Can two, four or eight‐hour urine collections after voluntary voiding be used instead of twenty ‐four hour collections for the estimation of creatinine clearance in healthy subjects

The accuracy of creatinine clearance estimations obtained from 4hour (16:0020:00, 20:0024:00, 08:0012:00, 12:0016:00) and 8hour (16:0024:00, 24:0008:00 and 08:0016:00) urine collections and the Cockcroft Gault formula compared with the standard 24hour collection, as well as the cyclical variation in creatinine excretion were studied in a group of 22 healthy subjects (Serum creatinine < 1.5mg/dl, Blood Urea Nitrogen < 50mg/dl) after voluntary voiding. The mean 4hour and 8hour creatinine clearances were not significantly different from the 24hour values. Clearance values from 8hour collections between 24:0008:00 and 16:0024:00 were found to be the most accurate and gave the best correlations. Furthermore only the mean absolute percentage deviations of the 8hour from the 24hour clearance values were significantly less than 20%. Significant cyclical variations in creatinine clearance over 24 hours were not observed. Time intervals between 23:0007:00 and 07:0009:00 were chosen for the comparisons between 8hour, 2hour, Cockcroft Gault creatinine clearance estimations and the 24hour values in 21 healthy subjects. The mean 2hour and 8hour creatinine clearances were not significantly different from the 24hour values. However, once again only the 8hour clearance values differed by less than 20% from the 24hour values and they were more accurate and better correlated than the 2hour values. As expected, in both groups of subjects, the percentage of clearance values that deviated by more than 20% from the 24hour values decreased as the length of the collection times increased. The Cockcroft Gault formula in both groups of volunteers gave less accurate clearance estimations, smaller correlation coefficients (not statistically significant in Group I subjects) and percentage deviations from the 24hour values greater than 20%. Undetected early stage renal insufficiency in three volunteers and the use of actual instead of normalized Scr values may have been the cause of these poor clearance estimations. In healthy subjects (Scr < 1.5mg/dl) 24hour creatinine clearance may be estimated from an 8hour urine collection with voluntary voiding if a 20% deviation from the 24hour value is considered clinically acceptable.     

Sex differences in the medication choice for hypertension in general practice. A study with written case simulations

The objective of this study was to explore explanations for the preference of physicians to prescribe blockers to hypertensive men and diuretics to hypertensive women.A qualitative study among 12 family physicians was conducted with a combination of written case simulations, semistructured interviews and statements on attitudes of physicians towards antihypertensive drug choice.Among the male hypertensive cases the most frequently prescribed drugs were blockers, whereas among the female hypertensive cases diuretics were more often prescribed. Physician characteristics associated with a preferred prescribing of blockers to hypertensive men and diuretics to hypertensive women were: older age (no residency in family medicine), the believe that blockers are more effective in men with regard to lowering blood pressure and that diuretics are more effective in women, a nonevidence based attitude and a sexrelated attitude towards the choice of blockers and diuretics in general, and in particular towards the prescribing of blockers to hypertensive men because men have a higher absolute risk of coronary heart disease than women. An additional explanation for these findings may be the higher prevalence of ankle oedema among women. Patient characteristics associated with more prescribing of blockers to hypertensive men and diuretics to hypertensive women were: current employment and a "highrisk" profile in terms of blood pressure level and additional cardiovascular risk factors.Although, most considerations underlying a preferred prescribing of blockers to hypertensive men and diuretics to hypertensive women were not evidencebased, the actual choice of antihypertensive drug (diuretic or blocker) was evidencebased. These considerations may also play a role in the sex difference in the choice of calcium antagonists and angiotensin converting enzyme inhibitors and require further investigation.     

