Biomedical subjects

T I Musch

Publications and source records attributed to T I Musch.

At least 37 records · Page 2Linked to original sources

PubMed1999

Effects of impaired Ca2+ homeostasis on contraction in postinfarction myocytes.

The significance of altered Ca2+ influx and efflux pathways on contractile abnormalities of myocytes isolated from rat hearts 3 wk after myocardial infarction (MI) was investigated by varying extracellular Ca2+ concentration ([Ca2+]o, 0.6-5.0 mM) and pacing frequency (0.1-5.0 Hz). Myocytes isolated from 3-wk MI hearts were significantly longer than those from sham-treated (Sham) hearts (125 +/- 1 vs. 114 +/- 1 micrometer, P < 0.0001). At high [Ca2+]o and low pacing frequency, conditions that preferentially favored Ca2+ influx over efflux, Sham myocytes shortened to a greater extent than 3-wk MI myocytes. Conversely, under conditions that favored Ca2+ efflux (low [Ca2+]o and high pacing frequency), MI myocytes shortened more than Sham myocytes. At intermediate [Ca2+]o and pacing frequencies, differences in steady-state contraction amplitudes between Sham and MI myocytes were no longer significant. Collectively, the interpretation of these data was that Ca2+ influx and efflux pathways were subnormal in MI myocytes and that they contributed to abnormal cellular contractile behavior. Because Na+/Ca2+ exchange activity, but not whole cell Ca2+ current, was depressed in 3-wk MI rat myocytes, our results on steady-state contraction are consistent with, but not proof of, the hypothesis that depressed Na+/Ca2+ exchange accounted for abnormal contractility in MI myocytes. The effects of depressed Na+/Ca2+ exchange on MI myocyte mechanical activity were further evaluated in relaxation from caffeine-induced contractures. Because Ca2+ uptake by sarcoplasmic reticulum was inhibited by caffeine and with the assumption that intracellular Na+ and membrane potential were similar between Sham and MI myocytes, myocyte relaxation from caffeine-induced contracture can be taken as an estimate of Ca2+ extrusion by Na+/Ca2+ exchange. In MI myocytes, in which Na+/Ca2+ exchange activity was depressed, the half time of relaxation (1.54 +/- 0.14 s) was significantly (P < 0.02) prolonged compared with that measured in Sham myocytes (1.10 +/- 0.10 s).

Animals↗

PubMed1999

Interactions between angiotensin II and nitric oxide during exercise in normal and heart failure rats.

We hypothesized that nitric oxide (NO) opposes ANG II-induced increases in arterial pressure and reductions in renal, splanchnic, and skeletal muscle vascular conductance during dynamic exercise in normal and heart failure rats. Regional blood flow and vascular conductance were measured during treadmill running before (unblocked exercise) and after 1) ANG II AT(1)-receptor blockade (losartan, 20 mg/kg ia), 2) NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME); 10 mg/kg ia], or 3) ANG II AT(1)-receptor blockade + NOS inhibition (combined blockade). Renal conductance during unblocked exercise (4.79 +/- 0.31 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased after ANG II AT(1)-receptor blockade (6.53 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.12 +/- 0.20 ml x 100 g(-1) x min(-1) x mmHg(-1)) and combined inhibition (3.96 +/- 0.57 ml x 100 g(-1) x min(-1) x mmHg(-1); all P < 0.05 vs. unblocked). In heart failure rats, renal conductance during unblocked exercise (5.50 +/- 0.66 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased by ANG II AT(1)-receptor blockade (8.48 +/- 0.83 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.68 +/- 0.22 ml x 100 g(-1) x min(-1) x mmHg(-1); both P < 0.05 vs. unblocked), but it was unaltered during combined inhibition (4.65 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)). Because our findings during combined blockade could be predicted from the independent actions of NO and ANG II, no interaction was apparent between these two substances in control or heart failure animals. In skeletal muscle, L-NAME-induced reductions in conductance, compared with unblocked exercise (P < 0.05), were abolished during combined inhibition in heart failure but not in control rats. These observations suggest that ANG II causes vasoconstriction in skeletal muscle that is masked by NO-evoked dilation in animals with heart failure. Because reductions in vascular conductance between unblocked exercise and combined inhibition were less than would be predicted from the independent actions of NO and ANG II, an interaction exists between these two substances in heart failure rats. L-NAME-induced increases in arterial pressure during treadmill running were attenuated (P < 0.05) similarly in both groups by combined inhibition. These findings indicate that NO opposes ANG II-induced increases in arterial pressure and in renal and skeletal muscle resistance during dynamic exercise.

