 5 Hz and train durations of 1–5 s. Ethylketocyclazone 0.01–1 mol/l and fentanyl 1 and 10 mol/l but not morphine 1 and 10 mol/l, Met-enkephalin 1 and 4 mol/l or d-Ala², d-Leu⁵-enkephalin 0.5 and 5 mol/l diminished the stimulation-evoked increase in heart rate. The effect of ethylketocyclazocine 0.1 mol/l was antagonized by naloxone 1 and 10 mol/l. In contrast, the effect of fentanyl was not changed by naloxone 10 mol/l. Ethylketocyclazocine 0.03 and 1 mol/l did not reduce the tachycardia elicited by exogenous noradrenaline. The results suggest that, under in vitro conditions, only presynaptic opioid - but not - or -receptors inhibit the release of noradrenaline from the sympathetic neurones innervating the sinus node.     

Lack of effect of long-term amlodipine on insulin sensitivity and plasma insulin in obese patients with essential hypertension

Summary To evaluate the effects of long-term treatment antihypertensive with the dihydropyridine calcium antagonist amlodipine on insulin sensitivity, plasma insulin, and lipoprotein metabolism in obese hypertensive patients.We measured the insulin sensitivity index (S_I), determined by the Minimal Model Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure in 20 obese, non-diabetic patients with essential hypertension before and after 6 weeks of placebo and again after 6 months of amlodipine. Ten patients [mean body mass index (BMI) 30.2 kg·m^–2] had been on prior treatment with a thiazide diuretic in low dosage and/or a -adrenoceptor blocker (group A), and 10 matched patients [BMI 31.8 kg·m^–2] had been previously untreated (group B). Amlodipine was started in a dose of 5 mg and was increased to 10 mg once daily in 14 patients who were hypertensive after 8 weeks on the lower dosage.At entry (before placebo), S_I was slightly but not significantly lower in group A than B [2.7 vs. 3.6×10^–4 ml·U^–4·min^–1]; fasting plasma insulin was 13.6 vs. 12.9 U·ml^–1. After 6 weeks on placebo, S_I averaged 3.7 in group A and 4.4×10^–4 U·ml^–1·min^–1 in group B; fasting plasma insulin was 14.6 vs. 15.1 U·ml^–1, and glucose 5.5 vs. 5.5 mmol·l^–1. After 6 months on amlodipine there were no differences in S_I [group A vs. group B, 5.2 vs. 3.8×10^–4 ml·U^–1·min^–1], fasting insulin [13.0 vs. 12.7 U·ml^–1], glucose [5.4 vs. 5.5 mmol·l^–1], serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions. Compared with placebo, amlodipine significantly reduced systolic and diastolic blood pressures. Heart rate, body weight, and 24 h urinary sodium excretion were unaltered.Long-term treatment with amlodipine does not affect insulin sensitivity, circulating insulin or glucose, or lipoprotein metabolism in obese, non-diabetic patients with essential hypertension.     

Pharmacokinetics and endocrine effects of terguride in healthy subjects

Summary Plasma levels of the partial dopamine agonist, terguride, were measured by RIA in healthy volunteers after a single i. v. dose of 50 g and on the first and seventh day of an oral treatment with 250 g, 500 g and 750 g b. d. Basal and releasing hormone (TRH, GHRH, CRF, LHRH) — stimulated pituitary hormone secretion (PRL, TSH, GH, FSH, LH) and cortisol were also determined by RIA.Following the i. v. injection, plasma terguride levels declined biphasically, with half-lives of 0.2 and 1.5 h; total clearance was 17 ml·min^–1·kg^–1. the oral bioavailability of terguride over all doses was about 20%. Basal and TRH-stimulated prolactin levels were dose-dependently depressed, but the secretion of other hormones remained unaffected. Tolerance of terguride was excellent and there was no negative effect on performance or mood, nor on mixed-function oxygenase activity, assessed as urinary 6-OH cortisol.     

Blockade of α2-adrenoceptors increases opioid μ-receptor-mediated inhibition of the firing rate of rat locus coeruleus neurones

Summary In pontine slices of the rat brain, the frequency of spontaneous action potentials of locus coeruleus (LC) neurones was recorded extracellularly. Noradrenaline 0.1–100 mol/l, UK 14,304 0.01–100 nmol/l, [Met⁵]-enkephalin 1–10,000 nmol/l and [D-Ala², D-Leu⁵]enkephalin 0.1–1,000 nmol/l, all depressed the firing rate. Rauwolscine 1 mol/l antagonized the effects of both noradrenaline and UK 14,304, but potentiated the effects of [Met']enkephalin and [D-Ala², D-Leu⁵]enkephalin. Idazoxan 1 mol/l acted in a similar manner. Prazosin 1 mol/l did not change the effects of either noradrenaline or [Met⁵]enkephalin. Naloxone 0.1 mol/l antagonized both [Met']enkephalin and [D-Ala², D-Leu⁵]enkephalin, but failed to alter the effects of either noradrenaline or UK 14,304. Rauwolscine, idazoxan and prazosin, all 1 mol/l, as well as naloxone 0.1 mol/l, did not influence the firing rate when given alone. Desipramine 1 mol/l inhibited the discharge of action potentials in a rauwolscine-antagonizable manner. Noradrenaline 10 mol/l produced the same depression of firing, both in the presence of noradrenaline 1 mol/l and [Met⁵]enkephalin 0.03 mol/l. Likewise, the effect of [Met⁵]enkephalin 0.3 mol/l was the same, irrespective of whether it was added to a medium containing [Met⁵]enkephalin 0.03 mol/l or noradrenaline 1 mol/l. The spontaneous activity of LC neurones is inhibited by somatic ₂-adrenoceptors and opioid -receptors. We suggest that the two receptors interact with each other at a site located between themselves and not in the subsequent common signal transduction system.Send offprint requests to: P. Illes at the above address     

