Our results suggest that NO plays a minimal role in vasodilation at peak RH but plays a modest yet significant role in maintaining vasodilation after peak vasodilation. Our results also suggest that reactive hyperemia in human forearms is caused largely by mechanisms other than NO.

The current evidence indicates that the resting activity of RVLM presympathetic neurons is determined by the balance of powerful tonic excitatory and inhibitory synaptic inputs. Ang II receptors also contribute to the raised resting activity of these neurons in some pathological conditions.

Physiological and anatomic methods were used to determine whether neurons in the rostral ventrolateral medulla (RVLM), nucleus tractus solitarius (NTS), or hypothalamic paraventricular nucleus (PVN) mediate the cardiovascular response evoked from the dorsomedial hypothalamic nucleus (DMH), which is believed to play a key role in mediating responses to stress. In urethane-anesthetized rats, activation of neurons in the DMH by microinjection of bicuculline resulted in a large increase in arterial pressure, heart rate, and renal sympathetic nerve activity. The pressor and sympathoexcitatory responses, but not the tachycardic response, were greatly reduced after bilateral muscimol injections into the RVLM even when baseline arterial pressure was maintained at a constant level. These responses were not reduced by muscimol injections into the PVN or NTS. Retrograde tracing experiments identified many neurons in the DMH that projected directly to the RVLM. The results indicate that the vasomotor and cardiac components of the response evoked from the DMH are mediated by pathways that are dependent and independent, respectively, of neurons in the RVLM.

Abstract-Angiotensin II type 1 (AT 1 ) receptors are located on pressor neurons in the rostral ventrolateral medulla, and their activation results in an increase in arterial pressure. However, the normal role of these AT 1 receptors in cardiovascular regulation is unknown. In this study, we tested the hypothesis that these receptors mediate synaptic excitation of rostral ventrolateral medullary pressor neurons in response to activation of the hypothalamic paraventricular nucleus. In anesthetized rats, microinjections of the ␥-aminobutyric acid receptor antagonist bicuculline were made into the paraventricular nucleus; this injection causes activation of the nucleus as a consequence of disinhibition. The pressor and sympathoexcitatory responses evoked by paraventricular nucleus activation were significantly reduced (by Ϸ40% to 50%) after microinjection of the specific AT 1 receptor antagonists losartan or L-158,809 into the rostral ventrolateral medulla on the ipsilateral, but not contralateral, side. These responses were reduced to a similar degree after microinjections of the neuroinhibitory compound muscimol into the ipsilateral, but not contralateral, rostral ventrolateral medulla. However, bilateral microinjections of the glutamate receptor antagonist kynurenic acid into the rostral ventrolateral medulla had no effect on the responses evoked from the paraventricular nucleus. Conversely, bilateral microinjections of kynurenic acid into the rostral ventrolateral medulla virtually abolished the somatosympathoexcitatory reflex, whereas bilateral microinjections of losartan or L-158,809 had no effect on this reflex. The results indicate that excitatory synaptic inputs to pressor neurons in the rostral ventrolateral medulla arising from activation of the paraventricular nucleus are mediated predominantly by AT 1 receptors. (Hypertension. 1999;34:1301-1307.)Key Words: angiotensin II Ⅲ blood pressure Ⅲ brain Ⅲ receptors, glutamate Ⅲ bicuculline Ⅲ blood vessels I t is well established that the rostral part of the ventrolateral medulla (RVLM) contains a group of spinally projecting sympathoexcitatory neurons that play a crucial role in the tonic and phasic regulation of sympathetic vasomotor activity and arterial blood pressure (for reviews see References 1 and 2). These neurons are a site of convergence of central pathways subserving many cardiovascular reflexes as well as responses evoked from higher brain regions. 1,2 Numerous studies have demonstrated that glutamate and ␥-aminobutyric acid (GABA) receptors play a major role in the synaptic regulation of RVLM sympathoexcitatory neurons. 1,2 There is also evidence, however, indicating that angiotensin (Ang) receptors may also play a role in the synaptic regulation of these neurons. First, studies using in vitro autoradiography have shown that there is a high density of Ang receptors in the RVLM of several mammalian species, including humans (for review see Reference 3). These receptors are predominantly Ang II type 1 (AT 1 ) receptors, and their location corresponds...

Long-term treatment with eicosapentaenoic acid (EPA) is known to improve impaired endothelium-dependent relaxations of atherosclerotic blood vessels in animals and humans. However, it remains to be determined which mechanisms are involved in this beneficial effect of EPA. In this study, we investigated our hypothesis that EPA improves both nitric oxide (NO)-mediated and non-NO-mediated endothelium-dependent vasodilatation in patients with coronary artery disease. The study included eight patients with documented coronary artery disease. The forearm vascular responses to the endothelium-dependent vasodilator acetylcholine and substance P were examined before and after intraarterial infusion of NG-monomethyl-L-arginine (L-NMMA). Same measurements were repeated after the treatment with EPA (1,800 mg/day) for 6 weeks. The long-term treatment with EPA augmented forearm blood-flow response to both acetylcholine and substance P. Furthermore, acute administration of L-NMMA significantly inhibited the EPA-induced augmented response to acetylcholine but not that to substance P. The forearm vascular response to sodium nitroprusside was unchanged by the EPA treatment. These results indicate that long-term treatment with EPA augments both NO-dependent and non-NO-dependent endothelium-dependent forearm vasodilatation in patients with coronary artery disease. Thus the beneficial effects of EPA appear to extend to non-NO-dependent mechanism(s).

