Browsing by Author "Rose, Robert Alan"

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    Electrophysiological effects of C-type natriuretic peptide in the heart and in the central nervous system: the role of the NPR-C receptor
    (2005) Rose, Robert Alan; Giles, Wayne R.
    C-type natriuretic peptide (CNP) is one member of a group of related peptide hormones, which also includes atrial and brain natriuretic peptides, that elicit a wide range of effects in vertebrates, including humans. The natriuretic peptide C receptor (NPR-C) is functionally linked to an inhibitory G protein (Gi) that inhibits adenylyl cyclase (via the a subunit) and activates phospholipase C (PLC; via the ~y subunit). This thesis describes novel electrophysiological effects of CNP in cardiac myocytes, fibroblasts , and hypothalamic neurons that are specifically mediated by NPR-C. In isolated bullfrog atrial myocytes CNP (1 o-8 M) significantly shortened the duration and decreased the amplitude of the action potential. CNP and the NPR-C selective agonist, cANF (10-8 M), significantly decreased the L-type Ca2 + current Clca(L)) without altering the inward rectifier K+ current indicating that CNP inhibits Ica(L) when it binds NPR-C. To explore the selectivity of CNP effects voltage clamp studies on isolated sinoatrial (SA) node myocytes were performed. In these myocytes CNP and cANF strongly inhibited isoproterenol-stimulated Ica(L) without altering another cAMP sensitive current, Ir. Measurement of EC Gs in Langendorff-perfused mouse hearts revealed the ability of CNP and cANF to decrease heart rate. A similar pattern of results was observed in magnocellular neurosecretory cells (MN Cs) of the hypothalamus. In these neurons, which are responsible for the release of vasopressin and oxytocin, CNP and cANF selectively inhibited Ica(L)· Another voltage gated Ca2+ current, Ica(T), was not modulated by CNP. The inhibition oflca(L) resulted in a decrease in MNC excitability and a shortening of action potential duration in these neurons. In isolated cardiac fibroblasts, CNP and cANF activated an outwardly rectifying current with an apparent reversal potential near O m V. This current was inhibited by the transient receptor potential (TRP) channel blockers Gd3 \ SKF 96365 and 2-APB. The response was also antagonized by the PLC antagonist U73122. Together, these results indicate that CNP activates a TRP channel in cardiac fibroblasts following the activation of PLC by the NPR-C receptor. These data provide the first description of electrophysiological effects of CNP that are mediated by NPR-C in the heart and the hypothalamus.
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    Impacts of Aging and Hypertension on Fibrosis and Electrical Conduction in the Sinoatrial Node and Atria
    (2020-07-14) Mackasey, Martin; Rose, Robert Alan; Fedak, Paul; Nygren, Anders
    Sinoatrial node (SAN) and atrial fibrosis are major mediators of sinus node dysfunction (SND) and atrial fibrillation (AF), respectively. Both frequently co-exist in pathological states involving enhanced fibrotic remodeling. Aging and hypertension are characterized by electrical and structural remodeling and have been identified as important risk factors for the development of SND and AF. However, the underlying mechanisms facilitating these processes are incompletely understood. Natriuretic peptides (NPs) are a family of cardioprotective hormones that act partially through activation of the natriuretic peptide receptor type-C (NPR-C); although, its capacity to regulate cardiac remodeling is poorly understood. The studies presented examine the role of SAN and atrial fibrosis in regulating electrical conduction using two models associated with adverse remodeling: aging and Ang II-mediated hypertension. Aging studies also investigated the utility of assessing frailty to gain further insight into age-associated mechanisms of structural remodeling and arrhythmogenesis. Accordingly, aged and hypertensive mice exhibited enhanced SAN and atrial fibrosis as assessed by picrosirius red staining. This impacted electrical conduction as assessed by optical mapping experiments and promoted arrhythmogenesis. Frailty scores were correlated with several aspects of the remodeling process, including gene expression changes, indicating the potential for frailty score to provide additional insight into cellular and sub-cellular mechanisms. Aged and hypertensive mice exhibited distinct gene expression alterations in regulators of the cardiac extracellular matrix including collagens, transforming growth factor β1 (TGFβ1), lysyl oxidase (LOX), matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs). In studies examining the role of NPR-C in Ang II-mediated hypertension, NPR-C-/- mice displayed substantially worse outcomes with respect to SAN and atrial fibrosis as well as electrical impairments. These alterations were associated with changes in ECM-related gene expression. Conversely, a selective NPR-C agonist cANF potently prevented Ang II-mediated fibrosis and electrical impairments. However, these changes were generally not accompanied by ECM-related gene expression alterations. Taken together, these results demonstrate a crucial role for adverse fibrotic remodeling in influencing electrical conduction and arrhythmogenesis in the SAN and atria. Additionally, these studies show that NPR-C signaling exhibits potent anti-fibrotic effects that could be utilized for future therapeutic approaches in hypertension.
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