No abstract

The endothelium mitigates adrenergic reactivity in control arteries, which is lacking in diabetic arteries and results in enhanced reactivity to norepinephrine; increased sensitivity of diabetic arteries to acetylcholine, however, indicates a possible alteration at the receptor level.

1. Previous studies have suggested that elevated ketone levels are associated with increased survival time in rodents exposed to hypoxia. In this study the association between whole blood BHB (beta-hydroxybutyrate) and hypoxic survival time was investigated in hibernating and non-hibernating ground squirrels and in rats. 2. Non-hibernating ground squirrels and rats were exposed to hypoxia (4.5% O2). One hundred per cent of ground squirrels survived 1 hr of hypoxia vs 20% of rats. 3. Ketone levels were significantly higher in ground squirrels than rats during hypoxia, and rats surviving the longest had the highest ketone levels. 4. When hibernation was induced in ground squirrels there was a significant increase in beta-hydroxy-butyrate from 0.45 to 1.6 mM (P = 0.0005). 5. Ground squirrel heart mitochondrial respiratory control ratios and ATP synthesis rates indicated no preferential ketone utilization which might suggest a possible extramitochondrial role of BHB during hypoxia. 6. We conclude that elevated blood BHB levels are associated with increased hypoxic survival and they may have evolved in response to life-threatening hypoxia as experienced during hibernation.

Experiments were performed to assess the effects of acute moderate cooling on postjunctional alpha 1- and alpha 2-adrenoceptors in isolated rings of tail arteries from male Sprague-Dawley rats. Rings were contracted with norepinephrine (NE; 10(-9) to 10(-4) M) alone or in the presence of prazosin (Pz; 3 x 10(-7) M) or rauwolscine (Rw; 10(-7) M). NE concentration-response curves were inhibited by alpha 1-blockade (Pz) but not significantly affected by alpha 2-blockade (Rw). In all rings, cooling caused an increase in the slope of the dose-response curve and a significant increase in the concentration of agonist required to evoke contractions, as assessed by that concentration of NE required to evoke a contraction equal to 10% of maximal (EC10). Cooling inhibited contractions evoked by the selective alpha 1-adrenergic agonist phenylephrine (PE) as assessed by EC10 but had no significant effect on the weak contractions elicited by the selective alpha 2-adrenergic agonist B-HT 920. Prior elevation of tone with either KCl or prostaglandin F2 alpha enhanced alpha 2-mediated contractions. These contractions were augmented by cooling, whereas those caused by either KCl or prostaglandin F2 alpha alone were not significantly affected. Our results suggest that alpha 2-adrenoceptor-mediated responses in this blood vessel are dependent on the level of preexisting tone and are potentiated by cooling.

IntroductionPrevious data in rat conductance vessels indicated that cellular mevalonate contributes to vascular tone (7,8). In a recent publication (9), we provided evidence that mevalonate availability was a novel regulatory mechanism contributing to the control of vascular tone and systemic blood pressure. In that study, in vitro exposure of rat conductance vessels (aorta) to lovastatin increased the response to vasoconstrictors and decreased endothelium-dependent and independent relaxations. These effects were independent of tissue changes in cholesterol content and reversed by co-incubation with mevalonate, suggesting that mevalonate derivatives other than cholesterol itself were vasoactive. Experiments conducted in vivo further supported this hypothesis, with lovastatin and mevalonate respectively increasing and decreasing systolic blood pressure in normotensive as well as hypertensive rats. Those observations were recently confirmed by Yamori et al. in a preliminary communication (10), using pravastatin, another HMG-CoA reductase inhibitor.Resistance arteries, including mesenteric artery resistance vessel (MARV), are critical determinants of systemic blood pressure (11,12). Therefore, the combined observation of impaired MARV reactivity and increased BP in animals receiving lovastatin (9) led us to postulate that lovastatin inhibition of the mevalonate pathway of resistance vessels increased vascular resistance and elevated systemic blood pressure. That hypothesis required experimental evidence of a direct effect of the drug on resistance vessels. Therefore, our first objectives in the present study was to describe the direct, in vitro effect of lovastatin and mevalonate on rat resistance vessels.In our earlier study (9), lovastatin appeared to act on several pathways including NE-induced contraction and acetylcholine and sodium nitroprusside (SNP)-induced relaxation. It is known that stimulation of membrane receptors, such as the adrenergic and muscarinic receptors, triggers the elevation of