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Cancer, a multifactorial disease characterized by uncontrolled cellular proliferation, remains a global health challenge with significant morbidity and mortality. Genomic and molecular aberrations, coupled with environmental factors, contribute to its heterogeneity and complexity. Chemotherapeutic agents like doxorubicin (Dox) have shown efficacy against various cancers but are hindered by dose-dependent cytotoxicity, particularly on vital organs like the heart and brain. Autophagy, a cellular process involved in self-degradation and recycling, emerges as a promising therapeutic target in cancer therapy and neurodegenerative diseases. Dysregulation of autophagy contributes to cancer progression and drug resistance, while its modulation holds the potential to enhance treatment outcomes and mitigate adverse effects. Additionally, emerging evidence suggests a potential link between autophagy, DNA damage, and caretaker breast cancer genes BRCA1/2, highlighting the interplay between DNA repair mechanisms and cellular homeostasis. This review explores the intricate relationship between cancer, Dox-induced cytotoxicity, autophagy modulation, and the potential implications of autophagy in DNA damage repair pathways, particularly in the context of BRCA1/2 mutations. [ABSTRACT FROM AUTHOR]

Introduction: Acquisition of a deeper understanding of microvascular function across physiological and pathological conditions can be complicated by poor accessibility of the vascular networks and the necessary sophistication or intrusiveness of the equipment needed to acquire meaningful data. Laser Doppler fluximetry (LDF) provides a mechanism wherein investigators can readily acquire large amounts of data with minor inconvenience for the subject. However, beyond fairly basic analyses of erythrocyte perfusion (fluximetry) data within the cutaneous microcirculation (i.e., perfusion at rest and following imposed challenges), a deeper understanding of microvascular perfusion requires a more sophisticated approach that can be challenging for many investigators. Methods: This manuscript provides investigators with clear guidance for data acquisition from human subjects for full analysis of fluximetry data, including levels of perfusion, single- and multiscale Lempel-Ziv complexity (LZC) and sample entropy (SampEn), and wavelet-based analyses for the major physiological components of the signal. Representative data and responses are presented from a recruited cohort of healthy volunteers, and computer codes for full data analysis (MATLAB) are provided to facilitate efforts by interested investigators. Conclusion: It is anticipated that these materials can reduce the challenge to investigators integrating these approaches into their research programs and facilitate translational research in cardiovascular science. [ABSTRACT FROM AUTHOR]

Although existing literature supports associations between cerebrovascular dysfunction and the emergence of depression and depressive symptoms, relatively little is known about underlying mechanistic pathways that may explain potential relationships. As such, an integrated understanding of these relationships in preclinical models could provide insight into the nature of the relationship, basic mechanistic linkages, and areas in which additional investment should be targeted. This scoping review was conducted in MEDLINE, EMBASE, and Scopus to outline the relationship between depressive symptoms and cerebrovascular dysfunction in preclinical animal models with an additional focus on the areas above. From 3,438 articles initially identified, 15 studies met the inclusion criteria and were included in the review. All studies reported a positive association between the severity of markers for cerebrovascular dysfunction and that for depressive symptoms in rodent models and this spanned all models for either pathology. Specific mechanistic links between the two such as chronic inflammation, elevated vascular oxidant stress, and altered serotonergic signaling were highlighted. Notably, almost all studies addressed outcomes in male animals, with a near complete lack of data from females, and there was little consistency in terms of how cerebrovascular dysfunction was assessed. Across nearly all studies was a lack of clarity for any "cause and effect" relationship between depressive symptoms and cerebrovascular dysfunction. At this time, it is reasonable to conclude that a correlative relationship clearly exists between the two, and future investigation will be required to parse out more specific aspects of this relationship. NEW & NOTEWORTHY: This scoping review presents a structured evaluation of all relevant existing literature linking cerebral vasculopathy to depressive symptom emergence in preclinical models. Results support a definite connection between vascular dysfunction and depressive symptoms, highlighting the importance of chronic elevations in inflammation and oxidant stress, and impaired serotonergic signaling. The review also identified significant knowledge gaps addressing male versus female differences and limited clear mechanistic links between cerebral vasculopathy and depressive symptoms. [ABSTRACT FROM AUTHOR]

