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Biomedical subjects

B Casadei

Publications and source records attributed to B Casadei.

At least 19 recordsLinked to original sources
PubMed2005

Disruption of inhibitory G-proteins mediates a reduction in atrial beta-adrenergic signaling by enhancing eNOS expression.

OBJECTIVE: Cardiac parasympathetic nerve activity is reduced in most cardiovascular disease states, and this may contribute to enhanced cardiac sympathetic responsiveness. Disruption of inhibitory G-proteins (Gi) ablates the cholinergic pathway and increases cardiac endothelial nitric oxide (NO) synthase (eNOS) expression, suggesting that NO may offset the impaired attenuation of beta-adrenergic regulation of supraventricular excitability. To test this, we investigated the role of endogenous NO production on beta-adrenergic regulation of rate (HR), contraction (CR) and calcium (Ca2+) handling in atria following blockade of Gi-coupled muscarinic receptors. METHODS: Mice were administered pertussis toxin (PTx, n=105) or saline (C, n=100) intraperitoneally. After 3 days, we measured CR, HR, and NOS protein levels in isolated atria. Intracellular calcium (Ca2+) transients and Ca2+ current density (I(Ca)) were also measured in atrial myocytes. RESULTS: PTx treatment increased atrial myocyte eNOS protein levels compared to C (P<0.05). This did not affect basal atrial function but was associated with a significant reduction in the CR and HR response to isoprenaline (ISO) compared with C. NOS inhibition normalized responses in PTx atria with respect to responses in C atria (P<0.05), which were unaffected. Furthermore, PTx did not affect ISO-stimulated HR and CR in eNOS gene knockout mice (n=40). In agreement with these findings, the ISO-mediated increase in Ca2+ transient was suppressed in PTx-treated myocytes (P<0.05), whereas I(Ca) did not differ between groups. CONCLUSION: eNOS-derived NO inhibits beta-adrenergic responses following disruption of Gi signaling. This suggests that increased eNOS expression may be a compensatory mechanism which reduces beta-adrenergic regulation of heart rate when cardiac parasympathetic control is impaired.

Adrenergic beta-Agonists↗
PubMed2003

Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling.

A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca2+ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca2+ cycling. To test this hypothesis, we have investigated myocardial Ca2+ handling and contractility in nNOS knockout mice (nNOS-/-) and in control mice (C) after acute nNOS inhibition with 100 micromol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3+/-0.6% in nNOS-/- versus 8.1+/-0.5% in C; P<0.05) and in vivo (LV ejection fraction 53.5+/-2.7 in nNOS-/- versus 44.9+/-1.5% in C; P<0.05). nNOS disruption increased ICa density (in pA/pF, at 0 mV, -11.4+/-0.5 in nNOS-/- versus -9.1+/-0.5 in C; P<0.05) and prolonged the slow time constant of inactivation of ICa by 38% (P<0.05), leading to an increased Ca2+ influx and a greater SR load in nNOS-/- myocytes (in pC/pF, 0.78+/-0.04 in nNOS-/- versus 0.64+/-0.03 in C; P<0.05). Consistent with these data, [Ca2+]i transient (indo-1) peak amplitude was greater in nNOS-/- myocytes (410/495 ratio 0.34+/-0.01 in nNOS-/- versus 0.31+/-0.01 in C; P<0.05). These findings have uncovered a novel mechanism by which intracellular Ca2+ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org.

Animals↗
PubMed2001

Identification of higher brain centres that may encode the cardiorespiratory response to exercise in humans.

