The striated muscle sarcomere contains the third filament comprising the giant elastic protein titin, in addition to thick and thin filaments. Titin is the primary source of nonactomyosin-based passive force in both skeletal and cardiac muscles, within the physiological sarcomere length range. Titin's force repositions the thick filaments in the center of the sarcomere after contraction or stretch and thus maintains sarcomere length and structural integrity. In the heart, titin determines myocardial wall stiffness, thereby regulating ventricular filling. Recent studies have revealed the mechanisms involved in the fine tuning of titin-based passive force via alternative splicing or posttranslational modification. It has also been discovered that titin performs roles that go beyond passive force generation, such as a regulation of the Frank-Starling mechanism of the heart. In this review, we discuss how titin regulates passive and active properties of striated muscle during normal muscle function and during disease.

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Preterm infants are highly susceptible to ischemic damage. This damage is most obvious in the brain, retina, and gastrointestinal tract. Studies focusing on the rheological properties of premature red blood cells (pRBCs) have consistently shown minimal or no RBC aggregation. Previously, measurements of pRBC aggregation kinetics indicated that specific plasma properties are responsible for the decreased RBC aggregation observed in the neonates, but that their specific RBC properties do not affect it. However, the strength of interaction in the pRBC aggregates as a function of medium composition has not been tested. In our previous research, we described clinically relevant parameters, that is, the aggregate resistance to disaggregation by flow. With the help of a cell flow property analyzer (CFA), we can monitor RBC aggregation by direct visualization of its dynamics during flow. We used the CFA to examine pRBC (from 9 premature babies) in the natural plasma and in PBS buffer supplemented with dextran (500 kDa) to distinguish between RBC intrinsic-cellular and plasma factors. pRBCs suspended in the native plasma showed minimal or no aggregation in comparison to normal adult RBC. When we transferred pRBCs from the same sample to the dextran solution, enhanced resistance to disaggregation by flow was apparent.

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Could the intrinsic characteristics of tolerance to hypoxia be retained in Tibetan high-altitude natives after they had migrated to a low altitude? To answer this question, we undertook a study of 33 healthy male adolescent Tibetans born and raised in a high plateau (3,700 m [12,140 ft] above sea level) who migrated to Shanghai (sea level) for 4 years. Ten age-matched healthy male Han adolescents born and raised in Shanghai were regarded as the control group. Acute hypoxia was induced in a hypobaric chamber for 2 h to simulate the 3,700 m altitude. At sea level, maximal oxygen consumption (VO_{2 max}) was not significantly different between the two groups. During acute hypoxia, the values of VO_{2 max}, tissue oxygen extraction, arterial oxygen pressure, and the arterial oxygen saturation showed markedly higher in Tibetan subjects than in Han subjects (1.41 ± 0.04 l/min/M² vs.1.25 ± 0.04 l/min/M², 55.0 ± 4.2% vs. 47.3 ± 9.1%, 7.2 ± 0.6 vs. 5.5 ± 0.2 kPa, and 87.9 ± 3.3% vs. 78.2 ± 1.6%, respectively, P < 0.05). The calculated “oxygen reserve capacity” and “cardiac reserve capacity” were better in the Tibetans than in the Han natives (P < 0.05), which suggests that physical work capacity is greater in the Tibetan group. The sympathetic stimulation was less, and there was no noticeable change in cardiac function during acute hypoxia in the Tibetan group. The results indicate that the better tolerance to hypoxia in the Tibetans is retained during the 4-year stay at sea level, implying that the intrinsic hypoxic adaptation still exists in the Tibetan high-altitude natives.

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There is strong evidence that oxidative stress plays a key role in the pathophysiology of several cardiovascular diseases. On the other hand, the presence of specific receptors for androgens and estrogens in the myocardium implies that sex hormones play a physiological role in cardiac function, myocardial injury, and the regulation of the redox state in the heart. The present study was designed to determine whether castration and androgen replacement result in changes in the capacity of the antioxidant defense system in the left ventricle (LV) of adult male rats. To assess this, the activities of antioxidant enzymes (superoxide dismutase [SOD], glutathione peroxidase [GPX], catalase [CAT], and glutathione reductase [GR]), concentrations of nonenzymatic antioxidants (reduced glutathione [GSH] and α- and γ-tocopherols), and oxidative stress biomarkers (tissue sulfhydryl groups, protein nitrotyrosine levels, and lipid peroxidation) were measured in castrated animals (CAS), castrates replaced with testosterone (CAS+T), and sham-operated controls (Sham). Testosterone was not detectable in serum from gonadectomized rats. The results indicate that castration significantly and negatively affected the antioxidant status of rat LV, as evidenced by a significant decline in activities of all antioxidant enzymes, by a tendency toward lower levels of GSH and protein thiol groups, and by enhanced lipid peroxidation and higher nitrotyrosine concentrations in left ventricular tissue. Increases in LV tissue concentrations of α- and γ-tocopherols seem to be a compensatory response to enhanced oxidative stress induced by gonadectomy. The reestablishment of physiological serum testosterone level by androgen replacement resulted in a tendency toward a further decrease in the antioxidant defense status in the LV tissue.