Toxicity of Organic Compounds to Marine Invertebrate Embryos and Larvae: A Comparison Between the Sea Urchin Embryogenesis Bioassay and Alternative Test Species

This study investigated the toxic effects of the insecticides lindane and chlorpyrifos, the herbicide diuron, the organometallic antifoulant tributyltin (TBT), and the surfactant sodium dodecyl sulfate (SDS) on the early life stages of Paracentrotus lividus (Echinodermata, Euechinoidea), Ciona intestinalis (Chordata, Ascidiacea), Maja squinado and Palaemon serratus (Arthropoda, Crustacea) in laboratory acute toxicity tests. The assays studied embryogenesis success from fertilized egg to normal larvae in P. lividus (48 h incubation at 20 °C) and C. intestinalis (24 h incubation at 20 °C), and larval mortality at 24 and 48 h in M. squinado and P. serratus. For P. lividus, the median effective concentrations (EC₅₀) reducing percentages of normal larvae by 50% were: 350 g l^–1 for chlorpyrifos, 5500 g l^–1 for diuron, 4277 g l^–1 for SDS, and 0.309 g l^–1 for TBT. For C. intestinalis, the EC₅₀ values affecting embryogenesis success were 5666 g l^–1 for chlorpyrifos, 24,397 g l^–1 for diuron, 4412 g l^–1 for lindane, 5145 g l^–1 for SDS, and 7.1 g l^–1 for TBT. The median lethal concentrations (LC₅₀) for M. squinado larval survival were 0.84 g l^–1 (24 h) and 0.79 g l^–1 (48 h) for chlorpyrifos, 2.23 g l^–1 (24 h) and 2.18 g l^–1 (48 h) for lindane, and 687 g l^–1 (48 h) for SDS. For P. serratus the LC₅₀ values obtained were 0.35 g l^–1 (24 h) and 0.22 g l^–1 (48 h) for chlorpyrifos, 3011 g l^–1 (24 h) and 3044 g l^–1 (48 h) for diuron, 5.20 g l^–1 (24 h) and 5.59 g l^–1 (48 h) for lindane, and 22.30 g l^–1 (24 h) and 17.52 g l^–1 (48 h) for TBT. Decapod larvae, as expected, were markedly more sensitive to the insecticides than sea urchins and ascidians, and SDS was the least toxic compound tested for these organisms. Lowest observed effect concentrations (LOEC) of TBT for sea urchin and ascidian embryos, chlorpyrifos and lindane for crustacean larvae, and SDS, were similar to those found in many coastal areas indicating that there would be a risk to invertebrate embryos and larvae from exposure in the field to these pollutants.     

Pharmacokinetics and tolerability of ascending intravenous doses of granisetron,a novel 5-HT3 antagonist,in healthy human subjects

The pharmacokinetics and tolerance of granisetron, a novel 5HT₃-receptor antagonist which is under development as an anti-emetic agent have been studied after administration of single 30 min intravenous infusions to three groups of 8 healthy male subjects, in a series of placebo-controlled ascending dose studies (50, 80, 100 and 130 g·kg^–1 to group 1; 150, 180, 200 and 230 g·kg^–1 to group 2 and 270 and 300 g·kg^–1 to group 3). Plasma and urine samples were analysed for granisetron by HPLC with fluorimetric detection.Administration of granisetron was well tolerated by the volunteers and there were no serious adverse effects reported. Pharmacokinetic parameters and dose-normalised plasma levels appeared to be independent of dose in the range 50 to 300 g·kg^–1, although there was extensive inter-subject variability. Granisetron was extensively distributed, with mean volumes of distribution ranging from 186–264 l at the various doses. Total plasma clearance was, in general, rapid (mean values of 37.0 to 49.9 l·h^–1) and predominantly non-renal, with most subjects excreting less than 20% of the dose unchanged in urine. Mean t_1/2 values ranged from 4.1 to 6.3 h and MRT from 5.2 to 8.1 h.     