1. Positron emission tomography (PET) was used to identify the neuroanatomical correlates underlying 'central command' during imagination of exercise under hypnosis, in order to uncouple central command from peripheral feedback. 2. Three cognitive conditions were used: condition I, imagination of freewheeling downhill on a bicycle (no change in heart rate, HR, or ventilation, V(I)): condition II, imagination of exercise, cycling uphill (increased HR by 12 % and V(I) by 30 % of the actual exercise response): condition III, volitionally driven hyperventilation to match that achieved in condition II (no change in HR). 3. Subtraction methodology created contrast A (II minus I) highlighting cerebral areas involved in the imagination of exercise and contrast B (III minus I) highlighting areas activated in the direct volitional control of breathing (n = 4 for both; 8 scans per subject). End-tidal P(CO(2)) (P(ET,CO(2))) was held constant throughout PET scanning. 4. In contrast A, significant activations were seen in the right dorso-lateral prefrontal cortex, supplementary motor areas (SMA), the right premotor area (PMA), superolateral sensorimotor areas, thalamus, and bilaterally in the cerebellum. In contrast B, significant activations were present in the SMA and in lateral sensorimotor cortical areas. The SMA/PMA, dorso-lateral prefrontal cortex and the cerebellum are concerned with volitional/motor control, including that of the respiratory muscles. 5. The neuroanatomical areas activated suggest that a significant component of the respiratory response to 'exercise', in the absence of both movement feedback and an increase in CO(2) production, can be generated by what appears to be a behavioural response.

Adult↗
PubMed2001

Nitric oxide does not modulate the hyperpolarization-activated current, I(f), in ventricular myocytes from spontaneously hypertensive rats.

OBJECTIVE: : In sinoatrial (SA) node cells, nitric oxide (NO) exerts a dual effect on the hyperpolarization-activated current, I(f), i.e. in basal conditions NO enhances I(f) whereas in the presence of beta-adrenergic stimulation it decreases it. Recent studies have shown that I(f) is present in ventricular myocytes from hypertrophied or failing hearts where it may promote abnormal automaticity. Since these pathological conditions are associated with increased sympathetic tone and upregulation of myocardial NO production, we set out to investigate whether I(f) is similarly modulated by NO in hypertrophied ventricular myocytes. METHODS: Left ventricular myocytes were isolated from 18-20-month-old spontaneously hypertensive rats (SHRs). Membrane current was measured under whole-cell or amphotericin-perforated patch-clamp conditions, at 35 degrees C. RESULTS: Application of diethylamine-NO (DEA-NO, 1-100 microM) did not alter the amplitude or voltage dependence of activation of I(f) under basal conditions (half-activation voltage, V(h): control -82.9+/-2.6, DEA-NO -84.0+/-2.6 mV). Similarly, I(f) was not affected by the inhibition of endogenous NO production (L-NMMA, 500 microM) or guanylate cyclase (ODQ, 10 microM). Forskolin (10 microM) or isoprenaline (100 nM) elicited a positive shift in V(h) but subsequent application of DEA-NO did not further affect the properties of I(f). CONCLUSIONS: Our results show that, unlike in SA node cells, in SHR ventricular myocytes basal and adrenergically stimulated I(f) is not modulated by exogenous NO or by constitutive NO or cGMP production.

Adenylyl Cyclases↗
PubMed2001

Hypertension is a major risk factor for aortic root dilatation in women with Turner's syndrome.

Women with Turner's syndrome (TS) have a threefold increase in mortality, primarily as a result of their cardiovascular complications. Recently, the risk of fatal aortic dissection has come to light as a major cause of mortality in women with TS. The aim of this study was to assess the prevalence of aortic root dilatation in a group of women with TS and to investigate the factors contributing to its development. Thirty-eight women with TS attending a dedicated adult Turner clinic were examined clinically and by M-mode and two-dimensional echocardiography on at least one occasion. Aortic root dilatation was defined as an aortic root diameter greater than the 95th centile for body surface area. Fasting serum lipid concentrations were measured in all women. Additionally, 18 subjects underwent noninvasive assessment of central arterial stiffness using applanation tonometry. Fifty percent of subjects were hypertensive and a similar number had an abnormal echocardiogram. A bicuspid aortic valve was present in 33% of subjects, 16 women (42%) had ascending aortic root dilatation. This was associated with a bicuspid aortic valve in four women and hypertension in 11. Two women had isolated aortic root dilatation. Aortic root diameter was significantly associated with systolic blood pressure (r = 0.5, P = 0.003) and left ventricular thickness (r = 0.5, P = 0.02). There was no association with serum lipids or arterial compliance. Structural cardiac abnormalities are present in up to 50% of women with Turner's syndrome. Aortic root dilatation is a significant risk in women with Turner's syndrome and is closely dependent on blood pressure. Aortic root dilatation does not appear to be related to atherosclerosis and is more likely to be due to a mesenchymal defect. Regular surveillance of the aortic root diameter is essential in all women with Turner's syndrome and hypertension should be treated aggressively when present in order to minimize the risk of potentially fatal aortic dissection.

