Altered plasma levels of cytokines in patients with ischemic heart disease.

BACKGROUND: Cytokines play an important role in mediating inflammatory-proliferative responses, including atherosclerosis. Alterations in the plasma levels of cytokines in patients with ischemic heart disease (IHD) remain to be examined. OBJECTIVE: To examine the possible alterations in the plasma levels of cytokines in patients with IHD and in controls. METHODS: Thirty-one patients with IHD and 16 controls were studied. The cytokines measured in our study included interleukin-6, macrophage-colony-stimulating factor (MCSF), transforming growth factor-beta (TGF-beta), and seven other major cytokines. The measurements were performed by using an enzyme-linked immunosorbent assay method. RESULTS: The MCSF levels were significantly higher in patients with IHD than they were in controls (P < 0.01), whereas the TGF-beta levels were significantly lower in patients with IHD than they were in controls (P < 0.01). Moreover, the levels of MCSF and those of TGF-beta were correlated negatively (P < 0.05). The interleukin-6 levels tended to be higher in patients with unstable angina. The plasma levels of other cytokines were below the detection levels in most cases. CONCLUSIONS: Results from studies in vitro suggested that the process of atherosclerosis is accelerated and inhibited by MCSF and TGF-beta, respectively. The present results thus suggest that the alterations in the plasma levels of MCSF and TGF-beta may be involved in the pathogenesis of IHD in humans.

Central GABAergic mechanisms are defective in salt-induced hypertension in borderline hypertensive rats.

We examined the role of central GABAergic mechanisms in salt-induced hypertension and exaggerated responses to stress in borderline hypertensive rats (BHR), the first offspring of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The studies were done in conscious BHR and WKY on high (H) (8% NaCl) or normal (N) (0.3% NaCl) salt diets for 5 weeks. A high-salt diet elevated arterial pressure (AP) (p < 0.01) and augmented pressor responses to shaker stress (p < 0.05) in BHR but not in WKY. Intravenous hexamethonium caused a greater decrease in AP in BHR-H than in BHR-N at rest. Muscimol (a GABA agonist) injected into the central ventricle (i.c.v.) caused a greater decrease in resting AP (p < 0.01) and heart rate (HR) (p < 0.05) and BHR-H than in BHR-N. Renal sympathetic nerve activity (RSNA) did not change in BHR-H, but increased (p < 0.05) in BHR-N during muscimol-induced hypotension, although the magnitudes of muscimol-induced hypotension were greater in BHR-N than in BHR-N. The increases in RSNA in response to intravenous nitroglycerin were similar in BHR-N and BHR-N. Muscimol attenuated pressor and tachycardic responses to stress more in BHR-N than in BHR-N (p < 0.01). Muscimol did not alter AP and HR at rest or their responses to stress in the two groups of WKY. The magnitudes of pressor response to bicuculline (a GABA antagonist) did not differ between the two groups of BHR. These results suggest that a high salt diet may alter the central GABAergic system in BHR, which contributes to salt-induced hypertension and augmented pressor and tachycardic responses to stress.

Monocyte-related cytokines in acute myocardial infarction.

To elucidate the role of monocytes in the cytokine system in acute myocardial infarction (AMI), we examined the time courses of plasma concentrations and generation capacities of monocyte-related cytokines in 17 consecutive patients with uncomplicated AMI (from day 1 to 28) and in 10 control subjects. The concentrations of monocyte-related cytokines were measured by enzyme immunoassay with horseradish peroxidase. Cytokine generation capacity was evaluated by cytokine concentrations in the culture solution 24 hours after incubation of 0.5 ml whole blood with 5 micrograms lipopolysaccharide. Two distinct patterns of increases in the cytokine concentrations were noted: transient (plasma interleukin [IL]-6) and sustained (plasma macrophage colony-stimulating factor and generation capacities of IL-1 alpha, IL-6, granulocyte colony-stimulating factor, and tumor necrosis factor alpha). There was no significant increase in the concentrations of other cytokines. These results indicate that the concentrations of the monocyte-related cytokines dynamically change during the course of AMI, suggesting that they may contribute to the inflammatory and subsequent proliferative responses in AMI.

Influence of arotinolol hydrochloride on heart rate spectrum in hypertensive subjects.