Blood flow regulation within the microvasculature reflects a complex interaction of regulatory mechanisms and varies spatially and temporally according to conditions such as metabolism, growth, injury, and disease. Understanding the role of microvascular flow distributions across conditions is of interest to investigators spanning multiple disciplines; however, data collection within networks can be labor-intensive and challenging due to limited resolution. To overcome these experimental challenges, computational network models that can accurately simulate vascular behavior are highly beneficial. Constrained constructive optimization (CCO) is a commonly used algorithm for vascular simulation, particularly well known for its adaptability toward vascular modeling across tissues. The present work demonstrates an implementation of CCO aimed to simulate a branching arteriolar microvasculature in healthy skeletal muscle, validated against literature including comprehensive rat gluteus maximus vasculature datasets, and reviews a list of user-specified adjustable model parameters to understand how their variability affects the simulated networks. Network geometric properties, including mean element diameters, lengths, and numbers of bifurcations per order, Horton's law ratios, and fractal dimension, demonstrate good validation once model parameters are adjusted to experimental data. This model successfully demonstrates hemodynamic properties such as Murray's law and the network Fahraeus effect. Application of centrifugal and Strahler ordering schemes results in divergent descriptions of identical simulated networks. This work introduces a novel CCO-based model focused on generating branching skeletal muscle microvascular arteriolar networks based on adjustable model parameters, thus making it a valuable tool for investigations into skeletal muscle microvascular structure and tissue perfusion. NEW & NOTEWORTHY: The present work introduces a CCO-based algorithm for generating branching arteriolar networks, with adjustable model parameters to enable modeling in varying skeletal muscle tissues. The geometric and hemodynamic parameters of the generated networks have been comprehensively validated using experimental data collected previously in-house and from literature. This is one of few validated CCO-based models to specialize in skeletal muscle microvasculature and acts as a beneficial tool for investigating the microvasculature for hypothesis testing and validation. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Arteriolar tone regulation plays a critical role in maintaining appropriate organ blood flow and perfusion distribution, which is vital for both vascular and overall health. Summary: This scoping review aimed to explore the interplay between five major regulators of arteriolar tone: metabolism (adenosine), adrenergic control (norepinephrine), myogenic activation (intravascular pressure), perivascular oxygen tension, and intraluminal flow rates. Specifically, the aim was to address how arteriolar reactivity changes in the presence of other vasoactive stimuli and by what mechanisms. The review focused on animal studies that investigated the impact of combining two or more of these stimuli on arteriolar diameter. Overall, 848 articles were identified through MEDLINE and EMBASE database searches, and 38 studies were included in the final review. Key Messages: The results indicate that arteriolar reactivity is influenced by multiple factors, including competitive processes, structural limitations, and indirect interactions among stimuli. Additionally, the review identified a lack of research involving female animal models and limited insight into the interaction of molecular signaling pathways, which represent gaps in the literature. [ABSTRACT FROM AUTHOR]