Absorption Enhancing Effect of Cyclodextrins on Intranasally Administered Insulin in Rats

The absorption enhancing effect of -, -, and -cyclodextrin (CD), dimethyl--cyclodextrin (DMCD), and hydroxypropyl--cyclodextrin (HPCD) on intranasally administered insulin was investigated in rats. Coadministration of 5% (w/v) DMCD to the insulin solution resulted in a high bioavailability, 108.9 ± 36.4% (mean ± SD, n = 6), compared to i.v. administration, and a strong decrease in blood glucose levels, to 25% of their initial values. Coadministration of 5% -CD gave rise to an insulin bioavailability of 27.7 ± 11.5% (mean ± SD, n = 6) and a decrease in blood glucose to 50% of its initial value. The rate of insulin absorption and the concomitant hypoglycemic response were delayed for the -CD-containing solution as compared to the DMCD preparation. The other CDs, HPCD (5%), -CD (1.8%), and -CD (5%), did not have significant effects on nasal insulin absorption. DMCD at a concentration of 5% (w/v) induces ciliostasis as measured on chicken embryo tracheal tissue in vitro, but this effect is reversible. In conclusion, DMCD is a potent enhancer of nasal insulin absorption in rats.     

Radioimmunoassay of β-endorphin basal and stimulated levels in extracted rat plasma

Summary A sensitive radioimmunoassay for -endorphin is described. Antibodies against human -endorphin which exhibit a high avidity for the C-terminal of the peptide were raised in rabbits following the injection of thyroglobulin-coupled human -endorphin (h-E) as immunogen. Methionineenkephalin, - -endorphin, as well as ACTH peptides did not cause interference in the radioimmunoassay. -Lipotropin, however, showed a 50% cross-reactivity. The sensitivity of the assay is 25 pg/0.5 ml tube volume for -endorphin. -Endorphin was extracted with a high recovery from the rat plasma using silicic acid and -endorphin levels as low as 100 pg/ml could be measured.Basal levels of -endorphin-like immunoreactivity in plasma of rats were about 400 pg/ml. -Endorphin levels in adrenalectomized rats and in animals chronically treated with the cortisol synthesis blocker metyrapone were found to be markedly increased (about 7-fold). Exposure of the rats to electrically induced foot-shocks caused a similar increase of immunoreactive -endorphin in plasma. A significant increase was also seen after insulin injection.     

Interferon-γ in Starch Microparticles: Nitric Oxide-Generating Activity in Vitro and Antileishmanial Effect in Mice

Recombinant mouse interferon- (mu IFN-) was covalently coupled to polyacryl starch microparticles, a lysosomotropic drug carrier. The microparticle-bound mu IFN- was found to activate cultured macrophages for nitrite production and had an anti-leishmanial effect in mice. Low doses of mu IFN-, which had no effect in the free form, when bound to microparticles significantly reduced the load of Leishmania donovani in infected mice. Further, inducement of nitrite production in cultured macrophages by microparticle-bound mu IFN- required intact cell membrane receptors.     

Intrathecal substance P depresses the tail-flick response — Antagonism by naloxone

Summary Substance P injected into the lumbar subarachnoid space of rats depressed the tail-flick response to radiant heat in a dose-dependent way. The effective doses ranged from 0.1 g to 100 g per rat (ED 50: 1.5 g/rat). The maximum of the effect was reached 20 min after intrathecal injection and the effect lasted for about 30 min. An antinociceptive effect was also observed after intrathecal injection of substance P 1 g to spinal rats. The depression of the tail-flick response produced by intrathecal administration of substance P was abolished by intrathecal (5 g/rat) or i.p. (0.5 mg/kg) injections of naloxone.Supported by the Sonderforschungsbereich 38 Membranforschung     

Cocaine-induced cocaine craving

In nine experienced users of cocaine, we examined the urge to use cocaine or other drugs following a 40 mg dose of intravenous (IV) cocaine with and without oral pretreatment with 2.5 mg bromocriptine. The urge to use cocaine was assessed with a questionnaire constructed to assess both wanting and craving for cocaine or other drugs. Fifteen minutes after the administration of cocaine (but not after placebo), subjects' ratings for both drug wanting and drug craving were significantly increased. Our results provide a laboratory demonstration of cocaine-induced increases in the urge to use drugs in humans. The findings, stressing the role of internal stimuli associated with drug administration, suggest the possibility of distinguishing among related, but perhaps distinct, components of the fluctuating levels of motivation to reuse drugs.     

