Relationship between chronotropic incompetence and β-blockers based on changes in chronotropic response during cardiopulmonary exercise testing

AbstractBackgroundChronotropic incompetence (CI), an attenuated heart rate (HR) response to exercise, is common in patients with cardiovascular disease. The aim of this study was to assess changes in the chronotropic response (CR) during cardiopulmonary exercise testing (CPET) in patients undergoing cardiac rehabilitation and investigate the effects of β-blockers.MethodsPatients undergoing cardiac rehabilitation performed CPET. Failure to achieve 80% of the age-predicted maximal HR (APMHR) defined CI. Values of the metabolic chronotropic relationship (MCR) were calculated from the ratio of the HR reserve to metabolic reserve at 4 stages, warm-up (MCR-Wu), anaerobic threshold (MCR-AT), respiratory compensation (MCR-Rc), and peak point (MCR-Pk), using the Wilkoff model. In patients who showed an increase in MCR at ≥3 of the 4 exercise stages, CR was considered to have improved.ResultsPatients with high BNP levels (≥80pg/ml) had a lower MCR at all stages compared with those with low BNP levels (<80pg/ml). Of the 80 patients, 47 showed an increase in both peak VO2 and AT, and of these 31 (66.0%) were taking β-blockers. Improvement in CR was observed in 30 of 47 patients with CI, and 70% of these were taking β-blockers. In patients not taking β-blockers, MCR-AT was lower than MCR-Rc, whereas in those taking β-blockers MCR-AT was higher than MCR-Rc.ConclusionsAn attenuated HR response may occur during the early stages of exercise. The HR response according to the presence or absence of β-blockers is clearly identifiable by comparing MCR-AT and MCR-Rc using the Wilkoff model

Relationship between chronotropic incompetence and β-blockers based on changes in chronotropic response during cardiopulmonary exercise testing

Chronotropic incompetence (CI), an attenuated heart rate (HR) response to exercise, is common in patients with cardiovascular disease. The aim of this study was to assess changes in the chronotropic response (CR) during cardiopulmonary exercise testing (CPET) in patients undergoing cardiac rehabilitation and investigate the effects of β-blockers. Patients undergoing cardiac rehabilitation performed CPET. Failure to achieve 80% of the age-predicted maximal HR (APMHR) defined CI. Values of the metabolic chronotropic relationship (MCR) were calculated from the ratio of the HR reserve to metabolic reserve at 4 stages, warm-up (MCR-Wu), anaerobic threshold (MCR-AT), respiratory compensation (MCR-Rc), and peak point (MCR-Pk), using the Wilkoff model. In patients who showed an increase in MCR at ≥ 3 of the 4 exercise stages, CR was considered to have improved. Patients with high BNP levels (≥ 80 pg/ml) had a lower MCR at all stages compared with those with low BNP levels (< 80 pg/ml). Of the 80 patients, 47 showed an increase in both peak VO2 and AT, and of these 31 (66.0%) were taking β-blockers. Improvement in CR was observed in 30 of 47 patients with CI, and 70% of these were taking β-blockers. In patients not taking β-blockers, MCR-AT was lower than MCR-Rc, whereas in those taking β-blockers MCR-AT was higher than MCR-Rc. An attenuated HR response may occur during the early stages of exercise. The HR response according to the presence or absence of β-blockers is clearly identifiable by comparing MCR-AT and MCR-Rc using the Wilkoff model

Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A

AbstractVoltage-gated Na+ channel (INa) is expressed under culture conditions in human smooth muscle cells (hSMCs) such as coronary myocytes. The aim of this study is to clarify the physiological, pharmacological and molecular characteristics of INa expressed in cultured hSMCs obtained from bronchus, main pulmonary and coronary artery. INa, was recorded in these hSMCs and inhibited by tetrodotoxin (TTX) with an IC50 value of approximately 10 nM. Reverse transcriptase/polymerase chain reaction (RT-PCR) analysis of mRNA showed the prominent expression of transcripts for SCN9A, which was consistent with the results of real-time quantitative RT-PCR. These results provide novel evidence that TTX-sensitive Na+ channel expressed in cultured hSMCs is mainly composed of Nav1.7

Inhibitory effects of ω-3 polyunsaturated fatty acids on receptor-mediated non-selective cation currents in rat A7r5 vascular smooth muscle cells

