Effects of sevoflurane and isoflurane on cardiac and coronary dynamics in chronically instrumented dogs

To assess the hemodynamic properties of the new inhalational anesthetic sevoflurane, 22 dogs were chronically instrumented for measurement of heart rate, aortic, left ventricular and left atrial pressures, cardiac output, and coronary blood flow. Dogs were randomly assigned to two groups, receiving either 1.2 and 2 MAC of sevoflurane (n = 11) or isoflurane (n = 11). At 1.2 and 2 MAC, sevoflurane produced an increase in heart rate (+60 +/- 12% and +54 +/- 9%, respectively), dose-dependent aortic hypotension (-22 +/- 4% and -38 +/- 4%, respectively), systemic vasodilation (-22 +/- 5% and -19 +/- 5%, respectively), dose-dependent decrease in stroke volume (-31 +/- 6% and -48 +/- 4%, respectively), and left ventricular dP/dt (-40 +/- 4% and -61 +/- 10%, respectively). Cardiac output decreased only at 2 MAC (-17 +/- 6%). Finally, coronary blood flow increased at 1.2 MAC of sevoflurane (+29 +/- 8%). Except for heart rate, sevoflurane and isoflurane produced similar effects. At 1.2 MAC, sevoflurane produced a greater increase in heart rate than isoflurane (+60 +/- 12% vs. +33 +/- 9%). The authors conclude that, except for heart rate, the effects of sevoflurane on cardiac function and coronary blood flow are almost identical to those induced by isoflurane in the chronically instrumented dog.     

Cardiovascular effects of acute changes in extracellular ionized calcium concentration induced by citrate and CaCl2 infusions in chronically instrumented dogs, conscious and during enflurane, halothane, and isoflurane anesthesia

To study the cardiovascular effects of low blood ionized calcium ion concentrations [Ca2+] induced by citrate infusion followed by high [Ca2+], induced by CaCl2 infusion awake and during enflurane (2.5% ET), halothane (1.2% ET), and isoflurane (1.6% ET) anesthesia, dogs were chronically instrumented to measure heart rate, aortic, left atrial, and left ventricular (LV) blood pressures, and cardiac output. In conscious dogs low [Ca2+] (decreased 0.35 mM); increased heart rate (HR) and mean aortic pressure (MAP) and decreased stroke volume (SV) and LV dP/dtmax. Low [Ca2+] increased HR during all three anesthetics and decreased LV dP/dtmax except during isoflurane anesthesia. Low [Ca2+] produced more hemodynamic depression during enflurane anesthesia than during anesthesia with halothane or isoflurane increasing left atrial pressure and decreasing MAP and SV. The differences seen were partially related to decreased systemic vascular resistance during halothane and isoflurane anesthesia. In conscious dogs following high [Ca2+] (increased 0.37 mM); only MAP and LV dP/dtmax increased. LVdP/dtmax was also increased by high [Ca2+] during all three anesthetics without a change in MAP. Cardiac output increased during halothane and isoflurane anesthesia but was unchanged during enflurane. It would appear that the hemodynamic sensitivity for the effects of changing [Ca2+] was enflurane greater than halothane greater than isoflurane greater than awake. The results suggest that the effects of changes in [Ca2+] induced by citrate and CaCl2 infusion are modified by the three volatile anesthetics.     

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. V. Role of pharmacokinetics and the autonomic nervous system in the interactions between verapamil and inhalational anesthetics

To assess the role of both pharmacokinetics and the autonomic nervous system in the interaction between inhalational anesthetics and verapamil, dogs were chronically instrumented to measure heart rate, PR interval, dP/dt, cardiac output, and aortic blood pressure. In a first group of seven dogs, studied awake and during halothane (1.2%), enflurane (2.5%), and isoflurane anesthesia (1.6%), verapamil was infused for 30 min in doses calculated to obtain similar plasma concentrations (83 +/- 10, 82 +/- 6, 81 +/- 10, and 77 +/- 9 ng.ml-1, respectively). For the latter purpose, the infusion dose was 3 and 2 micrograms.kg-1.min-1 awake and during anesthesia, respectively, preceded by a loading dose of 200, 150, and 100 micrograms.kg-1, awake, during isoflurane, and halothane and enflurane, respectively. In awake dogs, verapamil induced an increase in heart rate (24 +/- 5 bpm) and PR interval (35 +/- 9 msec) and a decrease in mean arterial pressure (-5 +/- 2 mmHg) and dP/dt (-494 +/- 116 mmHg/s). Although plasma concentrations were similar in awake and in anesthetized dogs, the only statistically significant changes induced by verapamil were an increase in heart rate and a decrease in dP/dt during halothane and enflurane, while left atrial pressure increased only with enflurane. In a second group of six dogs, verapamil pharmacokinetics were determined in the presence and absence of a ganglionic blocking drug (chlorisondamine, 2 mg.kg-1 iv). Blockade of ganglionic transmission resulted in a decrease in both initial volume of distribution and total clearance of verapamil--changes similar to those previously reported with inhalational anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Heteroligomerization of an Aquaporin-2 mutant with wild-type Aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus

Autosomal nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin, is caused by mutations in the Aquaporin-2 (AQP2) gene. Analysis of a new family with dominant NDI revealed a single nucleotide deletion (727deltaG) in one AQP2 allele, which encoded an AQP2 mutant with an altered and extended C-terminal tail. When expressed in oocytes, the tetrameric AQP2-727deltaG was retained within the cell. When co-expressed, AQP2-727deltaG, but not a mutant in recessive NDI (AQP2-R187C), formed hetero-oligomers with wild-type (wt) AQP2 and reduced the water permeability of these oocytes, because of a reduced plasma membrane expression of wt-AQP2. Expressed in renal epithelial cells, AQP2-727deltaG predominantly localized to the basolateral membrane and late endosomes/lysosomes, whereas wt-AQP2 was expressed in the apical membrane. Upon co-expressing in these cells, wt-AQP2 and AQP2-727deltaG mainly co-localized to late endosomes/lysosomes. In conclusion, hetero-oligomerization of AQP2-727deltaG with wt-AQP2 and consequent mistargeting of this complex to late endosomes/lysosomes results in absence of AQP2 in the apical membrane, which can explain dominant NDI in this family. Together with other mutants in dominant NDI, our data reveal that a misrouting, instead of a lack of function, is a general mechanism for the 'loss of function' phenotype in dominant NDI and visualizes for the first time a mislocalization of a wild-type protein to late endosomes/lysosomes in polarized cells after oligomerization with a mutant protein.     

Vascular system: role of nitric oxide in cardiovascular diseases

In contrast with the short research history of the enzymatic synthesis of nitric oxide (NO), the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin) is the first compound of this category. On October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning NO as a signaling molecule in the cardiovascular system. NO-mediated signaling is a recognized component in various physiologic processes (eg, smooth muscle relaxation, inhibition of platelet and leukocyte aggregation, attenuation of vascular smooth muscle cell proliferation, neurotransmission, and immune defense), to name only a few. NO has also been implicated in the pathology of many inflammatory diseases, including arthritis, myocarditis, colitis, and nephritis and a large number of pathologic conditions such as amyotrophic lateral sclerosis, cancer, diabetes, and neurodegenerative diseases. Some of these processes (eg, smooth muscle relaxation, platelet aggregation, and neurotransmission) require only a brief production of NO at low nanomolar concentrations and are dependent on the recruitment of cyclic guanosine monophosphate (cGMP)-dependent signaling. Other processes are associated with direct interaction of NO or reactive nitrogen species derived from it with target proteins and requires a more sustained production of NO at higher concentrations but do not involve the cGMP pathway.     

Structure and stereochemistry of the active metabolite of clopidogrel.

Clopidogrel (SR25990C, PLAVIX) is a potent antiplatelet drug, which has been recently launched and is indicated for the prevention of vascular thrombotic events in patients at risk. Clopidogrel is inactive in vitro, and a hepatic biotransformation is necessary to express the full antiaggregating activity of the drug. Moreover, 2-oxo-clopidogrel has been previously suggested to be the essential key intermediate metabolite from which the active metabolite is formed. In the present paper, we give the evidence of the occurrence of an in vitro active metabolite after incubation of 2-oxo-clopidogrel with human liver microsomes. This metabolite was purified by liquid chromatography, and its structure was studied by a combination of mass spectometry (MS) and NMR experiments. MS results suggested that the active metabolite belongs to a family of eight stereoisomers with the following primary chemical structure: 2-[1-[1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-4-sulfanyl-3-piperidinylidene]acetic acid. Chiral supercritical fluid chromatography resolved these isomers. However, only one of the eight metabolites retained the biological activity, thus underlining the critical importance of associated absolute configuration. Because of its highly labile character, probably due to a very reactive thiol function, structural elucidation of the active metabolite was performed on the stabilized acrylonitrile derivative. Conjunction of all our results suggested that the active metabolite is of S configuration at C 7 and Z configuration at C 3-C 16 double bound.