The effects of different doses of methylpentynol on escape/avoidance conditioning in two strains of rats selectively bred for high and low “emotionality”

Summary Animals from strains selectively inbred for high and low emotionality have been administered varying doses of methylpentynol and then subjected to a discrete escape/avoidance task (buzzer-shock). Results indicate an initial increase in avoidance scores associated with dose level followed by a decrease. There is also a clear dose and strain effect. No direct difference between the sexes was noted but there is a strong sex X strain interaction. The usual superiority of the non-emotional strain on tasks of this type of conditioning is reversed by the drug. The possible biphasic and dual effect of methylpentynol is discussed.We are indebted to The Nicholas Research Institute Ltd., Slough for the supply of Oblivon used throughout this experiment and for the partial financial support of one of us, B.D.G.     

Structure-activity relationship studies on mescaline: II. Tolerance and Cross-tolerance between mescaline and its analogues in the rat

Summary Using the CAR shuttle box technique, with male hooded rats as subjects, the development of tolerance to mescaline, 3,4-dimethoxyphenyl-ethylamine (DMPE) and NN-dimethylmescaline (DMM) and possible cross-tolerance between these drugs was studied. It was found that seven successive daily doses of mescaline induced tolerance to its inhibitory effect, but that the excitatory effect was increased. Tolerance developed to the predominantly inhibitory effect of DMPE, and to the excitatory effect of DMM.Partial cross-tolerance existed between DMPE and mescaline, and when the procedure was reversed, between mescaline and DMPE. Cross-tolerance was shown in the same manner between DMM and mescaline, and mescaline and DMM.The problems of quantification and interpretation of these results is discussed. It was concluded, on the basis of subsidiary experiments, that the inhibitory effect of mescaline was probably not caused by ataxia or by a peripheral effect.     

Identification of the neuroeffector transmitter in jejunal branches of the rabbit mesenteric artery

Summary Vasoconstriction or excitatory junction potentials (e.j.ps) evoked by nerve stimulation (15 field pulses at 2 Hz every 3 min) were recorded in rabbit isolated jejunal arteries. The resting diameter of the arteries and its decrease in response to stimulation was measured by a photoelectric method. Vasoconstriction was insensitive to prazosin 0.1 or 1 mol/l. Yohimbine 1 mol/l considerably enhanced, whereas ,-methylene ATP (,-meATP) 1 mol/l abolished the contractile response. In order to test the effect of exogenously applied transmitter candidates, noradrenaline (0.1–1 mol/l) and ATP (10–30 mol/l) were added in concentrations which evoked a vasoconstriction comparable to that induced by electrical stimulation. The action of noradrenaline was prevented by prazosin 0.1 mol/l, but was unaffected by both yohimbine 1 mol/l and ,-meATP 1 mol/l. ,-meATP 1 mol/l depressed the effect of ATP. The e.j.ps evoked by a train of 15 pulses showed facilitation up to the third response and thereafter depression; a partial summation was also observed. Prazosin 0.1 mol/l did not change the e j.p. amplitudes. By contrast, when yohimbine 0.1 or 1 mol/l was added to the prazosin-containing medium, both the late e j.ps in the train and the summation were enhanced in a concentration-dependent manner. ,-meATP 1 mol/l almost abolished the e.j.ps. In conclusion, in rabbit jejunal arteries, stimulation of postganglionic sympathetic nerves may release noradrenaline together with ATP which is probably the sole neuroeffector transmitter under our conditions. Transmitter release seems to be modulated by the activation of presynaptic ₂-adrenoceptors. Under the stimulation conditions of the present experiments the released transmitter does not activate postsynaptic ₁-adrenoceptors. Send offprint requests to P. Illes     

