Satoshi Morimoto

Interaction of α1-Adrenoceptor Subtypes With Different G Proteins Induces Opposite Effects on Cardiac L-type Ca2+ Channel

We examined the effect of &agr;1-adrenoceptor subtype-specific stimulation on L-type Ca2+ current (ICa) and elucidated the subtype-specific intracellular mechanisms for the regulation of L-type Ca2+ channels in isolated rat ventricular myocytes. We confirmed the protein expression of &agr;1A- and &agr;1B-adrenoceptor subtypes at the transverse tubules (T-tubules) and found that simultaneous stimulation of these 2 receptor subtypes by nonsubtype selective agonist, phenylephrine, showed 2 opposite effects on ICa (transient decrease followed by sustained increase). However, selective &agr;1A-adrenoceptor stimulation (≥0.1 &mgr;mol/L A61603) only potentiated ICa, and selective &agr;1B-adrenoceptor stimulation (10 &mgr;mol/L phenylephrine with 2 &mgr; mol/L WB4101) only decreased ICa. The positive effect by &agr;1A-adrenoceptor stimulation was blocked by the inhibition of phospholipase C (PLC), protein kinase C (PKC), or Ca2+/calmodulin-dependent protein kinase II (CaMKII). The negative effect by &agr;1B-adrenoceptor stimulation disappeared after the treatment of pertussis toxin or by the prepulse depolarization, but was not attriburable to the inhibition of cAMP-dependent pathway. The translocation of PKC&dgr; and ϵ to the T-tubules was observed only after &agr;1A-adrenoceptor stimulation, but not after &agr;1B-adrenoceptor stimulation. Immunoprecipitaion analysis revealed that &agr;1A-adrenoceptor was associated with Gq/11, but &agr;1B-adrenoceptor interacted with one of the pertussis toxin-sensitive G proteins, Go. These findings demonstrated that the interactions of &agr;1-adrenoceptor subtypes with different G proteins elicit the formation of separate signaling cascades, which produce the opposite effects on ICa. The coupling of &agr;1A-adrenoceptor with Gq/11-PLC-PKC-CaMKII pathway potentiates ICa. In contrast, &agr;1B-adrenoceptor interacts with Go, of which the &bgr;&ggr;-complex might directly inhibit the channel activity at T-tubules.

Pulsatile compression of the rostral ventrolateral medulla in hypertension

The rostral ventrolateral medulla (RVLM) has been known to be a major regulating center of sympathetic and cardiovascular activities. An association between essential hypertension and neurovascular compression of the RVLM has been reported in clinical observations, including magnetic resonance imaging (MRI) studies. To reconfirm this relationship, we performed MRI using a high-resolution 512 x 512 matrix in patients with essential and secondary hypertension and in normotensive subjects. The duration of hypertension and the degree of organ damage by hypertension were not significantly different between the two hypertension groups. Neurovascular compression of the RVLM was observed in 74% of the essential hypertension group, and the incidence of compression was significantly higher than in the secondary hypertension group (11%) or in the normotensive group (13%) (P < .01). These results from the clinical studies suggest that neurovascular compression of the RVLM is, at least in part, causally related to essential hypertension. Although blood pressure elevation by pulsatile compression of the RVLM in an experimental baboon model has already been reported, its underlying mechanism is not well known. Accordingly, we performed experiments to investigate whether pulsatile compression of the RVLM would increase arterial pressure and to elucidate the mechanism of the pressor response in rats. Sympathetic nerve activity, arterial pressure, heart rate, and plasma levels of epinephrine and norepinephrine were increased by pulsatile compression of the RVLM. The pressor response was abolished by intravenous treatment with hexamethonium or RVLM injection of kainic acid. In summary, the results from the MRI studies suggest that neurovascular compression of the RVLM is, at least in part, causally related to essential hypertension. This was supported by the results from experimental studies using rats indicating that pulsatile compression of the RVLM increases arterial pressure by enhancing sympathetic outflow.

