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The p66ShcA protein controls cellular responses to oxidative stress, senescence, and apoptosis. Here, we test the hypothesis that aging phenotype(s) commonly associated with the broad category of chronic kidney disease are accelerated in diabetic kidneys and linked to the p66ShcA locus. At the organ level, tissue stem cells antagonize senescent phenotypes by replacing old dysfunctional cells. Using established methods, we isolated a highly purified population of stem cell antigen-1-positive mesenchymal stem cells (Sca-1+ MSCs) from kidneys of wild-type (WT) and p66 knockout (p66 KO) mice. Cells were plated in culture medium containing normal glucose (NG) or high glucose (HG). Reactive oxygen species (ROS) metabolism was substantially increased in WT MSCs in HG medium in association with increased cell death by apoptosis and acquisition of the senescent phenotype. DNA microarray analysis detected striking differences in the expression profiles of WT and p66 KO-MSCs in HG medium. Unexpectedly, the analysis for p66 KO-MSCs revealed upregulation of Wnt genes implicated in self-renewal and differentiation. To test the in vivo consequences of constitutive p66 expression in diabetic kidneys, we crossed the Akita diabetic mouse with the p66KO mouse. Homozygous mutation at the p66 locus delays or prevents aging phenotype(s) in the kidney that may be precursors to diabetic nephropathy [ABSTRACT FROM AUTHOR]

Activation of the protein kinase C (PKC) family is a potential signaling mechanism by which high ambient glucose concentration modulates the phenotype and physiological function of cells. Recently, the cardiac renin angiotensin system (RAS) has been reported to promote PKC translocation in the diabetic heart via the angiotensin (ANG) II type 1 receptor (AT-1R). To evaluate the molecular events coupled with high glucose-induced PKC translocation and to examine the role of endogenously released ANG II in myocyte PKC signaling, primary cultures of adult rat ventricular myocytes were exposed to normal (5 mmol/l) or high (25 mmol/l) glucose for 12-24 h. Western blot analysis indicated that adult rat ventricular myocytes coexpress six PKC isozymes (alpha, beta(1,) beta(2,) delta, epsilon, and zeta). Translocation of five PKC isozymes (beta(1), beta(2), delta, epsilon, and zeta) was detected in response to 25 mmol/l glucose. Inhibition of phospholipase C with tricyclodecan-9-yl-xanthogenate blocked glucose-induced translocation of PKC-beta(2), -delta, and -zeta. Inhibition of tyrosine kinase with genistein blocked glucose-induced translocation of PKC-beta(1) and -delta, whereas chelation of intracellular Ca(2+) with 1,2-bis(2-aminophenoxy)ethane N,N,N,'N'-tetraacetic acid blocked translocation of PKC-beta(1) and -beta(2). Enzyme-linked immunosorbent assay performed on culture media from myocytes maintained in 25 mmol/l glucose detected a twofold increase in ANG II. Addition of an AT-1R antagonist (losartan; 100 nmol/l) to myocyte cultures blocked translocation of PKC-beta(1), -beta(2), -delta, and -epsilon. Phosphorylation of troponin (Tn) I was increased in myocytes exposed to 25 mmol/l glucose. Losartan selectively inhibited Tn I serine phosphorylation but did not affect phosphorylation at threonine residues. We concluded that 1) 25 mmol/l glucose triggers the release of ANG II by myocytes, resulting in activation of the ANG II autocrine pathway; 2) differential translocation of myocyte PKC isozymes occurs in response to 25 mmol/l glucose and ANG II; and 3) AT-1R-dependent PKC isozymes (beta(1), beta(2), delta, and epsilon) target Tn I serine residues. [ABSTRACT FROM AUTHOR]