Cardiostimulatory effects of cyclic 3′,5′-adenosine monophosphate and its acylated derivatives

Summary The effects of cyclic 3,5-AMP and of two acylated derivatives, dibutyryl (DBA) and dihexanoyl-3,5-AMP (DHA) were investigated in isolated perfused hearts of guinea pigs, rats and rabbits.In guinea pig hearts, DBA (Ca- and Na-salt) and DHA-Na in high doses (10 moles) produced strong and long lasting increases in the rate and amplitude of contractions, coronary flow, and moderate increases in phosphorylase activity in the majority of experiments. The positive ino- and chronotropic effects occured 3–5 min after injection of the drug, mostly in a fluctuating manner with several maxima. Theophylline augmented the effects of DBA-Na and revealed positive inotropic actions of non substituted 3,5-AMP.In rat hearts, similar, but more pronounced and dose-dependent effects were observed after 1, 5 and 10 moles DBA-Na. Propranolol (50 g) did not block the action of 10 moles DBA-Na. Non substituted 3,5-AMP, 5-AMP and ATP in doses of 10 moles had no significant positive inotropic effects.In rabbit hearts, DBA-Na (50 moles) produced moderate, non fluctuating rises in the amplitude of contraction.The results provide evidence that under certain conditions cyclic 3, 5-AMP itself, like its acylated derivatives DBA and DHA, may produce strong and direct positive inotropic and chronotropic effects in the heart. These findings support the view that cyclic 3,5-AMP is the cellular mediator of the cardiostimulant actions of substances that increase its rate of production in the myocardial cell.The excellent technical help of Mrs. Vera Bauer is gratefully acknowledged by the authors.     

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.     

“A” esterases and their role in regulating the toxicity of organophosphates

Esterases which can hydrolyse organophosphates without being inhibited by them are termed A esterases. Using paraoxon and pirimiphos-methyl oxon as substrates, high A esterase activity is found in the liver and plasma or serum of a range of mammalian species. In a study of serum A esterases of sheep and humans, over 80% of the activity separated into the high density lipoprotein (HDL) fraction following ultracentrifugation. When HDL fractions from sheep serum were run on Sepharose gel columns, most of the paraoxonase activity separated as a single peak of estimated molecular weight 360000, which corresponds to that of HDL₂ of humans.During the course of purification of A esterases by three different column procedures, contrasting esterase elution profiles were obtained with organophosphate and pyrethroid substrates. This was strong evidence for the existence of multiple forms of HDL A esterases.Levels of A esterase activity in plasma and liver of birds were much lower than those of mammals. This appears to be the main reason why birds are much more susceptible than mammals to organophosphates such as pirimiphos-methyl and diazinon which form active oxons that are good substrates for mammalian A esterases.No A esterase was detected in strains of rust red flour beetle (Tribolium castaneum) which were resistant to organophosphates. Similar observations have been made with strains of other insects resistant to organophosphates, raising the question to what extent esterases of this type are present in insects.Dedicated to Professor Dr. med. Herbert Remmer on the occasion of his 65th birthday     