Influence of arotinolol hydrochloride and atenolol on the balance between the sympathetic and parasympathetic nervous systems was evaluated in 8 hypertensive subjects by spectral analysis of heart rate (HR) and systemic blood pressure (BP). Before and after administration of either arotinolol (n = 7) or atenolol (n = 7) for 2 weeks, BP was continuously and non-invasively monitored by a finger-cuff manometry (Finapres). A time series of instantaneous HR was constructed from the BP signal. A time series of mean BP was also constructed. Spectral analysis was performed by the use of an autoregressive algorithm on these time series (approximately 180 sec). Each spectrum was subdivided into low-(0.05-0.15 Hz, LF) and high-frequency (0.15-0.4 Hz, HF) components, and each component was divided by the sum of the two for normalization. As a measure of the balance between the sympathetic and parasympathetic nervous systems, the ratio of LF to HF (LF/HF) was evaluated. Arotinolol increased fractional HF in the HR spectrum from 0.45 +/- 0.12 to 0.73 +/- 0.08 (p < 0.01) and decreased fractional LF from 0.55 +/- 0.12 to 0.27 +/- 0.08 (p < 0.01); consequently, it decreased LF/HF from 1.4 +/- 0.5 to 0.4 +/- 0.2 (p < 0.01). Atenolol had similar effects on these parameters. Neither of these beta-adrenergic blockades produced a discernible decrease in LF/HF in the BP spectrum. In conclusion, these beta-adrenergic blockades decreased LF/HF in the HR spectrum in hypertensive subjects, which suggests that they improved the balance between the sympathetic and parasympathetic nervous systems.

Effects of a novel orally effective V1-receptor antagonist, OPC-21268, on AVP-induced sympathoinhibition.

Arginine vasopressin (AVP) plays as important role in control of circulation and may be involved in pathophysiology of cardiovascular diseases. Recently a novel oral V1-receptor antagonist, OPC-21268, has been produced for possible human therapeutic use (Y. Yamamure et al. Science Wash. DC 252: 572-574, 1991). OPC-21268 is a nonpeptide antagonist and inhibits AVP-induced vasoconstriction in rats and humans. In this study, we examined the influence of OPC-21268 on the sympathoinhibitory and bradycardic effects of AVP in conscious rabbits. Before OPC-21268, AVP at doses of 1, 3, 10, and 30 mU/kg decreased renal sympathetic nerve activity (RSNA) by 24 +/- 5, 40 +/- 5, 65 +/- 6 and 86 +/- 5%, respectively, and decreased heart rate from 243 +/- 10 beats/min at control to 232 +/- 11, 221 +/- 10, 197 +/- 9, and 166 +/- 6 beats/min, respectively (n = 12). Oral OPC-21268 at 30 mg/kg (n = 12) and 90 mg/kg (n = 5) did not alter the baseline values of arterial pressure, heart rate, and RSNA. After oral OPC-21268 the decreases in RSNA and heart rate evoked with AVP at graded doses were partially but significantly attenuated (P < 0.01). The attenuation of the AVP-induced decreases in RSNA and heart rate was similar between the two doses of OPC-21268. In another group of rabbits (n = 6), intravenous OPC-21268 at 30 mg/kg almost completely abolished AVP-induced decreases in heart rate and RSNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Production of chronic congestive heart failure by rapid ventricular pacing in the rabbit.

OBJECTIVE: The aim was to produce a model of low output congestive heart failure by rapid pacing in rabbits. METHODS: To perform rapid pacing in rabbits, a custom made pacemaker was developed which is light (about 80 g) and can pace at up to 400 beats.min-1 for more than two weeks. A thoracotomy was done and two electrodes were sutured onto the left ventricle. A central venous pressure line was chronically implanted. With the use of this pacemaker, rabbits were paced at 350-400 beats.min-1 for several weeks. RESULTS: Central venous pressure increased from 1.4(SEM 0.2) to 6.4(0.5) mm Hg (p < 0.01, n = 14). After pacing for 16.1(1.6) d, haemodynamic studies were performed under anaesthesia with thiamylal sodium. Left ventricular end diastolic pressure was higher in the paced rabbits (n = 10) than in the control rabbits which underwent sham operation but were not paced (n = 6), at -0.6(0.6) v 19.3(2.0) mm Hg (p < 0.01). Cardiac output [673(56) v 536(45) ml.min-1, p < 0.10] and +dP/dt [1433(97) v 722(51) mm Hg.s-1, p < 0.01] were lower in the paced rabbits (n = 7-8) than in the control rabbits (n = 6). The paced rabbits had more ascites [1.9(1.0) v 45.9(18.9) ml, p < 0.05] and pleural effusion [0.4(0.3) v 12.9(6.7) ml, p < 0.10] than control rabbits. Plasma noradrenaline was higher in the paced rabbits (n = 11) than in the control rabbits (n = 7), at 1.59(0.43) v 0.60(0.05) ng.ml-1 (p < 0.05). The ratio of wet heart weight or lung weight to body weight was higher (p < 0.01) in the paced rabbits than in the control rabbits. CONCLUSIONS: Chronic biventricular congestive heart failure can be produced in rabbits by rapid pacing.