The PKC family of serine/threonine kinases have been implicated in a diverse array of cellular responses. Adult cardiac myocytes express multiple PKC isozymes, which participate in the response of muscle cells to extracellular stimuli, modulate contractile properties, and promote cell growth and survival. Recently, the classification of this ubiquitous family of signaling molecules has been expanded from three to four subfamilies. This review will focus on the application of pharmacologic and molecular approaches to explore the biology of cardiac PKC isozymes. The availability of transgenic mice and peptide PKC modulators have been instrumental in identifying target substrates for activated cardiac PKC isozymes, as well as the identification of specific isozymes linked to distinct growth characteristics and cell phenotype. The rapid growth of knowledge in the area of PKC signaling and PKC substrate interactions, may result in the development of therapeutic modalities with the potential to arrest or reverse the progression of cardiovascular diseases.

Constitutive overexpression of insulin-like growth factor-1 (IGF-1) in myocytes protects them from apoptosis and interferes with myocyte hypertrophy in the normal and pathological heart. Conversely, angiotensin II (Ang II) triggers cell death and promotes myocyte hypertrophy. Moreover, activation of p53 upregulates the cellular renin-angiotensin system (RAS). Therefore, IGF-1 overexpression in FVB.Igf+/- mice may downregulate the local RAS through the attenuation of p53 and p53-inducible genes. On this basis, p53 DNA binding activity to angiotensinogen (Aogen), bax, and the AT1 receptor was determined in left ventricular myocytes from FVB.Igf-/- and FVB.Igf+/- mice. The quantity of Bax, Bcl-2, Aogen, and AT1 receptor in these cells was evaluated. The presence of Mdm2-p53 complexes was also established. Finally, Ang II levels in myocytes were measured. Upregulation of IGF-1 in myocytes was associated with a protein-to-protein interaction between Mdm2 and p53, which attenuated p53 transcriptional activity for bax, Aogen, and AT1 receptor. Similarly, the amount of Bax, Aogen, and AT1 receptor proteins in these cells decreased. In contrast, the expression of Bcl-2 remained constant. The downregulation of Aogen in myocytes from FVB.Igf+/- mice was characterized by a reduction in Ang II. In conclusion, IGF-1 negatively influences the myocyte RAS through the upregulation of Mdm2 and its binding to p53. This may represent the molecular mechanism responsible for the effects of IGF-1 on cell viability and myocyte hypertrophy in the nonpathological and pathological heart in vivo.

Essential hypertension affects more than 40 million Americans, or one in four adults. The prevalence of hypertension is greater among the African-American population, with a distressingly high rate of end-organ complications. Although diabetes mellitus has surpassed hyper tension as the dominant etiology of end-stage renal disease in the United States, kidney failure secondary to hypertensive nephrosclerosis remains a significant problem, particularly among African Americans. During the past decade, a shift in the paradigm for the renin-angiotensin system (RAS) has evolved from a circulating vasoactive cascade toward angiotensin II (ANG II) formation at the cellular level. The molecular components of the RAS have been identified in cells, documenting the existence of an autocrine tissue RAS, as well as the presence of enzymes, which catalyze the formation of ANG II by angiotensin-converting-enzyme-independent pathways, providing new targets for therapeutic intervention. The latter challenge has important clinical implications, in view of recent evidence implicating ANG II in pathologic cell growth and cell death and fundamental events in the remodeling of the vascular wall and myocardium in the setting of hypertension. This review focuses on ANG II as a major determinant of end-organ damage in essential hypertension; the benefits of ANG II blockade at the end-organ level, which appear to be independent of the blood pressure-lowering effect; and the emerging role for ANG II receptor antagonists as first-line agents in the treatment of essential hypertension.

