Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report describes various old and new positive inotropic drugs with respect to their mechanisms of action. Drugs with established cardiotonic effects include cardiac glycosides, beta 1-adrenergic agents, glucagon, histamine and the methylxanthines. New agents discussed are prenalterol, beta 2- and alpha-adrenergic drugs, amrinone and sulmazole. Prenalterol is a beta 1-adrenergic agent. Beta 2-adrenergic drugs, amrinone and sulmazole, combine a positive inotropic and a vasodilator effect. The latter resemble theophylline and other methylxanthines in that they appear to act mainly as phosphodiesterase inhibitors with a subsequent increase in cyclic adenosine monophosphate (cAMP). The mechanism of the positive inotropic effect of alpha-adrenergic stimulating agents (for example, phenylephrine) is unknown. It is independent of the cAMP system and is not accompanied by changes in frequency.
J Am Coll Cardiol 1984 Aug
PMID:Inotropic drugs and their mechanisms of action. 633 Jan 95

The cardiac adenylate cyclase activity from normotensive and spontaneously hypertensive (SHR) rats was studied as a function of temperature between 17 degrees and 37 degrees C. Arrhenius plots of adenylate cyclase activity displayed a break around 31 degrees C when tested under basal conditions or in the presence of GTP but were linearized after activation with p[NH]ppG, NaF, secretin, glucagon or isoproterenol. The energy of activation of adenylate cyclase activity in the presence of GTP (9.5 +/- 0.5 kcal/mol) was significantly lower than in the presence of p[NH]ppG (17.7 +/- 0.8 kcal/mol). A hormone was without effect on the energy of activation observed with either GTP or p[NH]ppG but the simultaneous presence of hormone and nucleotide increased markedly the activity of the enzyme. The energies of activation were analyzed in terms of variation of enthalpy and entropy and discussed in relation with the process of activation and coupling of the guanine nucleotide regulatory protein. These thermodynamic characteristics were similar in cardiac membranes from normotensive and spontaneously hypertensive rats, suggesting that the impairment of hormone-stimulated adenylate cyclase activity observed in the heart membranes of hypertensive rats was not a consequence of a defect in the activation process of the enzyme.
J Mol Cell Cardiol 1983 Dec
PMID:Thermodependence of basal and stimulated cardiac adenylate cyclase activity in normotensive and spontaneously hypertensive rats. 666 29

We have previously shown that cardiostimulation produced by catecholamines, glucagon, tachycardia or CaCl2, resulted in a metabolically induced increase in coronary flow [9, 11, 12]. Slow infusion of prostaglandin E2 (PGE2) or its precursor, arachidonic acid, inhibited the development of metabolic coronary dilatation without major alterations of the effects of the cardiostimulating agents on the cardiac activity [9, 11, 12]. Since PGE2 synthesis is known to be enhanced by glutathione we thought that its addition to the perfused heart would intensify the inhibition of the metabolic coronary dilatation produced by arachidonic acid. While testing the influence of noradrenaline in the isolated perfused heart, we found that the inotropic action and the resulting coronary dilatation were markedly increased during glutathione administration. We diverted the investigation from its original purpose to further study this novel action of glutathione and we report here that catecholamines and glucagon inotropic effects, and resulting metabolic coronary dilatation are enhanced by glutathione. Neither the CaCl2 nor the coronary dilatations due to reactive hyperaemia or adenosine were altered by glutathione.
J Mol Cell Cardiol 1984 Jun
PMID:Enhancement by glutathione of the inotropic actions of catecholamines and glucagon. 674 92

