Search

We examined whether central nitric oxide is involved in blood pressure (BP) regulation in deoxycorticosterone acetate (DOCA)-salt hypertension. DOCA-salt rats were intracerebroventricularly infused (ICV) NG-monomethyl L-arginine (L-NMMA) for 4 weeks at either low (0.08 mg/kg/d; n = 8) or high (0.16 mg/kg/d; n = 8) dose. Saline ICV (n = 9) and intraperitoneal infused L-NMMA (low, n = 6; high dose, n = 6) were served as controls. Also, L-NMMA ICV (low, n = 6; high dose, n = 6) was conducted in normal rats. At week 3 and after, DOCA-salt with low L-NMMA ICV showed a higher BP than saline ICV (at week 4: 167.4 +/- 3.6 vs. 150.3 +/- 3.9 mm Hg, P < 0.01); this difference of BP was cancelled after ganglionic block. High L-NMMA ICV did not affect the trend of BP; however, it caused a reduced amount of saline drinking and a less estimated sodium retention than saline or low L-NMMA ICV (for 3 wk; 47.5 +/- 1.1 vs. 66.0 +/- 3.7 and 61.7 +/- 2.5 mmol, P < 0.01). In normal rats, high, but not low, L-NMMA ICV elevated BP with no effect on drinking behavior. Intraperitoneal infused L-NMMA did not affect the development of hypertension and/or sodium balance. These data suggested that, in DOCA-salt, central nitric oxide is involved in BP regulation through the dual action on sympathetic nervous activity and sodium balance.

An 81-year-old woman developed pilsicainide intoxication associated with dehydration. The patient had been taking pilsicainide (100 mg/day) for 1 year because of paroxysmal atrial fibrillation. Her renal function was within normal limits. One week before admission, she was suffering from pneumonia, and had appetite loss, fever, and severe fatigue. Physical examination revealed dehydration. The electrocardiogram (ECG) on admission showed atrioventricular dissociation, idioventricular rhythm with marked QRS widening and QTc prolongation. The plasma concentration of pilsicainide on admission was markedly elevated at 6.2 microg/ml, approximately 6 times the therapeutic range (0.25-1.0 microg/ml). Continuous saline infusion was initiated for the treatment of dehydration,which progressively improved. As a result, sinus rhythm was recovered 2 h after admission, and the QRS and JT intervals gradually normalized. This is an interesting case because the proarrhythmia of pilsicainide was induced by dehydration.

Baroreceptor reflex control of heart rate (HR) was examined before and 15 min after intracerebroventricular infusion (i.c.v.) of 10 microliters of high-Ca2+ solution (Ca2+, 16.3 mM) in conscious spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). The slope of the individual regression line of the relation between reflex HR changes (delta HR) and changes in mean arterial pressure (delta MAP) produced by bolus injections of phenylephrine or sodium nitroprusside (delta HR/delta MAP; beats/min/ mm Hg) for bradycardia was significantly less in SHR (-0.60 +/- 0.30; n = 10) than in WKY (-1.78 +/- 0.27; n = 10; p < 0.01) at baseline. The slope increased in SHR during administration of high Ca2+ to -1.39 +/- 0.17 (p < 0.01) but not in WKY: In contrast, no significant changes were observed for the reflex tachycardia both in SHR (n = 7) and WKY (n = 10). Further, we analyzed sigmoidal MAP-HR reflex curves in SHR with i.c.v. of either high Ca2+ (n = 6) or artificial cerebrospinal fluid (aCSF; n = 5). Administration of high Ca2+ reduced the bradycardic plateau and increased HR range without changes in average gain. Our results suggest a modulatory role for central Ca2+ in the baroreceptor reflex control of HR in SHR.

Abstract Proliferation of vascular smooth muscle cells (VSMCs) is considered to be one key event underlying the pathophysiology of restenosis after angioplasty. The parathyroid hormone–related peptide (PTHrP) and its receptor, a local autocrine and paracrine regulator of cellular growth in a variety of normal cell types, have been reported in the vicinity of VSMCs. To investigate how PTHrP might be involved in the process of neointimal formation after balloon angioplasty, we examined PTHrP expression in balloon-denuded rat carotid arteries and human coronary arteries that had been retrieved by directional atherectomy. In rat carotid arteries, the RNase protection assay and in situ hybridization demonstrated that PTHrP mRNA expression increased fourfold to sixfold 1 to 7 days after denudation and continued for 28 days, coincident with downregulation of PTH/PTHrP receptor mRNA expression. In situ hybridization and immunohistochemistry revealed that PTHrP expression in balloon-denuded carotid arteries was mainly localized to the neointima. To confirm the involvement of the PTHrP in human coronary artery restenotic lesions, immunohistochemical analysis of human coronary atherectomy specimens (23 primary and 10 restenotic lesions) was then performed. The number of intimal cells that expressed PTHrP protein was significantly higher in restenotic (407±53 cells/mm 2 ; range, 143 to 739) than in stable angina (50±12 cells/mm 2 ; range, 18 to 132; P 2 ; range, 21 to 232; P

Parathyroid hormone-related peptide (PTHrP) was originally characterized as a tumor product responsible for hypercalcemia of malignancy and was subsequently found to be produced in many normal tissues. PTHrP is now suggested to play a critical role in the local modulation of vascular smooth muscle function. To elucidate the involvement of PTHrP in coronary atherosclerosis, we immunohistochemically examined coronary arteries obtained from 76 patients with various grades of atherosclerosis and compared the correlation between PTHrP staining and the percent stenosis. Smooth muscle cells at sites of coronary atherosclerosis overexpressed PTHrP, while cells from normal coronary arteries did not. The in situ hybridization using PTHrP riboprobe has also proven the overexpression of PTHrPmRNA in the affected lesions following atherectomy. The intensity of PTHrP expression by smooth muscle cells was significantly correlated with the degree of coronary artery stenosis. Coronary arterial PTHrP overexpression is closely related to the severity and/or progression of coronary atherosclerosis.

We studied the expression of PTH-related peptide (PTHrP) and its mRNA in rat gastric smooth muscle in relation to various gastric motility states. Male rats were divided into groups subjected to fasting, feeding ad libitum, cold restraint stress, pyloric ligation, and carbachol stimulation. Cold restraint stress induced abnormal contractions. Rhythmic and moderate contractions were produced by carbachol administration, and marked distension was induced by pyloric ligation. PTHrP mRNA expression was weak in the physiological fasting and feeding states, but was markedly increased by pyloric ligation and carbachol stimulation. PTHrP and its mRNA were localized to the proper muscle layer and muscularis mucosa, but not in the mucosa by immunohistochemistry and in situ hybridization. The gene expression of PTHrP receptor in the gastric tissue was confirmed by reverse transcription-polymerase chain reaction, but serum PTHrP levels did not increase in all groups. These findings suggest that PTHrP acts as an autocrine or paracrine factor in gastric smooth muscle that responds to muscle activity caused by distension and cholinergic stimulation. However, PTHrP gene expression was decreased by stress despite the presence of strong contractions, and the sufficient relaxation did not occur. PTHrP suppression by stress is caused by the increase in corticosterone, as pretreatment of metyrapone, an inhibitor of 11 beta-hydroxylation, enhanced PTHrP gene expression in association with serum corticosterone suppression. In conclusion, PTHrP might be an important gastrointestinal peptide that regulates gastric contractile activity and is influenced by the serum corticosterone level.

