A decrease in the myocardial level of the mRNA encoding the Ca2+-ATPase of the sarcoplasmic reticulum (SR) has been recently reported during experimental cardiac hypertrophy and failure. To determine if such a deficit occurs in human endstage heart failure, we compared the SR Ca2+-ATPase mRNA levels in left (LV) and right ventricular (RV) specimens from 13 patients undergoing cardiac transplantation (6 idiopathic dilated cardiomyopathies; 4 coronary artery diseases with myocardial infarctions; 3 diverse etiologies) with control heart samples using a rat cardiac SR Ca2+-ATPase cDNA probe. We observed a marked decrease in the mRNA for the Ca2+-ATPase relative to both the 18S ribosomal RNA and the myosin heavy chain mRNA in LV specimens of patients with heart failure compared to controls (-48%, P < 0.01 and -47%, P < 0.05, respectively). The LV ratio of Ca2+-ATPase mRNA to 18S RNA positively correlated with cardiac index (P < 0.02).The RV ratio correlated negatively with systolic, diastolic and mean pulmonary arterial pressures (P < 0.02, P < 0.02, and P < 0.01, respectively). We suggest that a decrease of the SR Ca2+-ATPase mRNA in the myocardium plays an important role in alterations of Ca2+ movements and myocardial relaxation reported during human end-stage heart failure. (J. Clin. Invest. 1990. 85:305-309.) gene expression * heart failurehuman left ventricle -myosin heavy chain mRNA * sarcoplasmic reticulum Ca2+-ATPase mRNA

Cardiac Ca2+ current (I") was shown to be regulated by cGMP in a number of different species. Recently, we found that the NO-donor SIN-1 (3-morpholino-sydnonimine) exerts a dual regulation of Ic. in frog ventricular myocytes via an accumulation of cGMP. To examine whether NO also regulates Ca2" channels in human heart, we investigated the effects of SIN-1 on Ic. in isolated human atrial myocytes.An extracellular application of SIN-1 produced a profound stimulatory effect on basal IC. at concentrations > 1 pM.Indeed, 10 pM SIN-1 induced a s 35% increase in Ic.. The stimulatory effect of SIN-1 was maximal at 1 nM ( z 2-fold increase in ICa) and was comparable with the effect of a saturating concentration (1 ,uM) of isoprenaline, a 13-adrenergic agonist. Increasing the concentration of SIN-1 to 1-100 ,uM reduced the stimulatory effect in two thirds of the cells. The stimulatory effect of SIN-1 was not mimicked by SIN-1C, the cleavage product of SIN-1 produced after liberation of NO. This suggests that NO mediates the effects of SIN-1 on ICa. Because, in frog heart, the stimulatory effect of SIN-1 on Ic. was found to be due to cGMP-induced inhibition of cGMP-inhibited phosphodiesterase (cGI-PDE), we compared the effects of SIN-1 and milrinone, a cGI-PDE selective inhibitor, on Ic. in human. Milrinone (10 ,uM) induced a strong stimulation of 'Ca (-150%), demonstrating that cGI-PDE controls the amplitude of basal Ic. in this tissue. In the presence of milrinone, SIN-1 (0.1-1 nM) had no stimulatory effect on ICa, suggesting that the effects of SIN-1 and MIL were not additive. We conclude that NO may stimulate ICa in human atrial myocytes via inhibition

EHNA ( Erythro -9-[2-hydroxy-3-nonyl]adenine) is a wellknown inhibitor of adenosine deaminase. Recently, EHNA was shown to block the activity of purified soluble cGMPstimulated phosphodiesterase (PDE2) from frog, human, and porcine heart with an apparent K i value of ‫ف‬ 1 M and with negligible effects on Ca 2 ϩ /calmodulin PDE (PDE1), cGMP-inhibited PDE (PDE3), and low K m cAMP-specific PDE (PDE4) (Méry, P.

Background-Heart failure often complicates myocardial infarction (MI), and sarcoplasmic/endoplasmic reticulum Ca 2ϩ -ATPase (SERCA2a) is underexpressed in the failing myocardium. We examined the effect of preexisting cardiac SERCA2a protein overexpression on rat survival and left ventricular (LV) remodeling after MI. Methods and Results-Baseline myocardial SERCA2a expression was 37% higher in transgenic (TG) rats than in their wild-type (WT) controls, consistent with enhanced myocardial function. The mortality rate of TG rats during the 24 hours after surgical MI was higher than that of WT rats (71% versus 35%, PϽ0.001), associated with a higher frequency of ventricular arrhythmias, and was normalized by lidocaine treatment. The increased acute-phase mortality in TG rats was not accompanied by increased 6-month mortality. Function of the noninfarcted myocardium, as assessed by tissue Doppler imaging, was higher in TG rats than in WT rats for up to 1 month after MI, a beneficial effect no longer observed at 3 months. LV remodeling and global function were similar in TG and WT rats. No difference in papillary muscle function was found at 6 months. Conclusions-Constitutive cardiac SERCA2a overexpression has a transient beneficial effect on remote myocardium function in rat MI, with no improvement in LV global function or prevention of LV remodeling and failure. This benefit is associated with a higher risk of acute mortality, which is prevented by lidocaine treatment.