1. The effects of ω-3 polyunsaturated fatty acids on receptor-mediated non-selective cation current (I(cat)) and K(+) current were investigated in aortic smooth muscle cells from foetal rat aorta (A7r5 cells). The whole-cell voltage clamp technique was employed. 2. With a K(+)-containing solution, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA, 30 μM) produced an outward current at a holding potential of −40 mV. This response was inhibited by tetraethylammonium (20 mM) or Cs(+) in the patch pipette solution, and the reversal potential of the EPA-induced current followed the K(+) equilibrium potential in a near Nernstian manner. 3. Under conditions with a Cs(+)-containing pipette solution, both vasopressin and endothelin-1 (100 nM) induced a long-lasting inward current at a holding potential of −60 mV. The reversal potential of these agonist-induced currents was about +0 mV, and was not significantly altered by the replacement of the extracellular or intracellular Cl(−) concentration, suggesting that the induced current was a cation-selective current (I(cat)). 4. La(3+) and Cd(2+) (1 mM) completely abolished these agonist-induced I(cat), but nifedipine (10 μM) failed to inhibit it significantly. 5. ω-3 polyunsaturated fatty acids (3100 μM), EPA, DHA and docosapentaenoic acids (DPA), inhibited the agonist-induced I(cat) in a concentration-dependent manner. The potency of the inhibitory effect was EPA>DHA>DPA, and the half maximal inhibitory concentration (IC(50)) of EPA was about 7 μM. 6. Arachidonic and linoleic acids (10, 30 μM) showed a smaller inhibitory effect compared to ω-3 fatty acids. Also, oleic and stearic acids (30 μM) did not show a significant inhibitory effect on I(cat). 7. A similar inhibitory action of EPA was observed when I(cat) was activated by intracellularly applied GTPγS in the absence of agonists, suggesting that the site of action of ω-3 fatty acids is not located on the receptor. 8. These results demonstrate that ω-3 polyunsaturated fatty acids can activate a K(+) current and also effectively inhibit receptor-mediated non-selective cation currents in rat A7r5 vascular smooth muscle cells. Thus, the data suggest that ω-3 fatty acids may play an important role in the regulation of vascular tone

Molecular and pharmacological characteristics of transient voltage-dependent K(+) currents in cultured human pulmonary arterial smooth muscle cells

1. The A-type voltage-dependent K(+) current (I(A)) has been identified in several types of smooth muscle cells including the pulmonary artery (PA), but little is known about the pharmacological and molecular characteristics of I(A) in human pulmonary arterial smooth muscle cells (hPASMCs). We investigated I(A) expressed in cultured PASMCs isolated from the human main pulmonary artery, using patch-clamp techniques, reverse transcriptase–polymerase chain reaction (RT–PCR), quantitative real-time RT–PCR and immunocytochemical studies. 2. With high EGTA and ATP in the pipette, the outward currents were dominated by a transient K(+) current (I(A)), followed by a relatively small sustained outward current (I(K)). 3. I(A) was inhibited by 4-aminopyridine (4-AP) concentration-dependently, and could be separated pharmacologically into two components by tetraethylammonium (TEA) sensitivity. A component was sensitive to TEA, and the second component was insensitive to TEA. 4. I(A) was inhibited by blood depressing substrate (BDS)-II, a specific blocker of K(V)3.4 subunit, and phrixotoxin-II, a specific blocker of K(V)4.2 and 4.3. 5. Flecainide inhibited I(A) concentration-dependently, but it inhibited it preferentially in the presence of TEA (TEA-insensitive I(A)). 6. Systematic screening of expression of K(V) genes using RT–PCR showed the definite presence of transcripts of the I(A)-encoding genes for K(V)3.4, K(V)4.1, K(V)4.2 and K(V)4.3 as well as the I(K)-encoding genes for K(V)1.1, K(V)1.5 and K(V)2.1. The real-time RT–PCR analysis showed that the relative abundance of the encoding genes of I(A) α-subunit and K(V) channel-interacting proteins (KChIPs) was K(V)4.2>K(V)3.4>K(V)4.3 (long)>K(V)4.1, and KChIP3≫KChIP2, respectively. 7. The presence of K(V)3.4, K(V)4.2 and K(V)4.3 proteins was also demonstrated by immunocytochemical studies, and confirmed by immunohistochemical staining using intact human PA sections. 8. These results suggest that I(A) in cultured hPASMCs consists of two kinetically and pharmacologically distinct components, probably K(V)3.4 and K(V)4 channels