Adolescent↗
PubMed2001

Mechanisms of respiratory sinus arrhythmia in patients with mild heart failure.

The high-frequency (HF) component of the heart rate variability (HRV) is regarded as an index of cardiac vagal responsiveness. However, when vagal tone is decreased, nonneural mechanisms could account for a significant proportion of the HF component. To test this hypothesis, we examined the HRV spectral power in 20 patients with mild chronic heart failure (CHF) and 11 controls before and during ganglion blockade with trimethaphan camsylate (3-6 mg/min iv). A small HF component was still present during ganglion blockade, and its amplitude did not differ between CHF patients and controls. The average contribution of nonneural oscillations to the HF component was 15% (range 1-77%) in patients with CHF and 3% (range 0. 7-30%) in healthy controls (P < 0.005). During controlled breathing at 0.16 Hz, however, it decreased to 1% (range 0.2-13%) in healthy controls and 5% (range 1-44%) in CHF patients. Our results indicate that the HF component can significantly overestimate cardiac vagal responsiveness in patients with mild CHF. This bias is improved by controlled breathing, since this maneuver increases the vagal contribution to HF without affecting its nonneural component.

Arrhythmia, Sinus↗
PubMed2001

Determinants of spontaneous baroreflex sensitivity in a healthy working population.

Baroreflex sensitivity (BRS) by the spontaneous sequence technique has been widely used as a cardiac autonomic index for a variety of pathological conditions. However, little information is available on determinants of the variability of spontaneous BRS and on age-related reference values of this measurement in a healthy population. We evaluated BRS as the slope of spontaneous changes in systolic blood pressure (BP) and pulse interval from 10 minutes BP (Finapres) and ECG recordings in 1134 healthy volunteers 18 to 60 years of age. Measurement of BRS could be obtained in 90% of subjects. Those with unmeasurable spontaneous BRS had a slightly lower heart rate but were otherwise not different from the rest of the population. BRS was inversely related to age (lnBRS, 3.24-0.03xage; r(2)=0.23; P:<0.0001) in both genders. In addition, univariate analysis revealed a significant inverse correlation between BRS and heart rate, body mass index, and BP. Sedentary lifestyle and regular alcohol consumption were also associated with lower BRS. However, only age, heart rate, systolic and diastolic BP, body mass index, smoking, and gender were independent predictors of BRS in a multivariate model, accounting for 47% of the variance of BRS. The present study provides reference values for spontaneous BRS in a healthy white population. Only approximately half of the variability of BRS could be explained by anthropometric variables and common risk factors, which suggests that a significant proportion of interindividual differences may reflect genetic heterogeneity.

Adolescent↗
PubMed2000

Sympathetic denervation of the upper limb improves forearm exercise performance and skeletal muscle bioenergetics.

BACKGROUND: Sympathetic activation may limit exercise performance by restraining muscle blood flow or by negatively affecting skeletal muscle metabolic behavior. To test this hypothesis, we studied the effect of thoracoscopic sympathetic trunkotomy (TST) on forearm exercise duration, blood flow, and muscle bioenergetics in 13 patients with idiopathic palmar hyperhidrosis. METHODS AND RESULTS: Heart rate and beat-by-beat mean arterial pressure were recorded at rest and during right and left rhythmic handgrip before and 4 to 7 weeks after right TST. Forearm blood flow was measured bilaterally at rest and on the right during exercise. Right forearm muscle phosphocreatine content and intracellular pH were assessed by (31)phosphorus magnetic resonance spectroscopy. After right TST, exercise duration increased from 8.9+/-1.4 to 13.4+/-1.8 minutes (P<0.0001) with the right forearm and from 5.7+/-0.4 to 7.6+/-0.9 minutes (P<0.05) with the left (P<0.05 for the interaction between treatment and side). Right forearm blood flow at rest was 66% higher (P<0.01) after right TST, but this difference decreased as the exercise progressed. After right TST, a significant reduction occurred in muscle acidification and phosphocreatine depletion during ipsilateral forearm exercise. This was associated with a significantly reduced mean arterial pressure response to right handgrip, whereas the pressor response to left handgrip did not change. CONCLUSIONS: Sympathetic denervation of the upper limb significantly improves forearm skeletal muscle bioenergetics and exercise performance in patients with idiopathic palmar hyperhidrosis.

