Esters of N-tert-butylarterenol. Long-acting new bronchodilators with reduced cardiac effects.

The preparation of various esters of N-tert-butylarterenol is described. Esterification of the phenolic OH groups has increased bioavailability, prolonged bronchodilation, and reduced tachycardia. The substitution of aromatic esters compared with simple aliphatic esters improved markedly these pharmacological properties. Of a number of esters tested, compound 45 (bitolterol) demonstrated the most favorable pharmacological properties as a bronchodilator. Its long duration of action and significant bronchodilator-cardiovascular separation are briefly described.

Antiviral activity of some beta-diketones. 1. Aryl alkyl diketones. In vitro activity against both RNA and DNA viruses.

The discovery that 4-[3-ethyl-6-[(3,4-methylenedioxy)phenyl]-3-hexenyl]-3,5-heptanedione (40) exhibited an in vitro inhibitory effect against equine rhinovirus led to a structure--activity study to establish the criteria for optimum activity. Modification of the bridge included removal of the ethyl group and reduction of the double bond. The heptanedione was replaced with hexanedione and pentanedione with a minimal effect. The effect of replacing the heptanedione with beta-keto esters and monoketones was also investigated. Maintaining the hexamethylene bridge and heptanedione, the methylenedioxy group was replaced with various substitutents. In general, most substituents did not adversely affect activity particularly against equine rhinovirus although there was some variation in activity against herpesvirus. Strongly hydrophilic groups significantly reduced activity. Finally, the effect of varying the length of the alkyl bridge was examined in the 4-hydroxyphenyl series, where peak activity was attained with n = 8.

Prostacyclin releases endothelium-derived relaxing factor and potentiates its action in coronary arteries of the pig.

1. The possible interactions between prostacyclin and endothelium-derived relaxing factor were examined, in isolated coronary arteries of the pig treated with indomethacin (10(-5) M). 2. In organ chamber experiments, prostacyclin caused relaxations, which were potentiated in the presence of the endothelium; the potentiation was abolished by oxyhaemoglobin. 3. In bioassay experiments, prostacyclin caused minimal relaxations of bioassay rings without endothelium; these relaxations were potentiated when the bioassay ring was exposed to basally-released endothelium-derived relaxing factor (interaction between prostacyclin and basal endothelium-derived relaxing factor) and further augmented when the endothelial cells were exposed to the prostanoid (stimulated release of endothelium-derived relaxing factor). The endothelium-dependent, but not the direct effects of prostacyclin were augmented by superoxide dismutase plus catalase and abolished by oxyhaemoglobin. 4. Forskolin, a direct activator of adenylate cyclase, caused relaxations of rings without endothelium, which were augmented by the presence of the endothelium. 5. The relaxations induced by prostacyclin or forskolin also had an endothelium-dependent component in basilar and femoral arteries and in jugular veins of the pig. 6. The endothelium-dependent actions of prostacyclin probably reflect activation of adenylate cyclase.

Prejunctional beta 1-adrenoceptors inhibit cholinergic transmission in canine bronchi.

The aim of the present study was to determine in canine bronchi the effects produced by norepinephrine (released from adrenergic nerve terminals) on cholinergic neurotransmission. Electrical stimulation of canine bronchi activates cholinergic and adrenergic nerve fibers. The adrenergic neuronal blocker, bretylium tosylate, inhibited the increase in [3H]norepinephrine overflow evoked by electrical stimulation but did not prevent that caused by the indirect sympathomimetic tyramine. During blockade of the exocytotic release of norepinephrine with bretylium, the pharmacological displacement of the sympathetic neurotransmitter by tyramine significantly decreased the contractions evoked by electrical stimulation but did not affect contractions caused by exogenous acetylcholine. Metoprolol, a beta 1-adrenergic antagonist, abolished and propranolol significantly reduced the effect of tyramine during electrical stimulation. alpha 2-Adrenergic blockade, beta 2-adrenergic blockade, or removal of the epithelium did not significantly affect the response to tyramine. These results suggest that norepinephrine when released from sympathetic nerve endings can activate prejunctional inhibitory beta 1-adrenoceptors to depress cholinergic neurotransmission in the bronchial wall.

Release of endothelium-derived relaxing factor after subarachnoid hemorrhage.