This study used an anaesthetized rat model to directly observe changes in diameter of the vessels supplying the sciatic nerve in response to acetylcholine ([10.sup.-4] M), a muscarinic receptor agonist, and atropine ([10.sup.- 5] M), a muscarinic receptor antagonist. Topical application of acetylcholine resulted in increases in vessel diameter (baseline: 22.0 [+ or -] 2.5 [micro]m, acetylcholine: 28.8 [+ or -] 3.3 [micro]m), while topical application of atropine resulted in a decrease in diameter (baseline: 26.6 [+ or -] 3.2 [micro]m, atropine: 15.5 [+ or -] 3.6 [micro]m) of the epineurial vessels. Mean arterial pressure was not affected by either acetylcholine (baseline: 103.8 [+ or -] 1.8 mm Hg, acetylcholine: 102.8 [+ or -] 3.2 mm Hg) or atropine (baseline: 104.0 [+ or - ] 1.9 mm Hg, atropine: 105.2 [+ or -] 2.2 mm Hg). These data suggest that muscarinic-receptor-mediated responses can affect the diameter of the epineurial vessels at the sciatic nerve. In addition, muscarinic-receptor-mediated responses appear to contribute to baseline diameter of epineurial vessels at the sciatic nerve. Key words: sciatic nerve, epineurial vasculature, intravital microscopy, muscarinic receptor, acetylcholine, atropine. Dans cette etude, nous avons utilise un modele de rat anesthesie en vue d'observer directement les variations du diametre des vaisseaux alimentant le nerf sciatique en reaction a l'acetylcholine ([10.sup.-4] M), un agoniste des recepteurs muscariniques, et a l'atropine ([10.sup.-5] M), un antagoniste des recepteurs muscariniques. L'application topique d'acetylcholine a entraine une augmentation du diametre des vaisseaux de l'epinerve (depart: 22,0 [+ or -] 2,5 [micro]m, acetylcholine : 28,8 [+ or -] 3,3 [micro]m), tandis que l'application topique d'atropine a entraine leur diminution (depart: 26,6 [+ or -] 3,2 [micro]m, atropine : 15,5 [+ or -] 3,6 [micro]m). La tension arterielle moyenne n'etait pas affectee par l'acetylcholine (depart : 103,8 [+ or -] 1,8 mm Hg, acetylcholine : 102,8 [+ or -] 3,2 mm Hg) ni par l'atropine (depart : 104,0 [+ or -] 1,9 mm Hg, atropine : 105,2 [+ or -] 2,2 mm Hg). Ces donnees laissent entrevoir que des reactions mediees par les recepteurs muscariniques peuvent affecter le diametre des vaisseaux de l'epinerve du nerf sciatique. De plus, des reactions mediees par les recepteurs muscariniques semblent participer a l'etablissement du diametre de depart des vaisseaux de l'epinerve du nerf sciatique. [Traduit par la Redaction] Mots-cles: nerf sciatique, vaisseaux de l'epinerve, microscopie intravitale, recepteur muscarinique, acetylcholine, atropine., Introduction To maintain proper function, the peripheral nerves require sufficient blood flow. Decreases in peripheral nerve blood flow have been associated with decreased nerve conduction velocity, nerve atrophy, and cell [...]

Cardiac complications and heart failure are the leading cause of death in type 2 diabetic patients. Mitochondrial dysfunction is central in the pathogenesis of the type 2 diabetic heart. However, it is unclear whether this dysfunction is specific for a particular subcellular region. The purpose of this study was to determine whether mitochondrial dysfunction in the type 2 diabetic heart is specific to a spatially distinct subset of mitochondria. We investigated mitochondrial morphology, function, and proteomic composition of subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) in 18-wk-old db/db mice. Oxidative damage was assessed in subpopulations through the measurement of lipid peroxidation byproducts and nitrotyrosine residues. Proteomic profiles and posttranslational modifications were assessed in mitochondrial subpopulations using iTRAQ and multi-dimensional protein identification technologies, respectively. SSM from db/db hearts had altered morphology, including a decrease in size and internal complexity, whereas db/db IFM were increased in internal complexity. Db/db SSM displayed decreased state 3 respiration rates, electron transport chain activities, ATP synthase activities, and mitochondrial membrane potential and increased oxidative damage, with no change in IFM. Proteomic assessment revealed a greater impact on db/db SSM compared with db/db IFM. Inner mitochondrial membrane proteins, including electron transport chain, ATP synthesis, and mitochondrial protein import machinery, were predominantly decreased. We provide evidence that mitochondrial dysfunction in the type 2 diabetic heart is associated with a specific subcellular locale. Furthermore, mitochondrial morphological and functional indexes are impacted differently during type 2 diabetic insult and may result from the modulation of spatially distinct mitochondrial proteomes. mitochondria; diabetes; proteomics doi: 10.1152/ajpheart.00267.2010.