Adult↗
PubMed2000

Role of cGMP-inhibited phosphodiesterase and sarcoplasmic calcium in mediating the increase in basal heart rate with nitric oxide donors.

Nitric oxide (NO) donors increase heart rate (HR) through a guanylyl cyclase-dependent stimulation of the pacemaker current I(f), without affecting basal I(Ca-L). The activity of I(f)is known to be enhanced by cyclic nucleotides and by an increase in cytosolic Ca(2+). We examined the role of cGMP-dependent signaling pathways and intracellular Ca(2+)stores in mediating the positive chronotropic effect of NO donors. In isolated guinea pig atria, the increase in HR in response to 1-100 micromol/l 3-morpholino-sydnonimine (SIN-1; with superoxide dismutase, n=6) or diethylamine-NO (DEA-NO, n=8) was significantly attenuated by blockers of the cGMP-inhibited phosphodiesterase (PDE3; trequinsin, milrinone or Ro-13-6438, n=22). In addition, the rate response to DEA-NO or sodium nitroprusside (SNP) was significantly reduced following inhibition of PKA (KT5720 or H-89, n=15) but not PKG (KT5728 or Rp-8-pCPT-cGMPs, n=16). Suppression of sarcoplasmic (SR) Ca(2+)release by pretreatment of isolated atria with ryanodine or cyclopiazonic acid (2 micromol/l and 60 micromol/l, n=16) significantly reduced the chronotropic response to 1-100 micromol/l SIN-1 or DEA-NO. Moreover, in isolated guinea pig sinoatrial node cells 5 micromol/l SNP significantly increased diastolic and peak Ca(2+)fluorescence (+13+/-1% and +28+/-1%, n=6, P<0.05). Our findings are consistent with a functionally significant role of cAMP/PKA signaling (via cGMP inhibition of PDE3) and SR Ca(2+)in mediating the positive chronotropic effect of NO donors.

Animals↗
PubMed2000

Peripheral pre-synaptic pathway reduces the heart rate response to sympathetic activation following exercise training: role of NO.

OBJECTIVES: We tested the hypothesis that the attenuated heart rate (HR) response to sympathetic activation following swim training in the guinea pig (Cavia porcellus) results from a peripheral modulation of pacemaking by nitric oxide (NO). METHODS: Nitric oxide synthase (NOS) inhibition on the increase in heart rate with sympathetic nerve stimulation (SNS) was investigated in the isolated guinea pig double atrial/right stellate ganglion preparation from exercise trained (6-weeks swimming, n=20) and sedentary animals (n=20). Western blot analysis for neuronal nitric oxide synthase (nNOS) was performed on the stellate ganglion from both groups. RESULTS: Relative to the control group, the exercise group demonstrated typical exercise adaptations of increased ventricular weight/body weight ratio, enhanced skeletal muscle citrate synthase activity and higher concentrations of [3H]ouabain binding sites in both skeletal and cardiac tissue (P<0.05). The increase in heart rate (bpm) with SNS significantly decreased in the exercise group (n=16) compared to the sedentary group (n=16) from 30+/-5 to 17+/-3 bpm at 1 Hz; 67+/-7 to 47+/-4 bpm at 3 Hz; 85+/-9 to 63+/-4 bpm at 5 Hz and 101+/-9 to 78+/-5 bpm at 7 Hz stimulation (P<0.05). The increase in heart rate with cumulative doses (0.1-10 microM) or a single dose (0.1 microM) of bath-applied norepinephrine expressed as the effective doses at which the HR response was 50% of the maximum response (EC50) were similar in both exercise (EC50 -6.08+/-0.16 M, n=8) and sedentary groups (EC50 -6.18+/-0.07 M, n=7). Trained animals had significantly more nNOS protein in left stellate ganglion compared to the sedentary group. In the exercise group, the non-isoform selective NOS inhibitor, N-omega nitro-L-arginine (L-NA, 100 microM) caused a small but significant increase in the heart rate response to SNS. However, the positive chronotropic response to sympathetic nerve stimulation remained significantly attenuated in the exercise group compared to the sedentary group during NOS inhibition (P<0.05). CONCLUSIONS: Our results indicate that there is a significant peripheral pre-synaptic component reducing the HR response to sympathetic activation following training, although NO does not play a dominant role in this response.

