Inhibitors of phosphodiesterases PDE2, PDE3, and PDE4 do not increase the sinoatrial tachycardia of noradrenaline and prostaglandin PGE1 in mice.

Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial ß1- and ß2-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain. Prostaglandin PGE1 elicits sinoatrial tachycardia through EP receptors, but the control by phosphodiesterases is unknown. We investigated on spontaneously beating right atria of mice the effects of the PDE2 inhibitors Bay 60-7550 and EHNA on basal beating and the tachycardia produced by noradrenaline (3 nM) and PGE1 (1 µM). Bay 60-7550 (1 µM), but not EHNA (10 µM), increased basal sinoatrial beating. EHNA also failed to produce tachycardia in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin (10 µM), remaining inconclusive whether PDE2 reduces basal sinoatrial beating. Rolipram (10 µM) and cilostamide (300 nM) caused moderate tachycardia. The tachycardia evoked by Bay 60-7550 was similar in the absence and presence of rolipram. Noradrenaline elicited stable tachycardia that was not increased by Bay 60-7550. A stable tachycardia caused by PGE1 was not increased by the inhibitors of PDE2, PDE3, and PDE4. Unlike PDE3 and PDE4 which reduce murine basal sinoatrial beating, a possible effect of PDE2 needs further research. The stable tachycardia produced by noradrenaline and PGE1, together with the lack potentiation by the inhibitors of PDE2, PDE3, and PDE4, suggests that cAMP generated at the receptor compartments is hardly hydrolyzed by these phophodiesterases. Evidence from human volunteers is consistent with this proposal.

Congestive heart failure: differential adaptation of the diaphragm and latissimus dorsi.

Diaphragm and latissimus dorsi muscle functions, histochemistries, and morphometries were studied in anesthetized male Yucatan minipigs with congestive heart failure (CHF) induced by supraventricular tachycardia (n = 5). Sham-operated animals served as a control group (n = 5). In CHF animals, transdiaphragmatic pressure measured during supramaximal phrenic stimulation was reduced by 40% at low frequencies (< or = 20 Hz) and by 60% at higher frequencies. Twitch amplitude and half-relaxation time were also decreased. The cross-sectional areas of type I, IIa, and IIb fibers were reduced in the diaphragm. The proportion of type I fibers increased, whereas type IIa fibers decreased. Succinate dehydrogenase activity was elevated in type IIa and IIb fibers, but diaphragmatic fatigability was not altered. CHF reduced latissimus dorsi isometric force by 40% for stimulation frequencies > or = 30 Hz. The cross-sectional area of latissimus dorsi type IIb fibers was decreased, but twitch characteristics, fiber type composition, succinate dehydrogenase activity, and fatigability were unchanged. Experimental CHF appears to cause greater intrinsic adaptive changes in the diaphragm compared with those in the latissimus dorsi in the minipig. For both muscles, reduced contractile function was associated with atrophy. Impaired performance of the diaphragm may also be attributed to an increase in the relative contribution of type I fibers to the total tension-generating capacity of the muscle and to the pathophysiological mechanisms underlying the shortened relaxation time of the twitch response.

[Enzyme histochemical study of tha atrioventricular junction area. Correlation with slow and fast atrial pathways]. / Etude histo-enzymologique de la région pré-tawarienne. Essai de corrélation avec les voies auriculaires lente et rapide.

It was traditionally admitted that junctional tachycardia was based on an intranodal reentry pathway. However, lesions created at a distance from the atrioventricular node by surgery or other physical means (fulguration or radiofrequency energy ablation) demonstrated that the reentry circuit could use the slow and fast atrial pathways. This study performed in 6 human hearts less than 1 hour after death was undertaken to perform enzyme histochemical analysis of the atrial pre-nodal region. The specimens were rapidly frozen in liquid nitrogen and sliced with a cryostat. After localisation of the different regions by routine staining methods, histochemical reactions were performed using the semi-permeable membrane method for weakly bound enzyme. Ten enzymes were studied covering the principal metabolic pathways. Though routine histological stain did not show any particular structures, the enzyme histochemical reactions showed a band of myocardium following the septal insertion of the tricuspid valve, joining the orifice of the coronary sinus to the posterior part of the compact atrioventricular node. This zone of myocardium had an enzymatic make-up similar to that of the sinus node. An analogous structure was also observed above the insertion of the anterior mitral leaflet. These two regions could constitute the trajectory of the slow conduction pathways.

