Chronic exercise improves myocardial inotropic reserve capacity through alpha1-adrenergic and protein kinase C-dependent effects in Senescent rats.

We have previously demonstrated that alpha(1)-adrenergic (AR)-mediated contraction is diminished in the senescent rat heart, in part due to alterations in protein kinase C (PKC) signaling. Since chronic exercise training (EX) can exert independent effects on increasing alpha(1)-AR contraction in the adult rat heart, we sought to determine whether age-related defects in alpha(1)-AR contraction could be reversed by chronic EX. We further hypothesized that improved alpha(1)-AR contraction by EX may be PKC dependent. Adult (4 months; Y) and aged (24 months; O) male F344 rats were treadmill-trained (n = 12-13/group; TR) at approximately 70% of VO(2max) for 12 weeks or remained sedentary (YSED, YTR, OSED, OTR). Training status was verified by plantaris citrate synthase activity and left ventricular (LV) contractile responses (dP/dt) to alpha(1)-AR stimulation were assessed in Langendorff-perfused hearts using the alpha(1)-AR agonist phenylephrine (PE; 10(-5) M) with and without the PKC inhibitor chelerythrine (CE; 10(-6) M). alpha(1)-AR stimulation elicited greater increases in LV dP/dt in hearts isolated from OTR (4525.4 +/- 224.1 mmHg/s) versus OSED (3658.9 +/- 291.0 mmHg/s), while CE abolished PE-induced effects (OTR, 4069.2 +/- 341.2) versus (OSED, 3608.9 +/- 321.2) (p < .01). Upon western blotting, phosphospecific antibodies directed at PKCepsilon (pSer(729)) revealed greater levels in LV isolated from YTR versus YSED, and EX ameliorated aged-related reductions in OSED (p < .001). Basal PKCepsilon mRNA levels were also greater in YTR and OTR versus YSED (p < .01). PE-induced increases in phosphor-PKCdelta (pThr(507)) levels observed in OSED were attenuated in OTR (p < .03). Chronic EX was also associated with significant reductions in PKCalpha (pSer(657)) levels following PE in OTR (p < .002). The results indicate that age-related reductions in alpha(1)-AR contraction can be partially reversed by EX in the rat heart. These results further suggest that alterations in PKC levels underlie, at least in part, EX-induced improvements in alpha(1)-AR contraction.

Exercise intolerance during post-MI heart failure in rats: prevention with supplemental dietary propionyl-L-carnitine.

Exercise capacity in patients with several types of cardiovascular disease can be improved with dietary carnitine, or carnitine derivatives. Mechanisms underlying this improvement remain largely unknown in part due to a lack of animal models of cardiac pathology in which carnitine derivatives improve exercise tolerance. Our goal was to evaluate the ability of propionyl-L-carnitine (PLC) to improve exercise tolerance in a rat model of exercise intolerance. Fischer 344 rats were followed after either a moderate size MI (n = 22) or sham MI surgery (n = 14). Starting 10 days post-surgery 10 of the MI and 7 of the sham rats received 100 mg/kg/day PLC in drinking water, which increased plasma and LV total l-carnitine concentrations 15-23% (p < 0.05). Rats were followed longitudinally until a statistically significant decrease in exercise capacity occurred in one of the groups, at which time all rats were sacrificed for study of the isolated perfused hearts. At 12-weeks post-MI exercise capacity had decreased 16 +/- 7% (p < 0.05) in the MI group, but remained within 3% of baseline in the MI group that received PLC and the sham groups. Both MI groups exhibited the same degree of LV dilation, decrease in fractional shortening, and blunting of the response to isoproterenol. We conclude that supplemental dietary PLC attenuates the exercise intolerance that occurs secondary to post-MI heart failure in rats, but that this beneficial effect is not attributable to altered LV remodeling, an improved response to beta-adrenergic stimulation, or increased skeletal muscle citrate synthase activity.