Neurovascular Compression of the Rostral Ventrolateral Medulla Related to Essential Hypertension

The rostral ventrolateral medulla (RVLM) is thought to serve as a final common pathway for the integration of central cardiovascular information and to be important for the mediation of central pressor responses. An association between essential hypertension and neurovascular compression of the RVLM has been reported. To confirm this relationship and to quantitatively measure the distances between the RVLM and the neighboring arteries, we performed magnetic resonance imaging using a high-resolution 512x512 matrix and magnetic resonance angiography in 49 subjects (21 patients with essential hypertension, 10 patients with secondary hypertension, and 18 normotensive subjects). One patient with essential hypertension was excluded from the evaluations because of inadequate assessment due to poor images. Neurovascular compression of the RVLM was observed in 15 of 20 (75%) patients with essential hypertension. In contrast, neurovascular compression was observed in only 1 of 10 (10%) patients with secondary hypertension and only 2 of 18 (11%) normotensive subjects. The rate of observed neurovascular compression in the essential hypertension group was significantly higher than that in the secondary hypertension group and the normotensive group (P<.01 for both). The distances between the RVLM and the nearest arteries in the essential hypertension group were significantly shorter than those in the other groups (P<.05 for all). On the other hand, the distances between the surface of the medulla oblongata and the nearest arteries did not differ among these three groups. These results suggest that neurovascular compression of the RVLM, but not of the other regions of the medulla oblongata, is particularly related to essential hypertension.

Soluble (pro)renin receptor and blood pressure during pregnancy : a prospective cohort study

The renin–angiotensin system is believed to influence blood pressure (BP) during pregnancy, but the associations between BP during pregnancy and the soluble form of the (pro)renin receptor (s[P]RR), a new component of the tissue renin–angiotensin system, remain undetermined. In this prospective cohort study of 437 pregnant women with normal BP (systolic <140 mm Hg and diastolic <90 mm Hg) during early pregnancy (<16 weeks of gestation) regression analysis was performed to examine the associations between plasma s(P)RR concentrations and BP in 3 gestational stages (20–24, 28–32, and 36–40 weeks of gestation) and logistic regression analysis to evaluate the incidence of preeclampsia. Plasma s(P)RR concentrations at early, middle (16–28 weeks), and late pregnancy (>28 weeks) and at delivery averaged 29.7 ± 10.0, 31.3 ± 12.0, 39.2 ± 8.9, and 40.4 ± 10.2 ng/mL (mean±SD), respectively. A 1-ng/mL increase in plasma s(P)RR concentration in early pregnancy predicted systolic/diastolic BP elevation in the later 3 gestational stages: 0.11 (95% CI, 0.014–0.20)/0.093 (0.027–0.16) mm Hg for 20 to 24 weeks, 0.11 (0.029–0.19)/0.088 (0.027–0.15) mm Hg for 28 to 32 weeks, and 0.16 (0.058–0.26)/0.12 (0.043–0.19]) mm Hg for 36 to 40 weeks, respectively. Plasma s(P)RR concentrations in middle and late pregnancy were not associated with BP. Adjusted models revealed that women with plasma s(P)RR concentrations above the 75th percentile at delivery had a significantly increased risk of preeclampsia (odds ratio, 22.5 [95% CI, 1.8–279.9]). In conclusion, high circulating levels of s(P)RR at early pregnancy predicted a subsequent elevation in BP, and high concentrations at delivery were significantly associated with preeclampsia.

Decreases in Blood Pressure and Sympathetic Nerve Activity by Microvascular Decompression of the Rostral Ventrolateral Medulla in Essential Hypertension

BACKGROUND Neurovascular compression of the rostral ventrolateral medulla, a major center regulating sympathetic nerve activity, may be causally related to essential hypertension. Microvascular decompression of the rostral ventrolateral medulla decreases elevated blood pressure. CASE DESCRIPTION A 47-year-old male essential hypertension patient with hemifacial nerve spasms exhibited neurovascular compression of the rostral ventrolateral medulla and facial nerve. Microvascular decompression of the rostral ventrolateral medulla successfully reduced blood pressure and plasma and urine norepinephrine levels, low-frequency to high-frequency ratio obtained by power spectral analysis, and muscle sympathetic nerve activity. CONCLUSIONS This case suggests not only that reduction in blood pressure by microvascular decompression of the rostral ventrolateral medulla may be mediated by a decrease in sympathetic nerve activity but also that neurovascular compression of this area may be a cause of blood pressure elevation via increased sympathetic nerve activity.

