Gias U. Ahmmed

Responses of plasma norepinephrine and renin-angiotensin-aldosterone system to dynamic exercise in patients with congestive heart failure

BACKGROUND Neurohormonal activation is present and neurohormonal responses to dynamic exercise are altered in congestive heart failure (CHF). Responses of plasma norepinephrine in various degrees of heart failure have been investigated, but the responses of the renin-angiotensin-aldosterone system have not been studied in relation to the severity of CHF. The aim of this study was to determine if the responses of the renin-angiotensin-aldosterone system to exercise are augmented according to the severity of CHF. METHODS AND RESULTS Ventilatory and neurohormonal responses were assessed in 38 patients with CHF (New York Heart Association class: I, 13 patients; II, 14 patients; III, 11 patients) and 11 normal subjects during symptom-limited cardiopulmonary exercise testing. Plasma norepinephrine, renin activity, angiotensin II, and aldosterone were measured at rest and at peak exercise. The increments in neurohormones were divided by peak oxygen consumption, and these ratios (norepinephrine exercise ratio, plasma renin activity-exercise ratio, angiotensin II-exercise ratio, aldosterone-exercise ratio) were compared among groups. Peak oxygen consumption and anaerobic threshold decreased progressively with the severity of CHF. Neurohormonal profiles at rest showed that plasma norepinephrine levels were significantly higher, and the renin-angiotensin-aldosterone system was augmented only in patients with class III CHF. Neurohormones increased during exercise both in patients with CHF and in normal subjects, but patients with class III CHF had significantly higher plasma renin activity (10.11 +/- 2.32 ng/mL/h), angiotensin II (73.9 +/- 14.2 pg/mL), and aldosterone (265.2 +/- 61.1 pg/mL) than did normal subjects. Plasma renin activity-exercise ratio, angiotensin II-exercise ratio, and aldosterone-exercise ratio in patients with class III CHF were significantly higher compared to normal subjects. This augmentation of the renin-angiotensin-aldosterone system was not observed in class I or II patients. Peak plasma norepinephrine levels were not different among normal subjects and subgroups of CHF patients, but the norepinephrine-exercise ratio was significantly higher in classes II and III CHF compared to normal subjects. CONCLUSIONS These data suggest that neurohormonal excitation during exercise increases along with the severity of CHF when normalized for peak exercise level.

A novel mutation causing complete deficiency of thyroxine binding globulin

Thyroxine binding globulin (TBG) is a serum protein that transports thyroxine. Three naturally occurring mutations have been reported to produce complete deficiency of TBG (TBG‐CD). The first to be reported was TBG‐CD5 in caucasian families of French‐Canadian origin and consists of substitutions in exons 2 and 3. TBG‐CD of English ethnic origin (TBG‐CD6) is characterized by a thymine deletion in codon 165 (exon 1). In Japanese families with TBG‐CD (TBG‐CDJ), a variant has been characterized with a deletion of the first base of the codon for amino acid 352 (exon 4) in the common type TBG. In this communication we report a new type of TBG‐CD in a family of japanese ethnic origin that is characterized by a single nucleotide substitution in place of two nucleotides in exon 1. This is an uncommon mutation which we have been unable to find in other genes.

Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes. Atrioventricular difference of moricizine block.

The effects of moricizine on Na+ channel currents (INa) were investigated in guinea-pig atrial myocytes and its effects on INa in ventricular myocytes and on cloned hH1 current were compared using the whole-cell, patch-clamp technique. Moricizine induced the tonic block of INa with the apparent dissociation constant (Kd,app) of 6.3 microM at -100 mV and 99.3 microM at -140 mV. Moricizine at 30 microM shifted the h infinity curve to the hyperpolarizing direction by 8.6 +/- 2.4 mV. Moricizine also produced the phasic block of INa, which was enhanced with the increase in the duration of train pulses, and was more prominent with a holding potential (HP) of -100 mV than with an HP of -140 mV. The onset block of INa induced by moricizine during depolarization to -20 mV was continuously increased with increasing the pulse duration, and was enhanced at the less negative HP. The slower component of recovery of the moricizine-induced INa block was relatively slow, with a time constant of 4.2 +/- 2.0 s at -100 mV and 3.0 +/- 1.2 s at -140 mV. Since moricizine induced the tonic block of ventricular INa with Kd,app of 3.1 +/- 0.8 microM at HP = -100 mV and 30.2 +/- 6.8 microM at HP = -140 mV, and cloned hH1 with Kd,app of 3.0 +/- 0.5 microM at HP = -100 mV and 22.0 +/- 3.2 microM at HP = -140 mV, respectively, either ventricular INa or cloned hH1 had significantly higher sensitivity to moricizine than atrial INa. The h infinity curve of ventricular INa was shifted by 10.5 +/- 3.5 mV by 3 microM moricizine and that of hH1 was shifted by 5.0 +/- 2.3 mV by 30 microM moricizine. From the modulated receptor theory, we have estimated the dissociation constants for the resting and inactivated state to be 99.3 and 1.2 microM in atrial myocytes, 30 and 0.17 microM in ventricular myocytes, and 22 and 0.2 microM in cloned hH1, respectively. We conclude that moricizine has a higher affinity for the inactivated Na+ channel than for the resting state channel in atrial myocytes, and moricizine showed the significant atrioventricular difference of moricizine block on INa. Moricizine would exert an antiarrhythmic action on atrial myocytes, as well as on ventricular myocytes, by blocking Na+ channels with a high affinity to the inactivated state and a slow dissociation kinetics.

