Noninvasive measurement of pressure within the heart cavities and other internal organs (e.g., kidney, liver) has significant clinical value, but currently is not feasible. Noninvasive pressure estimation using encapsulated ultrasound (US) contrast agents (UCA) as sensors is a challenge because they supposedly respond to their ambient pressure, but they are more rigid and less sensitive to pressure than gas microbubbles. Here, Optison sensitivity was studied (f(resonance) = approximately 2 MHz) to varying pressures, when excited at 2 times and also at 0.5 times f(resonance). Cyclic momentary increases in ambient pressure of 0 to 5, 0 to 10, 0 to 15 or 0 to 20 kPa at 1.0 Hz, mimicking left ventricular (LV) pressure changes, caused amplitude decrease of echoes at 0.5, 1 and 2 times the transmitted frequency and decrease of attenuation. Changes at 0.5 times the transmitted frequency correlated best, but only after 70 to 150 s. The correlations (mean +/- SD) during 150 to 300 s were 0.706 +/- 0.072 for 0 to 10 kPa, 0.844 +/- 0.042 for 0 to 15 kPa and 0.859 +/- 0.031 for 0 to 20 kPa. Attenuation presented less correlation. For 1.0 Hz, 10 to 15 kPa or 15 to 20 kPa pressures, mimicking systemic pressures, the attenuation decayed fast and even faster for slow (0.05 Hz) cyclic varying pressures, or elevated steady-state pressures (of 10 kPa and 20 kPa). Thus, cyclic pressure effects on UCA are demonstrated to be reversible, but elevated static pressures cause UCA destruction. This allows cyclic pressure variations to be detected, using the subharmonics of the transmitted frequency, down to 10 kPa.