• The Korean Journal of Physiology
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• v.22 no.1
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• pp.13-29
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• 1988

In order to elucidate the regulatory mechanism of intracellular calcium ion concentrations, contractions or contractures induced by $Na^{+}-removal$, calcium-application or ouabain-treatment as an index of $Na^+/Ca^{2+}$ exchange activity were studied in atrial muscle or vascular smooth muscle (aorta and renal artery) of the rabbit. The magnitude of low sodium contractures in atrial trabeculae increased with sigmoid shape when external sodium concentrations were reduced to sodium-free condition, whereas that of calcium contracture intensified in a parabolic pattern when external calcium concentrations were elevated to 8 mM. $Na^{+}-removal$ contractures were induced in a duration-dependent manner to $K^{+}-free$ exposure and same findings were observed with ouabain treatment. $Na^{+}-free$ contractures were not affected by verapamil treatment, but stimulated by $100{\mu}M\;Mn^{2+}$ and inhibited by high concentrations of $Mn^{2+}\;(2{\sim}8mM)$ in a dose-dependent manner. Ryanodine which is known to suppress the release of calcium from internal store abolished spontaneous twitch contractions induced by $K^{+}-free$ solution, but had no effect on the development $Na^{+}-free$ contractures. Na-free contractures were not always induced in vascular smooth muscle preparations. Contractures by $O\;mM\;Na^+$ were usually seen in aorta, but not often in renal artery.$50\;mM\;K^+$, noradrenaline (NA) and angiotensin II (AII) always evoked very large contraction in all preparations of vascular smooth muscle. Contractures developed by $O\;mM\;Na^+$ were not sensitive to verapamil treatment as in atrial trabeculae, but were abolished by $100{\mu}M\;Mn^{2+}$. In contrast to $Na^{+}-free$ contractures, $Mn^{2+}(100{\mu}M)$ had no effect on the contractures induced by NA or 50 mM$K^+$. Caffeine in the concentration of 10 mM evoked transient contracture in the distal renal artery. The rate of spontaneous relaxation in caffeine contracture was dependent upon the concentrations of external sodium, and had double component of relaxation when the rate of relaxation was plotted in the semilogarithmic scale of relative tension versus time. Especially late components of relaxation had more direct relation to $Na^+$ concentrations. It could be concluded that $Na^+/Ca^{2+}$ exchange mechanism in the heart has a large capacity, inhibited by $Mn^{2+}$ but not by verapamil and ryanodine, while $Na^+/Ca^{2+}$ exchange system in vascular smooth muscle has a very low capacity especially in small artery, inhibited by low concentration of $Mn^{2+}\;(100{\mu}M)$ but not affected by verapamil and ryanodine.

• Journal of Yeungnam Medical Science
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• v.36 no.1
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• pp.26-35
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• 2019

Background: Dysregulation of hepatic glucose production (HGP) contributes to the development of type 2 diabetes mellitus. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), has various ancillary effects in addition to common blood pressure-lowering effects. The effects and mechanism of telmisartan on HGP have not been fully elucidated and, therefore, we investigated these phenomena in hyperglycemic HepG2 cells and high-fat diet (HFD)-fed mice. Methods: Glucose production and glucose uptake were measured in HepG2 cells. Expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase ${\alpha}$ ($G6Pase-{\alpha}$), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ${\zeta}$ ($PKC{\zeta}$) were assessed by western blot analysis. Animal studies were performed using HFD-fed mice. Results: Telmisartan dose-dependently increased HGP, and PEPCK expression was minimally increased at a $40{\mu}M$ concentration without a change in $G6Pase-{\alpha}$ expression. In contrast, telmisartan increased phosphorylation of IRS-1 at Ser302 ($p-IRS-1-Ser^{302}$) and decreased $p-IRS-1-Tyr^{632}$ dose-dependently. Telmisartan dose-dependently increased $p-PKC{\zeta}-Thr^{410}$ which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative $PKC{\zeta}$ significantly attenuated telmisartan-induced HGP and $p-IRS-1-Ser^{302}$ and -inhibited $p-IRS-1-Tyr^{632}$. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor ${\gamma}$ ($PPAR{\gamma}$) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased $p-IRS-1-Ser^{302}$ and decreased $p-IRS-1-Tyr^{632}$, which was accompanied by an increase in $p-PKC{\zeta}-Thr^{410}$. Conclusion: These results suggest that telmisartan increases HGP by inducing $p-PKC{\zeta}-Thr^{410}$ that increases $p-IRS-1-Ser^{302}$ and decreases $p-IRS-1-Tyr^{632}$ in a $PPAR{\gamma}$-independent manner

