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William A Cupples

Publications and source records attributed to William A Cupples.

10 recordsLinked to original sources
PubMed2007

Assessment of renal autoregulation.

The kidney displays highly efficient autoregulation so that under steady-state conditions renal blood flow (RBF) is independent of blood pressure over a wide range of pressure. Autoregulation occurs in the preglomerular microcirculation and is mediated by two, perhaps three, mechanisms. The faster myogenic mechanism and the slower tubuloglomerular feedback contribute both directly and interactively to autoregulation of RBF and of glomerular capillary pressure. Multiple experiments have been used to study autoregulation and can be considered as variants of two basic designs. The first measures RBF after multiple stepwise changes in renal perfusion pressure to assess how a biological condition or experimental maneuver affects the overall pressure-flow relationship. The second uses time-series analysis to better understand the operation of multiple controllers operating in parallel on the same vascular smooth muscle. There are conceptual and experimental limitations to all current experimental designs so that no one design adequately describes autoregulation. In particular, it is clear that the efficiency of autoregulation varies with time and that most current techniques do not adequately address this issue. Also, the time-varying and nonadditive interaction between the myogenic mechanism and tubuloglomerular feedback underscores the difficulty of dissecting their contributions to autoregulation. We consider the modulation of autoregulation by nitric oxide and use it to illustrate the necessity for multiple experimental designs, often applied iteratively.

Animals↗
PubMed2007

Interactions contributing to kidney blood flow autoregulation.

PURPOSE OF REVIEW: Autoregulation of renal blood flow has traditionally been considered to stabilize glomerular filtration, and thus tubular load, in the face of blood pressure fluctuations. This view arose because of the contribution of tubuloglomerular feedback, which senses distal tubular fluid composition, to regulation and autoregulation of renal blood flow. Studies have indicated a more important role for the myogenic mechanism. It has been proposed that the 'purpose' of autoregulation is to defend glomerular structure. Both these views may be incomplete because neither takes into consideration the complex interactions between tubuloglomerular feedback and the myogenic mechanism and among nephrons whose afferent arterioles derived from a common interlobular artery. RECENT FINDINGS: Recent findings indicate that it is now indisputable that effective autoregulation is necessary for defense of glomerular structure. Extensive modulation of the myogenic mechanism by tubuloglomerular feedback has been shown using a variety of experimental designs that have illuminated one pathway (neuronal nitric oxide synthase at the macula densa) by which this occurs. SUMMARY: These findings indicate that the myogenic mechanism can no longer be considered as a purely vascular mechanism in the kidney and instead receives information via tubuloglomerular feedback about the status of renal function.

Animals↗
PubMed2006

Genetic determinants of systolic and pulse pressure in an intercross between normotensive inbred rats.

By continuous monitoring of abdominal aortic blood pressure via telemetry in conscious rats, we have observed that systolic, diastolic, and pulse pressures of male Brown-Norway rats were all significantly lower than that of male Wistar-Kyoto rats, despite the fact that all of the values in both strains were within normotensive ranges. Further analyses performed in 166 animals from the progeny of an F2 intercross between Brown-Norway and Wistar-Kyoto rats revealed that, despite a high correlation between systolic blood pressure and diastolic blood pressure, there was no correlation between pulse pressure and diastolic blood pressure, and the value of the correlation between systolic blood pressure and pulse pressure was lower than that of systolic blood pressure with diastolic blood pressure. Two major and highly significant (P<0.001) quantitative trait loci linked to pulse pressure were found on chromosome 4 (Pp1) and 16 (Pp2). Only suggestive quantitative trait loci were found for systolic blood pressure, but the strongest one (Sbp1) had the same peak and linkage probability profile as Pp1. Altogether, these data show that genetic determinants affecting pulse pressure in normotensive animals are either stronger or independent from the ones affecting systolic blood pressure and are of interest in light of evidence showing that pulse pressure is highly heritable in humans and that elevated pulse pressure is a predictor of cardiovascular risk.

Animals↗
PubMed2006

Interactive modulation of renal myogenic autoregulation by nitric oxide and endothelin acting through ET-B receptors.