[Ca.sup.+] entry is delicately controlled by inactivation of L-type calcium channel (LTCC) composed of the pore-forming subunit [alpha]1C and the auxiliary subunits [beta]1 and [alpha]2[delta]. Calmodulin is the key protein that interacts with the COOH-terminal motifs of [alpha]1C, leading to the fine control of LTCC inactivation. In this study we show evidence that a hyperpolarization-activated cyclic nucleotide-gated channel, HCN2, can act as a non-channel regulatory protein to narrow the L-type [Ca.sup.2+] channel current-voltage curve. In the absence of LTCC auxiliary subunits, HCN2 can induce [alpha]1C inactivation. Without [alpha]2[delta], HCN2-induced fast inactivation of [alpha]1C requires calmodulin. With [alpha]2[delta], the [alpha]1C/HCN2/[alpha]2[delta] channel inactivation does not require calmodulin. In contrast, [beta]1-subunit plays a relatively minor role in the interaction of [alpha]1C with HCN2. The N[H.sub.2] terminus of HCN2 and the IQ motif of [alpha]1C subunit are required for [alpha]1C/HCN2 channel interaction. [Ca.sup.+] channel inactivation is significantly slowed in hippocampus neurons (HNs) over-expressing HCN2 mutant lacking NH2 terminus and accelerated in HNs overexpressing the wild-type HCN2 compared with HN controls. Collectively, these results revealed a potentially novel protection mechanism for achieving the LTCC inactivation via interaction with HCN2. L-type calcium channel inactivation; hyperpolarization-activated cyclic nucleotide-gated channels; calmodulin; hippocampal neuron doi: 10.1152/ajpcell.00355.2009.

Previous study suggests that with evolution of the metabolic syndrome, patterns of arteriolar reactivity are profoundly altered and may constrain functional hyperemia. This study investigated interactions between parameters of vascular reactivity at two levels of resistance arterioles in obese Zucker rats (OZR), translating these observations into perfusion regulation for in situ skeletal muscle. Dilation of isolated and in situ resistance arterioles from OZR to acetylcholine, arachidonic acid (AA), and hypoxia (isolated arterioles only) were blunted vs. lean Zucker rats (LZR), although dilation to adenosine was intact. Increased adrenergic tone (phenylephrine) or intralumenal pressure (ILP) impaired dilation in both strains (OZR>LZR). Treatment of OZR arterioles with Tempol (superoxide dismutase mimetic) or SQ-29548 (prostaglandin [H.sub.2]/thromboxane [A.sub.2] receptor antagonist) improved dilator reactivity under control conditions and with increased ILP, but had minimal effect with increased adrenergic tone. Arteriolar dilation to adenosine was well maintained in both strains under all conditions. For in situ cremasteric arterioles, muscle contraction-induced elevations in metabolic demand elicited arteriolar dilations and hyperemic responses that were blunted in OZR vs. LZR, although distal parallel arterioles were characterized by heterogeneous dilator and perfusion responses, [alpha]-Adrenoreceptor blockade improved outcomes at rest but had minimal effect with elevated metabolic demand. Treatment with Tempol or SQ-29548 had minimal impact at rest, but lessened distal arteriolar perfusion heterogeneity with increased metabolic demand. In blood-perfused gastrocnemius of OZR, perfusion was constrained primarily by adrenergic tone, while myogenic activation and endothelium-dependent dilation did not appear to contribute significantly to ischemia. These results of this novel, integrated approach suggest that adrenergic tone and metabolic dilation are robust determinants of bulk perfusion to skeletal muscle of OZR, while endothelial dysfunction may more strongly regulate perfusion distribution homogeneity via the impact of oxidant stress and AA metabolism. peripheral vascular disease; microcirculation; regional blood flow; obesity

