Effects of catecholamines and adrenergic-blocking agents on plasma and urinary cyclic nucleotides in man

Studies were performed in healthy volunteers to determine the effects of catecholamines and adrenergic-blocking agents on plasma and urinary levels of adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP).Plasma cyclic AMP rose in response to infusions of the beta-adrenergic agent, isoproterenol, or in response to infusions of either epinephrine or norepinephrine alone or in combination with the alpha-adrenergic-blocking agent, phentolamine. Although urinary cyclic AMP also rose, the percentage increase was less than that observed in the plasma. These treatments caused no increase in plasma cyclic GMP.Plasma cyclic GMP rose in response to infusions of alpha-adrenergic agents, viz., epinephrine or norepinephrine infused together with the beta-blocking agent, propranolol. These treatments caused no increase in plasma cyclic AMP.These observations are consistent with the current concept that the actions of beta-adrenergic agents are mediated by increases in cyclic AMP formation in target tissues. Such a mediating role has not been established for cyclic GMP, but the data suggest the possibility that cyclic GMP metabolism is responsive either to alpha-adrenergic stimulation or to parasympathetic stimulation which occurs as a reflexive consequence of the pressor effect of alpha-adrenergic agents.     

Comparative metabolism and pharmacokinetics of diisobutyl ketone and diisobutyl carbinol in male SD rats

Diisobutyl ketone (DIBK) and diisobutyl carbinol (DIBC) are important organic solvents widely used as industrial intermediates. It was hypothesized that DIBC and DIBK have common metabolic pathways and metabolites, and as such, toxicological data on DIBK could be used to characterize the hazards of DIBC. To confirm or refute this hypothesis a comparative metabolism and pharmacokinetics assessment of DIBK and DIBC was conducted. Dosing was via single oral gavage dosing in male SD rats, followed by blood collection, metabolite identification, major biomarker quantitation, and pharmacokinetics analysis. Overall, the major metabolites of both DIBC and DIBK in blood were their corresponding monohydroxylated metabolites (DIBC alcohol and DIBK alcohol) with the site of hydroxylation at the σ and σ-1 positions, respectively. Quantitative analysis of DIBC, DIBK, DIBC-alcohol, and DIBK-alcohol in blood samples collected from 5 min to 120 h after single dosing indicated the following: (1) DIBC and DIBK are both well absorbed following oral gavage with substantial evidence of enterohepatic recirculation of DIBK, DIBC, DIBK-alcohol, and DIBC-alcohol; (2) DIBK and DIBC are interconverted metabolically in rats; (3) DIBC and DIBK have similar bioavailability after oral administration; (4) higher systemic exposure was found for DIBK-alcohol than DIBC-alcohol, implying that DIBC-alcohol may be more easily conjugated and eliminated in bile. In summary, the metabolic similarities and the difference in systemic exposure to metabolites between these substances observed in the current study support the hypothesis that DIBC might have a lower potential toxicity than that of DIBK. The current study results support that toxicological data on DIBK could be used to characterize the hazards of DIBC     

A high velocity impact device for obtaining multiple,contiguous, myocardial biopsies

A method has been devised which allows multiple contiguous transmural biopsies to be obtained simultaneously from the left ventricular wall of the dog heart. The device is based upon the principle of high velocity impact. Cutting matrices can be constructed to retrieve any number of biopsies of any size over any defined area. Sampling and freezing can be achieved in less than 3 s. Preliminary studies have confirmed the adequacy of freezing (preservation of labile metabolites). Each biopsy sample can be further subfractionated and micoanalytical procedures are described which allow flow and multiple metabolites to be measured in each biopsy. The device may be used to study the metabolic and flow geometry of an area of regional ischemia during evolving myocardial infarction.     

Plasma and urine dopamine in man given sodium chloride in the diet.

1. Plasma and urine free dopamine were measured daily for 5 days in six normal subjects maintained on a low sodium diet. The subjects were then given dietary supplements of sodium chloride for 5 days and the measurements repeated. 2. Throughout the experiment the 24 h free dopamine excretion rates for all the subjects were higher than could be accounted for by renal clearance. Dopamine excretion increased significantly in response to the added sodium chloride whereas plasma dopamine remained unchanged. The rise in dopamine excretion preceded that of sodium excretion. 3. It is concluded that free dopamine is formed within the kidney in response to increased dietary sodium and may have a role in the control of sodium excretion.     

Syntactic impairments can emerge later: Progressive agrammatic agraphia and syntactic comprehension impairment

Background & Aims: Recent studies suggest that agrammatism is not a major feature of progressive nonfluent aphasia, at least not in the earlier years post-onset. We investigated the emergence of syntactic impairments over a 3-year period in CS, a 63-year-old man 8 years post-onset of progressive speech difficulties. CS has a range of progressive cognitive impairments, including progressive nonfluent aphasia, and limb and other apraxias (with a progressive non-aphasic and mostly non-dysarthric speech deterioration), but relatively intact intelligence, perception, orientation, long-term memory, semantics, and phonology. Writing impairments did not emerge until some 8 years after naming and speech impairments were first noticed, and after CS became mute. Methods & Procedures: We undertook detailed longitudinal examination of word and sentence writing and syntactic comprehension across a range of tasks and examined the impact of short-term memory. We were concerned to examine the data for evidence of agrammatic features, particularly in noun and verb use, and use of formulaic and simplified syntactic structures as the condition progressed. Outcomes & Results: Analysis showed a progressive emergence of deficits on tests of written syntax, syntactic comprehension, and auditory-verbal short-term memory. There was a progressive reduction in verb and noun use, but this was related to the kind of stimulus used. Features of agrammatism were evident in writing with a progressive dependence on formulaic and simplified syntax. Conclusions: It may be that agrammatism in PNFA is a feature that develops late in the progression, showing up only in writing because it is masked in speech by motor speech impairment. Increasing reliance on formulaic and simplified structures with progression suggests compensatory adaptation of CS's system. Impairments appeared to emerge in parallel with deterioration of syntactic comprehension and phonological short-term memory.