Ventricular function and Na+,K(+)-ATPase activity and distribution with chronic supraventricular tachycardia.

STUDY OBJECTIVE: The molecular and cellular mechanisms responsible for the dilated cardiomyopathy associated with chronic supraventricular tachycardia are not well understood. The purpose of this study was to examine Na+,K(+)-ATPase activity and distribution in a pacing induced model of dilated cardiomyopathy. DESIGN: Left ventricular function and Na+,K(+)-ATPase activity and distribution were examined in two groups of pigs: (1) atrially paced for 3 weeks (supraventricular tachycardia, 240 beats.min-1); (2) sham operated controls. SUBJECTS: 10 Yorkshire male swine (23-25 kg) were randomly assigned to the control group or the supraventricular tachycardia group. MEASUREMENTS AND MAIN RESULTS: Left ventricular function was examined using simultaneous pressure echocardiography. Na+,K(+)-ATPase activity was determined in tissue homogenates by measuring the rate of p-nitrophenol-phosphate (pNPP) hydrolysis. Changes in content and distribution of Na+,K(+)-ATPase were examined immuno-histochemically in tissue sections. Left ventricular fractional shortening decreased significantly with supraventricular tachycardia as compared to controls, at 15 (SEM 3)% v 31(3)%, respectively p less than 0.05. Supraventricular tachycardia resulted in a significant increase in end diastolic dimension [5.0(0.3) cm v 3.5(0.2) cm, respectively p less than 0.05] and pressure [22(4)mm Hg v 6(2)mm Hg, respectively p less than 0.05]. Maximal Na+,K(+)-ATPase activity (microgram pNPP.mg-1 protein.h-1) was significantly lower with supraventricular tachycardia than in controls, at 0.45(0.12) v 0.64(0.06), respectively p less than 0.05. In the presence of 7 microM digitalis, Na+,K(+)-ATPase activity was inhibited by 68% in control and by 45% in supraventricular tachycardia homogenates (p less than 0.05). In control sections all left ventricular myocytes showed a uniform immunostaining pattern along the sarcolemma for Na+,K(+)-ATPase, whereas a focal loss of staining was observed in myocytes from the supraventricular tachycardia group. CONCLUSIONS: The congestive cardiomyopathy produced by supraventricular tachycardia was associated with a reduction in sarcolemmal Na+,K(+)-ATPase activity and changes in enzyme distribution. The findings also suggest a reduction in digitalis sensitivity with chronic supraventricular tachycardia. These alterations in Na+,K(+)-ATPase activity may be one potential mechanism responsible for the depressed left ventricular function associated with chronic supraventricular tachycardia.

Paroxysmal supraventricular tachycardia in children: the role of infectious diseases and its relationship to serum enzyme.

The records of 28 children whose first episode of paroxysmal supraventricular tachycardia occurred before 12 years (median age 10 months) were reviewed. There were 17 males and 11 females. In 17 cases the first attack occurred before the first year and in 11 of these it occurred after the first year. One case had congenital heart disease (ASD). The WPW syndrome was diagnosed in 3 cases. When first seen, most of the infants presented with signs of incipient or manifest congestive heart failure. In almost nine-tenth of cases there was an increased of serum enzymes (lactic dehydrogenase, creatine-phosphokinase and glutamic oxaloaccetic transaminase. Digitals was effective against congestive heart failure and when continued, might prevent failure during subsequent attacks. Antiarrhythmic agents other than digitals were not used. It is recommended to continue digitalis treatment for at least one year in all patients with SVT, whether or not the first episode terminated spontaneously.