Angiotensin II↗

PubMed1999

Impaired capillary hemodynamics in skeletal muscle of rats in chronic heart failure.

Skeletal muscle blood flow is reduced and O(2) extraction is increased at rest in chronic heart failure (CHF). Knowledge of red blood cell (RBC) flow distribution within the capillary network is necessary for modeling O(2) delivery and exchange in this disease. Intravital microscopy techniques were used to study the in vivo spinotrapezius muscle microcirculation in rats with CHF 7 wk after myocardial infarction and in sham-operated controls (sham). A decrease in mean muscle fiber width from 51.3 +/- 1.9 microm in sham to 42.6 +/- 1.4 microm in CHF rats (P < 0.01) resulted in an increased lineal density of capillaries in CHF rats (P < 0.05). CHF reduced (P < 0.05) the percentage of capillaries supporting continuous RBC flow from 87 +/- 5 to 66 +/- 5%, such that the lineal density of capillaries supporting continuous RBC flow remained unchanged. The percentage of capillaries supporting intermittent RBC flow was increased in CHF rats (8 and 27% in sham and CHF, respectively, P < 0.01); however, these capillaries contributed only 2.3 and 3.3% of the total RBC flux in sham and CHF rats, respectively. In continuously RBC-perfused capillaries, RBC velocity (252 +/- 20 and 144 +/- 9 microm/s in sham and CHF, respectively, P < 0.001) and flux (21.4 +/- 2.4 and 9.4 +/- 1.1 cells/s in sham and CHF, respectively, P < 0.01) were markedly reduced in CHF compared with sham rats. Capillary "tube" hematocrit remained unchanged (0.22 +/- 0.02 and 0.19 +/- 0.02 in sham and CHF, respectively, P > 0.05). We conclude that CHF causes spinotrapezius fiber atrophy and reduces the number of capillaries supporting continuous RBC flow per fiber. Within these capillaries supporting continuous RBC flow, RBC velocity and flux are reduced 45-55%. This decreases the potential for O(2) delivery but enhances fractional O(2) extraction by elevating RBC capillary residence time. The unchanged capillary tube hematocrit suggests that any alterations in muscle O(2) diffusing properties in CHF are mediated distal to the RBC.

Animals↗

PubMed1999

In situ SR function in postinfarction myocytes.

