Heart failure with preserved ejection fraction diminishes peripheral hemodynamics and accelerates exercise-induced neuromuscular fatigue.

This study investigated the impact of HFpEF on neuromuscular fatigue and peripheral hemodynamics during small muscle mass exercise not limited by cardiac output. Eight HFpEF patients (NYHA II-III, ejection-fraction: 61 ± 2%) and eight healthy controls performed dynamic knee extension exercise (80% peak workload) to task failure and maximal intermittent quadriceps contractions (8 × 15 s). Controls repeated knee extension at the same absolute intensity as HFpEF. Leg blood flow (QL) was quantified using Doppler ultrasound. Pre/postexercise changes in quadriceps twitch torque (ΔQtw; peripheral fatigue), voluntary activation (ΔVA; central fatigue), and corticospinal excitability were quantified. At the same relative intensity, HFpEF (24 ± 5 W) and controls (42 ± 6 W) had a similar time-to-task failure (∼10 min), ΔQtw (∼50%), and ΔVA (∼6%). This resulted in a greater exercise-induced change in neuromuscular function per unit work in HFpEF, which was significantly correlated with a slower QL response time. Knee extension exercise at the same absolute intensity resulted in an ∼40% lower QL and greater ΔQtw and ΔVA in HFpEF than in controls. Corticospinal excitability remained unaltered during exercise in both groups. Finally, despite a similar ΔVA, ΔQtw was larger in HFpEF versus controls during isometric exercise. In conclusion, HFpEF patients are characterized by a similar development of central and peripheral fatigue as healthy controls when tested at the same relative intensity during exercise not limited by cardiac output. However, HFpEF patients have a greater susceptibility to neuromuscular fatigue during exercise at a given absolute intensity, and this impairs functional capacity. The patients' compromised QL response to exercise likely accounts, at least partly, for the patients' attenuated fatigue resistance.NEW & NOTEWORTHY The susceptibility to neuromuscular fatigue during exercise is substantially exaggerated in individuals with heart failure with a preserved ejection fraction. The faster rate of fatigue development is associated with the compromised peripheral hemodynamic response characterizing these patients during exercise. Given the role of neuromuscular fatigue as a factor limiting exercise, this impairment likely accounts for a significant portion of the exercise intolerance typical for this population.

Comparison of oral and tympanic temperatures in a Veterans Administration outpatient clinic.

BACKGROUND: To examine the accuracy of noncontact tympanic (NCT) temperatures in outpatients, we conducted a prospective study comparing NCT temperature with temperatures obtained by oral mercury thermometers. METHODS: The study included 410 patients in whom oral and NCT temperatures were obtained. RESULTS: Mean oral temperature was 36.47 +/- 0.44 degrees C and mean NCT temperature was 36.36 +/- 0.49 degrees C. On paired-sample, two-sided t-testing, oral temperature differed significantly from NCT temperature, with a P-value < 0.0001. The difference between simultaneous oral and NCT temperatures was > or = 1 degree F; in 63 cases, oral temperature was higher than NCT temperature. CONCLUSION: We conclude that NCT temperature measurement is not reliable in an internal medicine outpatient clinic setting.

Selective inhibition of cGMP-inhibitable cAMP phosphodiesterase decreases pulmonary vasoreactivity.

Guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) are mediators of smooth muscle relaxation. In this study, selective inhibitors of phosphodiesterase (PDE) isozymes were used to assess the role of cyclic nucleotide hydrolysis in angiotensin II (ANG II) and hypoxic pulmonary vasoconstriction. In isolated rat lungs, the hypoxic pressor response (HPR) was induced with a 95% N2-5% CO2 gas mixture. When administered during the plateau of the HPR, trequinsin (nonselective PDE inhibitor) and indolidan (cGMP-inhibitable cAMP PDE inhibitor) significantly (P = 0.01) decreased the pulmonary arterial pressure (Ppa) by 60 +/- 7 and 53 +/- 3%, respectively, compared with zaprinast (cGMP PDE inhibitor), rolipram (cGMP-insensitive cAMP PDE inhibitor), and the 0.1% dimethyl sulfoxide (DMSO) vehicle control, which decreased the Ppa by 6 +/- 3, 4 +/- 3, and 0%, respectively. In the trequinsin and indolidan groups, the subsequent ANG II pressor responses and HPRs were significantly (P = 0.01) decreased when compared with the zaprinast, rolipram, and DMSO groups. During normoxia, none of the PDE inhibitor (0.3-30 microM) had an effect on the baseline Ppa. These results suggest that cAMP hydrolysis by the cGMP-inhibitable cAMP PDE play a significant role in pulmonary vascular tone regulation.

Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activities in rabbit ventricular myocardium: relations to post-natal maturation.

Cytosolic and particulate Type IV (high-affinity) cAMP phosphodiesterase (PDE) activities were isolated from the ventricular myocardium of newborn (NB; 24 to 48 h), immature (IM; 14 to 16 days) and adult (AD; 6 to 8 months) rabbits. Cytosolic activity from each age group was resolved into three distinct peaks of activity by DEAE cellulose anion exchange chromatography. Type IV PDE activity was identified as a predominant activity in the cytosolic peak III activity in all three age groups when measured with 0.25 microM cAMP as substrate. A particulate Type IV PDE activity was associated with the sarcoplasmic reticulum (SR) fractions in each age group. No significant age-related changes in the affinity of the particulate enzyme for cAMP (apparent Km = 0.3 to 0.5 microM) were evident, but the Vmax for this SR-associated activity increased from 553 +/- 7 pmol/min/mg in the NB to 725 +/- 9 pmol/min/mg in the IM and 2450 +/- 33 pmol/min/mg in the AD. In each age group, milrinone, imazodan, piroximone and indolidan were more potent inhibitors of the SR-associated activity as compared with the cytosolic peak III activity. In contrast, RO 20-1724 and rolipram were relatively more selective inhibitors of the cytosolic peak III activity. Age-related differences in the sensitivity of type IV PDE to inhibition was dependent upon the selectivity of the inhibitor and the subcellular enzymic distribution. Cytosolic peak III PDE activity was further resolved by gel filtration chromatography into two peaks. Hydrolysis of cAMP by the higher molecular weight peak was inhibitable by cGMP (IC50 = 0.25 +/- 0.07 microM in NB and 0.07 +/- 0.01 microM in AD) whereas the lower molecular weight peak activity was relatively insensitive to inhibition by cGMP (IC50 greater than 100 microM). The lower molecular weight peak constituted a relatively greater proportion of the total peak III activity in the NB as compared to the AD. Analysis of the kinetics of cGMP inhibition of high-affinity cAMP hydrolysis was consistent with the presence of a greater number of high-affinity (presumably drug-sensitive) binding sites in the SR-associated activity as compared to the cytosolic peak III activity in both NB and AD. These results support the hypothesis that the cGMP-inhibitable Type IV PDE activity may be the primary site of action for certain newer cardiotonic drugs. Differences in drug action in young versus adult myocardium may be related to the selectivity of the cardiotonic drugs for this specific isozyme and its lower specific activity during the early stages of maturation.

Inotropic responses to cyclic nucleotide phosphodiesterase inhibitors in immature and adult rabbit myocardium.

Contractile dose-response relationships for amrinone, milrinone, piroximone, and sulmazole were compared in right ventricular papillary muscles isolated from adult and 14-16-day-old immature rabbits. These drugs were effective inotropic agents in immature myocardium as evidenced by substantial increases in the maximal rate of tension development. The rank order of maximum inotropic effect in the immature muscles was milrinone = sulmazole greater than piroximone greater than amrinone. Compared with adults, the relative magnitude of the inotropic response for each drug was greater in immature myocardium. Profiles of ventricular cytosolic cyclic nucleotide phosphodiesterase (PDE) activities resolved by anion exchange chromatography were similar for the two age groups. Immature myocardium was found to contain the Type IV (Peak III) high-affinity cAMP PDE that has been implicated in the mechanism of action of these drugs. Partially purified cytosolic Type IV PDE from immature and adult myocardium exhibited similar kinetic characteristics (cAMP Km = 0.9 microM; Vmax = 17 nmol/min/mg) and sensitivity to inhibition by cGMP. Except for piroximone, the inhibitory effect of each drug on cytosolic Type IV PDE activity from immature myocardium did not differ from the adult, as indexed by comparable concentrations required to inhibit activity by 50% (IC50) and Ki values (piroximone IC50 and Ki values were higher in the immature compared with the adult group). Thus, these studies demonstrated significant age-related differences in the contractile responses to amrinone, milrinone, piroximone, and sulmazole. These differences are not attributable to differences in myocardial cytosolic Type IV high-affinity cAMP PDE activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Molecular properties of cyclic nucleotide phosphodiesterase isozymes.