This study determined if altered vascular prostacyclin ([PGI.sub.2]) and/or thromboxane [A.sub.2] (Tx[A.sub.2]) production with reduced [Po.sub.2] contributes to impaired hypoxic dilation of skeletal muscle resistance arterioles of obese Zucker rats (OZRs) versus lean Zucker rats (LZRs). Mechanical responses were assessed in isolated gracilis muscle arterioles following reductions in [Po.sub.2] under control conditions and following pharmacological interventions inhibiting arachidonic acid metabolism and nitric oxide synthase and alleviating elevated vascular oxidant stress. The production of arachidonic acid metabolites was assessed using pooled arteries from OZRs and LZRs in response to reduced [Po.sub.2]. Hypoxic dilation, endothelium-dependent in both strains, was attenuated in OZRs versus LZRs. Nitric oxide synthase inhibition had no significant impact on hypoxic dilation in either strain. Cyclooxygenase inhibition dramatically reduced hypoxic dilation in LZRs and abolished responses in OZRs. Treatment of arterioles from OZRs with polyethylene glycol-superoxide dismutase improved hypoxic dilation, and this improvement was entirely cyclooxygenase dependent. Vascular [PGI.sub.2] production with reduced [Po.sub.2] was similar between strains, although Tx[A.sub.2] production was increased in OZRs, a difference that was attenuated by treatment of vessels from OZRs with polyethylene glycol-superoxide dismutase. Both blockade of [PGH.sub.2]/Tx[A.sub.2] receptors and inhibition of thromboxane synthase increased hypoxic dilation in OZR arterioles. These results suggest that a contributing mechanism underlying impaired hypoxic dilation of skeletal muscle arterioles of OZRs may be an increased vascular production of Tx[A.sub.2], which competes against the vasodilator influences of [PGI.sub.2]. These results also suggest that the elevated vascular oxidant stress inherent in metabolic syndrome may contribute to the increased vascular Tx[A.sub.2] production and may blunt vascular sensitivity to [PGI.sub.2]. skeletal muscle microcirculation; endothelium-dependent dilation; vascular reactivity; rodent models of obesity

Previous studies from this laboratory suggest that during juvenile growth, structural changes in the arteriolar network are accompanied by changes in some of the mechanisms responsible for regulation of tissue blood flow. To test the hypothesis that arteriolar myogenic behavior is altered with growth, we studied gracilis muscle arterioles isolated from Sprague-Dawley rats at two ages: 21-28 and 42-49 days. When studied at their respective in vivo pressures, the myogenic index (instantaneous slope of the active pressure-diameter curve) of arterioles from 42-49-day-old rats was more negative than that of arterioles from 21-28-day-old rats, indicating greater myogenic responsiveness. Endothelial denudation, or prostaglandin [H.sub.2] (PG[H.sub.2])/thromboxane [A.sub.2] (Tx[A.sub.2]) receptor antagonism without denudation, significantly reduced the myogenic responsiveness of arterioles from the older rats over a wide range of pressures but had no consistent effects on the myogenic responsiveness of arterioles from the younger rats. The heme oxygenase inhibitor chromium (III) mesoporphyrin IX chloride had no effect on the myogenic activity of arterioles from either age group. These findings indicate that microvascular growth in young animals is accompanied by an increase in the myogenic behavior of arterioles, possibly because PG[H.sub.2] or Tx[A.sub.2] assumes a role in reinforcing myogenic activity over this period. As a result, the relative contribution of myogenic activity to blood flow regulation in skeletal muscle may increase during rapid juvenile growth. skeletal muscle microcirculation; endothelium; postnatal growth; myogenic response

