Toshinori Makita

Atrial natriuretic peptide reduces the basal level of cytosolic free Ca2+ in guinea pig cardiac myocytes

The cytosolic free Ca2+ concentration ([Ca2+]i) was monitored in quiescent atrial and ventricular myocytes isolated from guinea-pig hearts by the fura-2 fluorescence ratio technique. Recombinant human atrial natriuretic peptide (ANP) was found to reduce their basal [Ca2+]i level in a dose-dependent manner. Dibutyryl-cGMP mimicked the effect of ANP. Neither the prior application of caffeine nor removal of extracellular Na+ impaired the ANP effect. ANP had no inhibitory effect on voltage-gated Ca2+ currents measured by a whole-cell patch clamp technique. The ANP-induced [Ca2+]i decrease was abolished by orthovanadate. Thus, it is concluded that ANP reduces the basal [Ca2+]i presumably through the cGMP-mediated activation of the plasma membrane Ca2(+)-pump in cardiac myocytes.

Liver fibrogenesis marker, 7S domain of collagen type IV in patients with acutely decompensated heart failure: Correlates, prognostic value and time course.

BACKGROUND Congestion in heart failure (HF) induces multiple organ injury, which may cause remodeling of extracellular matrix. We hypothesized that liver fibrogenesis marker, 7S domain of collagen type IV (P4NP 7S) was correlated with congestion and liver injury in HF. METHODS AND RESULTS We measured serum P4NP 7S in two cohorts. Cohort 1 included 70 patients undergoing catheterization. P4NP 7S was correlated with pulmonary capillary wedge pressure, right ventricular and atrial pressure (r=0.50, P<0.001, r=0.42, P<0.001, r=0.39, P=0.001, respectively) but not with cardiac index (r=-0.05. P=0.7). Cohort 2 included 145 patients with acute HF, in whom we serially measured P4NP 7S at admission, discharge, early (1-month) and late (6-month) post-discharge period. γ-Glutamyltransferase and B-type natriuretic peptide were independently correlated with P4NP 7S at discharge. The cumulative 1-year incidence of death or HF hospitalization was much higher in the 3rd tertile of P4NP 7S than in the 1st and 2nd tertiles (50%, 25%, and 24%, Log-rank P=0.004). P4NP 7S enhanced risk classification when added to conventional risk factors (net reclassification improvement=0.47, P=0.02). In patients without early readmission, P4NP 7S decreased during hospitalization and remained low for up to 6months, whereas in patients with early readmission, P4NP 7S was persistently elevated during hospitalization, further increased at second admission, and remained high at 6months. CONCLUSION P4NP 7S was correlated with hemodynamics. The results shed new light on the pathophysiology of HF.

Agonist-independent modulation of L-type Ca currents by basal Gs protein activities in single guinea pig ventricular myocytes.

Abstract The modulation of L-type Ca2+ currents (ICa,L) by the basal activities of G proteins was studied in adult guinea pig ventricular myocytes by whole-cell patch-clamp techniques. With intrapipette guanosine triphosphate (GTP) (100 μM), a specific inhibition of Gi proteins by pertussis toxin (PTX) produced an increase in the basal density of ICa,L (from 11.0 ± 0.8, n = 13, to 25.0 ± 2.0 pA/pF, n = 11, at 0 mV test potential). In addition, PTX shifted the forskolin (Fsk) concentration–ICa,L response relation significantly leftward (EC50 = 63.7 ± 12.5 vs 625 ± 75 nM). With intrapipette guanosine diphosphate (GDP)βS (1 mM), the Fsk–ICa,L relation was also shifted leftward (EC50 = 197 ± 18.3 vs 781 ± 82.5 nM). However, chronic GDPβS dialysis accelerated the rundown of ICa,L significantly, suggesting a potential contribution of Gs proteins in maintaining basal ICa,L. In contrast, intra-pipette GTPγS (100 μM) produced a transient rise in ICa,L from 11.0 ± 3.0 to 22.8 ± 7.0 pA/pF (in 3.4 min after whole-cell formation at 0 mV, n = 9), presumably through the activation of Gs proteins. It was followed by a gradual decline in ICa,L (to 15.5 ± 3.5 pA/pF), which was still enhanced by Fsk (EC50 = 1450 ± 98 nM), indicating that the current decay was not solely due to rundown but to activation of Gi proteins. Gs, in addition to Gi proteins, show sufficient basal activity to modulate ICa,L in an agonist-independent manner.

Circulating markers of collagen types I, III, and IV in patients with dilated cardiomyopathy: relationships with myocardial collagen expression: Serum CITP, PIIINP and P4NP 7S in patients with DCM

Collagen‐derived peptides such as collagen I C‐terminal telopeptide (CITP) and procollagen III N‐terminal propeptide (PIIINP) have been conventionally used as markers of cardiac fibrosis. Collagen IV 7S domain (P4NP 7S) has been recently reported to be correlated with haemodynamics in patients with acute heart failure. We investigated whether these markers reflect cardiac remodelling and myocardial collagen expression.