morphinans and Hypotension

MCRT (YPFPFRTic-NH(2)) is a chimeric opioid peptide based on morphiceptin and PFRTic-NH(2). In order to assess the cardiovascular effect of MCRT, it was administered by intravenous (i.v.) injection targeting at the peripheral nervous system and by intracerebroventricular (i.c.v.) injection targeting at the central nervous system. Naloxone and L-NAME were injected before MCRT to investigate possible interactions with MCRT. Results show that administration of MCRT by i.v. or i.c.v. injection could induce bradycardia and decrease in mean arterial pressure (MAP) at a greater degree than that with morphiceptin and PFRTic-NH(2). When MCRT and NPFF were coinjected, we observed a dose-dependent weakening of these cardiovascular effects by MCRT. Because naloxone completely abolished the cardiovascular effects of MCRT, we conclude that opioid receptors are involved in regulating the MAP of MCRT regardless of modes of injection. The effect of MCRT on heart rate is completely dependent on opioid receptors when MCRT was administered by i.c.v. instead of i.v. The central nitric oxide (NO) pathway is involved in regulating blood pressure by MCRT under both modes of injection, but the peripheral NO pathway had no effect on lowering blood pressure mediated by MCRT when it was administered by i.c.v. Based on the results from different modes of injection, the regulation of heart rate by MCRT mainly involves in the central NO pathway. Lastly, we observed that the cardiovascular effects of MCRT such as bradycardia and decrease of blood pressure, were stronger than that of its parent peptides. Opioid receptors and the NO pathway are involved in the cardiovascular regulation by MCRT, and their degree of involvement differs between intravenous and intracerebroventricular injection.

Topics: Analgesics, Opioid; Animals; Blood Pressure; Bradycardia; Endorphins; Heart Rate; Hypotension; Injections, Intravenous; Injections, Intraventricular; Male; Morphinans; Naloxone; Naltrexone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Rats; Rats, Wistar

The mechanisms underlying the cardiovascular responses evoked by milonine (i.v.), an alkaloid, were investigated in rats. In normotensive rats, milonine injections produced hypotension and tachycardia, which were attenuated after N(w) -nitro-L-arginine methyl esther (L-NAME; 20 mg/kg, i.v.). In phenylephrine (10 μM), pre-contracted mesenteric artery rings, milonine (10⁻¹⁰ M to 3 × 10⁻⁴ M) caused a concentration-dependent relaxation (EC₅₀ = 1.1 × 10⁻⁶ M, E(max) = 100 ± 0.0%) and this effect was rightward shifted after either removal of the vascular endothelium (EC₅₀ = 1.6 × 10⁻⁵, p < 0.001), or after L-NAME 100 μM (EC₅₀ = 6.2 × 10⁻⁵, p < 0.001), hydroxocobalamin 30 μM (EC₅₀ = 1.1 × 10⁻⁴, p < 0.001) or ODQ 10 μM (EC₅₀ = 1.9 × 10⁻⁴ p < 0.001). In addition, in rabbit aortic endothelial cells, milonine increased NO₃⁻ levels. The relaxant effect induced by milonine was attenuated in the presence of KCl (20 mM), a modulator efflux K(+) (EC₅₀ = 1.2 × 10⁻⁵, p < 0.001), or different potassium channel blockers such as glibenclamide (10 μM) (EC₅₀ = 6.3 × 10⁻⁵, p < 0.001), TEA (1 mM) (EC₅₀ = 2.3 × 10⁻⁵ M, n = 6) or Charybdotoxin (0.2 μM) plus apamin (0.2 μM) (EC₅₀ = 3.9 × 10⁻⁴ M, n = 7). In addition, pre-contraction with high extracellular potassium concentration prevented milonine-induced vasorelaxation (EC₅₀ = 1.0 × 10⁻⁴, p < 0.001). Milonine also reduced CaCl₂ -induced contraction in Ca²(+) -free solution containing KCl (60 mM). In conclusion, using combined functional and biochemical approaches, we demonstrated that the hypotensive and vasorelaxant effects produced by milonine are, at least in part, mediated by the endothelium, likely via nitric oxide release, activation of nitric oxide-cGMP pathway and opening of K(+) channels.

Topics: Alkaloids; Animals; Aorta; Apamin; Cells, Cultured; Charybdotoxin; Endothelium, Vascular; Glyburide; Hypotension; Linear Models; Male; Mesenteric Artery, Superior; Morphinans; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Potassium Channel Blockers; Potassium Chloride; Rabbits; Rats; Rats, Wistar; Tachycardia; Vasodilation; Vasodilator Agents

Topics: Animals; Diprenorphine; Hematocrit; Hypotension; Male; Morphinans; Naloxone; Nitroprusside; Rats; Rats, Inbred Strains; Saline Solution, Hypertonic; Shock; Vasopressins

Topics: Acepromazine; Analgesics; Animals; Blood Pressure; Bradycardia; Cyclopropanes; Dog Diseases; Dogs; Drug Combinations; Female; Heart Rate; Horse Diseases; Horses; Hypertension; Hypotension; Injections, Intravenous; Male; Morphinans; Narcotic Antagonists; Neuroleptanalgesia; Respiration; Tremor; Vagotomy; Venous Pressure

Topics: Adult; Ataxia; Auditory Perception; Blepharoptosis; Cognition Disorders; Hallucinations; Humans; Hypertension; Hypotension; Male; Morphinans; Speech Disorders; Substance Withdrawal Syndrome; Thebaine; Tinnitus; Visual Perception

Topics: Anesthesia; Anesthetics; Barbiturates; Blood Volume; Diazepam; Female; Fetal Diseases; Gestational Age; Heart Rate; Humans; Hypotension; Hypoxia; Maternal-Fetal Exchange; Morphinans; Muscle Relaxants, Central; Pregnancy; Pregnancy Complications; Respiration; Vascular Resistance