American journal of physiology. Regulatory, integrative and comparative physiology
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Am. J. Physiol. Regul. Integr. Comp. Physiol. · Jun 2010
ReviewThe Walter B. Cannon Memorial Award Lecture, 2009. Physiology in perspective: The wisdom of the body. In search of autonomic balance: the good, the bad, and the ugly.
Walter B. Cannon's research on the sympathetic nervous system and neurochemical transmission was pioneering. Wisdom has endowed our body with a powerful autonomic neural regulation of the circulation that provides optimal perfusion of every organ in accordance to its metabolic needs. ⋯ This short review, presented as The Walter B. Cannon Memorial Award Lecture for 2009, addresses the mechanisms that disrupt sensory signaling and result in a chronic maladjustment of the autonomic neural output that in many cardiovascular diseases results in excessive increases in the risks of dying. The hopes for any reduction of those risks resides in an understanding of the molecular determinants of neuronal signaling.
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Am. J. Physiol. Regul. Integr. Comp. Physiol. · May 2010
Effects of bladder outlet obstruction on properties of Ca2+-activated K+ channels in rat bladder.
In this study, we investigated the effects of bladder outlet obstruction (BOO) on the expression and function of large conductance (BK) and small conductance (SK) Ca(2+)-activated K(+) channels in detrusor smooth muscle. The bladder from adult female Sprague-Dawley rats with 6-wk BOO were used. The mRNA expression of the BK channel alpha-subunit, beta1-, beta2-, and beta4-subunits and SK1, SK2, and SK3 channels were investigated using real-time RT-PCR. ⋯ These blockers also increased the contractility and affinity of these strips for carbachol during cumulative applications. The facilitatory effects elicited by these K(+) channel blockers were larger in the strips from obstructed bladders compared with control bladders. These results suggest that long-term exposure to BOO for 6 wk enhances the function of both BK and SK types of Ca(2+)-activated K(+) channels in the detrusor smooth muscle to induce an inhibition of bladder contractility, which might be a compensatory mechanism to reduce BOO-induced bladder overactivity.
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Am. J. Physiol. Regul. Integr. Comp. Physiol. · Apr 2010
Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue.
Inhibitors of cyclooxygenase (COX)-2 prevent suppression of aquaporin-2 and reduce polyuria in the acute phase after release of bilateral ureteral obstruction (BUO). We hypothesized that BUO leads to COX-2-mediated local accumulation of prostanoids in inner medulla (IM) tissue. To test this, rats were subjected to BUO and treated with selective COX-1 or COX-2 inhibitors. ⋯ In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PGF(1alpha) and TxB(2) concentration in the kidney IM, and COX-2 is the predominant isoform that is responsible for accumulation of PGE(2) and PGF(2alpha) with minor, but significant, contributions from COX-1. PGD(2) synthesis is mediated exclusively by COX-1. In BUO, therapeutic interventions aimed at the COX-prostanoid pathway should target primarily COX-2.
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Am. J. Physiol. Regul. Integr. Comp. Physiol. · Jan 2010
Dorsomedial hypothalamus mediates autonomic, neuroendocrine, and locomotor responses evoked from the medial preoptic area.
Previous studies suggest that sympathetic responses evoked from the preoptic area in anesthetized rats require activation of neurons in the dorsomedial hypothalamus. Disinhibition of neurons in the dorsomedial hypothalamus in conscious rats produces physiological and behavioral changes resembling those evoked by microinjection of muscimol, a GABA(A) receptor agonist and neuronal inhibitor, into the medial preoptic area. We tested the hypothesis that all of these effects evoked from the medial preoptic area are mediated through neurons in the dorsomedial hypothalamus by assessing the effect of bilateral microinjection of muscimol into the DMH on these changes. ⋯ Prior bilateral microinjection of muscimol into the dorsomedial hypothalamus produced a modest depression of baseline heart rate and body temperature but completely abolished all changes evoked from the medial preoptic area. Microinjection of muscimol just anterior to the dorsomedial hypothalamus had no effect on autonomic and neuroendocrine changes evoked from the medial preoptic area. Thus, activity of neurons in the dorsomedial hypothalamus mediates a diverse array of physiological and behavioral responses elicited from the medial preoptic area, suggesting that the latter region represents an important source of inhibitory tone to key neurons in the dorsomedial hypothalamus.
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Am. J. Physiol. Regul. Integr. Comp. Physiol. · Jan 2010
Calcineurin activates interleukin-6 transcription in mouse skeletal muscle in vivo and in C2C12 myotubes in vitro.
Expression of the cytokine interleukin-6 (IL-6) by skeletal muscle is hugely increased in response to a single bout of endurance exercise, and this appears to be mediated by increases in intracellular calcium. We examined the effects of endurance exercise on IL-6 mRNA levels and promoter activity in skeletal muscle in vivo, and the role of the calcium-activated calcineurin signaling pathway on muscle IL-6 expression in vivo and in vitro. IL-6 mRNA levels in the mouse tibialis anterior (TA) were increased 2-10-fold by a single bout of treadmill exercise or by 3 days of voluntary wheel running. ⋯ Mutation of the MEF-2 DNA binding sites attenuated, while mutation of the NFAT DNA binding sites potentiated basal and calcineurin-activated IL-6 promoter activity. Finally, CREB and C/EBP were necessary for basal IL-6 promoter activity and sufficient to increase IL-6 promoter activity but had minimal roles in calcineurin-activated IL-6 promoter activity. Together, these results suggest that IL-6 transcription in skeletal muscle cells can be activated by a calcineurin-MEF-2 axis which is antagonized by NFAT.