To determine whether angiotensin II (Ang II) can induce apoptosis of neonatal ventricular myocytes, these cells were exposed to 10(-9) M Ang II for 24 h in vitro and the effects of this intervention on programmed myocyte cell death were examined by the terminal deoxynucleotidyl transferase assay and DNA gel electrophoresis. Ang II resulted morphologically in a 2.5-fold increase in the percentage of myocytes with double strand cleavage of the DNA and biochemically in the formation of DNA fragments equal in size to mono- and oligonucleosomes. Moreover, Ang II stimulation was characterized by a 37% increase in resting level of intracellular calcium and the activation of calcium-dependent endogenous endonuclease. In contrast, pH-dependent endogenous endonuclease was not enhanced by the addition of Ang II. Ang II-induced DNA damage was inhibited by the AT1 receptor antagonist, losartan. Similarly, the calcium chelator, BAPTA-AM, prevented Ang II-mediated cell death. Conversely, the calcium ionophore, A23187, triggered programmed cell death. Finally, the selective AT2 receptor subtype blocker, PD123319, failed to reduce myocyte apoptosis. In conclusion, ligand binding of AT1 receptors may initiate programmed myocyte cell death via an elevation in cytosolic calcium and the stimulation of calcium-dependent endogenous endonuclease.

To determine whether angiotensin II (Ang II) activates the suicide program of myocytes, primary cultures of adult rat ventricular myocytes were exposed to 10(-9) M of Ang II, for 24 h. Ang II resulted in a five-fold increase in programmed myocyte cell death (PMCD) documented by the terminal deoxynucleotidyl transferase assay and confirmed by DNA agarose gel electrophoresis. Ang II stimulation was associated with translocation of the epsilon and delta isoforms of protein kinase C (PKC) which was coupled with an increase in cytosolic Ca2+ in the cells. The PKC inhibitor chelerythrine abolished Ang II-mediated increases in cytosolic Ca2+ and PMCD. Similarly, pretreatment of cells with the intracellular Ca2+ chelator BAPTA/AM inhibited the formation of DNA strand breaks. Conversely, the Ca2+ ionophore A23187 markedly increased PMCD. Finally, the AT1 receptor antagonist, losartan, completely blocked Ang II-induced PMCD, whereas the AT2 receptor antagonist, PD123319, did not attenuate this phenomenon. In conclusion, ligand binding of AT1 receptors on myocytes triggers PMCD by a mechanism involving PKC-mediated increases in cytosolic calcium, which result in internucleosomal DNA fragmentation.

Objective: The purpose of this study was to determine whether the early chronic ischemic cardiomyopathy produced by non-occlusive coronary artery constriction was characterized by alterations in the regulation of beta-adrenoreceptor (beta-AR) signaling., Methods: Coronary artery narrowing was surgically induced in rats and the animals sacrificed at 7 and 14 days. The changes in the biochemical properties of the multiple components of the beta-AR pathway were examined in enzymatically dissociated myocytes., Results: Coronary stenosis, involving an average 55% reduction in luminal diameter, was associated with left ventricular failure and right ventricular dysfunction at both time intervals. A decrease in the quantity of beta-AR was detected at 7 days and preceded the loss of high-affinity binding sites. This regulatory modification was characterized by a reduction in beta 1 and beta 2 receptors and a shift in the isoproterenol dose response curve indicating a functional correlation between the decrease in beta-AR and attenuated inotropic support of the myocardium. The percentage of beta-AR binding agonist with high affinity decreased significantly at 14 days along with a further reduction in the density of beta 1 and beta 2 receptors. Reconstitution studies with cyc S49 lymphoma cells did not detect an impairment of Gs alpha functional activity, but the quantity of Gi alpha was increased at both intervals. Finally, activation of the catalytic unit of adenylyl cyclase by forskolin and GTP was not altered by coronary stenosis, however, basal cyclic AMP in myocytes was depressed at 14 days., Conclusions: Coronary stenosis induces distinct and progressive modifications in the beta-AR signaling cascade which may contribute to the impaired ventricular performance in this model of myocardial ischemia.

