Abstract The pharmacokinetics of chlorbutol were studied after oral administration in 4 healthy subjects on two occasions. Following the rapid attainment of peak concentrations, plasma concentrations fell by approximately 50 per cent in 24 h. After the first dose of chlorbutol, the terminal elimination half‐life was 10.3 ± 1.3 days (mean ± S.E.M), the volume of distribution was 233 ± 141 and the plasma clearance was 11.6 ± l.0 ml min −1 . The binding to plasma proteins was 57 ± 3 per cent. In 3 of the 4 subjects, there was a small but significant decrease in the terminal half‐life of chlorbutol after the second dose. The mean urinary recovery over 17 days in two of the subjects accounted for only 9.6 per cent of the dose, 7.4 per cent of the total as the glucuronide and sulphate conjugates and 2.2 per cent as unchanged chlorbutol. A significant factor in the elimination of chlorbutol may be its instability under physiological conditions. Its half‐life in vitro is 37 days at pH7.4. The long terminal half‐life of chlorbutol makes it unsuitable as a sedative drug because of the considerable accumulation which will occur when the drug is taken in multiple doses.
Water ingestion induces a sympathetically mediated increase in blood pressure in dysautonomic patients and the elderly, but not consistently in young healthy subjects. The aim of study was to determine the extent of the pressor response and changes of sympathetic activity biomarker salivary alpha-amylase (sAA) after water ingestion in young healthy subjects. Compared with ingestion of 50 mL of water, the blood pressure, total peripheral resistance and sAA significantly increased and the plasma osmolality decreased 25 min after drinking 500 mL of water. The results confirm the osmopressor response in young subjects and suggest that sAA may be used as a non-invasive marker of sympathetic activity in future studies.
Cooling causes hemodynamic instability as changes in blood pressure variability and heart rate variability (BPV, HRV). We observed that increased sympathomyogenic responses (SMR) as changes in very‐low frequency of BPV (VLF BPV ) and low frequency of BPV (LF BPV ) which were dependent on the evoked pressor to cooling; the present study was designed to examine whether the α2‐adrenoceptor (AR) is involved in such cooling effects of rats. Hemodynamic changes were telemetry monitored throughout the experiments. Vehicle or yohimbine (YOH, 2.5 or 5.0 mg/kg) was administered with a latency (5 min, 30 min) before a cooling impact (CI, 4±2 o C). Plasma nitric oxide (NO) was measured in presence or absence of the added hexamethonium (HEX). Spectral powers of high frequency (HF, 0.6‐3.0 Hz), low frequency (LF, 0.2‐0.6 Hz), and very‐low frequency (VLF, 0.02‐0.2 Hz) in BPV bands were compared with those in HRV bands. Results generally showed 1) cooling‐evoked pressor was significantly attenuated after YOH treatment, 2) Compared with vehicle prior to the CI start, YOH produced tachycardia and increased most frequency powers but reduced the normalized HF HRV (nHF HRV ), 3) In contrast, compared with control vehicle throughout the CI trial, YOH produced less pressor, more tachycardia, and increased nHF HRV but reduced most the other frequency powers. Besides, the dicrotic notch was undetectable and NO was increased in CI trial after YOH treatment, in which the increase in NO was diminished after HEX addition. This study confirmed a functional role of α2‐AR which is imperative for the immediate SMR to the cooling‐induced hemodynamic instability.
1. The aim of the present study was to examine the role of dopaminergic and glutamatergic receptors on different stages of the amphetamine (AMPH) sensitized effect in schedule-induced polydipsia (SIP) in rats. 2. Three experiments were designed to evaluate the roles of DAD2 receptor antagonist haloperidol (HAL) and glutamatergic N-methyl d-aspartate receptor antagonist MK-801 on both the induction and the expression stage of AMPH sensitization in SIP rats. First, the induction of AMPH sensitization in the SIP model was tested again to confirm previous findings. Second, HAL or MK-801 was co-administered with AMPH on five consecutive days and their effect on induction was examined 14 days after withdrawal. Finally, HAL or MK-801 was co-administered with AMPH on the final day of testing in SIP rats in which AMPH sensitization had been established previously. 3. The present results showed that HAL and MK-801 affected the effect of AMPH differently during the process of sensitization. Whereas HAL influenced the sensitization during both the induction and the expression phases, MK-801 affected only the induction phase; thus, once the sensitization had been established, MK-801 had no further influence. 4. These results suggest that the SIP model could be considered useful for the study of sensitization. In addition, the induction and expression of AMPH sensitization is influenced differently by the dopaminergic and glutamatergic systems.
