Mitochondrial potassium channel opener diazoxide preserves neuronal-vascular function after cerebral ischemia in newborn pigs

Background and Purpose-N-Methyl-D-aspartate (NMDA) elicits neuronally mediated cerebral arteriolar vasodilation that is reduced by ischemia/reperfusion (I/R). This sequence has been preserved by pretreatment with the ATP-sensitive potassium (K-ATP) channel opener aprikalim, although the mechanism was unclear. In the heart, mitochondrial K-ATP channels (mitoK(ATP)) are involved in the ischemic preconditioning-like effect of K+ channel openers. We determined whether the selective mitoK(ATP) channel opener diazoxide preserves the vascular dilation to NMDA after I/R. Methods-Pial arteriolar diameters were determined with the use of closed cranial window/intravital microscopy in anesthetized piglets. Vascular responses to NMDA were assessed before and 1 hour after 10 minutes of global cerebral ischemia induced by raising intracranial pressure. Subgroups received 1 of the following pretreatments before I/R: vehicle; 1 to 10 mu mol/L diazoxide; and coapplication of 100 mu mol/L 5-hydroxydecanoic acid (5-HD), a K-ATP antagonist with diazoxide. Results-NMDA-induced dose-dependent pial arteriolar dilation was not affected by diazoxide treatment only but was severely attenuated by I/R, In contrast, diazoxide dose-dependently preserved the NMDA vascular response after I/R; at 10 mu mol/L, diazoxide arteriolar responses were unaltered by I/R. The effect of diazoxide was antagonized by coapplication of 5-HD with diazoxide. Percent preservation of 100 mu mol/L NMDA-induced vasodilation after I/R was 53 +/- 19% (mean +/- SEM, n = 8) in vehicle-treated controls versus 55 +/- 10%, 85 +/- 5%, and 99 +/- 15% in animals pretreated with 1, 5, and 10 mu mol/L diazoxide (n = 8, n = 8, and n = 12, respectively) and 60 +/- 15% in the group treated with 5-HD+diazoxide (n = 5). Conclusions-The mitoK(ATP) channel opener diazoxide in vivo preserves neuronal function after I/R, shown by pial arteriolar responses to NMDA, in a dose-dependent manner. Thus, activation of mitoK(ATP) channels may play a role in mediating the protective effect of other K+ channel openers

Cerebral Microcirculatory Responses of Insulin-Resistant Rats are Preserved to Physiological and Pharmacological Stimuli

AbstractWe study a programming language with a built-in ground type for real numbers. In order for the language to be sufficiently expressive but still sequential, we consider a construction proposed by Boehm and Cartwright. The non-deterministic nature of the construction suggests the use of powerdomains in order to obtain a denotational semantics for the language. We show that the construction cannot be modelled by the Plotkin or Smyth powerdomains, but that the Hoare powerdomain gives a computationally adequate semantics. As is well known, Hoare semantics can be used in order to establish partial correctness only. Since computations on the reals are infinite, one cannot decompose total correctness into the conjunction of partial correctness and termination as is traditionally done. We instead introduce a suitable operational notion of strong convergence and show that total correctness can be proved by establishing partial correctness (using denotational methods) and strong convergence (using operational methods). We illustrate the technique with a representative example

Redirecting research efforts on the diversification-performance linkage: The search for synergy

We review the literature on the diversification-performance (D-P) relationship to a) propose that the time is ripe for a renewed attack on understanding the relationship between diversification and firm performance, and b) outline a new approach to attacking the question. Our paper makes four main contributions. First, through a review of the literature we establish the inherent complexities in the D-P relationship and the methodological challenges confronted by the literature in reaching its current conclusion of a non-linear relationship between diversification and performance. Second, we argue that to better guide managers the literature needs to develop along a complementary path – whereas past research has often focused on answering the big question of does diversification affect firm performance, this second path would focus more on identifying the precise micro-mechanisms through which diversification adds or subtracts value. Third, we outline a new approach to the investigation of this topic, based on (a) identifying the precise underlying mechanisms through which diversification affects performance; (b) identifying performance outcomes that are “proximate” to the mechanism that the researcher is studying, and (c) identifying an appropriate research design that can enable a causal claim. Finally, we outline a set of directions for future research