Behavioural and anticonvulsant effects of Ca2+ channel toxins in DBA/2 mice

This study investigated the behavioural and anticonvulsant effects of voltage-sensitive calcium channel blockers in DBA/2 mice.-Conotoxin MVIIC (0.1, 0.3 g ICV/mouse) and-agatoxin IVA (0.1, 0.3, 1 g ICV), which act predominantly at P- and/or Q-type calcium channels, prevented clonic and tonic sound-induced seizures in this animal model of reflex epilepsy (ED₅₀ values with 95% confidence limits for protection against clonic sound-induced seizures were 0.09 (0.04–0.36) g ICV and 0.09 (0.05–0.15) g ICV, respectively and against tonic seizures 0.07 (0.03–0.16) g ICV and 0.08 (0.04–0.13) g ICV, respectively). The N-type calcium channel antagonists-conotoxin GVIA and-conotoxin MVIIA were also tested in this model.-Conotoxin GVIA was anticonvulsant in DBA/2 mice, but only at high doses (3 g ICV prevented tonic seizures in 60% of the animals; 10 g ICV prevented clonic seizures in 60% and tonic seizures in 90% of the animals), whereas-conotoxin MVIIA did not inhibit sound-induced seizures in doses up to 10 g ICV. Both-conotoxin GVIA and-conotoxin MVIIA induced an intense shaking syndrome in doses as low as 0.1 g ICV, whereas-conotoxin MVIIC and-agatoxin IVA did not produce shaking at any of the doses examined. Finally,-conotoxin GI (0.01–1 g ICV) and-conotoxin SI (0.3–30 g ICV), which both act at acetylcholine nicotinic receptors, were not anticonvulsant and did not induce shaking in DBA/2 mice. These results confirm that blockers of N- and P-/Q-type calcium channels produce different behavioural responses in animals. The anticonvulsant effects of-conotoxin MVIIC and-agatoxin IVA in DBA/2 mice are consistent with reports that P- and/or Q-type calcium channel blockers inhibit the release of excitatory amino acids and are worthy of further exploration.     

Evidence for two separate vasoconstriction-mediating nucleotide receptors,both distinct from the P2X-receptor,in rabbit basilar artery: a receptor for pyrimidine nucleotides and a receptor for purine nucleotides

Summary Uridine 5-triphosphate- (UTP-) and adenosine 5-triphosphate-(ATP) induced vasoconstriction was studied in the rabbit basilar artery. The arteries were incubated and perfused at a constant rate of flow. Vasoconstriction was measured as an increase in perfusion pressure.Serotonin, histamine and noradrenaline caused concentration-dependent vasoconstriction, with potency decreasing in that order. Of the nucleotides tested, UTP, UDP, UMP, CTP, ATP, ADP, adenosine 5-O-(3-thio)triphosphate (ATPS), and ,-imido adenosine 5-triphosphate (AMP-PNP) elicited concentration-dependent vasoconstriction, whereas AMP, 2-methylthio-ATP, , -methylene-ATP and ,-methylene-ATP up to 10^–3 mol/l caused no or only a very small increase in perfusion pressure. The order of potency of the pyrimidine nucleotides was: UTP = UDP UMP = CTP; that of the purine nucleotides was: ATPS > AMP-PNP > ATP > ADP > 2-methylthio-ATP = , -methylene-ATP = ,-methylene-ATP. The vasoconstrictor effects of UTP and ATP were not or only to a minor degree influenced by: phentolamine; a mixture of atropine, diphenhydramine and methysergide; indometacin; nordihydroguaiaretic acid; denervation by 6-hydroxydopamine; or mechanical removal of endothelium. Prolonged exposure to ,-methylene-ATP elicited only a very small vasoconstriction and did not change the constrictor effects of UTP or ATP. Prolonged exposure to ATPS elicited marked vasoconstriction; subsequently, responses to ATP were reduced whereas those to UTP were, if anything, slightly enhanced. Reactive blue 2 reduced neither the UTP- nor the ATP-induced vasoconstriction. ATP 10^–3 mol/l elicited marked additional vasoconstriction after precontraction with UTP 10^–3 mol/l, whereas UTP elicited only a very small additional vasoconstriction when its concentration was doubled from 10^–3 to 2 × 10^–3 mol/l.It is concluded that, in the rabbit basilar artery, the vasoconstrictor response to UTP is mediated by a pyrimidine nucleotide receptor which is distinct from the P₂-purinoceptor, and that the vasoconstrictor response to ATP is mediated by a P₂-receptor which is distinct from the known P₂-subtypes.Send offprint requests to I. v. Kügelgen at the above address     

Der Einfluß von Codein,Dextromethorphan und Narkotin auf exspiratorisch entladende Neurone der Medulla oblongata der Katze

Ohne ZusammenfassungAuszüge einzelner Ergebnisse wurden beim Symposion über Expectoration und Expectorantien in Titisee (Schwarzwald) am 19. und 20. 3. 1965 vorgetragen und als Sitzungsbericht in der Zeitschrift Therapeutische Umschau veröffentlicht.     