The purpose of this study was to determine the cause of the loss of endothelium-dependent relaxation observed in chronic cerebral vasospasm. A bioassay system was developed to measure the release of endothelium-derived relaxing factor (EDRF) from canine basilar arteries. Subarachnoid hemorrhage (SAH) was induced in dogs by two injections of autologous blood into the cisterna magna. Angiograms were performed on the 7th day after SAH to check the presence of chronic vasospasm. The animals were sacrificed on the 8th day, and in vitro experiments were performed on rings harvested from the basilar artery. These confirmed loss of endothelium-dependent relaxation in response to bradykinin and arginine vasopressin in the group with SAH. The basilar arteries were perfused with modified Krebs-Ringer solution. The perfusate was bioassayed with a ring of coronary artery without endothelium (bioassay ring). The release of the EDRF was detected by relaxation of the bioassay ring contracted with prostaglandin F2 alpha. Arginine vasopressin and bradykinin added to the perfusate upstream of the basilar artery caused concentration-dependent release of the EDRF. The direct effect of these peptides on the smooth muscle of the bioassay ring was to cause contraction. The release of the EDRF was identical in basilar arteries from the control and the SAH groups. These results indicate that the release of the EDRF is not impaired during chronic vasospasm, and thus that the loss of the endothelium-dependent relaxation is due to a decreased transfer of the EDRF or a reduced responsiveness of the smooth muscle to the factor.

Anisodamine at higher concentrations in inhibiting alpha-adrenergic responses in isolated canine blood vessels.

The present study was designed to examine the effect of higher concentration of anisodamine on alpha-adrenergic responses in isolated canine blood vessels. Up to 10(-3) mol/L, anisodamine did not significantly affect the responses of saphenous vein to alpha 2-adrenergic agonist UK-14, 304. In contrast, anisodamine (10(-5), 10(-4), 10(-3) mol/L) caused the concentration-response curves of femoral artery to norepinephrine (pA2 = 4.81 +/- 0.11) to phenylephrine (pA2 = 4.86 +/- 0.20) shift markedly. However, the antagonism on the alpha 1-adrenergic responses of canine femoral artery to norepinephrine and phenylephrine by higher concentrations of anisodamine produces dose ratios which yield a linear Schild regression with a slope less than unity, indicating an inequilibrium between agonist, antagonist, and receptors. The probable mechanisms involved are discussed.

Anisodamine inhibits non-selectively muscarinic receptors in isolated canine veins.

Organ chamber experiments were designed to determine the effects of anisodamine, an alkaloid structurally related to atropine, on prejunctional M2- and postjunctional M2-muscarinic receptors in isolated canine saphenous veins. The results showed that both acetylcholine-induced contraction and dilatation were inhibited in a competitive manner by anisodamine or atropine. The affinity of anisodamine for pre- and postjunctional muscarinic receptors was comparable (pKB = 7.78 and 7.86, respectively). However, compared with atropine, the affinity of anisodamine for prejunctional M2-receptors was about 1/8; while that for postjunctional M1-receptors was only 1/25 of that of atropine (pKB = 8.69 and 9.25, respectively for atropine). The data demonstrate that anisodamine is a non-selective muscarinic antagonist, a modulator rather than a vasodilator. The probable mechanisms involved are discussed.

Anisodamine antagonizes acetylcholine-induced inhibition of adrenergic neurotransmission in the canine saphenous vein.

The effect of anisodamine, an alkaloid structurally related to atropine and isolated from a Chinese herb, on adrenergic neurotransmission was studied using isolated canine saphenous veins. Helical strips of vein were incubated in modified physiological salt solution containing L-(7- 3H)-norepinephrine (3 x 10(-7) mol/L) for two hours and then mounted for isometric tension recording and superfusion. Increases in isometric tension and efflux of total tritiated compounds and 3H-norepinephrine evoked by electrical stimulation were inhibited by acetylcholine (10(-6) mol/L). This effect of acetylcholine was antagonized to comparable levels by anisodamine (10(-6) mol/L) or atropine (10(-6) mol/L). The results demonstrate that anisodamine blocks prejunctional muscarinic receptors.

Alcohol consumption among Oklahoma women: before and during pregnancy. The PRAMS Working Group. Pregnancy Risk Assessment Monitoring System.

The Pregnancy Risk Assessment Monitoring System (PRAMS) utilizes a population-based survey of Oklahoma women with a recent live birth to examine the rates of alcohol consumption before and during pregnancy. Nearly one-half of Oklahoma women report using alcohol during the three months before pregnancy and one in thirteen women consume alcohol during the three months prior to delivery. Moderate to heavy alcohol use before pregnancy was associated with additional perinatal risk factors including unintended pregnancy, inadequate prenatal care, smoking, and physical abuse. Health providers play an important role in the prevention of alcohol related birth impairments such as fetal alcohol syndrome through early detection of problem drinking, patient education and appropriate referrals. However, one in four Oklahoma mothers report their health care provider did not talk to them about the harmful effects alcohol can have on their baby.

GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis.