Previous studies have shown lower systolic intracellular Ca(2+) concentrations ([Ca(2+)](i)) and reduced sarcoplasmic reticulum (SR)-releasable Ca(2+) contents in myocytes isolated from rat hearts 3 wk after moderate myocardial infarction (MI). Ca(2+) entry via L-type Ca(2+) channels was normal, but that via reverse Na(+)/Ca(2+) exchange was depressed in 3-wk MI myocytes. To elucidate mechanisms of reduced SR Ca(2+) contents in MI myocytes, we measured SR Ca(2+) uptake and SR Ca(2+) leak in situ, i.e., in intact cardiac myocytes. For sham and MI myocytes, we first demonstrated that caffeine application to release SR Ca(2+) and inhibit SR Ca(2+) uptake resulted in a 10-fold prolongation of half-time (t(1/2)) of [Ca(2+)](i) transient decline compared with that measured during a normal twitch. These observations indicate that early decline of the [Ca(2+)](i) transient during a twitch in rat myocytes was primarily mediated by SR Ca(2+)-ATPase and that the t(1/2) of [Ca(2+)](i) decline is a measure of SR Ca(2+) uptake in situ. At 5.0 mM extracellular Ca(2+), systolic [Ca(2+)](i) was significantly (P </= 0.05) lower (337 +/- 11 and 416 +/- 18 nM in MI and sham, respectively) and t(1/2) of [Ca(2+)](i) decline was significantly longer (0.306 +/- 0.014 and 0.258 +/- 0.014 s in MI and sham, respectively) in MI myocytes. The 19% prolongation of t(1/2) of [Ca(2+) ](i) decline was associated with a 23% reduction in SR Ca(2+)-ATPase expression (detected by immunoblotting) in MI myocytes. SR Ca(2+) leak was measured by a novel electrophysiological technique that did not require assigning empirical constants for intracellular Ca(2+) buffering. SR Ca(2+) leak rate was not different between sham and MI myocytes: the time constants of SR Ca(2+) loss after thapsigargin were 290 and 268 s, respectively. We conclude that, independent of decreased SR filling by Ca(2+) influx, the lower SR Ca(2+) content in MI myocytes was due to reduced SR Ca(2+) uptake and SR Ca(2+)-ATPase expression, but not to enhanced SR Ca(2+) leak.

Animals↗

PubMed1998

Effect of heart failure on muscle capillary geometry: implications for 02 exchange.

UNLABELLED: There is strong evidence that chronic heart chronic heart failure (CHF) impairs skeletal muscle function independent of blood flow and bulk O2 delivery. PURPOSE: This investigation sought to determine whether alterations in muscle capillary geometry and surface area that are thought to be primary determinants of the efficacy for blood-tissue 02 exchange might be altered in CHF and contribute to these changes. METHODS: Plantaris (fast twitch) and soleus (slow twitch) muscles from control (C) and 6- to 7-wk post myocardial infarcted (CHF) rates were perfusion-fixed in situ. These muscles were analyzed using morphometric techniques that facilitated determination of muscle sarcomere length fiber cross-sectional area, capillary tortuosity and branching coefficient (c(K,0)), capillary length, volume, and surface area. RESULTS: Normalized to a sarcomere length of 2.1 microns, plantaris fiber cross-sectional area decreased by 21% (P < 0.05), and capillary-to-fiber ratio decreased from 2.05 +2- 0.07 in C to 1.79 +2- 0.04 (P < 0.05) in CHF, but these variables were unchanged in soleus. These was no change in c(K,0) or capillary diameter in either muscle, and thus capillary length and surface area per fiber volume remained unchanged. From the measured fiber atrophy and capillary involution in plantaris reductions of total muscle capillary length, volume, and surface area of 11%, 9% and 17%, respectively, are estimated. CONCLUSION: These changes, coupled with reduced blood flow may impair the effective matching of muscle fiber 02 delivery to 02 requirement during repeated muscle contractions (i.e. exercise). The scenario is expected to reduce intramyocyte 02 partial pressure and thereby contribute to the greater fatigability characteristic of the CHF condition.

Animals↗

PubMed1998

Physical activity, muscle, and the HSP70 response.

Selye (1936) described how organisms react to various external stimuli (i.e., stressors). These reactions generally follow a programmed series of events and help the organism adapt to the imposed stress. The heat shock response is a common cellular reaction to external stressors, including physical activity. A characteristic set of proteins is synthesised shortly after the organism is exposed to stress. Researchers have not determined how heat shock proteins affect the exercise response. However, their role in adaptation to exercise and training might be inferred, since the synthetic patterns correlate well with the stress adaptation syndrome that Selye described. This review addresses the 70 kilodalton heat shock protein family (HSP70), the most strongly induced heat shock proteins. This paper provides an overview of the general heat shock response and a brief review of literature on HSP70 function, structure, regulation, and potential applications. Potential applications in health, exercise, and medicine are provided.

Amino Acid Sequence↗

PubMed1998

Sprint training attenuates myocyte hypertrophy and improves Ca2+ homeostasis in postinfarction myocytes.