The rate of glycogenolysis was measured using 13C-NMR in vivo in the rat heart following a glucagon bolus. Glycogen that had just been synthesized during a 50 min infusion of D-[1-13C]glucose and insulin was degraded at a rate of 2.5 mumol/min/g wet wt following a 250 micrograms bolus of glucagon. If a second 50 min infusion of unlabelled glucose followed the D-[-13C]glucose, the rate of mobilization of the labelled glycogen following glucagon was slower (0.52 mumol/min/g wet wt), indicating that the labeled glycogen was less accessible to the activated phosphorylase. Glycogen phosphorylase a (GPa) activity was measured in hearts freeze-clamped at intervals after the glucagon bolus. Activity rose rapidly to 6-fold basal and then returned to basal over 20-30 min (t1/2 decay of phosphorylase activity = 5.1 min). This time course paralleled the exponential fall in heart glycogen which followed glucagon (t1/2 = 4.3 min). Throughout the post-glucagon period the activity of phosphorylase exceeded the rate of glycogenolysis. These findings suggest that the activity of the phosphorylated form of glycogen phosphorylase (GPa) is an important but not the sole determinant of glycogen breakdown in the heart after a glucagon bolus.
J Mol Cell Cardiol 1993 Feb
PMID:The time course of myocardial glycogenolysis stimulated by glucagon. 847 25

Changes in the redox state of liver mitochondria were investigated by measuring the arterial ketone body ratio (acetoacetate/3-hydroxybutyrate: AKBR) in nine healthy volunteers (eight males and one female, mean age 38.4 +/- 5.0 years) during exercise. The correlation between the changes in AKBR and levels of various hormones controlling energy metabolism was also investigated. Subjects participated in symptom-limited exercise test using the ramping bicycle ergometer with expired gas analysis, blood pressure and 12 lead electrocardiogram monitoring. Anaerobic threshold by gas exchange parameters (ATge) was determined from the expired gas data with the v-slope method. AKBR, glucose, non-esterified fatty acid (NEFA) and lactate were measured in arterial plasma samples. Catecholamines (epinephrine, norepinephrine, dopamine), insulin, glucagon, antidiuretic hormone (ADH), growth hormone (GH), thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), human-atrial natriuretic peptide (hANP) and brain natriuretic peptide (BNP) were measured in venous plasma samples. AKBR was gradually decreased by exercise from the resting value of 1.82 +/- 0.20. AKBR reduction was potentiated after ATge to 0.93 +/- 0.18 (p < 0.01 vs rest) at peak exercise. AKBR was further decreased during recovery to the minimum value of 0.70 +/- 0.06 (p < 0.01) at 6 min in the recovery phase. AKBR then began to increase and reached 0.95 +/- 0.07 30 min after peak exercise. Epinephrine increased from 45.9 +/- 11.0 to 210 +/- 75 pg/ml (p < 0.01), norepinephrine increased from 348 +/- 52 to 1,277 +/- 111 pg/ml (p < 0.01), and dopamine increased from 13.0 +/- 1.9 to 25.0 +/- 2.5 pg/ml (p < 0.01) between rest and peak exercise, respectively. Insulin decreased from 22.0 +/- 3.5 to 14.2 +/- 2.1 pg/ml (p < 0.05). No significant change was observed in glucagon, ADH, GH, TSH, T3, T4, hANP or BNP. Glucose decreased from 124 +/- 9 to 84 +/- 8 mg/dl (p < 0.05), whereas NEFA increased from 94 +/- 10 to 190 +/- 66 mg/dl (p < 0.05). A negative correlation was observed between AKBR and lactate (r = -0.41, p < 0.001). These results indicate that hepatic adenosine triphosphate production is promoted as energy demand increases by exercise, and maximizes early in the recovery phase when hepatic energy demand is maximum due to active gluconeogenesis. The levels of catecholamines, insulin and lactate contribute to the control of liver energy metabolism.
J Cardiol 1997 Feb
PMID:[Evaluation of changes in hepatic energy metabolism during exercise by ketone body ratio in humans]. 912 Jul 98