In rats, nitric oxide modulates renal autoregulation in steady-state experiments and the myogenic mechanism in dynamic studies. Interactive modulation of autoregulation by nitric oxide and endothelin-1, predominantly involving endothelin B receptors, has been reported although it remains unclear whether the interaction is synergistic or obligatory or whether it affects the myogenic component of autoregulation. Nonselective inhibition of nitric oxide synthase (L(omega)-nitro-l-arginine methyl-ester; l-NAME) with endothelin A and B selective receptor antagonists BQ-123 and BQ-788, all infused into the renal artery, plus time series analysis were used to test the interactive actions of nitric oxide and endothelin on renal vascular conductance and on autoregulation. Nonselective endothelin receptor antagonism blunted the constrictor response to subsequent l-NAME but had no effect on previously established l-NAME-induced vasoconstriction. BQ-123 did not affect conductance and caused only minor reduction in myogenic autoregulatory efficiency. Responses to BQ-123 and l-NAME were additive and not interactive. BQ-788 and l-NAME each caused strong vasoconstriction alone and in the presence of the other, indicating that coupling between nitric oxide- and endothelin B-mediated events is not obligatory. l-NAME augmented myogenic autoregulation, and subsequent BQ-788 did not alter this response. However, BQ-788 infused alone also enhanced myogenic autoregulation but resulted in significant impairment of myogenic autoregulation by subsequent l-NAME. Thus the interaction between nitric oxide and endothelin is clearly nonadditive and, because it is asymmetrical, cannot be explained simply by convergence on a common signal pathway. Instead one must postulate some degree of hierarchical organization and that nitric oxide acts downstream to endothelin B activation.

Animals↗
PubMed2005

Tubuloglomerular feedback-dependent modulation of renal myogenic autoregulation by nitric oxide.

Nonselective inhibition of nitric oxide (NO) synthase (NOS) augments myogenic autoregulation, an action that implies enhancement of pressure-induced constriction and dilatation. This pattern is not explained solely by interaction with a vasoconstrictor pathway. To test involvement of the Rho-Rho kinase pathway in modulation of autoregulation by NO, the selective Rho kinase inhibitor Y-27632 and/or the NOS inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) were infused into the left renal artery of anesthetized rats. Y-27632 and l-NAME were also infused into isolated, perfused hydronephrotic kidneys to assess myogenic autoregulation over a wide range of perfusion pressure. In vivo, l-NAME reduced renal vascular conductance and augmented myogenic autoregulation, as shown by increased slope of gain reduction and associated phase peak in the pressure-flow transfer function. Y-27632 (10 mumol/l) strongly dilated the renal vasculature and profoundly inhibited autoregulation in the absence or presence of l-NAME in vivo and in vitro. Afferent arteriolar constriction induced by 30 mmol/l KCl was reversed (-92 +/- 3%) by Y-27632. Phenylephrine caused strong renal vasoconstriction but did not affect autoregulation. Inhibition of neuronal NOS by N(5)-(1-imino-3-butenyl)-l-ornithine (l-VNIO) did not cause significant vasoconstriction but did augment myogenic autoregulation. Thus vasoconstriction is neither necessary (l-VNIO) nor sufficient (phenylephrine) to explain the augmented myogenic autoregulation induced by l-NAME. The effect of l-VNIO implicates tubuloglomerular feedback (TGF) and neuronal NOS at the macula densa in regulation of the myogenic mechanism. This conclusion was confirmed by the demonstration that systemic furosemide removed the TGF signature from the pressure-flow transfer function and significantly inhibited myogenic autoregulation. In the presence of furosemide, augmentation of myogenic autoregulation by l-NAME was significantly reduced. These results provide a potential mechanism to explain interaction between myogenic and TGF-mediated autoregulation.

Amides↗
PubMed2003

Inhibition of cyclooxygenases reduces complement-induced glomerular epithelial cell injury and proteinuria in passive Heymann nephritis.

In the passive Heymann nephritis (PHN) model of rat membranous nephropathy, complement induces glomerular epithelial cell injury and proteinuria, which is partially mediated by eicosanoids. Glomerular cyclooxygenase (COX)-1 and -2 are up-regulated in PHN and contribute to prostanoid generation. In the current study, we address the role of COX isoforms in proteinuria, using the nonselective COX inhibitor indomethacin and the COX-2-selective inhibitor 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone (DFU). Four groups of rats with PHN were treated twice daily, from day 7 through 14 with vehicle, 1 mg/kg DFU, 10 mg/kg DFU, or 2 mg/kg indomethacin. Vehicle-treated rats with PHN showed significant proteinuria on day 14 (163 +/- 15 mg/d, n = 19), compared with normal rats (10 +/- 4 mg/d, n = 3, p < 0.001). Treatment with DFU (1 or 10 mg/kg) reduced proteinuria significantly (by ~33%), compared with vehicle, but to a lesser extent than indomethacin (56% reduction). Glomerular eicosanoid generation was reduced significantly in the DFU and indomethacin groups, compared with vehicle. There were no significant differences among vehicle- or DFU-treated groups in [(3)H]inulin clearance, or in glomerular expression of COX-1 and -2. DFU did not affect the autologous immune response. In cultured rat glomerular epithelial cells, COX inhibition reduced complement-induced cytotoxicity, and this reduction was reversed by the thromboxane A(2) analog 9,11-dideoxy-9alpha,11alpha-methanoepoxyprostaglandin F(2alpha) (U46619). Thus, in experimental membranous nephropathy, selective inhibition of COX-2 reduces proteinuria, without adversely affecting renal function. However, inhibition of both COX-1 and -2 is required to achieve a maximum cytoprotective and antiproteinuric effect.

Actins↗