Animals↗
PubMed2000

Measurement of blood pressure using the auscultatory and oscillometric methods in the same cuff deflation: validation and field trial of the A&D TM2421 monitor.

We have evaluated under laboratory validation conditions and in an extensive field trial the behaviour of an ambulatory monitoring device that is capable of recording both by the Korotkoff-sound and oscillometric methods in a single cuff deflation (TM2421: A&D Co, Tokyo, Japan). The effects of subject age and blood pressure (BP) level on the accuracy and field reliability of the two methods implemented in the device have been determined. In the validation phase, automatic BP measurements were compared with readings by two trained observers in 96 subjects, and the results compared with the AAMI criteria for automatic BP monitors. In the field trial phase, the performances of Korotkoff-sound and oscillometric methods over a 24-h period of ambulatory BP monitoring were compared in 515 subjects, with analysis of the agreement between the two methods in patients where both provided satisfactory recordings. In the validation phase, the Korotkoff-sound method gave satisfactory results for both systolic and diastolic BP, but the oscillometric technique narrowly failed to meet the AAMI criteria for the measurement of either systolic or diastolic BP. In the field trial, the K-sound method failed to record BP accurately in 12% of subjects whereas the oscillometric method was successful in all of these. Where both methods provided technically adequate records, agreement between mean values for each method was close. In 18% of patients, the availability of the oscillometric measurement as a 'back-up' method for the K-sound method significantly improved the number of available measurements in the monitoring period, which should result in improved accuracy and reproducibility of the ambulatory mean values.

Adult↗
PubMed2000

The effect of hormone replacement therapy on cardiovascular hemodynamics in women with Turner's syndrome.

Women with Turner's syndrome, the majority of whom are estrogen deficient, have an increased incidence of coronary artery disease. The aim of this study was to assess the effects of hormone replacement therapy (HRT) on central arterial hemodynamics, insulin sensitivity, and lipids in adults with Turner's syndrome. Twenty-one women with Turner's syndrome were studied prospectively, on and off 3 months of estradiol valerate in combination with levonorgestrel. The following measurements were made: body mass index, waist/hip ratio, serum lipids, fasting insulin and glucose, and mean arterial blood pressure. Aortic root pressure and waveforms were estimated noninvasively and the augmentation index (AI), a measure of aortic stiffness, was calculated. The AI was significantly lower during estrogen therapy (22% vs. 15%; P = 0.008), suggesting a reduction in central arterial stiffness. Fasting insulin and glucose concentrations were also significantly lower during HRT (P = 0.01 and P = 0.0004, respectively). There was no difference in body mass index, serum lipids, or brachial and aortic blood pressures on and off treatment. Total cholesterol was correlated with the AI (r = 0.4; P = 0.03). These results suggest that HRT in women with Turner's syndrome has a favorable effect on central arterial hemodynamics and insulin sensitivity. The lack of effect on serum lipids suggests that the effects of HRT on aortic compliance may be mediated by an improvement in endothelial function.

Adolescent↗
PubMed1999

Changes in extracellular pH mediate the chronotropic responses to L-arginine.