Regulation of adenylate cyclase activity in hamster adipocytes

Summary In ghosts of hamster adipocytes, the regulation of adenylate cyclase (ATP: pyrophosphate lyase, cyclizing; EC 4.6.1.1) activity by prostaglandins, -adrenergic agonists and nicotinic acid was studied. These three classes of antilipolytic agents caused adenylate cyclase inhibition without an apparent lag phase. Maximal inhibitions observed ranged between about 45% (by -adrenergic agonists) and 60% (by prostaglandins and nicotinic acid). The order of potency for the inhibitory prostaglandins (PG) was PGE₁ PGE₂>PGF₂PGI₂>PGD₂>6-keto PGF₁. The IC₅₀ values obtained were about 0.007, 0.06, 0.3 and 1 M for PGE₁, PGF₂, PGD₂ and 6-keto PGF₁, respectively. -Adrenergic agonists, studied in the presence of the -adrenergic blocking agent, propranolol (30 M), inhibited the fat cell enzyme with the order of potency (1)-adrenaline > (1)--methylnoradrenaline (1)-noradrenaline > clonidine tetryzoline > (1)-phenylephrine. The IC₅₀ values obtained for (1)-adrenaline and (1)-noradrenaline were about 3 and 10 M, respectively. The inhibitory effect of (1)-adrenaline was blocked by the -adrenergic antagonists with the potency order yohimbine phentolamine > prazosin. These findings suggest that an ₂ of receptors is involved in this catecholamine-induced inhibition. Nicotinic acid (10 M) reduced adenylate cyclase activity by about 60% with half-maximal effectiveness at about 0.6 M. The nicotinic acid derivatives, nicotinamide, -pyridylcarbinol and NAD (up to 100 M), had no effect on enzyme activity.Inhibition of the hamster adipocyte adenylate cyclase by the antilipolytic agents required the presence of both GTP, which reduced basal activity by about 80% at 10 M, and sodium ions, which specifically activated the GTP-affected from of the enzyme. Inhibition was also observed in the presence of ACTH, which in a GTP-dependent manner increased adenylate cyclase activity. Pretreatment of the enzyme preparation with NaF (10 mM) partially reduced the inhibitory effect, and preactivation with the stable GTP analogue, guanylyl 5-imidodiphosphate (100 M), abolished the adenylate cyclase inhibition by the antilipolytic agents.Abbreviations PG prostaglandin - GMP-P(NH)P guanylyl 5-imidodiphosphate Some of the data were presented in abstract form (Aktories et al., 1979a)     

Preparation of Heptakis(2,6-di-O-ethyl)-β-cyclodextrin and Its Nuclear Magnetic Resonance Spectroscopic Characterization

Heptakis(2,6-di-O-ethyl)--cyclodextrin (DE--CyD) was prepared and its ¹H and ¹³C nuclear magnetic resonance (NMR) signals in DMSO-d₆ were unequivocally assigned by two-dimensional COSY and ROESY. The results on ¹H coupling constants indicated that all ethylated glucose units are in a ⁴C₁ chair conformation. The average spin-lattice relaxation times (T ₁) of ring carbons of DE--CyD were only slightly shorter, and their standard deviations from the mean T _l value were larger, than those of -cyclodextrin (-CyD) and heptakis(2,6-di-O-methyl)--cyclodextrin (DM--CyD), suggesting the presence of slightly irregular internal motion in the ethylated glucose units. The temperature dependence of chemical shift of DE--CyD in DMSO-d₆ suggested that the C3 hydroxyl protons may participate as proton donor in the intramolecular hydrogen bond to the C2 ethoxyl groups of neighboring glucose, and the intramolecular hydrogen bond of DE- and DM--CyDs is much stronger than that of -CyD, suggesting the stable macrocyclic ring structure of DE--CyD.     

