In this thesis an attempt has been made to try to dissect out the relative importance of atrial natriuretic peptides (ANP) and the renin-angiotensin-aldosterone system in the control of sodium balance in normal man. At the same time the thesis examines the relevance of ANP in the pathophysiology of essential hypertension and cardiac transplantation and the potential therapeutic value of manipulating the ANP system. The studies described in this thesis were important in suggesting a dominant role of suppression of the renin-angiotensin-aldosterone system in permitting excretion of short term increases in intravenous or oral sodium intake. The permissive effects of suppression of angiotensin II or aldosterone for the excretion of an intravenous sodium load showed clear time differences, with suppression of angiotensin II important immediately but the response to suppression of aldosterone delayed. In contrast, there appears to be only a transient role for changes in circulating levels of ANP in the response to an intravenous sodium load and little evidence that changes in ANP release are important in responding to acute increases in dietary sodium intake in normal subjects. However, the sensing mechanism for ANP release is clearly activated by sustained changes in dietary sodium intake. Studies of prolonged dietary sodium alteration in normal subjects clear evidence for a role of ANP in the medium term regulation of sodium balance and further dietary studies suggested an important role for the ANP system in pathophysiology in essential hypertension and in cardiac transplant recipients.

Hypertension is accompanied by structural and mechanical abnormalities in resistance arteries. The effects of resveratrol, a phenolic phytoalexin found naturally in various foods, on systolic blood pressure and resistance artery structure and stiffness were assessed in spontaneously hypertensive rats (SHRs). Vascular geometry and mechanical properties of pressurized mesenteric resistance arteries were calculated from media and lumen dimensions measured using pressure myography. Compared to normotensive Wistar-Kyoto (WKY) rats, resistance arteries from SHRs displayed remodeling with narrowed lumen diameters (246.2±21.0 vs. 308.1±14.3 μm, p<0.05), thickened media widths (39.8±4.6 vs. 28.5±2.7 μm, p<0.05) and augmented media-to-lumen ratios (17.7±2.6 vs. 9.3±1.0, p<0.05). Calculations of remodeling and growth indices revealed that SHR vessels underwent mostly eutrophic remodeling. Systolic blood pressure was elevated in 20-week-old SHR versus WKY rats (219±6 vs. 155±6 mmHg, p<0.01) and was unaffected by resveratrol (2.5 mg/Kg/d). In SHRs, resveratrol treatment attenuated eutrophic remodeling and normalized increased vessel compliance (p<0.01) as determined by a restorative leftward shift in the stress-strain curve of SHR arteries (p<0.01). Resveratrol treatment restored stiffness in SHRs (4.2±0.4 vs. 6.6±0.5, p<0.05) through the normalization of vessel geometry. Immunoblotting revealed that resveratrol negated typical pronounced ERK1/2 signaling in SHR arteries. Thus, the results of this study suggest that resveratrol restores vascular mechanical properties in SHRs and attenuates remodeling. Furthermore the attenuation of remodeling in SHR arteries with resveratrol treatment is associated with the inhibition of ERK1/2 activity.

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Hypertension is a risk factor for myocardial ischemia via the promotion of endothelial dysfunction and atherosclerosis (Ogita et al., 2004). Hypertension not only a predisposes the heart to ischemic events, but as shown by clinical and experimental studies, exacerbates the heart’s susceptibility to ischemia-reperfusion injury (Golden et al., 1994; Besík et al., 2007; Snoeckx et al., 1986) due to impairments in regulation of calcium handling, ion homeostasis, and energy metabolism (Galiñanes et al., 2004). Nutraceuticals have demonstrated beneficial and protective effects on both hypertension and ischemia reperfusion injury. Resveratrol, a naturally occurring polyphenol which is present in grapes and wine, acts as a cardioprotective agent and can be used to protect the heart against ischemia reperfusion injury. Here we investigate the effectiveness of chronic dietary resveratrol intake in normotensive and hypertensive rats on protection against ischemia-reperfusion injury, assessed in an isolated perfused Langendorff heart model. Rats ingested either a High dose of 2.7mg/day-which mimicked the resveratrol content in daily supplemental intake levels, a Low dose of 0.027mg/day- which mimicked the resveratrol content in moderate red wine intake, or no resveratrol in the drinking water for 28 days, at which point hearts were excised and mounted on a Langendorff apparatus. Once stable conditions were established all hearts were subjected to 30 minutes of no flow ischemia followed by 2 hours of reperfusion. Interestingly, SHR animals did not exhibit reduced recovery, or increased infarct size as compared to WKY. Infarct size as measured by triphenyltetrazolium chloride staining after 2 hours of reperfusion was significantly reduced in High and Low groups (combined WKY and SHR) as compared to Controls (19.9±0.9 and 19.4±0.8 vs 27.7±0.7 % of baseline, p<0.0001). Left ventricular developed pressure was significantly improved 2 hours post ischemia in both High and Low groups (combined SHR and WKY) compared to Controls (83.1±4.1 and 78.6±3.4 vs.67.9±3.2% of baseline, p<0.01). A higher rate of maximal pressure development was maintained in High and Low groups (combined SHR and WKY) compared to Controls (90.5±4.7 and 95.6±5.0 vs.73.5±4.8% of baseline, p<.05). Resveratrol treatment at a High and Low dose reduced contracture of the myocardium as compared to Control (7.2±3.0 and 6.9±2.9 vs. 20.1±2.9 mmHg- LVEDP, p<0.01). In conclusion resveratrol treatment at both a High and Low dose protects against a decline in cardiac function, and reduces infarct size post ischemia reperfusion. Additionally, tolerance to ischemia reperfusion injury in SHR is not reduced as compared to WKY.

