Growth factors prevent changes in Bcl-2 and Bax expression and neuronal apoptosis induced by nitric oxide.
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Recent studies have shown that nitric oxide (NO) donors can trigger apoptosis of neurons, and growth factors such as insulin-like growth factor-1 (IGF-1) and basic fibroblast growth factor (bFGF) can protect against NO-induced neuronal cell death. The purpose of this study was to elucidate the possible mechanisms of NO-mediated neuronal apoptosis and the neuroprotective action of these growth factors. Both IGF-1 and bFGF prevented apoptosis induced by NO donors, sodium nitroprusside (SNP) or 3-morpholinosydnonimin (SIN-1) in hippocampal neuronal cultures. Incubation of neurons with SNP induced caspase-3-like activation following downregulation of Bcl-2 and upregulation of Bax protein levels in cultured neurons. Treatment of neurons with a bax antisense oligonucleotide inhibited the caspase-3-like activation and neuronal death induced by SNP. In addition, treatment of neurons with an inhibitor of caspase-3, Ac-DEVD-CHO, together with SNP did not affect the changes in the protein levels, although it inhibited NO-induced cell death. Pretreatment of cultures with either IGF-1 or bFGF prior to NO exposure inhibited caspase-3-like activation together with the changes in Bcl-2 and Bax protein levels. These results suggest that the changes in Bcl-2 and Bax protein levels followed by caspase-3-like activation are a component in the cascade of NO-induced neuronal apoptosis, and that the neuroprotective actions of IGF-1 and bFGF might be due to inhibition of the changes in the protein levels of the Bcl-2 family. (+info)
In vitro nitric oxide effects on basal and gonadotropin-releasing hormone-induced gonadotropin secretion by pituitary gland of male crested newt (Triturus carnifex) during the annual reproductive cycle.
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The objective of this study was to test the possible nitric oxide (NO) involvement in pituitary gonadotropin secretion in the male crested newt, Triturus carnifex. Pituitaries were incubated in vitro with medium alone, GnRH, NO donor (NOd, sodium nitroprusside), NO synthase inhibitor (NOSi, Nomega-nitro-L-arginine methyl ester), cGMP analogue (cGMPa, 8-bromo-cGMP), soluble guanylate cyclase inhibitor (sGCi, cystamine), GnRH plus NOSi, GnRH plus sGCi, and NOd plus sGCi during the annual reproductive cycle: pre-reproduction, reproduction (noncourtship and courtship), and the refractory, recovery, and estivation periods. To determine pituitary gonadotropin secretion indirectly, newt testes were superfused in vitro with preincubated pituitaries, and androgen release was determined. NO synthase (NOS) activity and cGMP levels were assessed in the preincubated pituitaries. Medium alone- and GnRH-preincubated pituitary increased androgen secretion during pre-reproduction, noncourtship, courtship, and recovery; the GnRH-induced increase was higher than the medium alone-induced increase during pre-reproduction, noncourtship, and recovery. NOd and cGMPa increased androgens in all reproductive phases considered except courtship; the NOd- and cGMP-induced increase was higher than the medium alone-induced increase during pre-reproduction, noncourtship, and recovery. NOS activity was highest during courtship and lowest during the refractory and estivation periods. GnRH increased NOS activity during pre-reproduction, noncourtship, and recovery. Cyclic GMP levels were highest during courtship and lowest during the refractory period and estivation. GnRH increased cGMP levels during pre-reproduction, noncourtship, and recovery, while NOd did so during all reproductive phases considered. These results suggest that basal and GnRH-induced gonadotropin secretion are up-regulated by NO in the pituitary gland of the male Triturus carnifex. (+info)
Relationship between left ventricular mass and endothelium-dependent vasodilation in never-treated hypertensive patients.
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BACKGROUND: Hypertensive patients are characterized by development of both left ventricular hypertrophy (LVH) and endothelial dysfunction METHODS AND RESULTS: We enrolled 65 never-treated hypertensive patients (36 men and 29 women aged 45.6+/-6.0 years) to assess the possible relationship between echocardiographic left ventricular mass (LVM) and endothelium-dependent vasodilation. Left ventricular measurements were performed at end diastole and end systole according to the recommendations of the American Society of Echocardiography and the Penn Convention. LVM was calculated with the Devereux formula and indexed by body surface area and height raised to the 2.7th power. The endothelial function was tested as responses of forearm vasculature to acetylcholine (ACh), an endothelium-dependent vasodilator (7.5, 15, and 30 microg. mL-1. min-1, each for 5 minutes), and sodium nitroprusside (SNP), an endothelium-independent vasodilator (0.8, 1.6, and 3.2 microg. mL-1. min-1, each for 5 minutes). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by strain-gauge plethysmography. A negative significant relationship between indexed LVM and peak of increase in FBF was found during ACh infusions (r=-0. 554; P<0.0001). In addition, hypertrophic patients had a significantly lower responsive to ACh than patients without LVH (the peak increase in FBF was 9.9+/-3.7 versus 16.1+/-8.1 mL per 100 mL of tissue per minute; P<0.0001). No significant correlation was observed between LVM and FBF during SNP infusion. CONCLUSIONS: Our data provide the first evidence that echocardiographic LVM in hypertensive patients is inversely related to FBF responses to the endothelium-dependent vasodilating agent ACh, but it is likely that both endothelium and LVM are damaged by hypertension. (+info)
Lisinopril improves arterial function in hyperlipidaemia.