Objective: To determine whether alpha 1 adrenergic receptor mediated myocyte contractility and growth are depressed acutely after non-occlusive coronary artery narrowing, the left coronary artery was constricted in rats and mechanical behaviour, cytosolic calcium, and regulation of alpha 1 adrenergic receptors were examined in myocytes seven days later., Methods: Coronary artery stenosis was surgically induced in rats and following the estimation of global cardiac performance myocytes were enzymatically dissociated and radioligand binding studies were performed. In addition, the isotonic contractile performance, cytosolic calcium transients and noradrenaline stimulated inositol phosphate generation in myocytes were measured in the presence of WB 4101 or after chlorethylclonidine treatment., Results: Estimations of cell mechanics in vitro established that peak shortening was decreased by 36% and 18% in left and right ventricular myocytes of coronary stenosed rats. Time to peak shortening was prolonged by 29% in left and 20% in right myocytes, whereas velocity of shortening was decreased by 27% in left myocytes. These alterations were associated with increases in cell length and width, indicative of myocyte hypertrophy. In addition, coronary stenosis was accompanied by reductions in the expression of alpha 1a and alpha 1b receptor subtypes in myocytes. alpha 1 Adrenergic receptor density and noradrenaline stimulated phosphoinositol turnover were decreased by 30% and 34% in left myocytes. alpha 1a Adrenergic receptor subtype mediated cytosolic calcium concentration and myocyte mechanical performance were also impaired in left myocytes only. The alpha 1a adrenergic receptor subtype antagonist WB 4101 abolished noradrenaline stimulated inositol phosphate generation in myocytes, whereas chlorethylclonidine at large doses only partially inhibited this response., Conclusions: In conclusion, coronary narrowing leads to defects in the regulation of alpha 1 adrenergic receptors on myocytes which are coupled with attenuation in the transmission of signals, possibly affecting myocyte cell function and ongoing reactive cellular hypertrophy.

To determine whether cardiac unloading by inhibition of angiotensin I (AI) to AII conversion by captopril or blockade of the AII receptor (AT1) by losartan was more effective in prevention of the detrimental hemodynamic consequences of myocardial infarction (MI), inhibition of metabolic production of AII by captopril was compared with blockade of AT1 with losartan in Sprague-Dawley rats with large MI. Infarcts were created by surgical occlusion of the left main coronary artery and oral drug therapy initiated immediately and continued until hemodynamic evaluation seven days later. Heart weight was unchanged in untreated infarcted animals, whereas captopril reduced heart weight in control animals and losartan increased heart weight in infarcted animals. Left ventricular (LV) peak systolic blood pressure (SBP) was lower in treated and untreated infarcted animals. Although captopril reduced end-diastolic pressure (EDP) to a greater degree than losartan, all infarcted group showed an increase in this parameter with respect to similarly treated controls. LV peak rates of pressure increase and decay in infarcted hearts were decreased significantly more by captopril than by losartan administration. Captopril also impaired right side cardiac function more than losartan when peak rate of pressure increase was evaluated. Thus, inhibition of the effects of AII during cardiac failure improved but did not normalize cardiac pump performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Approximately 50% of the annual mortality in patients with end-stage renal disease (ESRD) is attributed to cardiovascular-related events. Multiple factors, including volume overload, hypertension, electrolyte abnormalities, and the presence of comorbid diseases, such as diabetes mellitus, may have an adverse effect on left ventricular function in ESRD. The purpose of this brief review is to advance the hypothesis that parathyroid hormone (PTH) is a cardiotoxin and a potential mediator of cardiac dysfunction in uremia. Recent studies have provided evidence that cardiocytes possess a distinct class of binding sites for PTH, and the PTH receptor has recently been cloned. Furthermore, the PTH receptor may be coupled to more than one effector pathway. Finally, the possibility that a PTH-related protein autocrine system may be present in cardiocytes and the implications of this signaling pathway on cardiocyte function are discussed.