The endothelial layer of blood vessels is able to produce a number of vasoactive substances, and these substances can work to either relax or contract the underlying vascular smooth muscle. A hallmark of hypertension is the development of endothelial dysfunction, a shift in the balance of these substances to a state of increased contraction. Hydrogen sulfide (H2S) has recently garnered much interest as a gaseous signaling molecule with the discoveries that is can relax isolated blood vessels and lower blood pressure in young spontaneously hypertensive rats (SHR). Here we investigate whether chronic H2S treatment (56 μmol/kg of the H2S donor sodium hydrosulfide (NaHS), once daily for 5 weeks) can lower the blood pressure of adult aged SHR when compared to normotensive control Wistar Kyoto rats (WKY), and whether there are changes in the endothelium-dependent relaxation and contraction pathways. Invasive hemodynamic measurements including systolic, diastolic, and mean blood pressure, as well as heart rate were measured. Isolated vessel myography was performed on the common carotid artery to determine whether there were changes in the endothelium-dependent and independent relaxation and contraction pathways. This was achieved using a number of dose response curves. Changes in endothelium dependent dilation to ACh, VSM sensitivity to NO and H2S, and NO bioavailability were tested with dose response curves using ACh, SNP (an NO donor), H2S and indomethacin, respectively. TP receptor sensitivity, as well as COX-mediated constriction in quiescent vessels was also examined by using the TP receptor agonist U46619 and L-NAME (eNOS inhibitor), respectively. Biochemical analyses included Western blotting to assess protein levels of CSE (H2S generating enzyme) and eNOS (NO generating enzyme) as well as determining prostacyclin production. Determination of H2S concentration in the blood via a sulfide electrode was also performed to confirm that the H2S treatment was effective. There were no main effects of H2S treatment in any of the hemodynamic measurements taken. ACh dose response revealed a blunting in the recontraction at 10-5 and 10-4.5 log M concentrations (p<0.05) in SHR treated with H2S. No effects were observed, however, in any other myography protocol. Western blot analysis revealed no difference in the protein expression of CSE or eNOS with H2S treatment, and there were no differences in prostacyclin production with H2S treatment. In conclusion, these data suggest that H2S may not be an effective treatment for hypertension in adult SHR, in contrast to previous work finding a similar dosing regimen to be effective at lowering blood pressure in young SHR. Further work must be completed to ascertain the mechanism for the alteration in the ACh dose response curve and to determine at what time point the H2S treatment becomes ineffective.

Persistent elevation of portal venous pressure (portal hypertension- PH), is linked to chronic liver disease and invariably leads to multi-organ circulatory complications. Hallmarks of PH are renal dysfunction and a characteristic hemodynamic profile (hyperdynamic circulation), which synergistically cause the development of the fatal sequelae of PH. Despite extensive research, PH remains a serious clinical problem, with no effective treatment. In large part, this is due to lack of comprehensive knowledge regarding the initiation and early progression of renal dysfunction and the hyperdynamic circulation. The spleen, which is actively engaged in cardiovascular regulation, is intimately connected with the portal venous system such that splenic venous pressure (SVP) is also elevated in PH. We therefore investigated the contribution of the spleen to PH-related cardiovascular dysregulation. Specifically, we employed an acute rat model to elucidate the existence of neurohormonal pathways activated in early PH. It was known that PH-related renal dysfunction is functional and neurally mediated (via the hepato-renal reflex). We hypothesized that, in addition, selective elevation of splenic venous pressure (SVP) also increases renal vascular resistance and modulates renal vascular function, through reflex activation of splenic afferent and renal sympathetic nerves. Indeed, acutely elevated SVP by partial splenic vein occlusion (SVO) did increase splenic afferent nerve activity and reflexly increased renal sympathetic nerve activity (RSNA). Simultaneously, renal blood flow (RBF) and renal arterial conductance fell; this was α1 adrenergic receptor-mediated and dependent on intact splenic and renal nerves. Moreover, our data showed that, in the absence of increased SVP, PH did not affect RSNA or renal vascular function. Although splanchnic vasodilation is characteristic of the hyperdynamic circulation in PH, its development is thought to be contingent upon an initial transient mesenteric vasoconstriction. Our data revealed that increased SVP reflexly activates mesenteric efferent nerves, and reduces mesenteric arterial blood flow, vascular conductance and resistance artery diameter; this was primarily mediated through angiotensin II release (spleno-renal reflex-, renal baroreceptor-, and mesenteric angiotensinergic nerve-mediated). In conclusion, the spleen neurohormonally modulates renal and mesenteric circulations, thus contributing to the initiation of renal dysfunction and hyperdynamic circulation of PH.

Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 164 pages. Includes vita. Includes bibliographical references.

Thesis (M.S.) in Food Science and Human Nutrition--University of Maine, 2007. / Includes vita. Includes bibliographical references (leaves 90-116).