Inhibition of nitric oxide formation in the nucleus tractus solitarius increases renal sympathetic nerve activity in rabbits.

It has been shown that nitric oxide (NO) is synthesized in the central nervous system as well as in vascular endothelial cells. However, the physiological role of NO in cardiovascular regulation by the central nervous system remains unclear. This objective of this study was to examine the possibility that NO plays a role in neural transmission in the nucleus tractus solitarius (NTS) and thus contributes to control of sympathetic nerve activity in rabbits. We examined the effects of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of the formation of NO from L-arginine, microinjected into the NTS on arterial pressure (AP), heart rate (HR), and renal sympathetic nerve activity (RSNA). L-NMMA increased AP and RSNA in rabbits with intact as well as denervated sinoaortic baroreceptors and vagi. L-NMMA increased HR only in rabbits with sinoaortic denervation and vagotomy. Pretreatment with L-arginine microinjected into the NTS, which did not alter baseline AP, HR, and RSNA, prevented the increases in AP and RSNA evoked with subsequent L-NMMA. Pretreatment with D-arginine did not alter the effects of subsequent L-NMMA injections into the NTS. The gain of arterial baroreflex control of RSNA assessed by the slope of the regression line relating changes in AP and those in RSNA caused by intravenous phenylephrine or nitroglycerin did not differ before and after microinjections of L-NMMA. L-NMMA microinjected into the area postrema did not alter AP, HR, or RSNA. These results suggest that in rabbits NO is involved in the mechanism in the NTS that mediates tonic inhibition of RSNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of L-arginine on forearm vessels and responses to acetylcholine.

This study was designed to investigate the effects of L-arginine (the substrate of endothelium-derived nitric oxide) in human forearm vessels. We examined whether intra-arterial infusion of L-arginine dilated forearm vessels and augmented vasodilatory responses to acetylcholine in young, healthy humans. The left brachial artery was cannulated for drug infusions and direct measurement of arterial pressure. Forearm blood flow was measured by a strain gauge plethysmograph. Intra-arterial infusions of L-arginine at 10, 20, 40, and 60 mg/min increased forearm blood flow from 4.7 +/- 0.6 to 4.9 +/- 0.5, 5.7 +/- 0.5, 7.2 +/- 0.8, and 8.2 +/- 0.9 ml.min-1.100 ml-1, respectively (n = 8, p less than 0.01), whereas D-arginine at the same doses did not alter forearm blood flow (n = 7). Intra-arterial infusions of acetylcholine (n = 7) (4, 8, 16, and 24 micrograms/min) and sodium nitroprusside (n = 5) (0.2, 0.4, 0.8, and 1.2 micrograms/min) increased forearm blood flow dose dependently (p less than 0.01 for both). Arterial pressure was not altered with infusions of these drugs. Responses to acetylcholine were augmented with simultaneous intra-arterial infusion of L-arginine at 10 mg/ml (p less than 0.01) but not with D-arginine. Responses to sodium nitroprusside were not altered by L-arginine. These results in human forearm resistance vessels support the notion that vasodilation induced by acetylcholine is a result of the conversion from L-arginine to endothelium-derived nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients.

Animal studies suggest that some angiotensin converting enzyme inhibitors augment endothelium-dependent vasorelaxation. We aimed to determine if captopril augments endothelium-dependent vasodilation in middle-aged hypertensive patients. By using strain-gauge plethysmography, forearm vasodilation evoked with intra-arterial acetylcholine (4, 8, 16, and 24 micrograms/min) or nitroprusside (0.2, 0.4, 0.8, and 1.2 micrograms/min) was examined before and after captopril administration (25 mg per os). Before captopril, forearm vasodilation with acetylcholine was less in hypertensive patients (n = 12) than in age-matched (n = 7) or young (n = 7) normotensive subjects, but forearm vasodilation with nitroprusside did not differ among the three groups. Captopril improved forearm vasodilation in hypertensive patients (n = 7) with acetylcholine but nitroprusside did not. In contrast, nifedipine (10 mg per os) did not alter forearm vasodilation with acetylcholine or nitroprusside in hypertensive patients (n = 5). The decreases in mean blood pressure caused by captopril and nifedipine in hypertensive subjects were comparable. Captopril did not alter forearm vasodilation with acetylcholine or nitroprusside in young normotensive subjects (n = 7). These results suggest that captopril in hypertensive patients may acutely improve impaired endothelium-dependent forearm vasodilation that does not result from reduction in blood pressure per se.