To determine the effects of acute myocardial infarction on the expression of insulin-like growth factor1 (IGF1) and insulin-like growth factor1 receptors (IGF-1R) on the surviving myocytes of the left and right ventricles, large infarcts were produced in rats and the animals sacrificed 2 days later. Hemodynamic measurements of left and right ventricular pressures, +dP/dt and -dP/dt, and central venous pressure documented that coronary occlusion was associated with a severe impairment of cardiac function. By employing reverse transcriptase polymerase chain reaction (RTPCR), a low level of expression of IGF-1R mRNA was detected in myocytes from sham-operated rats. Acute myocardial infarction was found to enhance by nearly twofold the message for IGF-1R in viable myocytes biventricularly. Moreover, IGF1 mRNA increased 4.3-fold and 9.4-fold in left and right myocytes, respectively. In order to establish whether the upregulation of IGF1 and IGF-1R with infarction was coupled with induction of late growth related genes, which are known to be implicated in DNA replication and mitotic division, proliferating cell nuclear antigen (PCNA) and histone-H3 expression was assessed by Northern blot and RTPCR. The level of expression of PCNA mRNA was found to be increased 3.9-fold and 2.4-fold in left and right myocytes, respectively from infarcted hearts. Corresponding increments in histone-H3 mRNA were 25.5-fold and 5.3-fold, respectively. However, PCNA protein as detected by immunoperoxidase staining was restricted to a limited number of myocyte nuclei adjacent to the necrotic myocardium of the left ventricle. In conclusion, acute myocardial infarction is associated with enhanced expression of IGF1 and IGF-1R on stressed myocytes, and this phenomenon may activate genes essential for DNA synthesis, possibly affecting myocyte growth. These processes may be fundamental for the reconstitution of tissue mass and amelioration of function after infarction.

Objective: To determine the effects of increased sympathetic nervous system activity in humoral hypertension on the regulation of surface alpha 1 adrenoceptors and signal transduction, deoxycorticosterone acetate (DOCA) salt hypertension was induced in rats and the animals killed three weeks following the initiation of hypertension., Methods: Experiments were performed on male Sprague-Dawley rats, weighing 250-300 g, divided into two groups: DOCA-salt (n = 75), and control (n = 60). Radioligand binding studies of the alpha 1 adrenoceptors, noradrenaline stimulated phosphoinositol turnover, ADP ribosylation of 41 kD substrate by pertussis toxin, and myocardial noradrenaline content were measured in the ventricular myocardium. The expression of sarcomeric actin isoforms was examined by northern blot and hybridisation with specific oligonucleotide probes., Results: The density of alpha 1 adrenoceptors was decreased by 51% in DOCA-salt treated rats. However, noradrenaline stimulated phosphoinositol turnover in myocytes from DOCA-salt hearts was not diminished. The relative quantities of pertussis toxin labelled substrates did not differ in experimental and control hearts. Myocardial noradrenaline content was reduced by 60% in DOCA-salt hearts. Northern blots on RNA extracted from hypertrophic hearts of DOCA-salt treated rats showed an upregulation of alpha skeletal actin., Conclusions: The adrenergic state present in short term DOCA-salt hypertensive hypertrophy is characterised by enhanced signal transduction via the alpha 1 adrenoceptors and the re-expression of alpha skeletal actin in enlarging myocytes.

We have previously reported downregulation of the vascular alpha 1-receptor in the 5/6 renal ablation model. In this investigation we have examined the adaptive response of the heart following 5/6 renal ablation. Renal ablated and sham rats were maintained under identical conditions for 6 weeks. Despite the presence of systemic hypertension in renal ablated rats (185 +/- 10 mm Hg, P less than .01), heart weight did not differ from sham. [125I] +/- CYP binding was performed and myocardial norepinephrine (NE) content determined to evaluate myocardial sympathetic neuroeffector mechanisms. Scatchard analysis and 1-isoproterenol competition curves did not reveal a difference in the binding properties of the myocardial beta-receptor. No difference in myocardial NE was found in renal ablated and sham rats. Unexpectedly, 1-isoproterenol stimulation of adenylate cyclase was impaired in renal ablated rats (32.6 +/- 6 v 58.6 +/- 5 pmol/mg/min, P less than .01) and the dose response curve shifted to the right. We conclude that despite systemic hypertension an adaptive hypertrophic response was not present in hearts of renal ablated rats; myocardial sympathetic neuroeffector mechanisms are not altered in this model; and impaired stimulation of adenylate cyclase appears to be the result of a post-receptor defect.

