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The beta-adrenergic control of the L-type Ca2+ current (ICa) was examined as a function of extracellular pH (pHo) in guinea-pig ventricular myocytes using the whole-cell voltage-clamp technique. ICa was elicited in Cs(+)-loaded myocytes by depolarizing pulses from a holding potential of -40 mV. The maximum ICa density in response to 0.01 or 1 microM isoproterenol was significantly less in myocytes pretreated with acidic external solution (pHo 6.6 or 5.8) compared with cells studied at control pHo 7.4. This acidosis-induced decrease in beta-responsiveness was also accompanied by a similar reduction in basal current density. Myocytes studied under alkaline conditions (pHo 8.2) also had reduced beta-responsiveness although basal ICa density tended to be greater than control. In addition to the diminished effects of isoproterenol, acidic myocytes had smaller responses to extracellular forskolin and internally applied adenosine 3',5'-cyclic monophosphate, compared with control. The blunted responses to these latter stimuli were similar in magnitude to that observed with 1 microM isoproterenol. These findings suggest that protons interfere with the beta-adrenergic control of ICa primarily by a direct inhibition of the Ca2+ channel which independently masks the effects of the adenylyl cyclase cascade.

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Modulation of the beta-adrenergic control of cardiac L-type Ca2+ current (Ica) by human recombinant interleukin-1 beta (IL-1) was examined in adult guinea pig ventricular myocytes using the whole cell voltage-clamp technique. ICa was elicited in Cs(+)-loaded myocytes by depolarizing pulses from a holding potential of -40 mV. Isoproterenol (0.01 and 1 microM) exposed to myocytes pretreated with 1 ng/ml IL-1 evoked a significantly smaller increase in ICa density compared with control cells. This IL-1-mediated decrease in beta-responsiveness was usually observed with pretreatment periods of > 1 h and varied as a function of the L-arginine concentration of the pretreatment medium. In addition, it was prevented by 1) IL-1 receptor antagonist, 2) substituting D-arginine for L-arginine, or 3) incubating cells with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine. Thus the present data illustrate that IL-1 significantly alters the beta-adrenergic control of cardiac Ca2+ channels by cellular mechanisms that involve the activation of nitric oxide synthase. These mechanisms may play a role in altering ventricular function during cytokine-mediated inflammatory processes affecting the heart.

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Modulation of the beta-adrenergic control of the cardiac L-type Ca2+ current (ICa) by human recombinant interleukin-1 beta (IL-1) was examined in guinea pig ventricular myocytes using the whole cell voltage-clamp technique. ICa was evoked in Cs(+)-loaded myocytes by depolarizing pulses from a holding potential of -40 mV. In the presence of an acidic external solution (pH 5.8), the response of ICa to isoproterenol (Iso; 0.01 and 1 microM) was markedly decreased compared with control myocytes studied at pH 7.4. However, when cells were pretreated with 1 ng/ml IL-1 and then exposed to acid media, beta-responsiveness was significantly increased compared with untreated cells. Despite this effect of IL-1, maximum ICa density with 0.01 and 1 microM Iso was still 51 and 58%, respectively, less than that measured at pH 7.4. The enhanced beta-responsiveness produced by IL-1 was eliminated by adding amiloride to block Na+/H+ exchange or protein kinase C inhibitors staurosporine (10 nM) and calphostin C (50 nM). However, a direct activator of protein kinase C, phorbol 12-myristate 13-acetate, did not mimic the effects of the cytokine. These data demonstrate that IL-1 partially restores the beta-adrenergic control of cardiac Ca2+ channels suppressed under acidic conditions. Moreover, they suggest that IL-1 acts by enhancing Na+/H+ exchange through a second messenger pathway that may involve protein kinase C. These cellular mechanisms may play a role in altering ventricular function during cytokine-mediated inflammatory processes that are initiated by myocardial ischemia.

