cyclic-gmp and Drug-Hypersensitivity

This study was designed to evaluate the effect of carvedilol on nitrate tolerance in patients with chronic heart failure.. The attenuation of cyclic guanosine 5'-monophosphate (cGMP) production due to inactivation of guanylate cyclase by increased superoxide has been reported as a mechanism of nitrate tolerance. Carvedilol has been known to combine alpha/beta-blockade with antioxidant properties.. To evaluate the effect of carvedilol on nitrate tolerance, 40 patients with chronic heart failure were randomized to four groups that received either carvedilol (2.5 mg once a day [carvedilol group, n=10]), metoprolol (30 mg once a day [metoprolol group, n=10]), doxazosin (0.5 mg once a day [doxazosin group, n=10]) or placebo (placebo group, n=10). Vasodilatory response to nitroglycerin (NTG) was assessed with forearm plethysmography by measuring the change in forearm blood flow (FBF) before and 5 min after sublingual administration of 0.3 mg NTG, and at the same time blood samples were taken from veins on the opposite side to measure platelet cGMP. Plethysmography and blood sampling were obtained serially at baseline (day 0); 3 days after carvedilol, metoprolol, doxazosin or placebo administration (day 3); and 3 days after application of a 10-mg/24-h NTG tape concomitantly with carvedilol, metoprolol, doxazosin or placebo (day 6).. There was no significant difference in the response of FBF (%FBF) and cGMP (%cGMP) to sublingual NTG on day 0 and day 3 among the four groups. On day 6, %FBF and %cGMP were significantly lower in the metoprolol, doxazosin and placebo groups than on day 0 and day 3, but these parameters in the carvedilol group were maintained.. These results indicated that carvedilol may prevent nitrate tolerance in patients with chronic heart failure during continuous therapy with NTG.

Topics: Adrenergic Antagonists; Aged; Blood Flow Velocity; Blood Platelets; Blood Pressure; Carbazoles; Carvedilol; Chronic Disease; Cyclic GMP; Double-Blind Method; Doxazosin; Drug Hypersensitivity; Drug Therapy, Combination; Female; Follow-Up Studies; Forearm; Heart Failure; Heart Rate; Humans; Male; Metoprolol; Middle Aged; Nitroglycerin; Propanolamines; Vasodilator Agents

This study was designed to compare the preventive efect of nitrate tolerance between carvedilol with antioxidant properties and arotinolol without antioxidant properties.. The attenuation of cyclic guanosine monophosphate (cGMP) production due to inactivation of guanylate cyclase by increased superoxide has been reported as a mechanism of nitrate tolerance. Carvedilol has been known to combine alpha- and beta-blockade with antioxidant properties.. To evaluate the preventive effect of nitrate tolerance, 24 patients with untreated hypertension were randomized to receive either carvedilol (10 mg twice a day [carvedilol group, n=8]), arotinolol (10 mg twice a day [arotinolol group, n=8]), or placebo (placebo group, n=8). Vasodilatory response to nitroglycerin (NTG) was assessed with forearm plethysmography by measuring the change in forearm blood flow (FBF) before and 5 min after sublingual administration of 0.3 mg NTG, and at the same time blood samples were taken from veins on the opposite side to measure platelet cGMP. Plethysmography and blood sampling were obtained serially at baseline (day 0), 3 days after carvedilol, arotinolol or placebo administration (day 3) and 3 days after application of a 20 mg/24 h NTG tape concomitantly with carvedilol, arotinolol or placebo (day 6).. There was no significant difference in the response of FBF (%FBF) and cGMP (%cGMP) to sublingual administration of NTG on days 0 and 3 among the three groups. On day 6, %FBF and %cGMP were significantly lower in the arotinolol group and the placebo group than days 0 and 3, but these parameters in the carvedilol group were maintained.. The results indicated that carvedilol with antioxidant properties may prevent the development of nitrate tolerance during continuous therapy with NTG compared with arotinolol without antioxidant properties.

