Showing papers by "Mark E. Cooper published in 1995"

The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the Sprague-Dawley rat

Abstract: Advanced glycation is an important pathogenic mechanism in the development of diabetic complications. However, other biochemical processes, such as the polyol pathway or lipid and protein oxidation which can interact with advanced glycation can also yield tissue fluorescence and may also be implicated in the genesis of diabetic microangiopathy. Aminoguanidine is an inhibitor of advanced glycation, but it is not known if all of its effects are mediated by this mechanism. The present study explores the relative contributions of aldose reductase, oxidative stress and advanced glycation on the development of aortic and renal fluorescence and urinary albumin excretion in streptozotocin diabetic rats. The study groups included non-diabetic (control), streptozotocin diabetic rats and diabetic rats receiving aminoguanidine, the anti-oxidants butylated hydroxytoluene and probucol and the aldose reductase inhibitor, ponalrestat. Serial measurements of glycaemic control and urinary albumin excretion were performed every 8 weeks. At 32 weeks, animals were killed, tissues removed and collagen extracted for measurement of fluorescence. Diabetic rats had increased fluorescence in aorta, glomeruli and renal tubules. Aminoguanidine prevented an increase in fluorescence at all three sites suggesting that diabetes-related tissue fluorescence is predominantly due to advanced glycation. Ponalrestat retarded fluorescence in aorta only and butylated hydroxytoluene attenuated fluorescence at the renal sites but not in the aorta. Diabetic rats had increased renal cortical sorbitol levels. Ponalrestat normalized renal cortical sorbitol levels but aminoguanidine did not affect this parameter. The only agent to decrease plasma thiobarbituric acid reactive substances was butylated hydroxytoluene. Diabetic rats developed albuminuria over the 32-week period.(ABSTRACT TRUNCATED AT 250 WORDS)

A selection strategy to accommodate genotype-by-environment interaction for grain yield of wheat: managed-environments for selection among genotypes.

Abstract: Selection for grain yield among wheat lines is complicated by large line-by-environment (L × E) interactions in Queensland, Australia. Early generation selection is based on an evaluation of many lines in a few environments. The small sample of environments, together with the large L × E interaction, reduces the realised response to selection. Definition of a series of managed-environments which provides discrimination among lines, which is relevant to the target production-environments, and can be repeated over years, would facilitate early generation selection. Two series of managed-environments were conducted. Eighteen managed-environments were generated in Series-1 by manipulating nitrogen and water availability, together with the sowing date, at three locations. Nine managed-environments based on those from Series-1 were generated in Series-2. Line discrimination for grain yield in the managed-environments was compared to that in a series of 16 random production-environments. The genetic correlation between line discrimination in the managed-environments and that in the production-environments was influenced by the number and combination of managed-environments. Two managed-environment selection regimes, which gave a high genetic correlation in both Series-1 and 2, were identified. The first used three managed-environments, a high input (low water and nitrogen stress) environment with early sowing at three locations. The second used six managed-environments, a combination of a high input (low water and nitrogen stress) and medium input (water and nitrogen stress) with early sowing at three locations. The opportunities for using managed-environments to provide more reliable selection among lines in the Queensland wheat breeding programme and its potential limitations are discussed.

Amylin Stimulates Plasma Renin Concentration in Humans

Abstract: Although insulin resistance and hypertension are commonly associated, the underlying cause for this association remains unknown. Plasma concentrations of the recently described hormone amylin, which is cosecreted with insulin by the pancreatic beta cell, are reported to be elevated in various states of insulin resistance, including hypertension and obesity. Preliminary studies by our group have suggested that there are amylin binding sites in the kidney. In nine healthy humans an infusion of human amylin that resulted in steady state plasma amylin levels in the subnanomolar range led to significant increases in plasma renin and aldosterone concentrations. These changes occurred in the absence of significant changes in plasma electrolytes, catecholamines, vasopressin, total renin, or osmolality. Diastolic pressure at 30 minutes and plasma glucose at 60 minutes rose modestly. Since amylin has both metabolic and renal actions, this peptide may be an important link between hypertension, insulin resistance, and the renin-angiotensin system.

Acute renal hemodynamic effects of ACE inhibition in diabetic hyperfiltration: role of kinins.

