EFFECTS OF TREPPE AND CALCIUM ON INTRACELLULAR CALCIUM AND FUNCTION IN THE FAILING HEART FROM THE SPONTANEOUSLY HYPERTENSIVE RAT

We studied functional and intracellular calcium responses to treppe and extracellular calcium in spontaneously hypertensive rat (SHR) hearts during the transition from compensated pressure overload to failure. Intracellular calcium was measured using aequorin, a bioluminescent Ca2+ indicator. Experiments were performed with intact, isovolumically contracting, buffer-perfused hearts from three rat groups: (1) aging SHR with evidence of heart failure (SHR F), (2) age-matched SHR with no evidence of heart failure (SHR-NF), and (3) age-matched normotensive Wistar-Kyoto (WKY) rats. In each experiment, left ventricular pressure and intracellular calcium transients were simultaneously recorded. Hearts were studied at 30 degrees C and paced at a rate of 1.6 Hz while being perfused with oxygenated Krebs-Henseleit solution (95% O-2/5% CO2) at 100 mm Hg. At the baseline state, peak systolic pressure was greatest in the SHR-NF group and lowest in the SHR-F group. Peak and resting [Ca2+](i) were not significantly different among groups; however, the calcium transient was prolonged in the SHR-NF and SHR-F groups. With increasing perfusate [Ca2+](o) from 0.5 to 3.0 mmol/L, the relative increases in peak [Ca2+](i) and peak systolic pressure were similar among groups. When stimulation rate was increased from 1.6 to 2.0, 2.4, 2.8, and 3.2 Hz, peak [Ca2+](i), peak systolic pressure, and +/-dP/dt fell in SHR-F hearts. Peak systolic pressure decreased in the SHR-NF group at rates above 2.4 Hz but did not decline in the WKY group. Peak [Ca2+](i) increased in the WKY and SHR-NF groups with increasing heart rates. Peak systolic pressure did not fall significantly in the WKY group at any heart rate. Elevation of diastolic [Ca2+](i) and/or calcium transient and pressure alternans were present in 8 of 13 SHR-F hearts at the highest stimulation rate, findings that were absent in both the WKY and SHR-NF hearts. We conclude the following: (1) Under baseline conditions, depressed contractile function of failing myocardium cannot be explained by decreased peak [Ca2+](i); (2) relative increases in [Ca2+](i) and inotropy with increasing [Ca2+](o) are proportional among groups; and (3) although peak systolic [Ca2+](i) and inotropy are maintained with increasing stimulation rate in the WKY and SHR-NF groups, peak systolic [Ca2+](i) and pressure decrease in parallel in the SHR-F heart with increasing stimulation rate, suggesting that impaired calcium cycling may contribute to compromised pump function in the SHR-F heart.