Fetal and neonatal tissues are resistant to catecholamine-induced desensitization of essential physiological responses. We examined the mechanisms underlying the ontogeny of desensitization in neonatal rat heart for the beta-adrenergic receptor/adenylyl cyclase signaling cascade. Animals of different ages received isoproterenol daily or 4 days and cardiac membrane preparations were evaluated on the 5th day (6, 15, 25 days old and adults). Measurements were made of basal activity, activity stimulated by two agonists (isoproterenol or glucagon) that operate at different receptors but that share Gs as the transduction intermediate, or by forskolin-Mn' to assess total catalytic capacity of the cyclase subunit; we also assessed inhibition of activity by carbachol which acts via muscarinic cholinergic receptors and G. Adult rats exhibited robust desensitization of the adenylyl cyclase response but the effect was heterologous in that equivalent loss of activity was seen for basal, isoproterenol- and glucagon-stimulated activity forskolin-Mn(2+)-stimulated activity was also decreased. Two factors contributed to desensitization; generalized reduction in membrane protein concentrations caused by cell enlargement (reduced surface-to-volume ratio), and specific interference with the G-protein component that couples receptors to the cyclase. Thus, after adjustment for changes in membrane protein, the desensitization of the forskolin-Mn2, response was no longer evident, but the effects on the other measures were still present. In addition, isoproterenol treatment produced crosstalk with the carbachol/Gi signaling pathway, with significant reductions in the ability of carbachol to inhibit adenylyl cyclase activity. Heterologous desensitization by isoproterenol was also present in 15 and 25 day old rats, but involved only selective components of the effects seen in adults. At 25 days, uncoupling of signals operating through Gs and Gi was obtained without a reduction in forskolin-Mn(2+)-stimulated activity. At 15 days, only the effect on Gs coupling was seen. At 6 days, agonist-induced desensitization was not detectable and instead, heterologous sensitization was found. In these youngest animals, isoproterenol treatment produced a parallel increase in basal, isoproterenol-, glucagon- and forskolin-Mn(2+)-stimulated activity, unaccompanied by changes in membrane protein concentrations, indicating an increase in adenylyl cyclase catalytic activity. These results indicate that the ability to elicit desensitization is not an inherent property of cardiac cells but rather is acquired in distinct stages during development. Sensitization by agonists early in development may be important in preserving physiological responsiveness during ontogenetic surges of adrenergic activity.
J Mol Cell Cardiol 1997 Feb
PMID:Ontogeny of regulatory mechanisms for beta-adrenoceptor control of rat cardiac adenylyl cyclase: targeting of G-proteins and the cyclase catalytic subunit. 914 Aug 19

In the present studies we have investigated if the increased expression of Gi alpha proteins reported earlier in heart and aorta from SHR (spontaneously hypertensive rats) is the cause or effect of hypertension. The SHRs at various ages of the development of blood pressure (3-5 days, 2 weeks, 4 weeks and 8 weeks) and their age-matched WKY were used for these studies. The expression of Gi alpha-2 and Gi alpha-3 (inhibitory guanine nucleotide regulatory protein and Gs alpha (stimulatory guanine nucleotide regulatory protein) at protein and mRNA level was determined by immunoblotting and Northern blotting technique using specific antibodies and cDNA probes. The SHR at early ages up to 2 weeks did not show any increase in blood pressure, however it started to go up from 4 weeks. The levels of Gi alpha 2 and Gi alpha 3 at protein and mRNA in heart from SHR were not different in 3-5 days old SHR as compared to WKY (Wistar-Kyoto rats), however, the expression of Gi alpha-2 and Gi alpha-3 protein and mRNA was significantly increased in 2 weeks and older SHR. The mRNA level of the catalytic subunit type V enzyme was significantly decreased in SHR 2 weeks and later ages as compared to their age-matched WKY. On the other hand, the expression of Gs alpha was not different in SHR as compared to WKY at all the ages studied. In addition, the oxotremorine and C-ANF4-23 (a ring deleted analog of atrial natriuretic factor) mediated inhibitions of adenylyl cyclase in hearts and aorta were also significantly enhanced in 2 weeks and older SHRs as compared to WKY rats, whereas, at younger age of SHR (3-5 days old), no change in the percent inhibition of adenylyl cyclase by C-ANF4-23 was observed and oxotremorine was unable to inhibit adenylyl cyclase activity. Furthermore, the basal enzyme activity and the stimulatory responses of isoproterenol, NECA (N-ethylcarboxamideadenosine), glucagon and forskolin on adenylyl cyclase were significantly decreased at all ages of SHR as compared to WKY. These results suggest that the increased expression of genes for Gi alpha-2 and Gi alpha-3, decreased expression of type V enzyme mRNA and decreased cAMP levels precedes the development of blood pressure and may participate in the pathogenesis of hypertension.
J Mol Cell Cardiol 1997 Mar
PMID:Enhanced expression of Gi-protein precedes the development of blood pressure in spontaneously hypertensive rats. 915 62