Abstract: Angiotensin converting enzyme (ACE) inhibitors not only reduce angiotensin II (ANG II) levels but also inhibit kinin degradation. The relative roles of ANG II and bradykinin in the acute action of ACE inhibitors on renal hemodynamic parameters in rats after 3 wk of diabetes were explored using antagonists of the ANG II type 1 (AT1) and the bradykinin B2 receptors. Conscious control and streptozotocin diabetic male Sprague-Dawley rats were randomized to receive vehicle, the ACE inhibitor, ramiprilat, the B2-receptor blocker, HOE-140, the AT1-receptor blocker, valsartan, or the combination of ramiprilat and HOE-140. Systolic blood pressure, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction and urinary flow, and sodium excretion were assessed before and during treatment. Diabetic animals had higher GFR and a tendency toward increased RPF and filtration fraction compared with control animals. Acute ramiprilat infusion decreased GFR significantly in diabetic but not in control animals. Valsartan and the combination of ramiprilat and HOE-140 reduced blood pressure to a similar degree to ramiprilat alone, yet did not reduce GFR. No decrease in GFR was observed in any control rat groups. Ramiprilat decreased RPF in diabetic rats but increased RPF in control rats. No such effects on RPF were observed with valsartan. HOE-140 alone did not influence any renal parameter in the diabetic rats. Diabetic rats had increased urinary flow and sodium excretion, but these parameters were not influenced by any drug regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Inheritance of osmotic adjustment to water stress in three grain sorghum crosses

Abstract: Water stress is one of the major constraints to the grain yield of sorghum in tropical and sub-tropical areas of the world. Osmotic adjustment has been widely proposed as a plant attribute that confers adaptation to water stress. The inheritance of osmotic adjustment to water stress was investigated in a series of generations derived from the three possible bi-parental crosses between two inbred sorghum lines with a high capacity for osmotic adjustment (Tx2813 and TAM422; high-OA lines) and one with a low capacity (QL27; low-OA line). Broad-sense heritability on a single-plant basis was generally found to be high. Analysis of segregation ratios by the mixture method of clustering identified two independent major genes for high osmotic adjustment. The line Tx2813 possessed a recessive gene which is given the symbol oa1; the line TAM422 possessed an additive gene which is given the symbol OA2. There was some evidence that there may be other minor genes which influence the expression of osmotic adjustment in these crosses as two putative transgressive segregants, with higher osmotic adjustment than the parents, were identified from the cross between Tx2813 and TAM422. Populations of recombinant inbred lines were developed and characterised for osmotic adjustment for two of the crosses (QL27 x TAM422, low-OA x high-OA; Tx2813 x TAM422, high-oal x high-OA2). These will be used to conduct experiments which test hypotheses about the contribution of the high-osmotic-adjustment genes to the grain yield of sorghum under a range of water-stress conditions.

Angiotensin-converting enzyme inhibition reduces diabetes-induced vascular hypertrophy: morphometric studies.

Abstract: Angiotensin-converting enzyme (ACE) activity and vascular mass are both increased in the mesenteric arteries of diabetic rats. As vascular hypertrophy may result from smooth muscle growth following increased formation of angiotensin II, we have examined the histological nature of the increase in mesenteric arterial mass and the role of elevated ACE activity in diabetic vascular hypertrophy by administration of an ACE inhibitor (perindopril). Cross-sectional area of the media was measured in perfusion-fixed mesenteric vessels of diabetic rats 3 weeks after streptozotocin injection. The media was significantly larger (63%) in mesenteric vessels of diabetic rats compared to age-matched control animals. Medial hypertrophy in these vessels was not associated with increased blood pressure or plasma renin activity but there was evidence for increased hemodynamic load due to hyperphagia and intestinal enlargement. Increased mesenteric ACE activity was involved in this process as there was significant inhibition of medial hypertrophy by perindopril. Other markers of cardiovascular hypertrophy such as left ventricular weight and aortic medial area were less affected, but increased in the diabetic group when corrected for significant body weight effects, consistent with a systemic influence of diabetes on cardiovascular mass. These data provide new insights into the mechanisms of vascular complications of diabetes and may have implications for the use of ACE inhibitors in preventing or arresting diabetes-associated vascular pathology.

Vascular changes in the diabetic kidney: effects of ACE inhibition.

