Central injections of capsaicin cause antidiuresis mediated through neurokinin-1 receptors in rat hypothalamus and vasopressin release.
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Intracerebroventricular injections of capsaicin at 100-500 nmol elicited dose-dependent decreases in urine outflow volume in anesthetized, hydrated rats. The capsaicin (500 nmol)-induced antidiuresis was inhibited by pretreatment with CP96345 (30 nmol, a neurokinin-1-receptor antagonist), but not by that with phenoxybenzamine (20 nmol, an alpha-adrenoceptor antagonist), timolol (100 nmol, a beta-adrenoceptor antagonist) or atropine (300 nmol, a muscarinic antagonist) into the hypothalamic supraoptic nucleus (SON). Intravenous injections of d(CH2)5-D-Tyr(Et)VAVP (50 microg/kg, a vasopressin-receptor antagonist) completely blocked the antidiuresis. In intra-SON microdialysis experiments, acetylcholine concentration in the perfusate of the capsaicin-injected rats was not different from that of the vehicle-injected rats. These findings suggested that capsaicin stimulated substance P release in the SON and caused the antidiuresis as a result of the increased release of vasopressin into the circulation from the neurohypophysis mediated through neurokinin-1 receptors in the SON. (+info)
Effects of exogenous [Arg8]-vasopressin on borderline-hypertensive Hiroshima rats.
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The interaction between [Arg8]-vasopressin and a vasopressin receptor antagonist, [d(CH2)5(1), O-Me-Tyr2, Arg8]-vasopressin, was examined in Hiroshima rats and normotensive control rats under pentobarbital anesthesia. [Arg8]-vasopressin dose-dependently increased the arterial pressure in both the Hiroshima and control rats, the pressor effect being greater in the Hiroshima rats. After the administration of a vasopressin antagonist (0.01 mg/kg), which by itself decreased arterial pressure only in the Hiroshima rats, the dose-response curve for [Arg8]-vasopressin was much more greatly shifted to the right in the control rats. These results indicate that with or without a vasopressin antagonist, the exogenous [Arg8]-vasopressin induced more powerful pressor actions in the Hiroshima rats compared to the control rats. (+info)
Cerebrospinal fluid concentrations of propofol during anaesthesia in humans.
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The concentration of propofol in and surrounding the human brain during propofol anaesthesia is unknown. We measured simultaneously the concentration of propofol in cerebrospinal fluid (CSF) from an indwelling intraventricular catheter and the concentration in arterial blood in five neurosurgical patients before, during induction (at 2.5 and 5 min) and during a maintenance propofol infusion (at 15 and 30 min). After induction of anaesthesia with propofol 2 mg kg-1, anaesthesia was maintained with an infusion of 8 mg kg-1 h-1 for 15 min and then reduced to 6 mg kg-1 h-1. The plasma concentration of propofol increased rapidly during induction and reached a plateau concentration of mean 2.24 (SD 0.66) micrograms ml-1 after 5 min. The concentration of propofol in CSF showed a slower increase during induction and remained almost constant at 35.5 (19.6) ng ml-1 at 15-30 min after induction. The CSF concentration of propofol that we measured was 1.6% of the plasma concentration and consistent with the high protein binding of the drug in plasma. (+info)
Cardiopulmonary effects of the alpha2-adrenoceptor agonists medetomidine and ST-91 in anesthetized sheep.
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To test the hypothesis that pulmonary alterations are more important than hemodynamic changes in alpha2-agonist-induced hypoxemia in ruminants, the cardiopulmonary effects of incremental doses of (4-[1-(2,3-dimethylphenyl)ethyl]-1H-imadazole) hydrochloride (medetomidine; 0.5, 1.0, 2.0, and 4 micrograms/kg) and 2-(2, 6-diethylphenylamino)-2-imidazol (ST-91; 1.5, 3.0, 6.0, and 12 micrograms/kg) were compared in five halothane-anesthetized, ventilated sheep using a placebo-controlled randomized crossover design. Pulmonary resistance (RL), dynamic compliance, and tidal volume changes in transpulmonary pressure (DeltaPpl) were determined by pneumotachography, whereas cardiac index (CI), mean pulmonary artery pressure (Ppa), and pulmonary artery wedge pressure (Ppaw) were determined using thermodilution and a Swan-Ganz catheter. The most important finding was the fall in partial pressure of oxygen in arterial blood (PaO2) after administration of medetomidine at a dose (0.5 micrograms/kg) 20 times less than the sedative dose. The PaO2 levels decreased to 214 mm Hg as compared with 510 mm Hg in the placebo-treated group. This decrease in PaO2 was associated with a decrease in dynamic compliance and an increase in RL, DeltaPpl, and the intrapulmonary shunt fraction without changes in heart rate, CI, mean arterial pressure, pulmonary vascular resistance, Ppa, or Ppaw. On the other hand, ST-91 only produced significant changes in PaO2 at the highest dose. After this dose of ST-91, the decrease in PaO2 was accompanied by a 50% decrease in CI and an increase in mean arterial pressure, Ppa, Ppaw, and the intrapulmonary shunt fraction without significant alterations of RL and DeltaPpl. The study suggests that the mechanism(s) by which medetomidine and ST-91 produce lower PaO2 are different and that drug-induced alterations in the pulmonary system are mainly responsible for the oxygen-lowering effect of medetomidine. (+info)
Pharmacokinetics of new calcium channel antagonist clevidipine in the rat, rabbit, and dog and pharmacokinetic/pharmacodynamic relationship in anesthetized dogs.
