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Negative inotropic drugs alter indexes of cytosolic [Ca²⁺]-left ventricular pressure relationships after ischemia

Anesthesiology Research Laboratories, ¹Department of Anesthesiology and ²Department of Physiology, and ³Cardiovascular Research Center, The Medical College of Wisconsin, Milwaukee 53226, ⁴Research Service, Veterans Affairs Medical Center, Milwaukee 53295, ⁵Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin 53223; and ⁶Department of Anesthesiology and Intensive Care Medicine, University Hospital Münster, 48129 Münster, Germany

Submitted 2 December 2003 ; accepted in final form 29 March 2004

Negative inotropic agents may differentially modulate indexes of cytosolic [Ca²⁺]-left ventricular (LV) pressure (LVP) relationships when given before and after ischemia. We measured and calculated [Ca²⁺], LVP, velocity ratios {[(d[Ca²⁺]/dt_max)/(dLVP/dt_max); VR_max] and [(d[Ca²⁺]/dt_min)/(dLVP/dt_min); VR_min]}, and area ratio (AR; area [Ca²⁺]/area LVP per beat) before and after global ischemia in guinea pig isolated hearts. Ca²⁺ transients were recorded by indo 1-AM fluorescence via a fiberoptic probe placed at the LV free wall. [Ca²⁺]-LVP loops were acquired by plotting LVP as a function of [Ca²⁺] at multiple time points during the cardiac cycle. Hearts were perfused with bimakalim, 2,3-butanedione monoxime (BDM), nifedipine, or lidocaine before and after 30 min of ischemia. Before ischemia, each drug depressed LVP, but only nifedipine decreased both LVP and [Ca²⁺] with a downward and leftward shift of the [Ca²⁺]-LVP loop. After ischemia, each drug depressed LVP and [Ca²⁺] with a downward and leftward shift of the [Ca²⁺]-LVP loop. Each drug except BDM decreased d[Ca²⁺]/dt_max; nifedipine decreased d[Ca²⁺]/dt_min, whereas lidocaine increased it, and bimakalim and BDM had no effect on d[Ca²⁺]/dt_min. Each drug except bimakalim increased VR_max and VR_min before ischemia; after ischemia, only BDM and nifedipine increased VR_max and VR_min. Before and after ischemia, BDM and nifedipine increased AR, whereas lidocaine and bimakalim had no effect. At 30 min of reperfusion, control hearts exhibited marked Ca²⁺ overload and depressed LVP. In each drug-pretreated group Ca²⁺ overload was reduced on reperfusion, but only the group pretreated with nifedipine exhibited both higher LVP and lower [Ca²⁺]. These results show that negative inotropic drugs are less capable of reducing [Ca²⁺] after ischemia so that there is a relatively larger Ca²⁺ expenditure for contraction/relaxation after ischemia than before ischemia. Moreover, the differential effects of pretreatment with negative inotropic drugs on [Ca²⁺]-LVP relationships after ischemia suggest that these drugs, especially nifedipine, can elicit cardiac preconditioning.

bimakalim; butanedione monoxime; nifedipine; lidocaine; indo 1; Ca²⁺ transients; Ca²⁺ concentration

This article has been cited by other articles:

				S. S. Rhodes, K. M. Ropella, A. K. S. Camara, Q. Chen, M. L. Riess, P. S. Pagel, and D. F. Stowe Ischemia-reperfusion injury changes the dynamics of Ca2+-contraction coupling due to inotropic drugs in isolated hearts J Appl Physiol, March 1, 2006; 100(3): 940 - 950. [Abstract] [Full Text] [PDF]