Abstract: The effects of angiotensin-converting enzyme (ACE) inhibition with perindopril on renal vascular structure were studied in control and streptozotocin diabetic male Sprague-Dawley rats after 3 weeks. After kidneys were perfusion-fixed at systolic blood pressure, morphometric analysis of vascular structural changes in the media of the renal vasculature at the cortico-medullary junction was performed. Vascular hypertrophy was present in the diabetic vessels, as assessed by an increase in medial cross-sectional area for a given lumen size. This relative increase in medial area was prevented by perindopril treatment, consistent with an antitrophic effect on diabetic kidney vessels by ACE inhibition. The diabetic kidney had an increased proportion of small vessels less than 50 μm diameter at the cortico-medullary junction, perhaps representing diabetes induced angiogenesis. This subpopulation of vessels was reduced in number after perindopril treatment. Our data support a role for increased activity of angiotensin converting enzyme as a mechanism for vascular hypertrophy, which may be involved in the pathogenesis of diabetic vasculopathy and nephropathy.

Variation among low rainfall white clover (Trifolium repens L.) accessions for morphological attributes and herbage yield

Abstract: The importance of passport data on rainfall at collection sites of accessions as a guide to identifying germplasm to be used in the genetic improvement was assessed by using 40 white clover accessions from the germplasm collection at Glen Innes, New South Wales. This set together with 2 standard cultivars, Haifa and Huia, were evaluated in the field. The objectives were to: (i) estimate the magnitude of genotypic variation among accessions for morphological attributes and herbage yield in a dryland summer rainfall environment; and (ii) compare estimates of genotypic variation for, and correlations among, the attributes and herbage yield for the 40 accessions with results from a study based on a random sample of accessions from the same collection. Herbage yield was measured in 4 seasons (autumn 1992-summer 1993) together with stolon and other plant attributes which were measured in 1 season (summer 1993). There was significant (P<0.05) variation for herbage yield among accessions. Hierarchical agglomerative classification was used to group the accessions based on herbage yield. This identified a single member group with greater herbage yield than the 2 groups which contained the cultivars Haifa and Huia. There was no association between the composition of the accession groups identified by classification and the passport data on average annual rainfall at the collection sites of accessions. There was some consistency between the estimates of repeatability, genotypic variation and genotypic correlations obtained from the low rainfall set of accessions used in this study and the random sample previously examined. It was concluded that selection of accessions from the collection for use in genetic improvement of herbage yield and the morphological attributes for dryland summer rainfall environments of the Northern Tablelands of New South Wales, should not be confined to specific groups originating from low rainfall regions.

Diabetes and hypertension: prognostic and therapeutic considerations.

Abstract: Hypertension and diabetes are common disorders which frequently co-exist. Both are risk factors for atherosclerotic vascular disease and their combination is associated with an increased incidence of nephropathy, ischaemic heart disease, peripheral vascular disease, and stroke. Several trials such as the HDFP and SHEP studies that included diabetic patients have demonstrated the beneficial effects of antihypertensive therapy in reducing mortality. In diabetes, studies have focussed predominantly on the efficacy of antihypertensive therapy in reducing the progression of diabetic kidney disease. Such therapy has been shown to decrease albuminuria in the setting of "normal" and elevated blood pressure in both type I and type II diabetic patients. This reduction in albuminuria has been observed in microalbuminuric diabetic patients and also in those with overt renal disease. Recent studies in type I diabetic patients with overt nephropathy indicate that these effects on urinary albumin excretion are associated with reduction in the rate of decline in renal function and development of end-stage renal failure. Indeed, several groups have shown that the initiation of antihypertensive therapy improves the prognosis of type I diabetic patients with nephropathy. While certain classes of drugs may reduce the rate of progression of complications such as nephropathy, others have side effect profiles that are disadvantageous in patients with diabetes.

Diabetic vascular hypertrophy and albuminuria: Effect of angiotensin converting enzyme inhibition

Abstract: The role of angiotensin-converting enzyme (ACE) inhibition with ramipril on mesenteric vascular hypertrophy and urinary albumin excretion was explored in a normotensive model of experimental diabetes. Serial measurements of albuminuria were performed in Sprague-Dawley control, diabetic rats, and diabetic rats treated with ramipril. Over 24 weeks, urinary albumin excretion showed a continuous rise in the untreated diabetic rats. Ramipril prevented the increase in albuminuria over the whole study period. After 6 months, animals were perfused with glutaraldehyde and sacrificed for measurement of mesenteric vessel wall/lumen ratio and kidney weight. Diabetes was associated with increased mesenteric wall/lumen ratio and kidney weight. ACE inhibition, despite no effect on glycemic control, attenuated mesenteric vascular hypertrophy but did not decrease kidney weight. In addition to the well-described renoprotective effects of ACE inhibition in diabetes, this class of agents may have a favorable effect on diabetic vascular disease.