Carbon monoxide has been shown to act as a neurotransmitter and neuronal messenger in the brain. Heme oxygenase catalyzes the conversion of heme to carbon monoxide and biliverdin. We have recently reported that carbon monoxide was involved in central cardiovascular regulation. Carbon monoxide modulated the baroreflex and may affect glutamatergic neurotransmission. In addition, metabotropic glutamate receptors may be coupled to the activation of heme oxygenase in the nucleus tractus solitarii of rats. The present study was designed to investigate the possible interactions of carbon monoxide and metabotropic glutamate receptor groups in the nucleus tractus solitarii. Unilateral microinjection of several agonists for metabotropic glutamate receptor groups such as (R,S)-3,5-dihydroxyphenylglycine (DHPG) (group I) (0.03 nmol), 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) (group II) (0.3 nmol), and l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) (group III) (0.3 nmol) produced a significant decrease in blood pressure and heart rate. Among the metabotropic glutamate receptor agonists, prior administration of zinc protoporphyrin IX, an inhibitor of heme oxygenase activity, significantly attenuated the cardiovascular effects of APDC and l-AP4, and failed to attenuate the cardiovascular responses of DHPG. These results indicated interactions between carbon monoxide and group II and III metabotropic glutamate receptors in central cardiovascular regulation.
Rapid cooling stress (CS) elicits hemodynamic perturbations (CEHP). We previously reported that CEHP is highly relevant to the sympathetic activation and nitric oxide (NO) production. This study identifies the role of NO in CEHP. Conscious rats were pretreated with the NO‐synthase inhibitor (L‐NAME) alone or superimposition of sympatholytic interventions using hexamethonium (HEX) or guanethidine (GUA), and then subjected to a CS trial. Cardiovascular indices were monitored via an implanted telemetric device throughout experimental protocol. The analyses included measurements of blood pressure (BP); heart rate (HR); the variability of BP and HR (BPV, HRV); spectral powers and coherence linkage at very‐low, low, and high frequency regions (VLF: 0.02–0.2 Hz, LF: 0.2–0.6 Hz, and HF: 0.6–3.0 Hz); and dicrotic notch (Dn). When compared with control vehicle under CS, the L‐NAME alone (a) increased BP, Dn, VLF BPV , VLF HRV , LF HRV , and HF HRV but decreased HR, HF BPV , and LF/HF ratio; (b) converted negative correlation into positive correlation for LF pair (LF HRV /LF BPV ) and VLF pair (VLF HRV /VLF BPV ); and (c) enhanced the coherence linkage between BPV and HRV at the LF region but weakened them at the HF region. We also noted divergent patterns of spectra responsiveness to HEX or GUA superimposed on L‐NAME. The effects of HEX+L‐NAME versus GUA+L‐NAME, particularly on LF and VLF between BPV and HRV, indicated an essential role for a functional adrenal medulla to release epinephrine under CS. Our results indicate that endogenous NO play an inhibitory role on the sympathovascular activation and subsequently the myogenic vascular oscillations in CEHP. Support or Funding Information Grant in aid: the Ministry of Science and Technology (MOST 102 &103‐2320‐B‐350‐001) and the National Defense Medical Center (MAB101‐40; MAB‐102‐81), Taiwan, R.O.C.
alpha-Methyldopa acts through a metabolite in the central nervous system. Of the three metabolites most prominently considered as potential mediators of alpha-methyldopa hypotension--alpha-methyldopamine, alpha-methylnorepinephrine (MNE), and alpha-methylepinephrine (ME)--ME is the most potent depressor agent following intravenous infusion into rats, following injection into the lateral ventricle, and following injection into the solitary tract nucleus (NTS). The depressor effect of ME in the NTS is attenuated as effectively by timolol as by yohimbine, while the combination of both timolol and yohimbine completely abolishes the pharmacological activity of ME in the NTS. ME is approximately eightfold more potent than MNE in the NTS and also has a greater susceptibility to timolol attenuation.
Studies in patients with an impaired efferent baroreflex led us to discover that ingesting water induces a robust increase in blood pressure and vascular resistance. This response was also present in healthy subjects with intact baroreflexes, described as osmopressor response. This study was to discover the physiology of the osmopressor response by determining functional activation of the aquaporin-1 water channel receptor on red blood cell membranes in young healthy subjects. In a randomized, controlled, crossover fashion, 22 young healthy subjects (age, 19-27 years) ingested either 500 or 50 mL of water. Heart rate, blood pressure, cardiac index, and total peripheral vascular resistance were measured using a Finometer hemodynamic monitor. Blood sampling was performed at 5 minutes before and at 25 and 50 minutes after either the water ingestion or control session. Immunoblotting for aquaporin-1 tyrosine phosphorylation was performed before and after subjects ingested either 500 or 50 mL of water. At 25 minutes after the ingestion of 500 mL of water, total peripheral resistance increased significantly, and plasma osmolality decreased. Functional expression of aquaporin-1 tyrosine phosphorylation on red blood cell membranes increased significantly at 25 and 50 minutes after subjects ingested 500 mL of water compared with that before water ingestion. This study concludes that water ingestion produces upregulation of aquaporin-1 tyrosine phosphorylation on red blood cell, which presents as a novel biological marker that occurs simultaneously with the osmopressor response.
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