To examine the role of serine proteases in the control of aldosterone (Ald) secretion, we studied the effects of nafamostat mesilate (Naf), a serine protease inhibitor, on in vivo Ald secretion and Ald content in the rat adrenal gland. Either Naf (2 mg/kg/h; n =10) or saline (2 ml/h; n =10) was administered intravenously for 30 min to anesthetized Wistar rats whose left adrenal vein was cannulated selectively via the inferior vena cava. Naf caused a significant decrease in Ald secretion rate compared to saline (1.99±0.32 vs. 3.42±0.56 ng/min, p

In August 1998, the patient, a 75-year-old woman, was diagnosed with pericardial effusion (PE) during an investigation of cardiomegaly. The PE disappeared after the administration of diuretics, but in February 1999, shortness of breath and general fatigue developed, and PE was again present. Diagnostic pericardiocentesis revealed bloody fluid. Chest computed tomography revealed a markedly expanded and tortuous right coronary artery (RCA). Coronary angiography (CAG) confirmed a RCA-coronary sinus fistula, and there was a significant step-up of O2 saturation at the right atrium. Cardiac tamponade developed soon after CAG, so the patient underwent surgical closure of the CAVF. Although a bleeding point was not identified, the PE was disappeared after operation. Histopathologically, parts of the wall of the fistula were quite thin and erythrocytes and lymphocytes had infiltrated the pericardial space. The clinical course and the findings indicate that the CAVF caused chronic PE.

The depressor effect by oral calcium supplementation is known to be more pronounced in salt-dependent than in renin-dependent hypertension. This study was conducted to investigate the role of central calcium on two different pathophysiologic subtypes of experimental hypertension; (a) salt-dependent, deoxycorticosterone acetate-salt hypertensive rats (DOCA), and (b) renin-dependent, 2-kidney, 1 clip (2-K, 1C) hypertensive rats. In DOCA (n = 10), high-calcium solution (Ca+2, 65.2 mM, 10 microl) given centrally (i.c.v.) elicited a marked decrease in mean blood pressure (MBP; 170 +/- 4 to 138 +/- 5 mm Hg, p < 0.01) with a decrease in heart rate (HR; 390 +/- 18 to 344 +/- 17 beats/min, p < 0.05) lasting for 40 min. In 2-K, 1C (n = 10), high-Ca2+ i.c.v. showed a lesser decrease in MBP (178 +/- 4 to 171 +/- 5 mm Hg) and HR (419 +/- 10 to 395 +/- 12 beats/min) with shorter duration (for 20 min) than in DOCA. This significant depressor and bradycardic response to Ca2+ i.c.v. observed in DOCA was dose dependent at Ca2+ concentrations between 65.2 and 130.4 mM. In DOCA, high Ca2+ i.c.v. reduced the plasma noradrenaline (Nad) concentration significantly (479 +/- 81 to 319 +/- 62 pg/ml, p < 0.05). These results suggest that central Ca2+ plays a more important role in regulating sympathetic nerve activity and BP in salt-dependent than in renin-dependent experimental hypertension.