Comparative study of the vasorelaxant activity, superoxide-scavenging ability and cyclic nucleotide phosphodiesterase-inhibitory effects of hesperetin and hesperidin

This study investigated the vasorelaxant activity, superoxide radicals (O₂^–)-scavenging capacity and cyclic nucleotide phosphodiesterase (PDE)-inhibitory effects of hesperidin and hesperetin, two flavonoids mainly isolated from citrus fruits. Hesperetin concentration-dependently relaxed the isometric contractions induced by noradrenaline (NA, 1 M) or by a high extracellular KCl concentration (60 mM) in intact rat isolated thoracic aorta rings. However, hesperetin (10 M–0.3 mM) did not affect the contractile response induced by okadaic acid (OA, 1 M). Mechanical removal of endothelium and/or pretreatment of aorta rings with glibenclamide (GB, 10 M), tetraethylammonium (TEA, 2 mM) or nifedipine (0.1 M) did not significantly modify the vasorelaxant effects of this flavonoid. Hesperetin (10 M–0.1 mM) did not affect the basal uptake of ⁴⁵Ca²⁺ but decreased the influx of ⁴⁵Ca²⁺ induced by NA and KCl in endothelium-containing and endothelium-denuded rat aorta. Hesperetin (10 M–0.1 mM) did not scavenge O₂^– generated by the phenazine methosulfate (PMS)-reduced -nicotinamide adenine dinucleotide (NADH) system. Hesperetin (0.1 mM) significantly reversed the inhibitory effects of NA (1 M) and high KCl (60 mM) on cyclic nucleotide (cAMP and cGMP) production in cultured rat aortic myocytes. Hesperetin preferentially inhibited calmodulin (CaM)-activated PDE1 and PDE4 isolated from bovine aorta with IC₅₀ values of about 74 M and 70 M respectively. In contrast, the 7-rhamnoglucoside of hesperetin, hesperidin (10 M–0.1 mM), was inactive in practically all experiments, although it inhibited basal and cGMP-activated PDE2 isolated from platelets (IC₅₀ values of 32±4 M and 137±34 M respectively). These results suggest that the vasorelaxant effects of hesperetin are basically due to the inhibition of PDE1 and PDE4 activities.     

The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers

Summary We have studied the effects of intravenous nicorandil, a mixed arterial and venous vasodilator, in 48 healthy volunteers. Nicorandil (20, 28, 39, 54, 74, 103, 144, or 200 g·kg^–1) or placebo were given over 5 min to subjects supine (16 subjects, 2 doses) or sitting (32 subjects, 1 dose) in a single-blind crossover design. Electro-cardiographic intervals, blood pressure, and heart rate were measured before and for 8 h after dosing. Blood and urine safety laboratory studies were also performed before and after dosing.All intravenous infusions of nicorandil and placebo were well tolerated and there were no clinically important safety concerns. The most frequent adverse event after nicorandil was headache (24 events by 19 subjects), although its occurrence was not strictly dose related. One subject experienced transient symptomatic hypotension (144 g·kg^–1).Mean plasma nicorandil concentrations were dose-related and fell with a half-life of 0.7 to 1.2 h. Systemic clearance and volume of distribution tended to decrease as dose increased. Sitting subjects showed marginally lower (<20%) systemic clearances and larger values of C_max and AUC.Nicorandil produced dose-related reductions in blood pressure, with consistent statistically significant differences from placebo after the 144 and 200 g·kg^–1 doses. The falls in blood pressure were greater for diastolic pressure and in this supine position. At 200 g·kg^–1, the mean falls in systolic/diastolic pressures (mm Hg) during the first hour were 10.9/14.7 supine and 6.1/9.1 sitting; systolic pressure returned to baseline after 8 h and diastolic pressure after 4 h. Heart rate increased transiently (mean peak increase of 17–24 bpm at the end of the 144 and 200 g·kg^–1 infusions). Blood pressure and heart rate changes over time were statistically significantly correlated with plasma nicorandil concentrations. Individual areas under the blood pressure and heart rate change curves likewise correlated with plasma concentration curve areas.     

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 site of action of muscle relaxant purine nucleosides

Summary The effects of a series of purine nucleosides, including the novel marine natural product 1-methylisoguanosine, have been examined on muscle relaxation in conscious animals and on spinal reflexes and neuromuscular transmission in mice anaesthetized with sodium pentobarbitone. 1-Methylisoguanosine (5–15 mol kg^–1) and 2-chloroadenosine (1–5 mol kg^–1), both of which cause muscle relaxation in conscious animals, depressed both mono- and polysynaptic spinal reflexes but did not affect neuromuscular transmission. At much higher doses (300 mol kg^–1) both compounds did depress neuromuscular transmission. Adenosine and 1-methyladenosine did not produce muscle relaxation in conscious animals and only slightly depressed polysynaptic reflexes at the highest doses tested (300 mol kg^–1). Theophylline 50 mol kg^–1 enhanced polysynaptic reflexes and antagonized the depression of these reflexes by 1-methylisoguanosine. Neither adenosine nor 1-methylisoguanosine affected the development of tension by isolated diaphragm muscles in vitro. It is concluded that the muscle relaxant purine nucleosides 2-chloroadenosine and 1-methylisoguanosine produce their effects primarily by depressing activity in the central nervous system. Transmission at the neuromuscular junction is not affected at doses in the range of those producing muscle relaxation.