• Childhood Kidney Diseases
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• v.3 no.1
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• pp.20-26
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• 1999

Purpose : Several modulatory factors for renal peripheral benzodiazepine receptor (PBR) has been reported, but their physiological significance remains elusive. Tissue-specific, stress-induced down-regulation of renal PBR coupled with the pharmacological stimulation of these effects by angiotensin II suggested that physiological significance of renal PBR may be related to the pathophysiology of stress-induced hypertension. The boderline hypertensive rat (BHR) has been used extensively to study the interaction of environmental factors, such as stress and blood pressure. The BHR is the first-generation progeny of a cross between the spontaneously hypertensive rat and the control Wistar-Kyoto rat. The pathogenesis of stress induced hypertension in this model is not demonstrated well. Methods In this study, BHR (male, 150-200 g) and Sprague-Dawley (SD, male, 150-200 g) rats were treated by repeated immobilization to induce anxiety. We used plus-maze performance to observe the level of anxiety by measuring percent open crosses and percent time in open. Results : Percent open crosses and percent time in open in BHR were lower than in SD rats (P<0.05). Receptor densities of renal PBR in BHRs were significantly lower than those of SDs (P<0.05). We also observed that the renal PBR was upregulated in the repeatedly stressed (immobilization, 2 hours daily, for 2 weeks) rats, both in the BHR and SD. However, the density of renal PBR in the stressed BHR was still lower than that of stressed SD. Renal PBR has been suggested to be an important organs which Is responsible for the production of cholesterol-derived products during stress. Conrlusion : From these results, it can be summarized that the lowed density of renal PBR may be involved in the pathogeneis of stress-induced hypertension.

• Tuberculosis and Respiratory Diseases
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• v.42 no.5
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• pp.752-759
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• 1995

Background: Bronchial asthma is characterized by noctunal dyspnea, cough and wheezing because of airway hyperresponsiveness to nonspecific stimuli. These symptoms and signs are also observed in patients with congestive heart failure. Therefore, this is so called "cardiac asthma". There are lots of experimental and clinical datas to suggest that airway dysfunctions occur in acute and chronic congestive heart failure. However, it is still controversial whether bronchial hyperresponsiveness is present in patients with congestive heart failure. To assess whether bronchial hyperresponsiveness is present in patients with congestive heart failure and to demonstrate the relationship between bronchial responsiveness and vascular pressure, we performed methacholine provocation test in 11 patients with mitral valvular heart disease. Methods: All patients were in the New York Heart Association functional class II and treated continuously with digoxin and/or dichlozid and/or angiotensin converting enzyme inhibitor except one patient. All patients were undergone right and left side heart catheterization for hemodynamic measurements. A 20 percent fall of peak expiratory flow rate were considered as positive response to methacholine provocation test. Results: 1) Only one patient who has normal pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac index was positive in methacholine provocation test. 2) Their mean pulmonary artery pressure, pulmonary capillary wedge pressure were $21.72{\pm}9.70mmHg$, $15.45{\pm}8.69mmHg$ respectively which were significantly higher. Conclusion: It is speculated that in stable congestive heart failure patients, bronchial responsiveness as assessed by methacholine provocation test may not be increased.