Thesis--University of Wisconsin--Madison. / Typescript. Vita. Includes bibliographical references (leaves 158-173).

The chronotropic and inotropic responses to isoprenaline and salbutamol were determined in the chloralose anaesthetized dog. The myocardium was denervated, sympathetically and parasympathetically to prevent direct neural influence on the heart rate and myocardial contractility. The heart rate was determined from the E.C.G. Myocardial contractility was indicated by the change in the maximum rate of rise of left ventricular pressure (dP/dt max) at a constant electrically paced heart rate. The structure-activity relationships for salbutamol and isoprenaline were determined from dose-response curves and by plotting the change in contractility (ΔdP/dt max) against the change in heart rate (ΔHR). The data obtained from this series of experiments indicated that the only difference between the effects of the agonists on the inotropic and chronotropic responses of the myocardium was the lower affinity of salbutamol for the adrenergic receptor as indicated by the 100 times greater concentration required to produce the same response level. Previously reported in vitro studies with the guinea pig atrium and dog papillary muscle had indicated that a smaller inotropic response to salbutamol should have been expected. To test this discrepancy between the present in vivo experimentation, and the previous in vitro work, studies were designed to test the guinea pig atrium and the dog papillary muscle in vitro. The effects of the agonists were studied on the isolated guinea pig atrium in a manner that paralleled the in vivo dog study. With the organ bath at 25°C, the chronotropic response, measured by the change in free contraction rate (ΔR), and the inotropic response, determined from the change in peak tension developed (ΔT) during electrical stimulation at 2 Hz, to a single randomly ordered dose of salbutamol or isoprenaline were determined. Salbutamol acted as a partial agonist, that is, had a lower efficacy than isoprenaline. However, the relative effect of each drug on the inotropic and chronotropic responses was almost identical. In the isolated dog papillary muscle, salbutamol displayed a much lower efficacy, producing only 20% of the maximum isoprenaline increase in peak tension developed to the cummulative addition of agonist. The affinity of salbutamol for the adrenergic receptor in this preparation was much lower than that observed in vivo when compared with isoprenaline, 5,000:1 and 100:1 respectively. The structure-activity relationships for salbutamol and isoprenaline showed that the relative effects of these agonists on the in vivo denervated dog myocardial inotropic and chronotropic responses were similar. This observation indicates that the adrenergic receptors of the dog myocardium mediating the inotropic and chronotropic responses are structurally similar at a site complementary to the phenyl ring of the agonist molecule. However,, a definite conclusion regarding the adrenergic receptors responsible for the inotropic response cannot be made because of the unexplained difference in inotropic response observed with ventricular muscle in vivo and in vitro. Examination of the structure-activity relationships for salbutamol and isoprenaline in the in vitro guinea pig atrium indicates that, in this preparation also, the adrenergic receptors involved in the two measured responses are probably structurally similar. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

No description available.

Dissertation (Ph.D.).--University of Texas Graduate School of Biomedical Sciences at San Antonio, 2008. / Vita. Includes bibliographical references.

Thesis (doctoral)--Katholieke Universiteit te Nijmegen.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1985. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 178-200).

Thesis (M.Sc.). / Written for the Dept. of Neurology and Neurosurgery. Title from title page of PDF (viewed 2008/05/14). Includes bibliographical references.

No description available.

The purpose of this study was to examine exercise responses during acute and chronic administration of BB, Beta Blockade. Twenty-eight healthy males performed maximal treadmill exercise tests after 1 day and 9 days of 3 double-blind, randomized conditions: a placebo (Pl), propanolol (Pr) 80 mg bid, and atenolol (At) 100 mg daily. Maximal heart rate (HR), oxygen consumption (VO₂), ventilation (VE), and treadmill time (TT) were significantly reduced by Pr and At after an acute and chronic dose. An acute dose of Pr and At caused a greater decrease in maximal HR compared to chronic administration (143.1 ± 5.0 b min⁻¹ at day 1 vs. 147.7 ± 4.2 b min⁻¹ at day 9). However, the overall exercise response was not effected by the change in HR in either the TR or UT subjects. These data indicate that there is no difference in exercise response to acute and chronic BB in young healthy males. (Abstract shortened with permission of author.)

Dexmedetomidine is α2-adrenergic agent and commonly used in the intensive care setting. It is used primarily to sedate critically ill patients in various surgical, endoscopic and radiologic procedures. This medication gained superiority with other sedatives with a distinct advantage of less depression of the respiratory system. Although dexmedetomidine is often administered to septic patients, the vascular effect has not been fully studied in this clinical setting. In this thesis, rats were administered saline or bacterial lipopolysaccharide (LPS) 1, 10 and 20 mg/kg. Aortic rings were obtained after two, 24 and 72 hours exposure and dexmedetomidine-induced contractions were investigated. Rats could not tolerate prolonged exposure to 20 mg/kg LPS and died during the process. Systolic, diastolic and mean arterial pressures were reduced after LPS exposure while heart rates were elevated. Body temperatures were elevated after LPS administration (all doses and time), except a reduction at two hours with 1 mg/kg LPS. LPS increased the plasma levels of tissue necrosis factor-α and interleukin-6 after two hours LPS administration but not at 24 and 72 hours. In aortic rings with functional endothelium from rats with or without LPS exposure, dexmedetomidine had no effect on resting tension. Dexmedetomidine produced concentration-dependent contractions (10 nM to 10 μμM) after incubation with endothelial nitric oxide synthase (NOS) inhibitor L-NAME or removal of endothelium in rings without and with exposure to LPS for two, 24, 72 hours. LPS administration dose-dependently attenuated dexmedetomidine-induced contractions. In the presence of 1400W (inducible NOS inhibitor) the contractile response to dexmedetomidine was potentiated suggesting a role of NO produced by iNOS. Treatment with MnTMPyP attenuated dexmedetomidine-induced contractions indicating that the superoxide dismutase mimetic might increase NO availability by reducing superoxide. A significant role of iNOS was further supported by the detection of iNOS expression in aortic rings after LPS exposure at two, 24, and 72 hours when compared to non-LPS exposed group. Use of selective α2A and α2B receptor antagonists (BRL44408 and ARC239 respectively) showed that dexmedetomidine-induced contractions were mediated mostly via α2A receptor subtype as the former but not the latter agent significantly reduced contractions. Serotonin (5-HT, 10 nM to 100 μμM) and phenylephrine (1 nM to 100 μμM) produced concentration-dependent contractions in aortic rings with and without LPS exposure. The maximal responses to 5-HT and phenylephrine were increased at 10 mg/kg LPS as compared to a reduction in contractions by dexmedetomidine with LPS exposure at 1 and 10 mg/kg supporting alterations in α2 receptors occurred after LPS administration. In conclusion, the present study demonstrated that the vascular contractile responses of dexmedetomidine in the absence of endothelium or in the presence of eNOS inhibition were reduced in the presence of LPS at different time points and at different doses in aortic rings while two other receptor mediated vasoconstrictors, 5-HT and phenylephrine were affected. Our findings suggest that LPS may preferentially reduce the vascular contractile responses of dexmedetomidine and it is essential to exercise caution when the drug is administered to critically ill patients or with endothelial dysfunction. / published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy