Loss of cardiac contractile response to tetrahydropapaveroline with advanced age and hypertension.

Tetrahydropapaveroline (THP), a condensation product of ethanol-derived acetaldehyde, potentiates cardiac function through beta-adrenoceptor. We have recently shown that THP-induced cardiac contractile action is likely due to its action at the single myocyte level, and is markedly diminished during early hypertension. Cardiac function alters with advanced age reminiscent of hypertension. This study was to examine cardiac contractile response to THP with advanced age and hypertension. Left ventricular papillary muscles and myocytes were isolated from normotensive (WKY) or hypertensive (SHR) rats, and stimulated to contract at 0.5 Hz. Mechanical parameters evaluated include: peak tension developed (PTD)/peak shortening (PS), time-to-PTD/PS (TPT/TPS), time-to-90% relaxation/relengthening (RT90/TR90), and maximal velocities of contraction/relaxation (+/- VT/+/- dLdt). Intracellular Ca2+ transients were measured as fura-2 fluorescence intensity changes (AFFI). THP (0.1-100 microM) increased PTD in 10- but not 36-wk-old WKY rat myocardium. THP elicited positive, negative or no response on PS in myocytes from 10-wk WKY, 36-wk WKY, and 36-wk SHR groups, respectively. Interestingly, THP elicited discrepant response on intracellular Ca2+ transient compared with that of myocyte shortening. THP increased AFFI in 10-wk WKY and 36-wk SHR myocytes while exhibiting a significant inhibiting action in 36-wk WKY myocytes. Lastly, THP shortened TPT/TPS, RT90/TR90 and increased +VT in all animal groups. These results indicate that the THP-induced myocardial contractile response is altered in advanced age and hypertension, in a manner similar to early stage of hypertension. It is possible that altered intracellular Ca2+ responsiveness may be involved in THP-induced action.

Basal and ethanol-induced cardiac contractile response in lean and obese Zucker rat hearts.

Obesity plays a pivotal role in metabolic and cardiovascular diseases. Certain types of obesity may be related to alcohol ingestion, which itself leads to impaired cardiac function. This study analyzed basal and ethanol-induced cardiac contractile response using left-ventricular papillary muscles and myocytes from lean and obese Zucker rats. Contractile properties analyzed include: peak tension development (PTD), peak shortening amplitude (PS), time to PTD/PS (TPT/TPS), time to 90% relaxation/relengthening (RT(90)/TR(90)) and maximal velocities of contraction/shortening and relaxation/relengthening (+/-VT and +/-dL/dt). Intracellular Ca(2+) transients were measured as fura-2 fluorescence intensity (DeltaFFI) changes and fluorescence decay time (FDT). In papillary muscles from obese rats, the baseline TPT and RT(90) were significantly prolonged accompanied with low to normal PTD and +/-VT compared to those in lean rats. Muscles from obese hearts also exhibited reduced responsiveness to postrest potentiation, increase in extracellular Ca(2+) concentration, and norepinephrine. By contrast, in isolated myocytes, obesity reduced PS associated with a significant prolonged TR(90), normal TPS and +/-dL/dt. Intracellular Ca(2+) recording revealed decreased resting Ca(2+) levels and prolonged FDT. Acute ethanol exposure (80-640 mg/dl) caused comparable concentration-dependent inhibitions of PTD/PS and DeltaFFI, associated with reduced +/-VT in both groups. Collectively, these results suggest altered cardiac contractile function and unchanged ethanol-induced depression in obesity.

Influence of age on inotropic response to insulin and insulin-like growth factor I in spontaneously hypertensive rats: role of nitric oxide.

Insulin-like growth factor-1 (IGF-1) and insulin stimulate cardiac growth and contractility. Recent evidence suggests a relationship between essential hypertension, left ventricular hypertrophy, and circulating IGF-1 levels. Advanced age alters cardiac function in a manner similar to hypertension. The aim of this investigation was to evaluate the effects of IGF-1 and insulin on the force generating capacity of cardiac muscle in hypertension and the influence of age on this response. Contractile responses to IGF-1 and insulin were examined using papillary muscles from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at 10 and 25 weeks of age. Muscles were electrically stimulated at 0.5 Hz, and contractile properties, including peak tension development (PTD), time-to-peak tension, time-to-90% relaxation, and the maximal velocities of contraction and relaxation, were evaluated. PTD was similar in WKY and SHR myocardium at both age groups. At 10 weeks of age, IGF-1 (1-500 ng/ml) caused a dose-dependent increase in PTD in WKY but not SHR myocardium, whereas insulin (1-500 nM) had no effect on PTD in either group. At 25 weeks of age, the positive inotropic effect of IGF-1 was attenuated in the WKY group, and IGF-1 exerted no inotropic action in the SHR group. Pretreatment with the nitric oxide synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME, 100 microM), did not alter the IGF-1-induced positive inotropic response in 10-week-old WKY myocardium, whereas it unmasked a positive inotropic action in muscles from age-matched SHR animals. At 25 weeks of age, L-NAME abolished IGF-1-induced a positive inotropic response in WKY myocardium, and did not unmask an IGF-induced inotropic response in SHR myocardium. Our results suggest that alterations in nitric oxide modulation of IGF-1-induced contraction may underlie resistance to this inotropic peptide with advancing age, and/or hypertension.

Dietary magnesium supplementation attenuates ethanol-induced myocardial dysfunction.

Hypomagnesemia is positively correlated with a number of cardiovascular abnormalities and recent evidence suggests that magnesium supplementation prevents ethanol-induced development of hypertension. The purpose of our study was to assess whether dietary magnesium supplementation effectively reverses or attenuates chronic ethanol-induced cardiac dysfunction, both at the tissue and the cellular level. Therefore, the influence of dietary magnesium supplementation during chronic ethanol ingestion on the mechanical properties of cardiac muscle was studied using isolated papillary muscles and ventricular myocytes from rat heart. In addition, the acute effects of ethanol on cardiac muscle from animals chronically exposed to ethanol in the absence and presence of dietary magnesium supplementation were also examined. Chronic ethanol exposure caused significant cardiac, hepatic, and renal enlargement, increased systolic blood pressure, and produced hypomagnesemia. After chronic ethanol exposure, the baseline force generating capacity of papillary muscles was markedly depressed and was associated with a significant slowing in the maximum velocities of contraction and relaxation. By contrast, in isolated myocytes, long-term ethanol exposure increased the extent of cell shortening associated with a significant reduction in the duration of relengthening and an increase in both the maximum velocities of shortening and relengthening. Dietary magnesium supplementation among animals chronically ingesting ethanol effectively normalized heart size, systolic blood pressure, and reduced plasma ethanol concentration. Magnesium supplementation also attenuated chronic ethanol-induced depression of contractile force and increased the extent of cell shortening. As expected, acute ethanol exposure caused a dose-dependent inhibition of both isometric force and isotonic shortening associated with a decrease in the intracellular calcium transient. However, the extent of the acute ethanol-induced reduction in isometric force and isotonic shortening was always slightly greater among preparations from animals chronically exposed to ethanol. Dietary magnesium supplementation normalized the acute inhibitory action of ethanol on isometric force, isotonic shortening, and the intracellular calcium transient. Our results suggest that dietary magnesium supplementation may attenuate chronic ethanol-induced alterations in baseline myocardial mechanical function and normalize the cardiac response to acute ethanol exposure.