The non-receptor tyrosine kinase Src is a major player in multiple physiological responses including growth, survival and differentiation. Overexpression and/or oncogenic mutation in the Src gene have been documented in human tumors. The v-Src protein is an oncogenic mutant of Src, which promotes cell survival, migration, invasion and division. GRIM-19 is an antioncogene isolated using a genome-wide knockdown screen. Genes associated with Retinoid-IFN-induced Mortality (GRIM)-19 binds to transcription factor STAT3 and ablates its pro-oncogenic effects while v-Src activates STAT3 to promote its oncogenic effects. However, we found that GRIM-19 inhibits the pro-oncogenic effects of v-Src independently of STAT3. Here, we report the identification of functionally inactivating GRIM-19 mutations in a set of head and neck cancer patients. While wild-type GRIM-19 strongly ablated v-Src-induced cell migration, cytoskeletal remodeling and tumor metastasis, the tumor-derived mutants (L(71)P, L(91)P and A(95)T) did not. These mutants were also incapable of inhibiting the drug resistance of v-Src-transformed cells. v-Src downregulated the expression of Pag1, a lipid raft-associated inhibitor of Src, which was restored by wild-type GRIM-19. The tumor-derived mutant GRIM-19 proteins failed to upregulate Pag1. These studies show a novel mechanism that deregulates Src activity in cancer cells.

[Resuscitation of a pregnant patient--don't hesitate to perform a perimortem caesarean section]. / Reanimatie van een zwangere patiënt. Aarzel niet met het verrichten van een perimortem sectio.

Cardiac arrest is a rare and life-threatening complication during pregnancy. We present the case of a 26-year-old patient in her first pregnancy who during induction of labour at 41 weeks had a cardiac arrest caused by an amniotic fluid embolism. As part of the resuscitation procedure, a perimortem caesarean section was performed in the delivery room within five minutes. Following the caesarean section, she developed diffuse intravascular coagulation and massive, life-threatening haemorrhage which necessitated supravaginal uterus amputation. Afterwards mother and son recovered well and were discharged from hospital in good condition after 13 days. Pregnancy-induced changes in anatomy and physiology warrant a different approach during resuscitation. All medical personnel involved in the care of pregnant women should be trained to act promptly in acute situations. Training should increase knowledge of the aforementioned changes and stress the importance of performing a perimortem caesarean section, when necessary, on site and without hesitation.

Laryngeal transplantation in 2005: a review.

There is no good surgical, medical or prosthetic solution to the problems faced by those with a larynx whose function is irreversibly damaged by tumor or trauma. Over the past 10 years, the pace of research designed to establish laryngeal transplantation as a therapeutic option for these persons has increased steadily. The biggest milestone in this field was the world's first true laryngeal transplant performed in Cleveland, Ohio in 1998. The recipient's graft continues to function well, in many respects, even after 7 years. However, it has also highlighted the remaining barriers to full-scale clinical trials. Stimulated by these observations, several groups have accumulated data which point to answers to some of the outstanding questions surrounding functional reinnervation and immunomodulation. This review seeks to outline the progress achieved in this field by 2005 and to point the way forward for laryngeal transplantation research in the 21st century.

Preoperative magnetic resonance angiography in fibular-free flap reconstruction of head and neck defects.

BACKGROUND: Conventional angiography has been recommended for imaging of the leg prior to fibular-free flap harvest. Magnetic resonance angiography (MRA) offers a similar level of accuracy at no risk to the patient and at a lower cost. METHODS: Thirty-two patients who were considered for fibular-free flap were retrospectively reviewed. Preoperative MRA of the lower extremities was performed on all patients and used to evaluate vessel patency. The decision of free flap donor site was based upon MRA findings. RESULTS: The choice of side harvested was changed in four (12.5%) patients and the fibula was excluded as a donor site in three patients (9%). Flap design was altered in one patient found to have abnormally short peroneal arteries. The usual correlation between palpable distal pulses and proximal patent arteries was found to be unreliable. All 29 patients underwent successful free flap reconstruction with no ischemic complications. CONCLUSIONS: Preoperative MRA is useful when choosing the side of fibular harvesting and in excluding patients from the fibula as a donor site. We feel that the cost of obtaining preoperative imaging is outweighed by avoiding potential ischemic complications and additional operating room time with no risk to the patient's health.

Inhibition of adrenergic neurotransmission in isolated veins of the dog by potassium ions.