Cardiac ventricular β2-adrenoceptors in guinea-pigs and rats are localized on the coronary endothelium

Summary In mammalian heart tissue ₂ are known to coexist with ₁. In the present study, evidence that ₂ in guinea-pig and rat ventricles are primarily localized on the coronary endothelium is provided by competition binding studies with the subtype-selective -adrenoceptor antagonists ICI 89.406 (₁) and ICI 118.551 (₂) on four different plasma membrane preparations. (1) Following density gradient centrifugation of cardiac ventricular microsomes from rats or guinea-pigs, endothelial plasma membranes migrated at slightly higher density than the sarcolemmal membranes, as verified by endothelial (angiotensin converting enzyme) and sarcolemmal markers (adenylate cyclase, [³H] ouabain binding). At the activity peak of angiotensin converting enzyme, the relative amount of ₂ in guinea-pigs and rats was 25% and 65%, respectively. (2) On sarcolemmal membranes corresponding to the activity peak of adenylate, cyclase, -adrenoceptors consisted of the ₁ exclusively (guinea-pig), or to at least 90% (rat). (3) Cultures of coronary endothelial cells derived from guinea-pigs revealed only ₂. (4) Isolated guinea-pig cardiomyocytes contained only ₁, a finding recently established in rat myocytes as well.     

Chronic β1-adrenoceptor blockade sensitises the H1 and H2 receptor systems in human atrium: role of cyclic nucleotides

We have reported that chronic treatment of patients with ₁-adrenoceptor blockers sensitises isolated atrial preparations to adrenaline, noradrenaline and 5-HT. We have now examined the effect of chronic treatment with -adrenoceptor blockers on responses to histamine of human right atrial appendages. We compared the effects of histamine on contractile force, cyclic AMP and cyclic GMP levels as well as cyclic AMP-dependent protein kinase (PKA) activity and explored the arrhythmogenic effects of histamine in preparations obtained from patients chronically treated or not treated with -adrenoceptor blockers.Histamine increased contractile force in paced preparations; the effects were blocked by the H₂ receptor antagonist famotidine (0.1–30 mol/1). The maximum inotropic response to histamine was doubled and the inotropic potency of histamine 0.4 log units greater in atria from -adrenoceptor blocker-treated compared to non -adrenoceptor blocker-treated patients. Histamine elicited frequency-dependent arrhythmias that were blocked by famotidine (30 mol/1) but not by mepyramine (1 mol/1). The incidence of arrhythmias was higher in atria from -adrenoceptor blocker-treated compared to untreated patients. Histamine increased both cyclic AMP and cyclic GMP levels, as well as PKA activity, significantly more in atria from -adrenoceptor blocker-treated compared to those from untreated patients. Mepyramine 1 mol/l prevented the histamine-evoked increase in cyclic GMP levels, reduced the inotropic hyperresponsiveness and abolished the hyperresponsiveness in cyclic AMP levels and PKA activity observed in patients chronically treated with blockers. Sodium nitroprusside 10 mol/l caused smaller increases of cyclic GMP levels than histamine and restored the contracile force depressed by mepyramine to its original level in atria from -adrenoceptor blocker-treated patients.The evidence is consistent with sensitisation of both the histamine H₁ and histamine H₂ receptor systems by chronic ₁-adrenoceptor blockade. H₁ receptor-mediated increases in cyclic GMP, enhanced through an as yet unknown mechanism by chronic ₁-adrenoceptor blockade, may inhibit phosphodiesterase 3 activity, thereby causing enhanced histamine-evoked increases in cyclic AMP levels and PKA activity, and accounting partially for the increased inotropic responses to histamine through H₂ receptors.