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 an d 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 Ca 2+ indicator. Experiments were performed with intact, isovolumically c ontracting, buffer-perfused hearts from three rat groups: (1) aging SH R with evidence of heart failure (SHR F), (2) age-matched SHR with no evidence of heart failure (SHR-NF), and (3) age-matched normotensive W istar-Kyoto (WKY) rats. In each experiment, left ventricular pressure and intracellular calcium transients were simultaneously recorded. Hea rts were studied at 30 degrees C and paced at a rate of 1.6 Hz while b eing perfused with oxygenated Krebs-Henseleit solution (95% O-2/5% CO2 ) at 100 mm Hg. At the baseline state, peak systolic pressure was grea test in the SHR-NF group and lowest in the SHR-F group. Peak and resti ng [Ca2+](i) were not significantly different among groups; however, t he calcium transient was prolonged in the SHR-NF and SHR-F groups. Wit h 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 am ong 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 g roup 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 g roup at any heart rate. Elevation of diastolic [Ca2+](i) and/or calciu m transient and pressure alternans were present in 8 of 13 SHR-F heart s at the highest stimulation rate, findings that were absent in both t he WKY and SHR-NF hearts. We conclude the following: (1) Under baselin e conditions, depressed contractile function of failing myocardium can not be explained by decreased peak [Ca2+](i); (2) relative increases i n [Ca2+](i) and inotropy with increasing [Ca2+](o) are proportional am ong groups; and (3) although peak systolic [Ca2+](i) and inotropy are maintained with increasing stimulation rate in the WKY and SHR-NF grou ps, peak systolic [Ca2+](i) and pressure decrease in parallel in the S HR-F heart with increasing stimulation rate, suggesting that impaired calcium cycling may contribute to compromised pump function in the SHR -F heart.