The objective of these experiments was to investigate the effects of various membrane receptor-mediated and receptor-independent vasodilators on the resistance and capacitance vessels of conscious, unrestrained rats by measuring mean arterial pressure (MAP) and mean circulatory filling pressure (MCFP), an index of total body venous tone. ln the first set of experiments the dose-response effects of the directly-acting vasodilators nitroglycerin, sodium nitroprusside and hydralazine were determined in intact rats as well as in rats treated with the ganglionic blocker, hexamethonium. The effects of these drugs were compared with those of the vehicle, normal saline, in control rats. In intact rats, iv infusion of nitroglycerin did not alter MAP while iv infusions of nitroprusside and hydralazine caused dose-dependent decreases in MAP. In intact rats, nitroglycerin and sodium nitroprusside did. not affect MCFP while hydralazine increased MCFP. After treatment with hexamethonium all three drugs decreased MCFP, though the decreases in MCFP caused by hydralazine were not significantly different from the corresponding changes in saline-treated rats. Therefore, sodium nitroprusside and hydralazine but not nitroglycerin were effective arteriolar dilators in intact rats; all three drugs dilated arterioles in ganglionic-blocked rats, ln intact rats, the direct venodilator actions of nitroprusside and nitroglycerin were masked by endogenous sympathetic tone. When sympathetic nerve activity was attenuated, both drugs had venodilatory effects. Hydralazine, on the other hand, hao insignificant venodilatory effects both in the presence and absence of the sympathetic reflexes. In the second set of experiments we determined the dose-response effects of hexamethonium, phentolamine, prazosin and rauwolscine — the latter being non-selective ⍺, ⍺₁-selective, and ⍺₂-selective adrenoceptor antagonists, respectively — in intact rats. Prazosin and rauwolscine were also administered to rats with reflexly increased venous tone induced by the infusion of hydralazine. In intact rats iv infusions of prazosin, phentolamine and rauwolscine all caused dose-dependent decreases in MAP; only rauwolscine reduced MCFP to levels slightly below control. Hexamethonium caused a aecrease in MAP as well as a markea reduction in MCFP. After venous tone was raised by the infusion of hydralazine, both prazosin and rauwolscine dose-dependently decreased MCFP. Therefore, the resistance and capacitance vessels contain both ⍺₁- and ⍺₂-adrenoceptors. in the intact rat, however, the capacitance vessels are somewhat resistant to the effects of postjunctionally acting ⍺-antagonists in contrast to the effects of hexamethonium which acts at the level of the ganglion. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Indiana University-Purdue University Indianapolis (IUPUI) / The passive properties of the venous wall are important in the development of venous pathology. Increase in venous pressure due to retrograde flow (reflux) and obstruction of venous flow by intrinsic and extrinsic means are the two possible mechanisms for venous hypertension. Reflux is the prevailing theory in the etiology of venous insufficiency. The objective of this thesis is to quantify the passive biomechanical response and structural remodeling of veins subjected to chronic venous reflux and hypertension. To investigate the effects of venous reflux on venous mechanics, the tricuspid valve was injured chronically in canines by disrupting the chordae tendineae. The conventional inflation-extension protocol in conjunction with intravascular ultrasound (IVUS) was utilized to investigate the passive biomechanical response of both control common iliac veins (from 9 dogs) and common iliac veins subjected to chronic venous reflux and hypertension (from 9 dogs). The change in thickness and constituent composition as a result of chronic venous reflux and hypertension was quantified using multiphoton microscopy (MPM) and histological evaluation. Biomechanical results indicate that the veins stiffened and became less compliant when exposed to eight weeks of chronic venous reflux and hypertension. The mechanical stiffening was found to be a result of a significant increase in wall thickness (p < 0.05) and a significant increase in the collagen to elastin ratio (p < 0.05). After eight weeks of chronic reflux, the circumferential Cauchy stress significantly reduced (p < 0.05) due to wall thickening, but was not restored to control levels. This provided a useful model for development and further analysis of chronic venous insufficiency and assessment of possible intervention strategies.