Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110␣) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110␣) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult (ϳ4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice (ϳ15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF , suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110␣) and AF. (Am J Pathol

We have examined the role of the renal sympathetic nerves in the renal blood flow (RBF) response to hemorrhage in seven conscious rabbits. Hemorrhage was produced by blood withdrawal at 1.35 ml ⋅ min−1 ⋅ kg−1for 20 min while RBF and renal sympathetic nerve activity (RSNA) were simultaneously measured. Hemorrhage was associated with a gradual increase in RSNA and decrease in RBF from the 4th min. In seven denervated animals, the resting RBF before hemorrhage was significantly greater (48 ± 1 vs. 31 ± 1 ml/min intact), and the decrease in RBF did not occur until arterial pressure also began to fall (8th min); however, the overall percentage change in RBF by 20 min of blood withdrawal was similar. Spectral analysis was used to identify the nature of the oscillations in each variable. Before hemorrhage, a rhythm at ∼0.3 Hz was observed in RSNA, although not in RBF, whose spectrogram was composed mostly of lower-frequency (<0.25 Hz) components. The denervated group of rabbits had similar frequency spectrums for RBF before hemorrhage. RSNA played a role in dampening the effect of oscillations in arterial pressure on RBF as the transfer gain between mean arterial pressure (MAP) and RBF for frequencies >0.25 Hz was significantly less in intact than denervated rabbits (0.83 ± 0.12 vs. 1.19 ± 0.10 ml ⋅ min−1 ⋅ mmHg−1). Furthermore, the coherence between MAP and RBF was also significantly higher in denervated rabbits, suggesting tighter coupling between the two variables in the absence of RSNA. Before the onset of significant decreases in arterial pressure (up to 10 min), there was an increase in the strength of oscillations centered around 0.3 Hz in RSNA. These were accompanied by increases in the spectral power of RBF at the same frequency. As arterial pressure fell in both groups of animals, the dominant rhythm to emerge in RBF was centered between 0.15 and 0.20 Hz and was present in intact and denervated rabbits. It is speculated that this is myogenic in origin. We conclude that RSNA can induce oscillations in RBF at 0.3 Hz, plays a significant role in altering the effect of oscillations in arterial pressure on RBF, and mediates a proportion of renal vasoconstriction during hemorrhage in conscious rabbits.

We examined the ability of different frequencies in sympathetic nerve activity (SNA) to induce oscillations in renal blood flow (RBF). In anesthetized rabbits the renal nerves were stimulated using modulated sine patterns (base frequency 5 Hz, 5-ms duration pulses) that varied in amplitude between 0 and 10 V at a frequency between 0.04 and 1.0 Hz. The strengths of the induced oscillations in RBF were calculated using spectral analysis. Although faster rhythms in simulated SNA >0.6 Hz contributed to the level of vascular tone, 95% of the power in the frequency response curve was below this frequency, indicating a low-pass filtering/integrating characteristic of the vasculature. Frequencies <0.6 Hz were associated with increasing ability to induce oscillations in RBF. The ability of an SNA rhythm at 0.6 Hz to induce a rhythm in RBF was 21 times less than that at 0.25 Hz. At 0.16 Hz there was a distinct peak in the frequency response curve, indicating the vasculature was more sensitive in this frequency band to sympathetic stimulation. Blockade of endogenous nitric oxide by N G-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg) did not alter resting RBF levels nor was the low-pass filtering/integrating characteristic of the vasculature to nerve stimulation changed (i.e., the curve was not shifted left or right); however, there was a selective increase in the sensitivity to stimulation at 0.16 Hz, i.e., larger oscillations in RBF were evoked. These results indicate an ability of SNA to induce resonant oscillations in the renal vasculature and that there may be active and passive modulators of these responses. Naturally occurring oscillations in SNA <0.6 Hz are likely to contribute to the dynamic control of RBF, ensuring it responds rapidly and with high gain to the stimuli of daily life, while filtering out the faster oscillations ensures stable glomerular filtration.

A new measure of the MBPS, BP(Power) which is based on a mathematical estimate of the rate and amplitude of the rise, is higher in hypertensives, white coat hypertensives, and is modifiable by some specific antihypertensive therapies suggests that it may be theoretically useful to highlight those subjects at greatest risk of cardiovascular events and for determining the most benefit of antihypertensive therapy.

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Analysis of 24-h recordings by a new logistic curve method reveals distinct asymmetric circadian patterns of cardiovascular and activity changes in rats. The greater surge in arousal blood pressure in SHR is not associated with differences in HR or activity changes and may be inherent to the underlying mechanisms contributing to the hypertension in SHR.

Background and Purpose: The vasomotor role of K2P potassium channels during early postnatal development has never been investigated. We tested the hypothesis that TASK-1 channel (K2P family member) contribution to arterial vascular tone and BP is higher in the early postnatal period than in adulthood. Experimental Approach: We studied 10-to 15-day-old ("young") and 2-to 3-monthold ("adult") male rats performing digital PCR (dPCR) (using endothelium-intact saphenous arteries), isometric myography, sharp microelectrode technique, quantitative PCR (qPCR) and Western blotting (using endothelium-denuded saphenous arteries), and arterial pressure measurements under urethane anaesthesia. Key Results: We found mRNA of Kcnk1-Kcnk7, Kcnk12, and Kcnk13 genes to be expressed in rat saphenous artery, and Kcnk3 (TASK-1) and Kcnk6 (TWIK-2) were most abundant in both age groups. The TASK-1 channel blocker AVE1231 (1 μmol•L −1) prominently depolarized arterial smooth muscle and increased basal tone level and contractile responses to methoxamine of arteries from young rats but had almost no effect in adult rats. The level of TASK-1 mRNA and protein expression was higher in arteries from young compared with adult rats. Importantly, intravenous administration of AVE1231 (4 mg•kg −1) had no effect on mean arterial pressure in adult rats but prominently raised it in young rats. Conclusion and Implications: We showed that TASK-1 channels are important for negative feedback regulation of vasocontraction in young but not adult rats. The influence of TASK-1 channels most likely contributes to low BP level at perinatal age.