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The Centers for Disease Control reported in October 1991 that many people at risk for human immunodeficiency virus (HIV) infection had not been tested for antibodies to HIV. This study identifies differences among 110 gay and bisexual men in three small cities in Pennsylvania who decided whether to be tested for antibodies to HIV and, if so, whether to return for results. These men were given self-administered questionnaires and were offered free and confidential HIV antibody tests. Fifty percent of the men refused testing. Of those tested, only 35 percent returned to obtain test results. Contrary to other health prevention data, education was significantly and inversely related to being tested and to returning for results. Men who most often participated in the institutionalized gay community were least likely to be tested. The findings suggest that gay men who are most aware of the potential psychosocial problems associated with HIV antibody testing are more likely to avoid testing.

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BACKGROUND: Previous studies have shown that class Ic antiarrhythmic agents are effective in suppressing ectopic atrial rhythms and accessory pathway conduction. METHODS AND RESULTS: To explore the potential mechanisms for their effectiveness, we investigated the concentration-dependent effects of the Ic agent flecainide acetate (0.5 to 10 micrograms/mL) on atrial ectopic automaticity and exit conduction in isolated rabbit tricuspid valves. This experimental model consists of three major cell types as defined anatomically and by intracellular recordings: pacemaker, transitional, and working atrial muscle. Simultaneous recordings from these cell types before and during flecainide superfusion (n = 7) showed that the drug produced a slight, concentration-dependent slowing of pacemaker-transitional conduction but elicited third-degree transitional-working atrial muscle block in six of seven preparations at 10 micrograms/mL. Flecainide caused a significant dose-dependent reduction in the initial phase of diastolic depolarization of pacemaker cells but produced only a small, biphasic change in spontaneous pacemaker cycle length. It also caused a significant prolongation in action potential duration in pacemaker and transitional cells and reduction in upstroke velocity in atrial cells. Of note in four additional preparations, flecainide caused a concentration-dependent upward shift in the strength-duration curve for atrial fibers. CONCLUSIONS: These data suggest that flecainide has little direct effect on ectopic atrial automaticity but rather causes exit conduction slowing and block between transitional and atrial muscle fibers. The mechanism for the induction of block is likely due to a decrease in atrial excitability creating a greater electrical load on generated impulses.

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INTRODUCTION: Triggered activity initiated from delayed after-depolarizations has been proposed as a possible cause of arrhythmias during reperfusion of ischemic myocardium. However, the potential for abnormal repolarization and early afterdepolarizations (EADs) to develop under similar conditions has not been fully explored. METHODS AND RESULTS: Repolarization of the cell membrane during recovery from ischemic-like conditions was analyzed from transmembrane recordings in isolated rabbit Purkinje fibers paced at different basic cycle lengths. Preparations were exposed to conditions of hypoxia (defined as oxygen tension < 30 mmHg, high potassium, and zero substrate) plus lactic acidosis (pH 6.7) for 45 minutes followed by recovery in normal Tyrode's solution. Compared to control, action potentials during recovery at basic cycle length of 3,000 msec (n = 11) were characterized by a: (1) -7.2 +/- 2.1 mV shift in plateau potential (P < 0.01); (2) 126.1 +/- 63.6 msec increase in plateau duration (P < 0.05); and (3) 0.29 +/- 0.07 V/sec slowing of the maximum rate of terminal repolarization (phase 3; P < 0.01). These changes were larger when 10 to 20 microM amiloride was added to the hypoxic, acidotic test solution but were smaller when tissues were conditioned with hypoxia alone (zero lactate, pH 7.4). Following hypoxia plus acidosis, with or without amiloride, repolarization at long basic cycle lengths was often accompanied by EADs predominantly generated from potentials positive to -40 mV. These afterpotentials were blocked by Ca2+ channel antagonists and exhibited an activation threshold of -26.3 +/- 1.8 mV (n = 7). CONCLUSION: These data are consistent with the hypothesis that the combined negative voltage shift in the plateau and increase in its duration lead to the genesis of low membrane potential EADs by allowing reactivation of Ca2+ channels. Moreover, these results suggest that bradycardia-dependent EADs in Purkinje tissue may underlie arrhythmias in the intact heart during reperfusion of ischemic myocardium by mechanisms that are related in part to the acidosis established during the preceding ischemic conditions.

