Thèse (M.Sc.)--Université Laval, 2004. / Bibliogr. Publié aussi en version électronique.

Thesis (Ph. D.)--Lehigh University, 2006. / Includes vita. Includes bibliographical references (leaves 250-257).

Thesis (Ph. D.)--University of Michigan, 1939. / Cover title. "Reprinted from the Physical review, vol. 56, no. 2, July 15, 1939." Includes bibliographical references.

Thesis (PH. D.)--University of Michigan, 1938. / Reprinted from an article, by Paul Rood and R.A. Sawyer, published in the Astrophysical journal, v. 87, no. 1, January 1938.

Thesis (M.S.)--University of Wisconsin--La Crosse, 2002. / Includes bibliographical references.

In coordination with the New York City Medical Examiner's Office, we received the sequence of a mutated SCN5A gene that was found in a five-week-old girl who died in her sleep. SCN5A codes for the voltage-gated cardiac sodium channel alpha subunit (Nav1.5) and is responsible for the fast depolarization in phase zero of the cardiac action potential. The mutations that were present in the girl's SCN5A gene were a missense mutation, Q1832E, and a truncation mutation, R1944X. In order to gain an understanding of the conditions that led to the patient's death, we carried out a functional analysis on the mutant channels and measured how their properties differed from wild type Nav1.5 properties. For our functional analysis we carried out mutagenesis reactions to produce three experimental constructs in order to examine independent effects of Q1832E or R1944X, and to examine their interaction (mutant Nav1.5 that contains both Q1832E or R1944X; as was found in the genetic screen). These constructs were transfected into HEK 293 cells and studied using the patch clamp analysis using the whole cell configuration. Experiments were carried out to test the Nav1.5 current voltage relationships, the recovery from inactivation properties, and steady state inactivation properties. The data demonstrated that each of the three constructs resulted in a significantly reduced current density when compared to wild type Nav1.5 currents. The gating properties of the mutant channels were similar to those of wild type Nav1.5, though Nav1.5-R1944X did show a statistically significant slower recovery from inactivation than the wild type channel. Though more experimentation is needed to determine the mechanism behind the reduced current in the mutant channels, our data shows that each of the mutations is sufficient to produce a severely dysfunctional channel and this is likely the cause of the patient's death.

Hypertension is both a domestic and international health issue – diagnosed in 1 in 3 U.S. adults and classified by the World Health Organization as the number one risk factor for mortality worldwide. It has been established that salt plays a role in the development of hypertension, and that a salt-sensitive phenotype indicates heightened sensitivity to salt consumption. Here, we studied the roles of the afferent renal nerves, which travel from the kidney to the central nervous system, and the sodium-chloride cotransporter in fluid and electrolyte homeostasis and blood pressure regulation. Our laboratory utilized a novel technique of afferent renal nerve ablation on Sprague-Dawley rats to examine the effects of afferent renal nerve mechanoreceptors and chemoreceptors in response to acute sympathoinhibitory challenges. Additionally, salt-sensitive and salt-resistant rats were randomly subjected to chronic normal salt (0.6% NaCl) or high salt (8% NaCl) diets, and examined for levels of norepinephrine and substance-P release. A different group of salt-resistant and salt-sensitive rats were subcutaneously infused with terazosin, a selective -1 adrenoreceptor antagonist, or propranolol, a selective -adrenoreceptor antagonist, and then randomly subjected to normal salt (0.6% NaCl) or high salt (4% NaCl) diets for 21 days. We subsequently examined these rats, and analyzed the effects of high salt intake on blood pressure, sodium-chloride cotransporter activity, and expression of the sodium-chloride cotransporter and its relevant kinases. In response to an acute mechanoreceptor-specific stimulus, Sprague-Dawley rats that underwent afferent renal nerve ablation were unable to modulate blood pressure or natriuresis after regaining consciousness. Chronic high salt (8% NaCl) consumption in salt-sensitive rats resulted in increased levels of plasma norepinephrine, renal norepinephrine, and norepinephrine-evoked Substance-P release. In addition, salt-sensitive rats subjected to a 21-day high salt (4% NaCl) diet exhibited increased blood pressure, elevated sodium-chloride cotransporter activity, and upregulated levels of the sodium-chloride cotransporter and the kinases that regulate it. However, these observed increases in blood pressure, protein activity, and protein expression were abolished in salt-sensitive rats experiencing -1 adrenoreceptor antagonism due to terazosin administration. In conclusion, our findings indicate that mechanoreceptor-driven afferent renal nerve activation is needed to maintain fluid and electrolyte homeostasis and regulate blood pressure in response to acute sympathoinhibitory challenges and chronic high salt intake. In addition, our data demonstrates that the sodium-chloride cotransporter is aberrantly upregulated in salt-sensitive rats through a norepinephrine-1-adrenoreceptor gated pathway, and this this upregulation results in excessive salt reabsorption. Thus, our experiments have generated new data that reveals selective 1-adrenoreceptor antagonism and renal denervation as potential treatment options for hypertensive individuals.

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