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Clevidipine is a new vascular selective calcium channel antagonist of the dihydropyridine type, structurally related to felodipine. Clinical trials have shown that the drug can be used to effectively control the blood pressure in connection with cardiac surgical procedures. The compound is tailored to be a short-acting drug and, due to incorporation of an ester linkage into the drug molecule, clevidipine is rapidly metabolized by ester hydrolysis. The pharmacokinetics of clevidipine and its primary metabolite, H 152/81, were studied in rats, rabbits, and dogs. In addition, the influence of the pharmacokinetics on the effect on mean arterial blood pressure was evaluated in anesthetized dogs. Compartmental nonlinear mixed effect regression analysis was used to calculate the population mean and individual pharmacokinetics of clevidipine, whereas nonlinear regression analysis of individual data was used to determine the pharmacokinetics of the primary metabolite. A linked Emax model was fitted to the individual pharmacodynamic/pharmacokinetic data in dogs. According to the results, clevidipine is a high-clearance drug with a relatively small volume of distribution, resulting in an extremely short half-life in all species studied. The median initial half-life of the individual value (Bayesian estimates) is 12, 20, and 22 s in the rabbit, rat, and dog, respectively. The primary metabolite is a high-clearance compound in the dog, whereas it is a low-clearance compound in the rat. A significant gender difference in the clearance of the metabolite was observed in the rat. The mean maximum reduction in arterial blood pressure is 38 +/- 12% (Emax) and is achieved at 85 +/- 46 nM (EC50). The half-life for reaching equilibrium between the central and the effect compartment (T1/2ke0) is 47 +/- 49 s. (+info)
Effects of Saiko-ka-ryukotsu-borei-to, a Japanese Kampo medicine, on tachycardia and central nervous system stimulation induced by theophylline in rats and mice.
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Effects of Saiko-ka-ryukotsu-borei-to (SRBT) on theophylline-induced tachycardia in anesthetized rats and theophylline-induced locomotion and convulsions in mice were examined. An intraduodenal administration of SRBT (1 g/kg) prevented theophylline (5 mg/kg, i.v.)-induced tachycardia in rats. SRBT also attenuated an increase in arterial blood pressure with a slow reduction in heart rate of rats treated with theophylline, with no influence on the plasma level of theophylline. However, SRBT did not change the beating rate of right atrium isolated from rats in the absence or presence of theophylline or isoproterenol. The locomotor activity of theophylline in mice was reduced by the treatment with SRBT. Furthermore, the latency of convulsions in mice induced by administration of theophylline at a higher dose (240 mg/kg, i.p.) was prolonged by treatment with SRBT (1 g/kg, p.o.) and seven out of fifteen mice were saved from death due to convulsions. These results suggest that theophylline-induced tachycardia and central nervous stimulation are suppressed by SRBT and that SRBT may reduce the undesirable actions of theophylline on the cardiovascular and central nervous systems. (+info)
Adrenergic induction of bimodal myocardial protection: signal transduction and cardiac gene reprogramming.
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This study tested the hypothesis that in vivo norepinephrine (NE) treatment induces bimodal cardiac functional protection against ischemia and examined the roles of alpha1-adrenoceptors, protein kinase C (PKC), and cardiac gene expression in cardiac protection. Rats were treated with NE (25 micrograms/kg iv). Cardiac functional resistance to ischemia-reperfusion (25/40 min) injury was examined 30 min and 1, 4, and 24 h after NE treatment with the Langendorff technique, and effects of alpha1-adrenoceptor antagonism and PKC inhibition on the protection were determined. Northern analysis was performed to examine cardiac expression of mRNAs encoding alpha-actin and myosin heavy chain (MHC) isoforms. Immunofluorescent staining was performed to localize PKC-betaI in the ventricular myocardium. NE treatment improved postischemic functional recovery at 30 min, 4 h, and 24 h but not at 1 h. Pretreatment with prazosin or chelerythrine abolished both the early adaptive response at 30 min and the delayed adaptive response at 24 h. NE treatment induced intranuclear translocation of PKC-betaI in cardiac myocytes at 10 min and increased skeletal alpha-actin and beta-MHC mRNAs in the myocardium at 4-24 h. These results demonstrate that in vivo NE treatment induces bimodal myocardial functional adaptation to ischemia in a rat model. alpha1-Adrenoceptors and PKC appear to be involved in signal transduction for inducing both the early and delayed adaptive responses. The delayed adaptive response is associated with the expression of cardiac genes encoding fetal contractile proteins, and PKC-betaI may transduce the signal for reprogramming of cardiac gene expression. (+info)
Oxygenation of the cat primary visual cortex.
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Tissue PO2 was measured in the primary visual cortex of anesthetized, artificially ventilated normovolemic cats to examine tissue oxygenation with respect to depth. The method utilized 1) a chamber designed to maintain cerebrospinal fluid pressure and prevent ambient PO2 from influencing the brain, 2) a microelectrode capable of recording electrical activity as well as local PO2, and 3) recordings primarily during electrode withdrawal from the cortex rather than during penetrations. Local peaks in the PO2 profiles were consistent with the presence of numerous vessels. Excluding the superficial 200 microm of the cortex, in which the ambient PO2 may have influenced tissue PO2, there was a slight decrease (4.9 Torr/mm cortex) in PO2 as a function of depth. After all depths and cats were weighted equally, the average PO2 in six cats was 12.8 Torr, with approximately one-half of the values being +info)