Intravenous diltiazem has become a preferred medication for treating supraventricular tachyarrhythmias in hospitalized patients. We present a case of inadvertent acute overdosage, its clinical effects, and successful treatment using intravenous glucagon.
Am J Cardiol 1997 Jun 01
PMID:Use of glucagon for acute intravenous diltiazem toxicity. 918 62

In the fetus and neonate, beta-adrenoceptor stimulation fails to produce physiological desensitization. The current study explores the mechanisms underlying the response pattern in neonatal rats. Homologous cardiac beta-adrenergic desensitization caused by isoproterenol treatment in vivo was demonstrable in adult rats by the immediate (2h) and specific loss of the ability of isoproterenol, but not glucagon, to stimulate adenylyl cyclase in vitro. Homologous desensitization was absent when the same treatment was given to neonates. By 12 h post-treatment, the adults showed heterologous desensitization (loss of the response to glucagon), an effect which was once again absent in the immature rats. The absence of desensitization in neonates did not reflect a deficiency in the activity or subcellular distribution of beta ARK1, the enzyme that initiates the phosphorylation and consequent desensitization of beta-adrenoceptors. On the other hand, neonates showed relatively poor receptor-Gs transduction as assessed by the GTP-induced shift in receptor ligand binding. Repeated isoproterenol treatment of adult rats led to uncoupling of receptor-G-protein transduction but the same treatment in neonates enhanced transduction. Furthermore, neonatal sympathectomy with 6-OHDA interfered with the ontogenetic rise in beta-adrenoceptor-Gs interactions. These results indicate that the maintenance of agonist responses in the face of neonatal adrenergic stimulation does not reflect simply an absence of the ability to elicit homologous or heterologous desensitization but rather represents an active regulatory mechanism in which neural input exerts a positive trophic role at the level of G-protein function.
J Mol Cell Cardiol 1999 Feb
PMID:Ontogeny of cardiac beta-adrenoceptor desensitization mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting uncoupling. 1009 53

The incidence of poisoning with calcium channel blockers, accidental or intentional, has increased in recent years, associated with more frequent use. We present a clinical case of bradycardia and shock of unknown cause, which came to be revealed a poisoning by 3240 mg of slow-release diltiazem, managed with temporary transvenous pacing and dopamine in high concentration. We make a review of the cardiovascular manifestations of the three classic calcium channel blockers: verapamil, diltiazem and nifedipine; namely, hypotension, rhythm and conduction disturbances. We point out the late appearance of the beginning of manifestations with the use of slow releasing formulations. The toxicity by calcium channel blockers can lead to a wide variety of manifestations in the central nervous system, gastrointestinal system, endocrine-metabolic, hematologic and respiratory systems. There is a high clinical suspicion when the following factors are present: hypotension with bradycardia, mental state disturbances, lactic acidosis, hyperglycemia, sinus pauses and refractory shock. Treatment is based on general measures of intoxication support, decreasing the drug absorption and improvement of cardiac function. The bradyarrhythmias are corrected with the use of intravenous calcium, glucagon, atropine and pacemaker. If the intoxication causes depression of cardiac contractility, the use of calcium or/and glucagon is indicated. If there is refractoriness with these measures, catecholamines should be employed. There are alternative and adjuvant drugs such as amrinone, insulin-glucose, 4-aminopyridine and calcium entry promoters. Charcoal hemoperfusion can be useful in the overdose of sustained release preparations, but hemodialysis is unworthy of therapeutical interest.
Rev Port Cardiol 2001 Dec
PMID:Poisoning with calcium channel blockers--a case report and review of the literature. 1186 85


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