With most cardiovascular disease risk factors, endothelium-dependent dilation of skeletal muscle resistance arterioles is compromised, although with hypercholesterolemia, impairments to reactivity are not consistently observed. Using apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) gene deletion male mouse models of hypercholesterolemia at 20 wk of age, we tested the hypothesis that arteriolar dilation would be maintained due to an increased stimulus-induced production of dilator metabolites via cyclooxygenase and cytochrome P-450 epoxygenase pathways. Arterioles from both strains demonstrated mild reductions in dilation to hypoxia and acetylcholine versus responses in C57/B1/6J (C57) controls. However, although inhibition of nitric oxide synthase (NOS) attenuated dilation in arterioles from C57 controls, this effect was absent in ApoE or LDLR strains. In contrast, cyclooxygenase-dependent portions of dilator reactivity were maintained across the three strains. Notably, although combined NOS and cyclooxygenase inhibition abolished arteriolar responses to hypoxia and acetylcholine in C57 controls, significant reactivity remained in ApoE and LDLR strains. Whereas inhibition of cytochrome P-450 [omega]-hydroxylase and epoxygenases had no effect on this residual reactivity in ApoE and LDLR strains, inhibition of 12/15-lipoxygenase with nordihydroguaiaretic acid abolished the residual reactivity. With both hypoxic and methacholine challenges, arteries from ApoE and LDLR strains demonstrated an increased production of both 12(S)- and 15(S)-hydroxyeicosatetraenoic acid, end products of arachidonic acid metabolism via 12/15-lipoxygenase, a response that was not present in C57 controls. These results suggest that with development of hypercholesterolemia, mechanisms contributing to dilator reactivity in skeletal muscle arterioles are modified such that net reactivity to endothelium-dependent stimuli is largely intact. skeletal muscle microcirculation; mouse models of cardiovascular disease

Previous studies from this laboratory suggest that during maturation, rapid microvascular growth is accompanied by changes in the mechanisms responsible for regulation of tissue blood flow. To further define these changes, we studied isolated gracilis muscle arterioles from weanling (~25 days) and juvenile (~44 days) Sprague-Dawley rats to test the hypothesis that endothelial mechanisms for the control of arteriolar tone are altered with growth. Responses to the endothelium-dependent dilator acetylcholine (ACh) were greater in weanling arterioles (WA) than in juvenile arterioles (JA), whereas there were no consistent differences between age groups in arteriolar responses to other endothelium-dependent agonists (A-23187, vascular endothelial growth factor, and simvastatin). Inhibition of nitric oxide synthase (NOS) with [N.sup.[omega]]-nitroL-arginine methyl ester (L-NAME) attenuated ACh-induced dilation in JA but not in WA. In JA, combined inhibition of NOS and cyclooxygenase (with indomethacin) reduced the dilator responses to ACh and simvastatin by ~90% and ~70%, respectively, but had no effect in WA. Cytochrome P450 epoxygenase inhibition [with 2-(propargyloxyphenyl) hexanoic acid] had no effect on responses to ACh or simvastatin in either age group. Inhibition of [Ca.sup.+]-activated or ATP-dependent potassium channels (with tetraethylammonium or glibenclamide, respectively) reduced these arteriolar responses in JA but not those in WA. These findings suggest that in fully grown microvascular networks, endothelium-dependent arteriolar dilation is mediated by the combined release of endothelial nitric oxide and vasodilator prostanoids, and in part through activation of [Ca.sup.2+]-activated and ATP-dependent potassium channels. However, during earlier microvascular growth, this dilation is mediated by other factors yet to be identified. This may have significant implications for the regulation of tissue perfusion during microvascular development. skeletal muscle microcirculation; endothelium; postnatal growth; nitric oxide; endothelium-derived hyperpolarizing factor

Reduced skeletal muscle microvessel density (MVD) in the obese Zucker rat (OZR) model of the metabolic syndrome is a function of a chronic reduction in vascular nitric oxide (NO) bioavailability. Previous studies suggest that exercise can improve NO bioavailability and reduce chronic inflammation and that low vascular NO bioavailability may be associated with impaired angiogenic responses via increased matrix metalloproteinase (MMP)-2 and MMP-9 activity. As such, we hypothesized that chronic exercise (EX) would increase NO bio-availability in OZR and blunt microvascular rarefaction through reduced MMP activity, and potentially via altered plasma cytokine levels. Ten weeks of treadmill exercise (1 h/day, 5 days/wk, 22 m/min) reduced body mass and fasting insulin and triglyceride levels in EX-OZR vs. sedentary (SED) OZR. In EX-OZR, gastrocnemius muscle MVD was improved by 19 [plus or minus] 4%, whereas skeletal muscle arteriolar dilation and conduit arterial methacholine-induced NO release were increased. In EX-OZR, functional hyperemia was improved vs. SED-OZR, and minimum vascular resistance within perfused gastrocnemius muscle was reduced, although no change in arteriolar stiffness was identified. Western blotting and gelatin zymography demonstrated that neither expression nor activity of MMP-2 or MMP-9 was altered in skeletal muscle of EX vs. SED animals. Plasma markers of inflammation associated with angiogenesis, monocyte chemoattractant protein- 1 and IL- 1 [beta], were increased in SED-OZR and were reduced with training, whereas IL-13 was reduced in SED-OZR and increased with exercise. These data suggest that exercise-induced improvements in skeletal muscle MVD in OZR are associated with increased NO bioavailability and may stem from altered inflammatory profiles rather than MMP function. skeletal muscle microcirculation; regulation of skeletal muscle perfusion; microvessel density; vascular remodeling; vascular resistance