Tonic block of the Na+ current in single atrial and ventricular guineapig myocytes, by a new antiarrhythmic drug, Ro 22-9194

Summary— Ro 22‐9194 reduced the Na+ current in the atrial myocytes as well as ventricular myocytes in a tonic block fashion. Ro 22‐9194 had a higher affinity to the inactivated state Na+ channels (Kd1 = 3.3 μM in atrial myocytes, Kd1 = 10.3 μM in ventricular myocytes) than to those in the rested state (KdR = 91 μM in atrial myocytes, KdR = 180 μM in ventricular myocytes), which indicated that Ro 22‐9194 had a higher affinity to the Na+ channels in atrial myocytes than in ventricular myocytes. Ro 22‐9194 shifted the inactivation curve in the hyperpolarized direction in both atrial and ventricular myocytes. These findings suggest that Ro 22‐9194 more strongly inhibited the Na+ channel of the atrial myocytes of the diseased hearts with the depolarized membranes potentials than the Na+ channels in ventricular myocytes.

Responses of Plasma Catecholamines, Renin-Angiotensin-Aldosterone System, and Atrial Natriuretic Peptide to Exercise in Patients with Essential Hypertension

Neurohormonal responses to exercise have not been studied fully in patients with essential hypertension (HT). This study determined if neurohormonal responses to exercise are altered between three subgroups of HT categorized by basal plasma renin activity (PRA). Plasma norepinephrine, epinephrine, atrial natriuretic peptide (ANP), PRA, angiotensin II (AII), and aldosterone were measured at rest and after submaximal treadmill exercise in 39 patients with essential HT (WHO classes I-II) and 13 controls. Patients with HT were divided into three subgroups based on the PRA level [low-renin (< 0.5) HT (n = 14), normal-renin (0.5-2.0) HT (n = 13), and high-renin (> 2.0) HT (n = 12)]. Patients with HT had higher blood pressure during exercise compared to controls, but blood pressure responses were similar among low-, normal-, and high-renin HT. Neurohormonal factors were comparable between all hypertensives and controls, except for higher plasma AII at rest in patients with HT. When neurohormones were compared among three subgroups of HT, plasma norepinephrine and epinephrine responses were similar. Patients with high-renin HT had higher PRA and AII, and lower ANP levels at rest and after exercise. In all hypertensives, negative correlations were observed between resting PRA and resting ANP (r = -0.41, p < 0.01), as well as peak PRA and peak ANP (r = -0.33, p < 0.05). Thus, neurohormonal responses to exercise varied with similar cardiac responses among subgroups of essential HT stratified according to renin levels. Patients with high-renin HT had augmented renin-angiotensin system activity with a decrease in ANP levels both at rest and after exercise. A reciprocal relationship between renin-angiotensin system activity and ANP was observed both at rest and after exercise in HT.

Amitriptyline inhibits the G protein and K+ channel in the cloned thyroid cell line

We have reported that thyroid K+ channel is activated by extracellular application of the thyroid-stimulating hormone (TSH) using single channel recording method performed on cloned normal rat thyroid cell (FRTL-5) membrane. Treatment of dibutyryladenosine cyclic monophosphate (Bt2 cAMP) also activated the TSH-dependent K+ channel. These findings indicate that the thyroid K+ channel is activated through the TSH-adenosine cyclic monophosphate (cAMP)-protein kinase A system. We examined the effects of amitriptyline on TSH-guanosine triphosphate binding protein (G protein)-adenylate cyclase-cAMP-K+ channel system in the cloned normal rat thyroid cell line FRTL-5. Amitriptyline inhibited the cAMP production induced by TSH. Amitriptyline also inhibited the cAMP production induced by cholera toxin, indicating that amitriptyline inhibited the thyroid G protein. Amitriptyline had no effect on TSH-receptor binding and cAMP production by forskolin (adenylate cyclase stimulator). Amitriptyline inhibited the K+ channel activation by cAMP, indicating that the suppressing mechanism is not the inhibition of TSH receptor or G protein but the direct suppression of K+ channel. It was concluded that amitriptyline inhibited the thyroid G protein and K+ channel.

Mechanism of inhibition of the Na current by tocainide in guinea-pig isolated ventricular cells.

Tocainide blocked the Na current (I(Na)) in ventricular myocytes in either a tonic or a phasic block manner, having a higher affinity for the inactivated state (K(di) = 18 microM) than for the rested state (Kd(rest) = 606 microM). The degree of phasic block was enhanced and the onset of phasic block was faster with an increase in pulse duration as well as at less-negative holding potential (HP). The recovery-time constant from the phasic block of I(Na) induced by tocainide was independent of either the HP or the removal of fast inactivation. After removal of fast inactivation, tocainide showed the pulse-duration dependency of phasic block but not the voltage dependency. These results suggest that tocainide could bind to the inactivated-state receptor through the hydrophilic pathway and leave the receptor through the hydrophobic pathway, producing the tonic and phasic block of I(Na).

Influence of extracellular H+ and Ca2+ on Ro 22-9194-induced block of sodium current in cardiac myocytes.

1. Ro 22-9194 reduced the Na current in ventricular myocytes in either a tonic block or phasic block manner. 2. Ro 22-9194 had a higher affinity to the inactivated state (Kdi = 10.3 microM) than to the rested state (Kdrest = 180 microM). 3. Extracellular acidification enhanced the tonic block but reduced the phasic block. 4. Elevation of extracellular Ca2+ inhibited the enhancing effects of extracellular acidification. 5. These findings suggest that Ro 22-9194 strongly inhibits Na+ channels of the ventricular myocytes of the diseased hearts, characterized by the depolarized cell membranes and by acid conditions.