Myocytes isolated from rat hearts 3 wk after myocardial infarction (MI) had decreased Na+/Ca2+ exchange currents (I Na/Ca; 3 Na+ out:1 Ca2+ in) and sarcoplasmic reticulum (SR)-releasable Ca2+ contents. These defects in Ca2+ regulation may contribute to abnormal contractility in MI myocytes. Because exercise training elicits positive adaptations in cardiac contractile function and myocardial Ca2+ regulation, the present study examined whether 6-8 wk of high-intensity sprint training (HIST) would ameliorate some of the cellular maladaptations observed in post-MI rats with limited exercise activity (Sed). In MI rats, HIST did not affect citrate synthase activities of plantaris muscles but significantly increased the percentage of cardiac alpha-myosin heavy chain (MHC) isoforms (57.2 +/- 1.9 vs. 49.3 +/- 3.5 in MI-HIST vs. MI-Sed, respectively; P < or = 0.05). At the single myocyte level, HIST attenuated cellular hypertrophy observed post-MI, as evidenced by reductions in cell lengths (112 +/- 4 vs. 130 +/- 5 micrograms in MI-HIST vs. MI-Sed, respectively; P < or = 0.005) and cell capacitances (212 +/- 8 vs. 242 +/- 9 pF in MI-HIST vs. MI-Sed, respectively; P < or = 0.015). Reverse I Na/Ca was significantly lower (P < or = 0.0001) in myocytes from MI-Sed rats compared with those from rats that were sham operated and sedentary. HIST significantly increased reverse I Na/Ca (P < or = 0.05) without affecting the amount of Na+/Ca2+ exchangers (detected by immunoblotting) in MI myocytes. SR-releasable Ca2+ content, as estimated by integrating forward I Na/Ca during caffeine-induced SR Ca2+ release, was also significantly increased (P < or = 0.02) by HIST in MI myocytes. We conclude that the enhanced cardiac output and stroke volume in post-MI rats subjected to HIST are mediated, at least in part, by reversal of cellular maladaptations post-MI.

Animals↗

PubMed1997

In vivo microvascular structural and functional consequences of muscle length changes.

As muscles are stretched, blood flow and oxygen delivery are compromised, and consequently muscle function is impaired. We tested the hypothesis that the structural microvascular sequellae associated with muscle extension in vivo would impair capillary red blood cell hemodynamics. We developed an intravital spinotrapezius preparation that facilitated direct on-line measurement and alteration of sarcomere length simultaneously with determination of capillary geometry and red blood cell flow dynamics. The range of spinotrapezius sarcomere lengths achievable in vivo was 2.17 +/- 0.05 to 3.13 +/- 0.11 microns. Capillary tortuosity decreased systematically with increases of sarcomere length up to 2.6 microns, at which point most capillaries appeared to be highly oriented along the fiber longitudinal axis. Further increases in sarcomere length above this value reduced mean capillary diameter from 5.61 +/- 0.03 microns at 2.4-2.6 microns sarcomere length to 4.12 +/- 0.05 microns at 3.2-3.4 microns sarcomere length. Over the range of physiological sarcomere lengths, bulk blood flow (radioactive microspheres) decreased approximately 40% from 24.3 +/- 7.5 to 14.5 +/- 4.6 ml.100 g-1.min-1. The proportion of continuously perfused capillaries, i.e., those with continuous flow throughout the 60-s observation period, decreased from 95.9 +/- 0.6% at the shortest sarcomere lengths to 56.5 +/- 0.7% at the longest sarcomere lengths and was correlated significantly with the reduced capillary diameter (r = 0.711, P < 0.01; n = 18). We conclude that alterations in capillary geometry and luminal diameter consequent to increased muscle sarcomere length are associated with a reduction in mean capillary red blood cell velocity and a greater proportion of capillaries in which red blood cell flow is stopped or intermittent. Thus not only does muscle stretching reduce bulk blood (and oxygen) delivery, it also alters capillary red blood cell flow dynamics, which may further impair blood-tissue oxygen exchange.