Topics: Adrenergic Antagonists; Adult; Aged; Blood Flow Velocity; Blood Platelets; Blood Pressure; Carbazoles; Carvedilol; Cyclic GMP; Double-Blind Method; Drug Hypersensitivity; Drug Therapy, Combination; Female; Follow-Up Studies; Forearm; Heart Rate; Humans; Hypertension; Male; Middle Aged; Nitroglycerin; Propanolamines; Vasodilator Agents

Phosphodiesterase 2A (PDE2A) is an evolutionarily conserved enzyme that catalyzes the degradation of the cyclic nucleotides, cyclic adenosine monophosphate, and/or cyclic guanosine monophosphate. Recent studies reported the expression of PDE2A in the dorsal horn of the spinal cord, pointing to a potential contribution to the processing of pain. However, the functions of PDE2A in spinal pain processing in vivo remained elusive.. Immunohistochemistry, laser microdissection, and quantitative real-time reverse transcription polymerase chain reaction experiments were performed to characterize the localization and regulation of PDE2A protein and messenger RNA in the mouse spinal cord. Effects of the selective PDE2A inhibitor, BAY 60-7550 (Cayman Chemical, Ann Arbor, MI), in animal models of inflammatory pain (n = 6 to 10), neuropathic pain (n = 5 to 6), and after intrathecal injection of cyclic nucleotides (n = 6 to 8) were examined. Also, cyclic adenosine monophosphate and cyclic guanosine monophosphate levels in spinal cord tissues were measured by liquid chromatography tandem mass spectrometry.. The authors here demonstrate that PDE2A is distinctly expressed in neurons of the superficial dorsal horn of the spinal cord, and that its spinal expression is upregulated in response to hind paw inflammation. Administration of the selective PDE2A inhibitor, BAY 60-7550, increased the nociceptive behavior of mice in animal models of inflammatory pain. Moreover, BAY 60-7550 increased the pain hypersensitivity induced by intrathecal delivery of cyclic adenosine monophosphate, but not of cyclic guanosine monophosphate, and it increased the cyclic adenosine monophosphate levels in spinal cord tissues.. Our findings indicate that PDE2A contributes to the processing of inflammatory pain in the spinal cord.

Topics: Animals; Behavior, Animal; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Drug Hypersensitivity; Imidazoles; Immunohistochemistry; Inflammation; Injections, Spinal; Male; Mice; Mice, Inbred C57BL; Microdissection; Neuralgia; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Posterior Horn Cells; Real-Time Polymerase Chain Reaction; Spinal Cord; Triazines; Up-Regulation; Zymosan

Topics: Acetylcholine; Adult; Asthma; Bronchi; Cyclic AMP; Cyclic GMP; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Prostaglandins F

The effects of exogenous nucleotides on the histamine hypersensitivity of pharmacologically beta-blocked mice were investigated. Female HLA-SW (ICR) mice, 27-29 gm, were injected intraperitoneally with 20 to 100 mug of propranolol 45 min before intraperitoneal challenge with 1 mg histamine. These animals had a mortality which averaged approximately 80%. At various time intervals before histamine, doses of from 0.5 to 12 mumoles of nucleotides were administered intravenously. Noncyclic nucleotides, adenosine, adenosine 5'-monophosphate (AMP), and guanosine 5'-monophosphate (GMP) showed clear, dose-response protection against histamine death of propranolol-treated mice when they were given 45 to 90 min before histamine. Cyclic AMP showed significant protection only when it was given at a dose of 8 mumoles 45 to 90 min before histamine, and lower or higher doses gave equivocal or no protection. Cyclic GMP WAS Not protective at any dose tested. Propranolol treatment also produced enhanced sensitivity to passive systemic anaphylaxis. Mice were passively sensitized by intraperitoneal injection of mouse anti-egg albumin antibody 6 hr before intravenous challenge with 0.5 mg egg albumin. The mortality from anaphylaxis in the group treated with 20 mug propranolol 45 min before antigen challenge increased to 83%, while that of the group not given propranolol was only 10%. Nucleotides were given intravenously 45 min before antigen challenge. The nucleotides that protected mice from death due to histamine challenge also protected them from death due to systemic anaphylaxis. These protective nucleotides were the same nucleotides that had been reported previously to be protective against Bordetella pertussis-induced hypersensitivity to histamine and anaphylaxis.

Topics: Adenosine; Adenosine Monophosphate; Anaphylaxis; Animals; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Guanine Nucleotides; Histamine; Lethal Dose 50; Mice; Mice, Inbred ICR; Nucleotides; Propranolol