Nitric oxide (NO) is shown to be synthesized in the central nervous system as well as in vascular endothelial cells. However, the physiological role of NO in cardiovascular regulation in the central nervous system remains unclear. The present study examines whether NO plays a role in the regulation of neuronal activity in the nucleus tractus solitarius (NTS). Single-unit extracellular recordings were obtained from NTS neurons in slices (400 microns) of the rat brainstem, which had spontaneous discharges at a frequency of 0.5 to 3 spikes per second. Eighty-one neurons were tested for sensitivity to L-arginine, which is the physiological precursor of NO. L-Arginine (10(-7) to 10(-4) mol/L) increased neuronal activity dose dependently in 33 (40.7%) of 81 neurons tested, but D-arginine (10(-5) mol/L) did not. The neurons that responded to L-arginine responded to glutamate as well. NG-Monomethyl-L-arginine (10(-5) to 3 x 10(-5) mol/L), an inhibitor of the formation of NO, dose-dependently blocked increases in the neuronal activity evoked with L-arginine (10(-5) mol/L). Hemoglobin (1.5 mg/L), a trapper of NO, and methylene blue (10(-5) mol/L), an inhibitor of guanylate cyclase, also blocked increases in the neuronal activity evoked with L-arginine (10(-5) mol/L). Sodium nitroprusside (SNP, 10(-5) to 10(-4) mol/L), which spontaneously produces NO, increased the neuronal activity in the neurons that responded to L-arginine. SNP did not alter the neuronal activity of the neurons that did not respond to L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Background-Rho-kinase is suggested to have an important role in enhanced vasoconstriction in animal models of heart failure (HF). Patients with HF are characterized by increased vasoconstriction and reduced vasodilator responses to reactive hyperemia and exercise. The aim of the present study was to examine whether Rho-kinase is involved in the peripheral circulation abnormalities of HF in humans with the Rho-kinase inhibitor fasudil. Methods and Results-Studies were performed in patients with HF (HF group, nϭ26) and an age-matched control group (nϭ26). Forearm blood flow was measured with a strain-gauge plethysmograph during intra-arterial infusion of graded doses of fasudil or sodium nitroprusside. Resting forearm vascular resistance (FVR) was significantly higher in the HF group than in the control group. The increase in forearm blood flow evoked by fasudil was significantly greater in the HF group than in the control group. The increased FVR was decreased by fasudil in the HF group toward the level of the control group. By contrast, FVR evoked by sodium nitroprusside was comparable between the 2 groups. Fasudil significantly augmented the impaired ischemic vasodilation during reactive hyperemia after arterial occlusion of the forearm in the HF group but not in the control group. Fasudil did not augment the increased FVR evoked by phenylephrine in the control group significantly. Conclusions-These results indicate that

Abstract-Release of free fatty acid (FFA) from adipose tissue is implicated in insulin resistance and endothelial dysfunction in patients with visceral fat obesity. We demonstrated previously that increased FFA levels cause endothelial dysfunction that is prevented by inhibition of the renin-angiotensin system (RAS) in humans. However, the mechanisms for FFA-mediated activation of RAS and the resultant endothelial dysfunction were not elucidated. We investigated effects of elevated FFA on activity of circulating and vascular RAS, angiotensin II-forming activity of leukocytes, and leukocyte activation of normotensive subjects. We showed that increased FFA levels significantly enhanced angiotensin II-forming activity in human mononuclear (mean fold increase: 3.5 at 180 minutes; Pϭ0.0016) and polymorphonuclear (2.0; Pϭ0.0012) cells, whereas parameters of the circulating and vascular RAS were not affected. We also showed that FFA caused angiotensin II-dependent leukocyte activation, which impaired endothelial function partly via increased myeloperoxidase release and presumably enhanced adhesion of leukocytes. We propose that the enhanced production of angiotensin II by FFA in mononuclear and polymorphonuclear cells causes activation of leukocytes that consequently impairs endothelial function. RAS in leukocytes may regulate the leukocyte-vasculature interaction as the mobile RAS in humans. T he levels of circulating free fatty acid (FFA), mainly originating from lipolysis in adipose tissue, are increased in patients with metabolic syndrome and type 2 diabetes mellitus, 1-3 reflecting resistance to the antilipolytic action of insulin. Increased plasma FFA concentrations cause endothelial dysfunction, 4 insulin resistance, 5 and endothelial apoptosis. 6 These observations, together with results from epidemiological studies, 7,8 suggest that FFA is involved in atherosclerosis in subjects with insulin resistance. Recently, we have found that FFA-induced endothelial dysfunction is prevented by the inhibition of the renin-angiotensin (Ang) system (RAS) in humans, 9 suggesting that RAS activation by FFA may predominantly contribute to FFA-induced endothelial dysfunction. This hypothesis appears plausible because of the close relationship between obesity and RAS activity in humans. 10,11 In addition, RAS activation is also associated with enhanced oxidative stress, 12 which is an intermediary mechanism by which FFA adversely alters vascular function. 13 However, although the proatherogenic action of excessive Ang II has been well documented, there is little information regarding the mechanism of RAS activation in individuals with obesity. Indeed, only a few studies have investigated the effects of elevated FFA on RAS activity. 14 The aim of the present study was to investigate effects of elevated FFA on RAS and to elucidate mechanisms for FFA-induced endothelial dysfunction in humans. We also investigated the interaction between FFA and leukocytes, because FFA is involved in leukocyte activation through protein kinase C re...