Nitric oxide is an excitatory modulator in the rostral ventrolateral medulla in rats

Nitric oxide is a messenger molecule having various functions in the brain. Previous studies have reported conflicting results for the roles of nitric oxide in the rostral ventrolateral medulla, a major center that regulates sympathetic and cardiovascular activities. We hypothesized that in this region, nitric oxide may have a biphasic effect on cardiovascular activity. Microinjection of a low dose (1 nmol) of a nitric oxide donor sodium nitroprusside or a cyclic GMP agonist 8-bromocyclic GMP into this area increased arterial pressure, whereas injection of a nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester or a soluble guanylate cyclase inhibitor methylene blue decreased arterial pressure. Microinjection of a high dose (100 nmol) of sodium nitroprusside decreased arterial pressure and inhibited spontaneous respiration with concomitant production of peroxynitrite, a strong cytotoxic oxidant. Increases in arterial pressure caused by microinjection of L-glutamate were inhibited after preinjection of Nomega-nitro-L-arginine methyl ester or methylene blue. Increases in arterial pressure caused by microinjection of sodium nitroprusside (1 nmol) were inhibited after preinjection of a glutamate receptor antagonist kynurenate. These results suggest that low doses of nitric oxide may increase arterial pressure, whereas high doses of nitric oxide may decrease arterial pressure through cytotoxic effects in the rostral ventrolateral medulla. They also indicate that nitric oxide may stimulate neurons both through activation of the nitric oxide cyclic GMP pathway and through modulation of glutamate receptor stimulation, and therefore, increase arterial pressure in rats.

Prediction of Gestational Diabetes Mellitus by Soluble (Pro)Renin Receptor During the First Trimester

CONTEXT There are currently no factors that have been shown to predict gestational diabetes mellitus (GDM) during early pregnancy. The soluble (pro)renin receptor [s(P)RR] may contribute to the development of GDM. OBJECTIVE The objective of the study was to determine whether plasma s(P)RR concentrations during early pregnancy are associated with the development of GDM later in pregnancy. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study was conducted at a referral birth center. Pregnant women who first visited our hospital during the first trimester (<14 weeks of gestation) between 2010 and 2011 were enrolled. Inclusion criteria included singleton pregnancy and the absence of preexisting diabetes mellitus. A total of 716 women participated in this study. MAIN OUTCOME MEASURE The association of plasma s(P)RR concentrations with the onset of GDM later in pregnancy was measured. RESULTS Among 716 participants, 44 (6.1%) had GDM and 672 (93.9%) did not. There were 176 participants in the first plasma s(P)RR concentration quartile (Q1: < 25.8 ng/mL), 179 in the second (Q2: 25.8-30.2 ng/mL), 181 in the third (Q3: 30.2-34.2 ng/mL), and 180 in the fourth (Q4: > 34.2 ng/mL). GDM distribution was 7 (4.0%) in Q1, 5 (2.8%) in Q2, 13 (7.2%) in Q3, and 19 (10.6%) in Q4. A multivariate model adjusted for baseline characteristics, medical complications, and gestational characteristics revealed that the risk of developing GDM among women in Q4 compared with Q1 was 2.90 (95% confidence interval 1.11-7.49). CONCLUSION Increased s(P)RR concentrations during the first trimester may predict the development of GDM later in pregnancy.