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Because of new preventive therapies, HIV-antibody testing of asymptomatic individuals now has clear clinical benefits. Consequently, greater numbers of individuals are expected to seek testing. This article, based on the authors' experiences with disclosing HIV-antibody test results to a high-risk group of men, makes recommendations for how best to present HIV-antibody results. Disclosing HIV-antibody results provides an educational opportunity as well as a psychological challenge for clinicians. Some unusual client reactions are detailed in the case studies.

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BACKGROUND: The mechanisms underlying repetitive activity during reperfusion of ischemic myocardium are thought to include triggered responses elicited at short pacing cycle lengths. The potential to generate repetitive responses at longer pacing cycle lengths under similar conditions, however, has not been explored. Thus, the present study examined the role of cycle length on the cellular electrical changes produced during recovery from ischemic-like conditions and identified the major component precipitating nondriven, repetitive activity. METHODS AND RESULTS: Transmembrane potentials were recorded in vitro from isolated rabbit Purkinje fibers exposed to hypoxia (defined as PO2 less than 30 mm Hg, high [K+]o, and zero glucose) plus lactic acidosis (pH 6.7) for 45 minutes and during recovery in normal Tyrode's solution (pH 7.4). Compared with control, action potential duration (90% repolarization) during recovery increased transiently by 40.9 +/- 11.8 and 241.0 +/- 51.1 msec at respective basic cycle lengths of 1,000 and 3,000 msec (both p less than 0.005). In 81% of preparations, action potential prolongation was accompanied by early afterdepolarizations and triggered activity generated from low (positive to -40 mV) or high (negative to -40 mV) membrane potentials. In 62% of experiments, brief periods of abnormal automaticity also occurred. Triggered responses were 1) unaffected by 1 microM ryanodine, 2) abolished by pacing at short basic cycle lengths or by exposing tissues to 2.5 micrograms/ml lidocaine, and 3) more easily induced at long basic cycle lengths or by superfusing 2.5 micrograms/ml quinidine. When tissues were conditioned with hypoxia alone (pH 7.4), action potential prolongation on recovery was comparatively small, and nondriven responses did not develop. Conversely, addition of 10-20 microM amiloride to the hypoxic, acidic test solution augmented recovery-induced action potential prolongation. CONCLUSIONS: We conclude that acidosis, as a component of ischemia, plus slow pacing frequencies may mediate the genesis of early afterdepolarizations and triggered activity in Purkinje fibers on recovery, long after extracellular pH has been restored to normal. These data may have clinical relevance to the mechanisms of reperfusion arrhythmias in the intact human heart.

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The cellular electrophysiologic effects of exogenous phosphocreatine (PCr) were analyzed to ascertain its purported antiarrhythmic properties during myocardial ischemia and reperfusion. Transmembrane potentials were recorded from isolated guinea pig papillary muscles and Purkinje fibers studied in vitro. Under control, normoxic conditions, 10 mmol/L PCr significantly increased the action potential duration (measured at 90% of repolarization) in ventricular muscle by 14.6 +/- 3.3 msec and the effective refractory period by 11.5 +/- 3.8 msec (both p less than 0.01). Under ischemic-like conditions (hypoxia, lactic acidosis, elevated [K+]o, zero substrate) PCr had no effect. Phosphocreatinine, a related compound that is not a direct substrate in the creatine kinase reaction, acted similarly to PCr suggesting that alterations induced by PCr did not involve a change in the energy state of cells. However, PCr reduced free [Ca2+]o by nearly 20%, and its electrical effects under normoxic conditions could be largely reversed by a concomitant 20% increase in [Ca2+]o. In Purkinje fibers superfused with low [K+]o-Tyrode's solution to elicit conditions of Ca2+ overload, delayed afterdepolarizations and triggered responses were reversibly inhibited by PCr. These data suggest that the antiarrhythmic effects of PCr in situ may involve prolongation of the effective refractory period in nonischemic tissue or attenuation of membrane changes elicited by Ca2+ overload in ischemic cells. The mechanism by which PCr produces these effects may be related in part to changes in extracellular Ca2+ composition.

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