1. In the intact organism, an increase in K+ concentration decreases the reactivity of blood vessels to sympathetic stimulation. The present experiments were designed to determine whether or not K+ interferes with adrenergic neurotransmission. 2. Helical strips cut from dogs' saphenous veins were incubated (4 hr) in Krebs-Ringer solution containing [7-3H]norepinephrine (5 times 10(-8) g/ml). The preparations were mounted for superfusion and isometric tension recording; the superfusate was collected for estimation of total radioactivity and for chromatographic separation of 3H-labelled norepinephrine and metabolites. 3. Supramaximal electric stimulation (5 Hz, 9 V, 2 msec) increased the tension and the [3H]norepinephrine efflux. Increasing the K+ concentration from 5-9 to 1, 15, and 20 m-equiv/l. caused a progressive depression of these contractions and diminished the total 3H efflux in proportion to the relaxation; the decrease in 3H efflux reflected a decrease in intact [3H]norepinephrine. The same increase in K+ concentration did not alter basal tension or basal 3H efflux. 4. Addition of tyramine (4 times 10(-6) g/ml. min) to the superfusate augmented both the tension and the efflux, but these actions were not depresesd by increasing the K+ concentration. 5. Cocaine, phentolamine, and phenoxybenzamine did not prevent the depression by K+ of the response to electric stimulation. 6. These experiments show that K+ causes relaxation of venous smooth muscle constricted by sympathetic stimulation and does so by inhibiting the release of norepinephrine from nerve endings. By contrast, K+ does not inhibit norepinephrine release in response to tyramine. 7. During submaximal electric stimulation (5 Hz, 1-8--3 V, 2 msec), increasing the K+ concentration from 5-9 to 10 and 15 m-equiv/l. potentiated the contractions and increased the [3H]norepinephrine efflux; at 20 m-equil/l, K+ caused transient increases in tension and 3H efflux followed by relaxation and decreased norepinephrine release. After addition of cocaine (10(-5) g/ml. min), K+ only caused relaxation and decrease in 3H efflux, showing that, in addition to inhibition of norepinephrine release, K+ also inhibits the reuptake process. 8. In higher concentrations (40 m-equil/l.), K+ caused both a liberation of norepinephrine and a direct activation of the smooth muscle cells.

Prejunctional adrenergic inhibition by aggregating platelets in canine blood vessels.

Experiments were performed to determine the effect of aggregating platelets on adrenergic neurotransmission. Rings of canine saphenous veins and left circumflex coronary arteries were incubated with [3H]norepinephrine and suspended for superfusion. Aggregating platelets and exogenous 5-hydroxytryptamine decreased the overflow of [3H]norepinephrine evoked by electrical stimulation of the adrenergic nerve endings. The reduction of transmitter overflow caused by 5-hydroxytryptamine was prevented by the serotonergic antagonist methiothepin in a concentration that did not significantly affect the release of 5-hydroxytryptamine or thromboxane B2 from the aggregating platelets. Methiothepin decreased but did not abolish the inhibitory effect of aggregating platelets on neurotransmitter overflow. These experiments demonstrate that 5-hydroxytryptamine and other substances released from aggregating platelets can exert prejunctional inhibition of adrenergic neurotransmission in isolated blood vessels.

Na+,K+-ATPase inhibitors and the adrenergic neuroeffector interaction in the blood vessel wall.

Augmentation of the constrictor response of blood vessels to sympathetic nerve stimulation caused by inhibitors of Na+,K+-ATPase can be explained by (a) inhibition of neuronal uptake, (b) displacement of stored norepinephrine, (c) facilitation of exocytotic release of the adrenergic transmitter, (d) diminution in intraneuronal deamination, (e) reduction in extraneuronal uptake, (f) facilitation of postjunctional alpha 2-adrenoceptors, (g) inhibition of poststimulation relaxation, and, possibly, (h) prevention of endothelium-dependent relaxation.

Increased reactivity of venous smooth muscle by small decreases in extracellular sodium.

In dog saphenous vein strips, decreases in extracellular sodium from 5% to 23% did not alter basal tension, but progressively increased tension developed during electrical stimulation (1.0 to 10 Hz). The augmentation did not occur with similar reductions in chloride ions. When osmolality was maintained with sucrose, the response to electrical stimulation also was enhanced with a 5% reduction in sodium ions, but did not increase further with larger sodium reductions. The enhancement was due to some effect on the smooth muscle cells, because the overflow of [7-3H]norepinephrine during electrical stimulation was unaffected by the sodium reduction, whereas contractions caused by norepinephrine and barium chloride were potentiated. The potentiation did not depend on increased influx of extracellular calcium, because contractions induced by acetylcholine were unaffected by sodium reduction; and after blocking calcium influx with verapamil, the norepinephrine contractions still were augmented. It was concluded that a decrease in extracellular sodium by 5% (from the normal value of 143.3--131.1 meq/1) can enhance the response of venous smooth muscle to adrenergic stimuli.