Mammalian cells contain multiple molecular forms of cyclic nucleotide phosphodiesterase that differ in substrate specificity and kinetic and regulatory properties. Calcium/calmodulin and cyclic GMP are important regulators of the hydrolysis of cyclic AMP by either stimulating or inhibiting the activity of distinct forms of phosphodiesterase. Several isozymes of cyclic nucleotide phosphodiesterase have been purified to apparent homogeneity. Although some sequence homology is observed the isozymes appear genetically distinct by immunological criteria. Cyclic AMP- and calmodulin-dependent protein kinases can phosphorylate these enzymes and alter their kinetic and regulatory properties. Both tissue specificity and pharmacological selectivity of isozymes have been demonstrated for several drugs. In certain cases, e.g. cardiac muscle, the selective inhibition of a high affinity cAMP phosphodiesterase activity in a specific subcellular fraction correlates with pharmacologic responses. The results from molecular and pharmacologic studies of cyclic nucleotide phosphodiesterases have indeed expanded the role this system of isoenzymes exerts in the regulation of cellular function.

Inotropic responses change during postnatal maturation in rabbit.

Inotropic response to four different types of pharmacological stimuli were compared in isolated right ventricular papillary muscles from newborn (24-48 h of age), immature (14-16 days), and adult (6-7 mo) rabbits. Forskolin, a direct activator of adenylate cyclase, produced a 12.5-fold increase in the maximal rate of tension development in the newborn group. The maximum response to isoproterenol was only 45% of the maximum forskolin response, suggesting incomplete physiological coupling of myocardial beta-adrenergic receptors to adenylate cyclase at birth. In contrast to the substantial inotropic response to agents that stimulate adenosine 3',5'-cyclic monophosphate (cAMP) generation (forskolin and isoproterenol), a selective inhibitor of cAMP hydrolysis (milrinone) was relatively ineffective in the newborn group. Sulmazole, a drug that enhances calcium sensitivity of the contractile proteins, produced its greatest inotropic effect in immature myocardium. Cytosolic high-affinity cAMP phosphodiesterase activity was partially purified from ventricular homogenates by anion-exchange chromatography. The kinetics of cAMP hydrolysis (Km and Vmax) and inhibitory potency of milrinone were comparable in each age group. Thus the age-related differences in inotropic responsiveness may not be attributable to postnatal changes in myocardial cytosolic high-affinity cAMP phosphodiesterase activity.

Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activity in rabbit ventricular myocardium: relations to the effects of cardiotonic drugs.

Rabbit ventricular myocardium contains distinct cytosolic and particulate cyclic AMP (cAMP) phosphodiesterase activities that exhibit characteristics ascribed to a high-affinity type IV cAMP phosphodiesterase activity found in several tissues. The particulate activity associated with sarcoplasmic reticulum vesicles has an apparent Km for cAMP of about 0.3 microM and a Vmax of 2.45 +/- 0.55 nmol/min/mg. Cyclic GMP (cGMP) inhibits hydrolysis measured at 0.25 microM cAMP with an IC50 value of 0.28 microM. In comparison, a ventricular cytosolic high-affinity cAMP phosphodiesterase activity obtained by anion exchange chromatography (Peak III) has an apparent Km of 0.93 microM and a Vmax of 17 +/- 1 nmol/min/mg. Hydrolysis of 0.25 microM cAMP by this cytosolic activity is weakly inhibited by cGMP with an IC50 value of 142 microM. Particulate enzyme activity is 60-fold more sensitive to inhibition by milrinone than is the cytosolic form (Ki = 0.18 versus 11 microM, respectively); the pyridazinone imazodan is a 12-fold more potent inhibitor of the particulate activity than of the cytosolic form (Ki = 1.5 versus 18 microM, respectively). Inhibition of both cytosolic and particulate enzyme activities appears competitive in nature. Solubilization of particulate activity did not significantly alter its affinity for substrate or sensitivity to inhibition by cGMP. In the presence of a submaximally activating concentration of forskolin (0.4 microM), selective phosphodiesterase inhibitors potentiated the activation of protein kinase in isolated ventricular septal slices. Under these conditions, changes in cAMP-dependent protein kinase activity ratios correlated more closely with contractile responses than did changes in intracellular content of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)