Diminished tolerance of prehypertrophic, cardiomyopathic Syrian hamster hearts to Ca²⁺ stresses

Although abnormal myocardial calcium homeostasis in the cardiomyopathic hamster (CMH) has been documented in the hypertrophic stage of the disease, the Ca²⁺ tolerance before the hypertrophic stage has not been investigated. We studied isovolumic contractile function in response to a variety of Ca²⁺ stresses including increases in perfusate [Ca²⁺] (Ca(o)), the Ca²⁺ channel agonist Bay K 8644, and α- or β-adrenergic agonists of isolated perfused hamster hearts from 24-45-day-old male CMH, BIO 14.6 strain, and age- and sex-matched F1B strain controls. The coronary flow at a constant perfusion pressure did not differ between two groups at baseline or after any Ca²⁺ stress. At a Ca(o) of 1.0 mM, neither end-diastolic pressure (EDP) nor developed pressure (DP) nor half relaxation time (RT( 1/2 )) during stimulation at 1-3 Hz differed between the two groups; as Ca(o) was increased up to 10 mM, CMH hearts showed a lower threshold for the occurrence of a Ca²⁺ overload profile: EDP and RT( 1/2 ) increased to a greater, and DP to a lesser, extent in CMH than in control hearts. To determine whether calcium influx via Ca²⁺ channels mediates the lower threshold for Ca²⁺ overload in CMH hearts, we measured resting pressure and scattered laser light intensity fluctuation (SLIF) in unstimulated hearts. Prior studies have shown that SLIF is generated by microscopic tissue motion caused by diastolic spontaneous sarcoplasmic reticulum Ca²⁺ release and that SLIF amplitude reflects the extent of cell and sarcoplasmic reticulum Ca²⁺ loading. The Ca²⁺-dependent increase in resting pressure in unstimulated hearts was highly correlated with an increase in SLIF, and this relation was steeper in CMH than in control hearts. CMH hearts also showed a reduced threshold for the occurrence of a Ca²⁺ overload profile in response to the adrenergic receptor agonists and the Ca²⁺ channel agonist during electrical stimulation in a Ca(o) of 2.0 mM: maximum DP achieved with each agonist was significantly less and the dose-response curves to each agonist were shifted leftward in CMH versus control hearts. In CMH hearts EDP began to increase at a significantly lower concentration of each agonist, and the maximum extent of increase in EDP in response to all agonists was significantly enhanced compared with control hearts. In response to β-adrenergic or Ca²⁺ channel agonists, neither resting pressure nor SLIF in unstimulated hearts increased in control or in CMH hearts. In contrast, in response to α-adrenergic stimulation, both SLIF and resting pressure increased to a greater extent in CMH than in control hearts. These results indicate that in the prehypertrophic CMH heart contractile function is preserved, and no evidence of cellular Ca²⁺ overload is present during conditions requiring relatively low contractile performance. However, in response to an increase of Ca(o) or to the addition of adrenergic or Ca²⁺ channel agonists, CMH hearts evidenced a lower threshold for signs of Ca²⁺ overload than did control hearts. This indicates that this cardiomyopathy is not solely due to vascular pathology and that a latent Ca²⁺ intolerance of myocardial cells occurs in CMH at an early stage of the disease. That Ca²⁺ overload could be elicited by an increase in Ca(o) in the absence of electrical stimulation indicates that it is not mediated via Ca²⁺ influx via Ca²⁺ channels.