We investigated the role of nitric oxide (NO) in the control of myocardial O2 consumption in Fischer 344 rats. In Fischer rats at 4, 14, and 23 mo of age, we examined cardiac function using echocardiography, the regulation of cardiac O2 consumption in vitro, endothelial NO synthase (eNOS) protein levels, and potential mechanisms that regulate superoxide. Aging was associated with a reduced ejection fraction [from 75 +/- 2% at 4 mo to 66 +/- 3% (P < 0.05) at 23 mo] and an increased cardiac diastolic volume [from 0.60 +/- 0.04 to 1.00 +/- 0.10 ml (P < 0.01)] and heart weight (from 0.70 +/- 0.02 to 0.90 +/- 0.02 g). The NO-mediated control of cardiac O2 consumption by bradykinin or enalaprilat was not different between 4 mo (36 +/- 2 or 34 +/- 3%) and 14 mo (29 +/- 1 or 25 +/- 3%) but markedly (P < 0.05) reduced in 23-mo-old Fischer rats (15 +/- 3 or 7 +/- 2%). The response to the NO donor S-nitroso-N-acetyl penicillamine was not different across groups (35%, 35%, and 44%). Interestingly, the eNOS protein level was not different at 4, 14, and 23 mo. The addition of tempol (1 mmol/l) to the tissue bath eliminated the depression in the control of cardiac O2 consumption by bradykinin (25 +/- 3%) or enalaprilat (28 +/- 3%) in 23-mo-old Fischer rats. We next examined the levels of enzymes involved in the production and breakdown of superoxide. The expression of Mn SOD, Cu/Zn SOD, extracellular SOD, and p67phox, however, did not differ between 4- and 23-mo-old rats. Importantly, there was a marked increase in gp91phox, and apocynin restored the defect in NO-dependent control of cardiac O2 consumption at 23 mo to that seen in 4-mo-old rats, identifying the role of NADPH oxidase. Thus increased biological activity of superoxide and not decreases in the enzyme that produces NO are responsible for the altered control of cardiac O2 consumption by NO in 23-mo-old Fischer rats. Increased oxidant stress in aging, by decreasing NO bioavailability, may contribute not only to changes in myocardial function but also to altered regulation of vascular tone and the progression of cardiac or vascular disease.
Sarah McGrath (2008; 2011) argues that, when it comes to our controversial moral views, we have no reason to think that we are less likely to be in error than those who disagree with us. I refer to this position as the Moral Peer View (MPV). Under pressure from Nathan King (2011a; 2011b), McGrath admits that the MPV need not always have been true, though she maintains it is true now. Although King seems to think that there should be current counterexamples to the MPV, he holds back from actually proposing any. I argue that those of us who favor marriage equality and gender equality are currently in a position to reject the MPV with regard to these issues, and I propose conditions under which people can reasonably take their moral beliefs to be epistemically advantaged. King and McGrath agree that opponents of slavery like William Wilberforce could reasonably believe that they enjoyed an epistemic advantage over proponents of slavery, and I suggest that proponents of marriage equality and gender equality might make similar claims. I propose that we can make additional claims to epistemic advantages if we believe that (1) almost everyone who considers the matter admits that there are advantages, (2) those who disagree with us would admit that there are advantages and (3) we can give a plausible explanation as to why those who we think are epistemically disadvantaged have not noticed that they are disadvantaged. Finally, I argue that it is reasonable to think that our controversial beliefs are justified if we can find reasons to think that our opponents are mistaken, and do not see similar reasons to think ourselves mistaken. This is a better policy than supposing that we are just as prone to mistakes as our opponents, as the latter is both less defensible in theory, and more likely to stifle intellectual progress.
The Equal Weight View holds that, when we discover we disagree with an epistemic peer, we should give our peer’s judgment as much weight as our own. But how should we respond when we cannot tell whether those who disagree with us are our epistemic peers? I argue for a position I will call the Earn-a-Spine View. According to this view, parties to a disagreement can remain confident, at least in some situations, by finding justifiable reasons to think their opponents are less credible than themselves, even if those reasons are justifiable only because they lack information about their opponents.
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