Hypotheses concerning angiotensin's role in states characterized by severe and sustained renal vasoconstriction, must account for the poorly sustained renal response to this agent in healthy animals and man. To assess the specificity of renal vascular tachyphylaxis to angiotensin II (AII), renal blood flow was measured with an electromagnetic flowmeter in eight anesthetized dogs. Bolus injections of AII and norepinephrine into the renal artery were adjusted to produce at least a 50% reduction in renal blood flow, and were followed by a continuous infusion of AII sufficient to reduce renal blood flow acutely by 60 +/- 10%. The response to the continuous infusion was poorly sustained, blood flow returning to near baseline within 10 minutes: At this time the response to bolus administration of AII was lost, but the response to norepinephrine was sustained. At 30 minutes the response to norepinephrine was also reduced, and there was no response in three of the eight dogs. After stopping the AII infusion, renal vascular responsiveness to norepinephrine returned almost immediately, but 30-60 minutes were required before responsiveness to AII was restored. We conclude that there is true, specific renal vascular tachyphylaxis to AII--which may well reflect receptor modulation or occupation--and that with time an additional, non-specific vasodilator mechanism can come into play.

Radiographic contrast media (CM) (meglumine/sodium diatrizoate-76%; 1650 mOsm/kg) and other hypertonic solutions induce renal vasoconstriction by an unknown mechanism. In anesthetized dogs, renal blood flow (RBF) was measured with an electromagnetic flowmeter and filtration fraction (FF) and glomerular filtration rate (GFR) by the renal extraction of technetium-99m tin chelate. Ureteral pressure (UP) and wedged renal venous pressure (VP) were measured as indices of intrarenal pressure. Measurements of renal length (L), along with pressures, made it possible to examine the compliance of the system. A 4-cc intrarenal bolus of CM caused a 59% reduction in GFR (control: 0.63 +/- 0.04 to 0.26 +/- 0.04 ml/min X g, mean +/- SEM), in association with a 23% reduction in RBF (control: 3.10 +/- 0.11 to 2.39 +/- 0.26 ml/min X g) and a 44% decrease in FF (control: 0.32 +/- 0.01 to 0.18 +/- 0.03). These responses were compared with a 3-microgram intrarenal bolus of norepinephrine (NOREPI) which resulted in a 79.0 +/- 7.5% reduction in RBF, 68.3 +/- 7.3% reduction in GFR and 42.6 +/- 15.6% increase in FF. The NOREPI-induced vasoconstriction caused transient decreases in renal L, UP, and VP, whereas the CM-induced decrease in renal blood flow was associated with increases in these parameters. In studies employing ureteral occlusion to elevate intrarenal pressure, the magnitude (area, cm2) of the CM-induced decrease in renal perfusion was accentuated with increased UP (r = 0.79, n = 24, P less than 0.001). The CM-induced increase in renal L, UP, and VP must reflect osmotic forces and an increase in intrarenal pressure. The decreases in FF and GFR probably reflect Starling forces in the glomerular capillaries, with osmotic transients dominating. The results suggest a mechanical mechanism for the CM-induced decrease in RBF.