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In consideration of clinical implications, it is often complained that short-term experimental diseased heart models do not mimic long-term diseased hearts that are often clinically encountered. The aim of the present study was (i) to compare the left ventricular function between rat cardiac hypertrophy models treated with isoproterenol for 3 days (Iso 3d) and 7 days (Iso 7d) by pressure-volume measurements with a catheter method, and (ii) to follow up the left ventricular function in the same model treated with Iso up to 16 weeks with a less-invasive echocardiography. An infusion of either Iso (1.2 mg·kg⁻¹·day⁻¹ for 3 days–16 weeks) or vehicle (saline 24 μl·day⁻¹ for 3 days–16 weeks; Sa group) was performed by subcutaneously implanting an osmotic minipump. There were no significant differences in the systolic pressure-volume area at midrange left ventricular volume (PVA_mLVV: a mechanical work capability index) between Iso 3d and 7d groups, though PVA_mLVV in both groups was significantly reduced from that in the Sa group. From echocardiography, the left ventricular function of the hypertrophy models at 3 days, 1 week, and 2 weeks was unchanged, but the model at a term longer than 4 weeks resulted in prolonged systolic failure. The results indicated that (i) no marked differences in the left ventricular mechanical work capability were found between the Iso 3d and 7d groups, and that (ii) only a 3-day Iso infusion induced the hypertrophy model similar in shape and function to that induced by a 2-week Iso infusion. We concluded that the 3-day model was sufficient.

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Maintenance of arterial pressure (AP) under orthostatic stress against gravitational fluid shift and pressure disturbance is of great importance. One of the mechanisms is that upright tilt resets steady-state baroreflex control to a higher sympathetic nerve activity (SNA). However, the dynamic feedback characteristics of the baroreflex system, a hallmark of fast-acting neural control, remain to be elucidated. In the present study, we tested the hypothesis that upright tilt resets the dynamic transfer function of the baroreflex neural arc to minify the pressure disturbance in total baroreflex control. Renal SNA and AP were recorded in ten anesthetized, vagotomized and aortic-denervated rabbits. Under baroreflex open-loop condition, isolated intracarotid sinus pressure (CSP) was changed according to a binary white noise sequence at operating pressure ± 20 mmHg, while the animal was placed supine and at 60° upright tilt. Regardless of the postures, the baroreflex neural (CSP to SNA) and peripheral (SNA to AP) arcs showed dynamic high-pass and low-pass characteristics, respectively. Upright tilt increased the transfer gain of the neural arc (resetting), decreased that of the peripheral arc, and consequently maintained the transfer characteristics of total baroreflex feedback system. A simulation study suggests that postural resetting of the neural arc would significantly increase the transfer gain of the total arc in upright position, and that in closed-loop baroreflex the resetting increases the stability of AP against pressure disturbance under orthostatic stress. In conclusion, upright tilt resets the dynamic transfer function of the baroreflex neural arc to minify the pressure disturbance in total baroreflex control.

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Using patch-clamp technique, we studied the role of the Ca²⁺/calmodulin kinase II (CaMK II)-mediated phosphorylation process on the K⁺ channel with an inward conductance of 90 pS in opossum kidney proximal tubule cells (OKPCs). The intracellular Ca²⁺ concentration ([Ca]_i) was measured by use of the fluorescent dye fura 2. The following results were obtained: (i) In cell-attached patches, the channel activity was inhibited by a decrease in [Ca]_i induced by perfusion with low Ca²⁺ (10⁻⁸ M), La³⁺ (100 μM), or EGTA/AM (100 μM) contained in the bath solution. The application of KN-62 (10 μM) or KN-93 (5 μM), inhibitors of CaMK II, also inhibited the channel activity. (ii) The membrane potential measured with nystatin-perforated patches was significantly decreased by the fall in [Ca]_i induced by the perfusion with EGTA- or La³⁺-containing solution. Also, the application of KN-62 (10 μM) or KN-93 (5 μM) to the bath significantly decreased the membrane potential. (iii) In inside-out patches, the channel activity was significantly stimulated by the application of CaMK II (300 pM) at 10⁻⁷ M Ca²⁺ in the bath. Furthermore, the application of KN-62 (10 μM) to the bath significantly decreased the channel activity. Our findings show that the constitutive activity of inwardly rectifying K⁺ channel at physiological [Ca]_i is mediated by the Ca²⁺/CaMK II pathway in OKPCs.

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We constructed a chassis that tightly fixes catheters for cannulation to the muscle. It can buffer pulling forces to avoid a mechanical tearing of the skin of mice as a result of movement. A simple hydraulic swivel was also made for blood pressure recording and drug infusion in freely moving mice.

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