This study attempted to determine whether central magnesium (Mg) influences the regulation of blood pressure (BP). An intracerebroventricular (icv) injection of a high Mg2+ solution (190.0 mEq/L, 10 microL), made by adding MgC12 to artificial cerebrospinal fluid, increased the mean BP in both conscious spontaneously hypertensive rats (SHR; n = 17, p < 0.001) and Wistar Kyoto rats (WKY; n = 8, p < 0.005). Spontaneously hypertensive rats showed a greater pressor response than WKY (+11.7 +/- 0.9 mm Hg versus +3.5 +/- 1.1 mm Hg, p < 0.001). This pressor response to Mg2+ given icv was dose-dependent in the range of Mg2+ concentration between 47.5 and 190.0 mEq/L in SHR. A high Mg2+ solution (190.0 mEq/L), made by adding MgSO4 given icv, also increased the mean BP in SHR (n = 7, p < 0.001) and WKY (n = 6, p < 0.01), whereas the high osmolarity solution (340 mOsm/kg H2O) given icv did not change the mean BP in either SHR or WKY. Also administered was a high Mg2+ solution icv after either hexamethonium bromide (Hx; 50 mg/kg intravenously) or arginine vasopressin antagonist (aAVP, (CH2)5Tyr(Me)AVP, 30 micrograms/kg i.v.). The pressor response to the high Mg2+ solution was abolished by arginine vasopressin antagonist both in SHR and WKY, although it was not canceled by Hx. A high Mg2+ solution administered icv caused a 3.5-fold increase in plasma arginine vasopressin concentration in SHR (n = 5, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The role of central Ca2+ in the regulation of blood pressure (BP) was investigated in conscious spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). Ten microliters of a high Ca2+ solution (Ca2+: 32.6 mM) administered intracerebroventricularly (i.c.v.) decreased the mean arterial pressure (MAP) for more than 20 min in SHR (n = 7, P0.005), while no change of MAP was observed in the WKY (n = 6). This depressor response to Ca2+ i.c.v. was dose-dependent at Ca2+ concentrations between 16.3 and 65.2 mM. We also investigated the effect of high Ca2+ i.c.v. in SHR after pretreatment with Ca2+ channel blockers, diltiazem (60 micrograms/10 microliters) or nisoldipine (4, 8, 16 and 32 micrograms/10 microliters), administered i.c.v., the autonomic ganglion blocker, hexamethonium (50 mg/kg), administered i.v. and alpha-methyl-p-tyrosine (100 and 400 micrograms/10 microliters) delivered i.c.v. Pretreatment with i.c.v. diltiazem (n = 8) or nisoldipine (n = 5 for 8 micrograms, n = 6 for 4, 16, 32 micrograms) abolished and/or blunted the decrease of MAP due to high Ca2+. Hexamethonium administered i.v. (n = 6) also canceled the depressor action of i.c.v. Ca2+. Pretreatment with 100 micrograms of i.c.v. alpha-methyl-p-tyrosine could not prevent the depressor action of i.c.v. Ca2+; however, 400 micrograms of alpha-methyl-p-tyrosine administered i.c.v. abolished the effect of i.c.v. Ca2+. Furthermore Ca2+ channel blockers administered i.c.v. in themselves increased MAP in SHR (P0.05). These results suggest that central Ca2+ is involved in the central regulation of BP in SHR. This effect may be mediated through changes in sympathetic activity.

The contribution of the central interaction between calcium and sodium to hemodynamic regulation was assessed in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. The effect of a high calcium solution (Ca2+, 130 mg/dl, 10 microliters) infused into the cerebral ventricle (i.c.v.) on hemodynamic responses induced by a high sodium solution (Na+, 1,000 mEq/1, 10 microliters) i.c.v. and the mechanism by which high Ca2+ affects the hemodynamic responses induced by high Na+ i.c.v. were studied. High Na+ i.c.v. induced a pressor response with tachycardia in the SHRs, but induced a pressor response with reflex bradycardia in the WKYs. Prior treatment with high Ca2+ i.c.v. attenuated the pressor response induced by high Na+ i.c.v. (+55.6 +/- 4.4 to +33.1 +/- 3.2 mmHg, P0.01) and restored reflex bradycardia (+86.4 +/- 7.7 to -26.7 +/- 7.6 bpm, P0.01) in SHRs. Whereas prior treatment with high Ca2+ i.c.v. attenuated the pressor response (+35.7 +/- 2.0 to +22.2 +/- 4.0 mmHg, P0.05), it did not alter the degree of reflex bradycardia (-81.7 +/- 7.1 to -69.2 +/- 120 bpm, n.s.) in WKYs. Ganglionic blockade attenuated the pressor response (+56.9 +/- 3.5 to +42.9 +/- 2.3 mmHg, P0.05) and restored reflex bradycardia (+82.1 +/- 10.3 to -65.9 +/- 11.0 bpm, P0.01) in SHRs, whereas, inhibition of arginine vasopressin attenuated the pressor response without modification of the tachycardic response.(ABSTRACT TRUNCATED AT 250 WORDS)