Inheritance of anthracnose resistance in the tropical pasture legume Stylosanthes hamata

Abstract: Eight tetraploid accessions of the tropical pasture legume Stylosanthes hamata with varying levels of response to the anthracnose pathogen (Colletotrichum gloeosporioides) were crossed in a half diallel scheme. Based on mean disease severity ratings (MDR), two parents, 55830 and 75164, were grouped as resistant (R), 55828 and 65365 were susceptible (S), and the remaining four, cvv. Verano and Amiga and 65371 and 75162 were moderately resistant (MR). Of these, the two resistant parents appear to carry different genes for resistance. The MDR of 20 of the 28 F2 populations was significantly different from their mid-parent MDR and the expression of resistance, in most cases, was recessive. Only a limited number of the F2 distributions for crosses between RxS, RxMR and MRxS parents conformed to a single gene model. The inheritance patterns observed were considered to be predominantly quantitative. Variation for general combining ability, was as large as or larger than that for specific combining ability suggesting that a large proportion of the genetic differences among the parents was additive. The finding that the resistance is inherited as a quantitative trait is consistent with results on the epidemiology of anthracnose in tetraploid S. hamata.

Vascular albumin permeability and hypertrophy in a rat model combining streptozotocin-induced diabetes and genetic hypertension.

Abstract: Objective : To investigate the effects of hypertension and diabetes mellitus on vascular albumin permeability and hypertrophy in 11-week-old Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) with and without 3 weeks of streptozotocin-induced diabetes. Methods : Vascular albumin permeability was measured as tissue content of intravenously injected Evans blue dye. Results : Diabetic rats showed hypertrophy of the kidneys, and hypertensive rats showed hypertrophy of the heart. In the mesenteric artery there was an additive hypertrophic effect of diabetes and hypertension. The Evans blue content in kidneys was higher in diabetic SHR than in diabetic and in control WKY rats. The kidney : plasma Evans blue ratio was higher in diabetic SHR than in the other three groups, and the heart : plasma Evans blue ratio was higher in diabetic SHR than in control WKY rats or control SHR. The Evans blue content and tissue : plasma Evans blue ratio did not differ in aorta, mesenteric artery or skeletal muscle among the groups. There was no positive correlation between vascular albumin permeability and hypertrophy in any of the tissues studied. Conclusions : There was no relationship between vascular albumin permeability and hypertrophy, but increased vascular albumin permeability was found in kidneys and hearts of rats with both diabetes and hypertension. This suggests an additive or synergistic effect of diabetes and hypertension in producing vascular changes.

Natural history of early diabetic nephropathy: What are the effects of therapeutic intervention?

Abstract: Several studies have shown that lowering of blood pressure slows the rate of progression of diabetic renal disease. Some placebo-controlled studies have also shown that angiotensin-converting enzyme (ACE) inhibitors decrease or stabilize albuminuria in incipient nephropathy and slow the rate of progression of advanced nephropathy. However, it is not yet clear if prolonged treatment with ACE inhibitors or with other agents exerts a specific renoprotective effect in incipient diabetic nephropathy. It is proposed that such an effect should be independent from changes in systemic blood pressure and should be characterized by amelioration of the rate of rise of albumin excretion rate (AER) and the rate of fall of glomerular filtration rate (GFR) and independence from changes in other parameters known to influence AER (glycemic control, protein intake, sodium intake). In addition, there should be evidence that the potentially reversible effects of therapeutic intervention on AER and GFR are translated to long-term changes in renal function and structure. This paper reviews the evidence on which the concept of renoprotection is based, with particular reference to choice of end points, heterogeneity of study groups, and complexities of the disease process, and relates this evidence to the natural history of nephropathy in type I and type II diabetes. Based on the above, an assessment is made of the comparative effects of ACE inhibitors and other antihypertensive agents on AER and GFR. It is suggested that longitudinal intra-individual analysis of both variables may be necessary in order to determine whether ACE inhibitors exert greater renoprotection than calcium channel blockers or other antihypertensive agents.