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Articles by J. F.R Paton
Total Records ( 2 ) for J. F.R Paton
  C Sun , J Zubcevic , J. W Polson , J. T Potts , C Diez Freire , Q Zhang , J. F.R Paton and M. K. Raizada

Rationale: Central angiotensin (Ang) II inhibits baroreflex and plays an important role in the pathogenesis of hypertension. However, the underlying molecular mechanisms are still not fully understood.

Objective: Our objective in the present study was to characterize the signal transduction mechanism of phosphatidylinositol 3-kinase (PI3K) involvement in Ang II–induced stimulation of central neuronal activity in cultured neurons and Ang II–induced inhibition of baroreflex in spontaneously hypertensive rats (SHR) versus WKY rats.

Methods and Results: Application of Ang II to neurons produced a 42% greater increase in neuronal firing in cells from the SHR than the WKY rat. Although the Ang II–mediated increase in firing rate was abolished entirely by the protein kinase (PK)C inhibitor GF109230 in the WKY, blockade of both PKC and PI3K activity was necessary in the SHR. This was associated with an increased ability of Ang II to stimulate NADPH oxidase–reactive oxygen species (ROS)–mediated signaling involving phosphorylation of the p47phox subunit of the NADPH oxidase and was dependent on the activation of PI3K in the SHR. Inhibition of PI3K resulted in the reduction of levels of p47phox phosphorylation, NADPH oxidase activity, ROS levels, and ultimately neuronal activity in cells from the SHR but not the WKY rat. In addition, in working heart–brainstem preparations, inhibition of PKC activity in the nucleus of the solitary tract in situ abolished the Ang II–mediated depression of cardiac and sympathetic baroreceptor reflex gain in the WKY. In contrast, PKC inhibition in the nucleus of the solitary tract of SHR only partially reduced the effect of Ang II on the baroreceptor reflex gain.

Conclusions: These observations demonstrate that PI3K in the cardiovascular brainstem regions of the SHR may be selectively involved in Ang II–mediated signaling that includes a reduction in baroreceptor reflex function, presumably via a NADPH-ROS mediated pathway.

  Z. Y Tan , Y Lu , C. A Whiteis , A. E Simms , J. F.R Paton , M. W Chapleau and F. M. Abboud

Rationale: Increased sympathetic nerve activity has been linked to the pathogenesis of hypertension in humans and animal models. Enhanced peripheral chemoreceptor sensitivity which increases sympathetic nerve activity has been observed in established hypertension but has not been identified as a possible mechanism for initiating an increase in sympathetic nerve activity before the onset of hypertension.

Objective: We tested this hypothesis by measuring the pH sensitivity of isolated carotid body glomus cells from young spontaneously hypertensive rats (SHR) before the onset of hypertension and their control normotensive Wistar–Kyoto (WKY) rats.

Methods and Results: We found a significant increase in the depolarizing effect of low pH in SHR versus WKY glomus cells which was caused by overexpression of 2 acid-sensing non–voltage-gated channels. One is the amiloride-sensitive acid-sensing sodium channel (ASIC3), which is activated by low pH and the other is the 2-pore domain acid-sensing K+ channel (TASK1), which is inhibited by low pH and blocked by quinidine. Moreover, we found that the increase in sympathetic nerve activity in response to stimulation of chemoreceptors with sodium cyanide was markedly enhanced in the still normotensive young SHR compared to control WKY rats.

Conclusions: Our results establish a novel molecular basis for increased chemotransduction that contributes to excessive sympathetic activity before the onset of hypertension.

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