The influence of gender on the association between hyperinsulinemia/insulin resistance and hypertension

The primary objective of this study was to examine the relationship between hyperinsulinemia / insulin resistance and hypertension in female rats. A link between these two conditions has been well established in studies employing male animal models as well as in human studies, however, it has not been possible to discern what role gender plays in this relationship, if any, based on these previous reports. To investigate the effect of gender on the association between hyperinsulinemia / insulin resistance, two different hyperinsulinemic, hypertensive rat models were used; the fructose fed hypertensive rat (FHR) and a chronically insulin treated rat. In the first set of experiments using fructose fed animals, we found that fructose causes hyperinsulinemia, insulin resistance and hypertension in males, but does not affect metabolism or blood pressure at all in females. However in a separate experiment, female rats that had been ovariectomized did develop insulin resistance and hypertension, indicating that normal levels of ovarian sex hormones are involved in protecting female rats against the effects of a fructose diet. In a second set of blood pressure experiments, we employed a chronic exogenous insulin treatment to attempt to create a state of insulin resistance in females. In this study, we observed that exogenous hyperinsulinemia causes insulin resistance in both male and female rats, however, this occurs to a greater degree in males. Furthermore, hyperinsulinemia and insulin resistance were only associated with hypertension in male rats. Several mechanisms have been proposed to play a role in the development of hypertension associated with hyperinsulinemia and insulin resistance. A secondary objective of this thesis was to identify potential mechanisms that might explain any gender differences observed. To this aim, we focused on vascular function. We examined the vascular effects of insulin and found that it tends to act more as a vasoconstrictor in female rats rather than a vasodilator, as we had previously demonstrated in males. We also demonstrated that there is a significant gender difference in the effect of U46619, a synthetic thromboxane analogue, which may be related to gender differences in the development of hypertension associated with hyperinsulinemia and insulin resistance.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat

Patient-Reported Outcomes in Metastatic Breast Cancer: A Review of Industry-Sponsored Clinical Trials

Introduction Patient-reported outcome (PRO) measures serve to capture vital patient information not otherwise obtained by primary study endpoints. This paper examines how PROs are utilized as endpoints in industry-sponsored metastatic breast cancer clinical trials. Methods A search was conducted in the clinicaltrials.gov web site for trials involving common treatments for metastatic breast cancer. Thirty-eight clinical trials were identified which included a PRO endpoint in the study, and data were extracted and summarized. Results Overall, 17 unique PRO questionnaires and 14 concepts of measurement were identified as secondary or exploratory endpoints. The Functional Assessment of Cancer Therapy—Breast was the most frequently utilized questionnaire, commonly implemented to assess quality of life. The EORTC QLQ-C30 was also frequently used to measure quality of life or pain. Conclusion This review shares insights into the role of PROs in trials for metastatic breast cancer from which treatment developers and other stakeholders can enhance successful implementation of the patient voice into future trials

NO/PGI(2)-independent vasorelaxation and the cytochrome P450 pathway in rabbit carotid artery

1. The nature and cellular mechanisms that are responsible for endothelium-dependent relaxations resistant to indomethacin and N(G)-nitro-L-arginine methyl ester (L-NAME) were investigated in phenylephrine (PE) precontracted isolated carotid arteries from the rabbit. 2. In the presence of the cyclo-oxygenase inhibitor, indomethacin (10 μM), acetylcholine (ACh) induced a concentration- and endothelium-dependent relaxation of PE-induced tone which was more potent than the calcium ionophore A23187 with pD(2) values of 7.03±0.12 (n=8) and 6.37±0.12 (n=6), respectively. The ACh-induced response was abolished by removal of the endothelium, but was not altered when indomethacin was omitted (pD(2) value 7.00±0.10 and maximal relaxation 99±3%, n=6). Bradykinin and histamine (0.01–100 μM) had no effect either upon resting or PE-induced tone (n=5). 3. In the presence of indomethacin plus the NO synthase inhibitor, L-NAME (30 μM), the response to A23187 was abolished. However, the response to ACh was not abolished, although it was significantly inhibited with the pD(2) value and the maximal relaxation decreasing to 6.48±0.10 and 67±3%, respectively (for both P<0.01, n=8). The L-NAME/indomethacin insensitive vasorelaxation to ACh was completely abolished by preconstriction of the tissues with potassium chloride (40 mM, n=8). 4. The Ca(2+)-activated K(+) (K(Ca)) channel blockers, tetrabutylammonium (TBA, 1 mM, n=5) and charybdotoxin (CTX, 0.1 μM, n=5), completely inhibited the nitric oxide (NO) and prostacyclin (PGI(2))-independent relaxation response to ACh. However, iberiotoxin (ITX, 0.1 M, n=8) or apamin (1–3 μM, n=6) only partially inhibited the relaxation. 5. Inhibitors of the cytochrome P450 mono-oxygenase, SKF-525A (1–10 μM, n=6), clotrimazole (1 μM, n=5) and 17-octadecynoic acid (17-ODYA, 3 μM, n=7) also reduced the NO/PGI(2)-independent relaxation response to ACh. 6. In endothelium-denuded rings of rabbit carotid arteries, the relaxation response to exogenous NO was not altered by either K(Ca) channel blockade with apamin (1 μM, n=5) or CTX (0.1 μM, n=5), or by the cytochrome P450 mono-oxygenase blockers SKF-525A (10 μM, n=4) and clotrimazole (10 μM, n=5). However, the NO-induced response was shifted to the right by LY83583 (10 μM, n=4), a guanylyl cyclase inhibitor, with the pD(2) value decreasing from 6.95±0.14 to 6.04±0.09 (P<0.01). 7. ACh (0.01–100 μM) induced a concentration-dependent relaxation of PE-induced tone in endothelium-denuded arterial segments sandwiched with endothelium-intact donor segments. This relaxation to ACh was largely unaffected by indomathacin (10 μM) plus L-NAME (30 μM), but abolished by the combination of indomethacin, L-NAME and TBA (1 mM, n=5). 8. These data suggest that in the rabbit carotid artery: (a) ACh can induce the release of both NO and EDHF, whereas A23187 only evokes the release of NO from the endothelium, (b) the diffusible EDHF released by ACh may be a cytochrome P450-derived arachidonic acid metabolite, and (c) EDHF-induced relaxation involves the opening of at least two types of K(Ca) channels, whereas NO mediates vasorelaxation via a guanosine 3′: 5′-cyclic monophosphate (cyclic GMP)-mediated pathway, in which a cytochrome P450 pathway and K(Ca) channels do not seem to be involved