Animals↗

PubMed1997

Decreased [3H]ouabain binding sites in skeletal muscle of rats with chronic heart failure.

Abnormalities intrinsic to skeletal muscle are thought to contribute to decrements in exercise capacity found in individuals with chronic heart failure (CHF). Na+-K+-adenosinetriphosphatase (the Na+ pump) is essential for maintaining muscle excitability and contractility. Therefore, we investigated the possibility that the number and affinity of Na+ pumps in locomotor muscles of rats with CHF are decreased. Myocardial infarction (MI) was induced in 8 rats, and a sham operation was performed in 12 rats. The degree of CHF was assessed approximately 180 days after surgery. Soleus and plantaris muscles were harvested, and Na+ pumps were quantified by using a [3H]ouabain binding assay. At the time of muscle harvest, MI and sham-operated rats were similar in age (458 +/- 54 vs. 447 +/- 34 days old, respectively). Compared with their sham-operated counterparts, MI rats had a significant amount of heart failure, right ventricular-to-body weight ratio was greater (48%), and the presence of pulmonary congestion was suggested by an elevated lung-to-body weight ratio (29%). Left ventricular end-diastolic pressure was significantly increased in the MI rats (11 +/- 1 mmHg) compared with the sham-operated controls (1 +/- 1 mmHg). In addition, mean arterial blood pressure was lower in the MI rats compared with their control counterparts. [3H]ouabain binding sites were reduced 18% in soleus muscle (136 +/- 12 vs. 175 +/- 13 pmol/g wet wt, MI vs. sham, respectively) and 22% in plantaris muscle (119 +/- 12 vs. 147 +/- 8 pmol/g wet wt, MI vs. sham, respectively). The affinity of these [3H]ouabain binding sites was similar for the two groups. The relationship between the reduction in Na+ pump number and the reduced exercise capacity in individuals with CHF remains to be determined.

Animals↗

PubMed1997

Changes in skeletal muscle biochemistry and histology relative to fiber type in rats with heart failure.

One of the primary consequences of left ventricular dysfunction (LVD) after myocardial infarction is a decrement in exercise capacity. Several factors have been hypothesized to account for this decrement, including alterations in skeletal muscle metabolism and aerobic capacity. The purpose of this study was to determine whether LVD-induced alterations in skeletal muscle enzyme activities, fiber composition, and fiber size are 1) generalized in muscles or specific to muscles composed primarily of a given fiber type and 2) related to the severity of the LVD. Female Wistar rats were divided into three groups: sham-operated controls (n = 13) and rats with moderate (n = 10) and severe (n = 7) LVD. LVD was surgically induced by ligating the left main coronary artery and resulted in elevations (P < 0.05) in left ventricular end-diastolic pressure (sham, 5 +/- 1 mmHg; moderate LVD, 11 +/- 1 mmHg; severe LVD, 25 +/- 1 mmHg). Moderate LVD decreased the activities of phosphofructokinase (PFK) and citrate synthase in one muscle composed of type IIB fibers but did not modify fiber composition or size of any muscle studied. However, severe LVD diminished the activity of enzymes involved in terminal and beta-oxidation in muscles composed primarily of type I fibers, type IIA fibers, and type IIB fibers. In addition, severe LVD induced a reduction in the activity of PFK in type IIB muscle, a 10% reduction in the percentage of type IID/X fibers, and a corresponding increase in the portion of type IIB fibers. Atrophy of type I fibers, type IIA fibers, and/or type IIB fibers occurred in soleus and plantaris muscles of rats with severe LVD. These data indicate that rats with severe LVD after myocardial infarction exhibit 1) decrements in mitochondrial enzyme activities independent of muscle fiber composition, 2) a reduction in PFK activity in type IIB muscle, 3) transformation of type IID/X to type IIB fibers, and 4) atrophy of type I, IIA, and IIB fibers.

Animals↗

PubMed1996

Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction.

Ranolazine was previously shown to stimulate cardiac glucose oxidation. Dichloroacetate (DCA) also does and was shown to improve exercise capacity in animals, but it has long-term toxicity problems. To test the hypothesis that ranolazine would increase exercise performance in the chronic heart failure (CHF) condition, we compared the exercise endurance capacities of rats with a surgically induced myocardial infarction (MI) with those of noninfarcted sham-operated (Sham) controls both before and after 14 and 28 days of drug administration. Chronic administration of ranolazine, 50 mg/kg twice daily (b.i.d.) oral, significantly reduced the endurance capacities of both Sham and MI rats (measured after a 12-h fast to reduce liver glycogen stores), as indicated by the reductions in run times to fatigue during a progressive treadmill test. Ranolazine produced reductions in resting plasma lactate and glucose concentrations of animals fasted for 12 h (consistent with stimulating glucose oxidation); however, tissue glycogen concentrations measured in various locomotor muscles located in the animal's hindlimb were unaffected when measured 48 h after the last treadmill test and after 12 h of fasting. Chronic administration of ranolazine did not increase the endurance capacity of rats with CHF induced by MI at the dosage and with the protocol used. To the contrary, the chronic administration of ranolazine appears to reduce the work capacity of all rats, suggesting that this drug may not be useful therapeutically in the treatment of CHF. Whether the decrements in endurance capacity produced by ranolazine are related to the high plasma concentrations of the drug produced in this study as compared with previous studies in humans remains subject to further experimentation.

Acetanilides↗

PubMed1996

Blood flow response to treadmill running in the rat spinotrapezius muscle.

The rat spinotrapezius muscle has been utilized to investigate the microcirculatory consequences of exercise training. It was the purpose of this investigation to determine whether, and to what extent, this muscle is recruited during treadmill exercise. Radioactive 15-micron microspheres were used to measure blood flow to the spinotrapezius and hind limb musculature as well as to the abdominal organs of female Wistar rats. Blood flows were measured at rest and during two levels of treadmill-running exercise (i.e., 0% grade, 15 m/min and 10% grade, 24 m/min). As expected, exercise increased blood flow to the soleus, plantaris, red gastrocnemius, mixed gastrocnemius, and white gastrocnemius muscles, whereas blood flow to the stomach, intestines, pancreas, spleen, and kidneys was decreased (P < 0.05). However, contrary to our expectation, blood flow to the spinotrapezius muscle decreased from 61 +/- 6 ml.100 g-1.min-1 at rest to 39 +/- 2 ml.100 g-1.min-1 at 0% grade, 15 m/min and 46 +/- 4 ml.100 g-1.min-1 at 10% grade, 24 m/min (P < 0.05). These findings support the premise that treadmill running does not recruit the spinotrapezius muscle and suggest that previous training-induced arteriolar adaptations produced in this muscle may result from mechanisms unrelated to augmented exercise blood flow or muscle metabolism.

Animals↗

PubMed1995

Differential sympathetic nerve responses to nitric oxide synthase inhibition in anesthetized rats.

Recent studies have suggested that the interaction between the sympathetic nervous system and nitric oxide (NO) or nitrosyl factors may be an important means by which arterial blood pressure is regulated. We investigated whether NO synthase (NOS) inhibition modulates basal sympathetic nerve discharge (SND) in baroreceptor-innervated and -denervated, chloralose-anesthetized Sprague-Dawley rats. We recorded mean arterial pressure (MAP), renal SND, and lumbar SND before and after administration of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg iv). Two minutes after L-NAME administration in baroreceptor-innervated rats, MAP increased (+23 +/- 3 mmHg), whereas renal (-45 +/- 6%, n = 7) and lumbar (-35 +/- 2%, n = 6) SND significantly decreased from control levels. These changes persisted for up to 20 min after L-NAME administration. In baroreceptor-denervated rats, L-NAME increased MAP (+40 +/- 6 mmHg) and decreased lumbar SND (n = 7) (-37 +/- 10% from control at 20 min post-L-NAME). In contrast, renal SND progressively increased (+33 +/- 8% at 20 min post-L-NAME) from control after L-NAME administration in baroreceptor-denervated rats (n = 7). These results demonstrate that NOS inhibition can produce nonuniform changes in SND in baroreceptor-denervated rats and suggest that endogenous nitrosyl factors provide tonic excitation to lumbar SND, whereas they provide a tonic restraint to renal SND.

Animals↗

PubMed1995

Contribution of endothelium-derived nitric oxide (EDNO) to the skeletal muscle blood flow response to exercise.

Blood flow (BF) to active muscle increases dramatically during exercise. This increase in BF is permitted by relaxation of smooth muscle (and ensuing vasodilation) in the vasculature of muscle tissue. Recently, attention has focused on the possible role of the endothelium-derived relaxing factor nitric oxide (EDNO) in the vasodilation of muscle vasculature during exercise. A variety of experimental approaches have been used in elucidating the role of EDNO. These include isolated vessel, isolated muscle or muscle group, and conscious exercising animal preparations. Studies utilizing isolated vessels have shown that arterioles from muscle dilate, in an endothelium-dependent manner, to stimuli present during exercise (e.g., increased flow rates). A limitation of such studies, however, is that only the potential for EDNO-induced vasodilation is indicated. The isolated muscle/muscle group approach has consistently demonstrated a role for EDNO in determining resting BF. Findings for muscle BF during contractions are equivocal. A limitation of this approach is that exercise is simulated by stimulating the motor neuron of the muscle of interest. Since this type of muscle activity elicits a relatively small active hyperemia, it may be that a role for EDNO in exercise-induced hyperemia is masked. Findings from exercising animals are equivocal. Some studies demonstrate a role for EDNO in permitting increased muscle blood flow during exercise, while others show no impact of inhibition of EDNO synthesis. Some studies suggest that the importance of EDNO may vary with the muscle (and its fiber type composition) studied. Additional research is needed to clarify the role of EDNO in mediating increased BF to skeletal muscle during exercise.

Animals↗

PubMed1995

Effects of nitric oxide synthase inhibition on the muscle blood flow response to exercise in rats with heart failure.

OBJECTIVE: The aim of this study was to investigate whether the role of nitric oxide (NO) in regulating blood flow (BF) to working skeletal muscle is impaired in chronic heart failure (CHF). METHODS: The effect of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, was studied in conscious rats with and without CHF due to myocardial infarction (MI). BF to the hindquarter musculature was measured with radiolabelled microspheres during exercise after 4 min of treadmill running (10% grade, 20 m/min) before and after L-NAME (20 mg/kg i.a.) administration. RESULTS: Before L-NAME administration, BF measured in the total hindquarter musculature was less (P < 0.05) during exercise in rats with a large MI (MI size; 44 +/- 2% of the left ventricular endocardial circumference; n = 8) when compared with sham-operated rats (SHAM; n = 10) and rats with a small MI (MI size; 25 +/- 4%; n = 5). The BF measured during exercise following L-NAME administration was similar between the 3 groups. Of the 28 individual hindquarter muscles, BF was reduced in 23 and 19 muscles following the administration of L-NAME for the SHAM rats and rats with a small MI, respectively. In comparison, BF was reduced to only 4 of 28 muscles in rats with a large MI. CONCLUSIONS: These results suggest that the contribution of the NO pathway to the hyperaemic BF responses found in the hindquarter muscles during exercise could be attenuated in rats with CHF. This attenuation of the NO pathway may be associated with the impairment of skeletal muscle BF distribution during exercise in CHF.

Animals↗

PubMed1994

Impaired cardiac function in rats with healed myocardial infarction: cellular vs. myocardial mechanisms.

The inotropic responsiveness of isolated perfused rat hearts and single left ventricular (LV) myocytes to extracellular Ca2+ ([Ca2+]o) was examined 3 wk after ligation of left main coronary artery. Myocytes isolated from myocardial infarcted (MI) hearts were 10% longer. At [Ca2+]o of 1.1 mM, cell shortening as well as intracellular Ca2+ concentration dynamics were similar between MI and sham LV myocytes. At [Ca2+]o of 4.9 mM, maximal extent of cell shortening was significantly less in MI myocytes (16 +/- 1 vs. 22 +/- 1%), and peak intracellular Ca2+ concentration was also substantially lower. Thus, under conditions of high [Ca2+]o, decreased sarcolemmal Ca2+ influx and Ca2+ release during excitation-contraction may contribute to systolic dysfunction in MI hearts. Perfused working hearts and isovolumic heart preparations with infarcted LV displayed depressed maximal systolic pressure and decreased sensitivity to the inotropic effects of [Ca2+]o. Our data also indicate that, in addition to possible abnormalities in the contractile response of single myocytes, global factors such as loss of functional myocardium, altered chamber geometry, tissue fibrosis, and/or subendocardial ischemia contributed to depressed LV function in post-MI hearts perfused at physiological [Ca2+]o.

Animals↗

PubMed1994

Regional differences in LV collagen accumulation and mature cross-linking after myocardial infarction in rats.

To determine the extent of and any regional differences in remodeling response of the extracellular matrix (ECM) to myocardial infarction (MI), moderate-to-large transmural infarcts were surgically produced in left ventricular (LV) free wall of rats. Animals were killed 13 wk after surgery. In comparison to age-matched controls, infarction was associated with an overall increase in heart weight, which included hypertrophy of both the right ventricle and LV. Although the remaining viable myocardium in LV free wall was significantly reduced, the interventricular septum was hypertrophied some 30% compared with control tissues (247 +/- 9 vs. 189 +/- 8 mg). Collagen concentration more than doubled in remaining viable free wall (8.92 +/- 0.59 vs. 3.95 +/- 0.25 mg/100 mg, P < 0.0001), and a smaller but still highly significant 27% increase occurred (P < 0.01) in the more remote septum. Degree of covalent cross-linking of collagen fibrils as assessed by hydroxylysylpyridinoline (HP) concentration also revealed regional differences in response of the ECM to infarction. Although HP concentration was increased 60% in viable free wall (P < 0.05) post-MI, it was unchanged in the septum. With respect to collagen characteristics of the transmural infarct per se, the scar exhibited still further increases in both collagen and HP concentrations compared with the already elevated values for these two parameters in viable free wall. The results indicate that any evaluation of the remodeling response of viable myocardium post-MI must include not only the myocyte but also the ECM, the principal component of which is collagen.

Amino Acids↗

PubMed1994

Effects of NO synthase inhibition on the muscular blood flow response to treadmill exercise in rats.

The functional role of nitric oxide (NO) release in regulating blood flow (BF) to exercising skeletal muscle was studied in conscious male Sprague-Dawley rats (603 +/- 28 g; n = 6). In this study, BF was measured using radiolabeled microspheres during treadmill exercise (10% grade, 20 m/min) before and after NO synthase (NOS) inhibition with NG-nitro-L-arginine methyl ester (30 mg/kg ia). After NOS inhibition, mean arterial blood pressure increased from resting baseline values and the duration of vasodilator responses to acetylcholine (ACh) injections (3.0 and 10.0 micrograms/kg ia) was diminished (P < 0.05), demonstrating reduced NOS function. During exercise, BF to the kidneys and organs of the gut was reduced after NOS inhibition. In addition, BF was reduced in 16 of the 28 individual hindquarter muscles or muscle parts. Moreover these reductions in BF were linearly correlated with the estimated sum of the percentage of fast-twitch oxidative glycolytic (FOG) and slow-twitch oxidative (SO) types of fibers found in each muscle [delta BF = -1.1 (%SO + %FOG) + 16.4; r = 0.88, P < 0.001]. These results suggest that NO-mediated vasodilation contributes to the BF responses within and among the muscles of the rat's hindquarters during exercise.

Acetylcholine↗