Reduction of white coat effect by cilnidipine in essential hypertension

Stress elevates blood pressure (BP) by increased sympathetic nerve activity. Cilnidipine, a novel dihydropyridine calcium antagonist that has inhibitory actions on N-type as well as L-type voltage-dependent calcium channels, has been reported to attenuate the cold stress-induced increase in plasma norepinephrine and BP in rats. Because white coat effect is associated with an enhanced pressor response to mental stress, we postulated that cilnidipine would attenuate white coat effect in patients with essential hypertension. Sixty-one consecutive outpatients (50 men, 11 women) with essential hypertension were studied prospectively. Twenty-nine patients were treated with either cilnidipine (n = 15) or nifedipine, a representative L-type voltage-dependent calcium antagonist (n = 14). Gender, age, body mass index, duration of hypertension, target organ damage of hypertension, and BP and heart rate (HR) were not significantly different between cilnidipine and nifedipine groups, and both systolic (SBP) and diastolic BP (DBP) were significantly decreased after treatment in both groups. White coat effects on systolic and DBP and HR were not significantly different between groups before antihypertensive treatment. Cilnidipine, but not nifedipine, significantly reduced white coat effects on SBP and HR. Furthermore, white coat effects on systolic BP and HR were significantly lower after treatment in the cilnidipine group compared with the nifedipine group. These data suggest that cilnidipine may reduce white coat effect in hypertensive patients by N-type calcium channel antagonism.

Reduction of insulin resistance attenuates the development of hypertension in sucrose-fed SHR.

We examined the effect of pioglitazone, a thiazolidinedione derivative that increases insulin sensitivity without increasing insulin secretion, on the development and maintenance of hypertension in sucrose-fed SHR. Nine-week-old male SHR received 12% sucrose dissolved in tap water as drinking water. For 5 weeks, half of the rats were given regular rat chow, and the rest were fed with rat chow containing 0.03% pioglitazone. In week 6, blood glucose and plasma insulin levels were examined before and after oral glucose administration by gavage. Sucrose treatment elicited a significant elevation of systolic blood pressure 3 weeks after the beginning of treatment; pioglitazone treatment attenuated this elevation. The insulin resistance and hyperinsulinemia observed in sucrose-fed SHR were prevented by pioglitazone treatment. Pioglitazone treatment also significantly reduced the urinary excretion of catecholamines and plasma renin activity, both of which were significantly greater in sucrose-fed SHR than in control SHR. Along with improving insulin sensitivity, pioglitazone treatment also attenuated the development of hypertension in SHR fed the regular rat chow, but not in WKY rats. These results indicate that insulin resistance and hyperinsulinemia play an important role in the development of hypertension in SHR probably through the activation of the renin-angiotensin system and sympathetic nervous outflow. This study also shows that chronic sucrose treatment exacerbated the development of hypertension through these mechanisms, precipitating insulin resistance.

Role of Ca2+/calmodulin-dependent protein kinase II in the regulation of the cardiac L-type Ca2+ current during endothelin-1 stimulation

Endothelin-1 (ET-1) shows a positive inotropic effect on cardiac muscle. Although the L-type Ca(2+) current (I(Ca)) is one of the important determinants of cardiac excitation-contraction coupling, the effect of ET-1 on the I(Ca) is not always clear. The controversial results appear to be due to different patch-clamp methods. The present study measured the effect of ET-1 on the I(Ca) of rat ventricular myocytes using the perforated patch-clamp technique. The holding potential was set to -40 mV, and depolarization was applied every 10 s. ET-1 (10 nM) increased the I(Ca) in a monophasic manner. The current reached a steady state 15 min after the application of ET-1, when the measurement was done. Endothelin receptor subtype expression was also investigated using Western immunoblotting. ET(A)-receptor protein was expressed, but ET(B)-receptor protein was not expressed, in the cell membranes of rat ventricular myocytes. The effect of ET-1 on the I(Ca) was inhibited by a selective ET(A)-receptor antagonist, BQ-123, but not by a selective ET(B)-receptor antagonist, BQ-788. The effect was inhibited by protein kinase C (PKC) inhibitor chelerythrine and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93, but not by its inactive analog KN-92. The effect of ET-1 was also blocked by another CaMKII inhibitor, autocamtide-2-related inhibitory peptide. These results suggest that ET-1 increases the I(Ca) via the ET(A)-receptor-PKC-CaMKII pathway.