Dietary sodium and the myocardial alpha 1-receptor have been implicated in the hypertrophic response of myocardial tissue. Alterations in sodium homeostasis have been demonstrated to influence sympathetic nervous function, centrally and peripherally. In this investigation, we have examined the effect of dietary sodium on the development of myocardial hypertrophy; and the role of sympathetic neuroeffector mechanisms in the hypertrophic response. Studies were performed in three groups of uninephrectomized rats: A-regular diet; B-1% saline/regular diet; C-1% Saline/doca/regular diet. Groups A and B did not develop systemic hypertension (SHT). Saline treatment increased heart weight and the density of surface alpha 1-receptors; myocardial norepinephrine (NE) was reduced. Group C developed SHT. Heart weight was greatest in Group C; and myocardial NE was severely depleted. Downregulation of myocardial alpha 1-receptors, a finding consistent with the hyperadrenergic state, was observed in Group C. Our results suggest dietary sodium may modulate hypertrophic response in myocardial tissue, by altering sympathetic neuroeffector mechanisms.

Adrenergic dysfunction in uremia has been well described. Several lines of evidence suggest disorders of blood pressure regulation and myocardial response may occur secondary to adrenergic dysfunction; attenuated pressor response to norepinephrine (NE) in uremia; attenuated chronotropic responses during dialysis induced hypotension. Since the adrenergic receptors are the effector component of the adrenergic nervous system, we have employed the partially nephrectomized uremic rat, to examine the effect of chronic uremia (4-6 weeks) on the binding properties of alpha 1 receptors in rat mesenteric artery and myocardial tissue. The results indicate that moderate levels of uremia alter the binding properties of both the alpha 1 vascular and myocardial receptor.

In this investigation we describe regulation of the vascular alpha-1 receptor and functional properties of resistance vessels in malignant hypertensive DOCA-salt rats (DOCA-salt). Uninephrectomized control and DOCA-salt rats were maintained for 6 weeks; microscopic renal morphology provided an index of vascular injury. Radioligand binding studies indicated a striking increase in the density of mesenteric alpha-1 binding sites in DOCA-salt (542 +/- 44 fm/mg) vs. salt control (206 +/- 4 fm/mg) and water control (223 +31 fm/mg) P less than .01. The affinity of the receptor for the radioligand [125I] (+/-) BE 2254 was reduced in DOCA-salt rats. Electrical nerve stimulation and agonist dose response curves were performed on isolated perfused mesenteric arteries. A singular correlation between increased receptor density and vascular responses in DOCA-salt rats could not be demonstrated. The norepinephrine (NE) content of mesenteric arteries was reduced in DOCA-salt (1001 +/- 32 ng/g) vs. water control (1522 +/- 44 ng/g) and saline control (1538 +/- 30 ng/g) P less than .01. Our results indicate, upregulation of the mesenteric alpha-1 receptor occurs in DOCA-salt rats, however, additional factors participate in the vascular response to adrenergic stimulation in this model.

Hypertonic solutions, such as contrast media (meglumine/sodium diatrizoate-76%; Renografin-76), induce vasoconstriction in the renal vascular bed via an unknown mechanism. We assessed a possible role of two vasoconstrictor hormones known to be released by the kidney, angiotensin II (AII) and the prostaglandin, thromboxane. Specific inhibition of AII at the smooth muscle receptor level by saralasin (0.33-0.75 microgram/kg/min, IA) did not attenuate the response. Inhibition of prostaglandin formation by indomethacin (4 mg/kg, IV), likewise, did not prevent the decrease in renal perfusion. We conclude that neither AII nor the prostaglandin system mediate the contrast medium-induced renal vasoconstriction.

Left ventricular (LV) function during rest and during exercise was evaluated in patients with end-stage renal disease (ESRD) in whom other causes of LV dysfunction were eliminated through rigid selection criteria. Autonomic function was also assessed in these patients with Valsalva's maneuver and plasma catecholamine determinations. Echocardiography and radionuclide ventriculography in the group with ESRD revealed no abnormalities of LV wall motion or ejection fraction. During graded exercise, patients with ESRD achieved 85% of age-predicted heart rate, and no differences in exercise tolerance or LV function were observed. Valsalva's response was abnormal in patients with ESRD, and post exercise the norepinephrine level was markedly increased (12.5 +/- 1.43 vs 8.28 +/- 0.82 nmol/L). Our results fail to indicate an independent adverse effect of ESRD on LV function.