UNLABELLED: We have recently shown that exogenous nitric oxide (NO) elicits a positive chronotropic response by stimulating the hyperpolarization activated current, I(f). OBJECTIVE: To examine whether L-arginine (L-Arg) can mimic the chronotropic effect of NO by enhancing its endogenous production. METHODS: In spontaneously beating guinea pig atria we evaluated the heart rate (HR) response to increasing concentrations of L-Arg (1 mumol/l to 10 mmol/l), and compared it with that for D-Arg or L-lysine (L-Lys) (all in free base (FB) or hydrochloride (HCl) formulation). RESULTS: L-ArgFB > 100 mumol/l caused a reversible dose-dependent increase in HR (peak effect +64 +/- 7 bpm at 10 mmol/l, P < 0.05, n = 8). However, a similar HR response occurred with D-ArgFB (n = 7) or L-LysFB (n = 6). All FB formulations increased the perfusate pH (peak [pH]o = 8.61 +/- 0.03). Although alkalinization can stimulate NO release from the endothelium, this is unlikely to have contributed to HR changes in our preparation, since neither NG-methyl-L-arginine, (100-500 mumol/l, which per se reduced HR by 8 +/- 1%, P < 0.05, n = 9) nor NO scavenging (fresh 5% red blood cells, n = 9) caused a rightward shift of the concentration-response curve to L-ArgFB. Furthermore, as opposed to FB formulations, L-ArgHCl, D-ArgHCl or L-LysHCl > 1 mmol/l significantly decreased HR and [pH]o (n = 17). The chronotropic effects of L-ArFB or L-ArgHCl were reproduced by changing [pH]o with NaOH (n = 8) or HCl (n = 7), whereas the HR increase with L-ArgFB was prevented by clamping [pH]o at 7.42 +/- 0.07 (n = 10). CONCLUSIONS: In vitro, L-Arg can markedly affect HR through a pH-mediated, NO-independent mechanism. Our data show that the opposing changes in [pH]o induced by different formulations of L-Arg can importantly confound the assessment of the biological effects of this amino acid.

Analysis of Variance↗
PubMed1999

Effect of exogenous nitric oxide on baroreflex function in humans.

Nitric oxide (NO) donors inhibit sympathetic neurotransmission and baroreceptor activity and can directly stimulate heart rate (HR) in vitro. To assess whether exogenous NO affects cardiovascular autonomic control in humans, we tested the baroreceptor-cardiac reflex [baroreflex sensitivity (BRS)] and the arterial blood pressure (BP) and HR variability during an infusion of the NO donor sodium nitroprusside (SNP, 2 micrograms . kg(-1). min(-1)) or 5% glucose in 16 healthy subjects. The hypotensive action of SNP was prevented by phenylephrine (PE, 0.9 +/- 0.15 micrograms . kg(-1). min(-1)). The SNP + PE infusion did not affect BRS or HR variability, but it caused a significant reduction in the diastolic and systolic BP low-frequency power. In addition, SNP + PE caused a sustained 12% increase in HR in the absence of changes in brachial and aortic BP. In conclusion, SNP had no effect on the cardiac-vagal limb of the baroreflex in humans but caused a substantial reduction in BP low-frequency power consistent with a decreased baroreflex/sympathetic control of peripheral resistance. The increase in HR in the absence of baroreceptor downloading confirms our previous finding of a direct positive chronotropic effect of NO donors.

Adult↗
PubMed1999

Nitric oxide donors can increase heart rate independent of autonomic activation.

Administration of nitric oxide (NO) donors in vivo is accompanied by a baroreflex-mediated increase in heart rate (HR). In vitro, however, NO donors can increase HR directly by stimulating a pathway that involves NO, cGMP, and the hyperpolarization-activated current (I(f)). The aim of this study was to assess the functional significance of this pathway in vivo by testing whether NO donors can increase HR in the anesthetized rabbit independent of the autonomic nervous system. New Zealand White rabbits were vagotomized, cardiac sympathectomized, and treated with propranolol (0.3 mg/kg iv). The NO donor molsidomine (0.2 mg/kg iv) caused a progressive increase (Delta) in HR (DeltaHR, 14 +/- 3 beats/min; P < 0.01). This effect was significantly reduced by the I(f) blocker ZD-7288 (0.2 mg/kg iv; DeltaHR, 2 +/- 3 beats/min; P = not significant). Similar results were seen with sodium nitroprusside. The positive chronotropic effect of sodium nitroprusside (50 microM) was confirmed in the isolated working rabbit heart preparation (DeltaHR, 17 +/- 3 beats/min; P < 0.01). In conclusion, NO donors exert a small, but significant, positive chronotropic effect in vivo that is independent of the autonomic nervous system. These results are also consistent with data in sinoatrial node cells that show that NO donors increase HR by stimulating I(f).

Adrenergic beta-Antagonists↗