Previous studies have demonstrated that skeletal muscle perfusion is impaired in obese Zucker rats (OZR) under control conditions and with elevated metabolic demand versus responses in lean Zucker rats (LZR). To further our understanding of processes contributing to impaired perfusion, we determined whether hyperemic responses following periods of occlusion were altered in skeletal muscle of OZR versus LZR. In isolated hindlimbs, basal blood flow in OZR was less than in LZR, and total perfusion responses after 30, 90, and 180 s of occlusion were reduced. Treatment of animals with an antioxidant (polythethylene glycol-superoxide dismutase) had no effect on reactive hyperemia, although blockade of [alpha]-adrenoreceptors ([[alpha].sub.1] > [[alpha].sub.2]) improved responses to 30 and 90 s of occlusion; responses to 180 s of occlusion were unaltered. Pump perfusion of a dilated distal hindlimb demonstrated that increased volume flow elicited a greater increase in perfusion pressure in OZR versus LZR, suggesting structural contributions to an increased vascular resistance. Responses were comparable for in situ cremaster muscle because reactive hyperemia following serial arteriolar occlusion was attenuated in OZR versus LZR, treatment with polythethylene glycol-superoxide dismutase was ineffective, and hyperemic responses were improved following inhibition of [alpha]-adrenoreceptors ([[alpha].sub.1] > [[alpha].sub.2]). Treatment of cremaster muscle with adenosine ([10.sup.-3] M) caused flow to increase to a level comparable to that following 180 s of occlusion in both strains, although this level was reduced in OZR versus LZR. These results suggest that increased adrenergic tone may constrain reactive hyperemia in OZR with brief occlusion, although structural increases in vascular resistance can contribute to constrained perfusion after longer periods of occlusion. microcirculation; blood flow regulation; rodent models of metabolic syndrome

In addition to the long-term renal complications, previous studies suggested that after acute renal failure (ARF), rats manifest an increased pressor response to an overnight infusion of ANG II. The present study tested whether recovery from ARF results in alterations in sensitivity to the peripheral vasculature. ARF was induced in Sprague-Dawley rats by 45 min of bilateral renal ischemia and reperfusion. Animals were allowed to recover renal structure and function for 5-8 wk, after which the acute pressor responses to ANG II were evaluated either in vivo in in situ skeletal muscle arterioles or in isolated gracilis muscle arteries in vitro. Baseline arterial pressure was not different in ARF rats vs. sham-operated controls, although ARF rats exhibited an enhanced pressor response to bolus ANG II infusion compared with control rats. Steady-state plasma ANG II concentration and plasma renin activity were similar between ARF and control rats. Constrictor reactivity of in situ cremasteric arterioles from ARF rats was enhanced in response to increasing concentrations of ANG II; however, no difference was observed in arteriolar responses to elevated P[O.sub.2], norepinephrine, acetylcholine, or sodium nitroprusside. Isolated gracilis muscle arteries from ARF rats also showed increased vasoconstriction in response to ANG II but not norepinephrine. In conclusion, recovery from ischemic ARF is not associated with hypertension but is associated with increased arteriolar constrictor reactivity to ANG II. Although the mechanisms of this altered responsiveness are unclear, such changes may relate, in part, to cardiovascular complications in patients with ARF and/or after renal transplant. ischemia; blood pressure