Effects of OPC-21268, an orally effective vasopressin V1 receptor antagonist in humans.

An orally effective, nonpeptide vasopressin V1 receptor antagonist, OPC-21268 was produced for possible human use. We investigated the effects of OPC-21268 on the vascular effects of intra-arterially infused arginine vasopressin in human forearm vessels. The brachial artery was cannulated for drug infusions and direct measurement of arterial pressure. Forearm blood flow was measured by a strain gauge plethysmograph, and forearm vascular resistance was calculated. Arginine vasopressin was infused intra-arterially at doses of 0.02, 0.06, 0.09, 0.2, 0.6, and 1.2 ng/kg/min. The lower doses of arginine vasopressin increased, whereas the higher doses of arginine vasopressin decreased forearm vascular resistance (p less than 0.01). Intra-arterial infusion of phenylephrine at doses of 0.2, 0.4, and 2.4 micrograms/min increased forearm vascular resistance dose-dependently (p less than 0.01). OPC-21268 (50 mg for two, 100 mg for six, and 200 mg for two subjects) given orally did not alter resting arterial pressure, forearm vascular resistance, or heart rate. OPC-21268 decreased vasoconstrictor responses to arginine vasopressin at doses of 0.02 (p less than 0.02) and 0.09 (p less than 0.05) ng/kg/min and augmented vasodilator responses to arginine vasopressin at a dose of 1.2 ng/kg/min (p less than 0.01). However, the vasoconstrictor responses to phenylephrine were not altered by OPC-21268. These results demonstrated that OPC-21268 effectively and specifically antagonized the V1 receptor-mediated vasoconstriction in human forearm resistance vessels. These results suggest that OPC-21268 may be useful therapeutically to antagonize the vasoconstriction caused by arginine vasopressin in some pathological states.

Endothelium-dependent forearm vasodilation to acetylcholine but not to substance P is impaired in patients with heart failure.

It has been shown that endothelium-dependent vasorelaxation in response to muscarinic stimulation is attenuated in patients as well as animals with heart failure. This study aimed to determine if endothelium-dependent forearm vasodilation evoked with substance P (SP) as well as acetylcholine (ACh) was impaired in patients with heart failure. Forearm blood flow was measured using a strain-gauge plethysmograph and forearm vascular responses to intra-arterial infusions of ACh, SP, or sodium nitroprusside (SNP) at graded doses were examined. The drugs caused the dose-dependent increases in forearm blood flow (FBF) and the decreases in forearm vascular resistance (FVR) in patients with heart failure as well as normal subjects. However, the percent decreases in FVR by ACh were less in patients with heart failure than in normal subjects (p < 0.01). In contrast, the percent decreases in FVR by SP or SNP did not differ between the two groups. These results suggest that endothelium-dependent vasodilation of forearm resistance vessels via muscarinic receptors is specifically impaired, whereas via SP receptors, is preserved in patients with heart failure.

Arginine vasopressin attenuates phenylephrine-induced forearm vasoconstriction in men.

1. The aim of this study was to examine whether arginine vasopressin modulates the vasoconstricting action of phenylephrine in human forearms. 2. In seven healthy subjects, we determined the percentage increases in forearm vascular resistance evoked by intra-arterial infusion of phenylephrine at graded doses during simultaneous intra-arterial infusion of saline or arginine vasopressin at two doses. Similarly, in another seven subjects, we examined the effects of intra-arterial infusions of saline or angiotensin II on the vasoconstricting action of intra-arterial phenylephrine. 3. Arginine vasopressin and angiotensin II caused small, but insignificant, increases in baseline forearm vascular resistance. Arginine vasopressin at the two doses significantly attenuated the percentage increases in forearm vascular resistance evoked with phenylephrine at graded doses. Angiotensin II did not alter the forearm vascular responses to phenylephrine. 4. Intra-arterial infusion of arginine vasopressin at doses of 0.6 and 1.8 ng/min raised the plasma arginine vasopressin concentration in the venous effluents from 1.6 +/- 0.3 (control) to 4.0 +/- 0.9 and to 16.4 +/- 6.9 pg/ml, respectively. 5. These results suggest that arginine vasopressin at physiological concentrations with a minimal direct effect on resistance arteries attenuates the vasoconstricting action of phenylephrine in human forearms.