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Endothelial function is defective in hypercholesterolaemia, and animal models have suggested that angiotensin-converting enzyme inhibitors may prevent arterial damage. We studied the effect of 6 months treatment with lisinopril on endothelial function in a group of patients with hypercholesterolaemia. Forty patients were studied. Forearm blood flow responses to acetylcholine and sodium nitroprusside were assessed by venous occlusion plethysmography. Subjects were then randomized in a double-blind fashion to receive either lisinopril, 20 mg/day (n=20), or placebo (n=20) for 6 months. Plethysmography was then repeated. Baseline variables between groups were comparable. In the lisinopril group blood pressure fell significantly [systolic: 145+/-4 to 128+/-4 mmHg (P<0.001); diastolic: 84+/-2 to 74+/-2 mmHg (P<0.001)]. An improvement was found in the vasodilatory response (expressed as a ratio of the infused/control arm) to acetylcholine, e.g. 3.33+/-0.3 (pre) versus 4.45+/-0.48 (post) at 30 microg/ml (P<0.03), and also to nitroprusside, e.g. 3.0+/-0.2 (pre) versus 3.86+/-0.3 (post) at 3.2 microg/ml (P<0.01). In the placebo group vasodilatation did not change significantly in response to acetylcholine, and nitroprusside responses were unchanged. The data presented suggest that 6 months of lisinopril therapy have a beneficial effect on arterial function in subjects with hyperlipidaemia. Further work should now investigate whether angiotensin-converting enzyme inhibitors are beneficial in reducing mortality and morbidity in hypercholesterolaemia. (+info)
Mechanisms of melatonin-induced vasoconstriction in the rat tail artery: a paradigm of weak vasoconstriction.
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1. Vasoconstrictor effects of melatonin were examined in isolated rat tail arteries mounted either in an isometric myograph or as cannulated pressurized segments. Melatonin failed by itself to mediate observable responses but preactivation of the arteries with vasopressin (AVP) reliably uncovered vasoconstriction responses to melatonin with maxima about 50% of maximum contraction. Further experiments were conducted with AVP preactivation to 5-10% of the maximum contraction. 2. Responses to melatonin consisted of steady contractions with superimposed oscillations which were large and irregular in isometric but small in isobaric preparations. Nifedipine (0.3 microM) reduced the responses and abolished the oscillations. Charybdotoxin (30 nM) increased the magnitude of the oscillations with no change in the maximum response. 3. Forskolin (0.6 microM) pretreatment increased the responses to melatonin compared to control and sodium nitroprusside (1 microM) treated tissues. The AVP concentration required for preactivation was 10 fold higher than control in both the forskolin and nitroprusside treated groups. 4. In isometrically-mounted arteries treated with nifedipine, melatonin receptor agonists had the potency order 2-iodomelatonin > melatonin > S20098 > GR196429, and the MT2-selective antagonist luzindole antagonized the effects of melatonin with a low pK(B) of 6.1+/-0.1. 5. It is concluded that melatonin elicits contraction of the rat tail artery via an mt1 or mt1-like receptor that couples via inhibition of adenylate cyclase and opening of L-type calcium channels. Calcium channels and charybdotoxin-sensitive K channels may be recruited into the responses via myogenic activation rather than being coupled directly to the melatonin receptors. 6. It is proposed that the requirement of preactivation for overt vasoconstrictor responses to melatonin results from the low effector reserve of the melatonin receptors together with the tail artery having threshold inertia. Potentiative interactions between melatonin and other vasoconstrictor stimuli probably also result from the threshold inertia. A simple model is presented and a general framework for consideration of interactions between weak vasoconstrictor agonists and other vasoconstrictor stimuli is discussed. (+info)
Inhibitory effect of 4-aminopyridine on responses of the basilar artery to nitric oxide.
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1. Voltage-dependent K+ channels are present in cerebral arteries and may modulate vascular tone. We used 200 microM 4-aminopyridine (4-AP), thought to be a relatively selective inhibitor of voltage-dependent K+ channels at this concentration, to test whether activation of these channels may influence baseline diameter of the basilar artery and dilator responses to nitric oxide (NO) and cyclic GMP in vivo. 2. Using a cranial window in anaesthetized rats, topical application of 4-AP to the basilar artery (baseline diameter = 240+/-5 microm, mean +/- s.e.mean) produced 10+/-1% constriction. Sodium nitroprusside (a NO donor), acetylcholine (which stimulates endothelial release of NO), 8-bromo cyclic GMP (a cyclic GMP analogue), cromakalim (an activator of ATP-sensitive K+ channels) and papaverine (a non-NO, non-K+ channel-related vasodilator) produced concentration-dependent vasodilator responses that were reproducible. 3. Responses to 10 and 100 nM nitroprusside were inhibited by 4-AP (20+/-4 vs 8+/-2% and 51+/-5 vs 33+/-5%, respectively, n=10; P<0.05). Responses to acetylcholine and 8-bromo cyclic GMP were also partially inhibited by 4-AP. In contrast, 4-AP had no effect on vasodilator responses to cromakalim or papaverine. These findings suggest that NO/cyclic GMP-induced dilator responses of the basilar artery are selectively inhibited by 4-aminopyridine. 4. Responses to nitroprusside were also markedly inhibited by 10 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (an inhibitor of soluble guanylate cyclase; 16+/-4 vs 1+/-1% and 44+/-7 vs 7+/-1%; n=10; P<0.05). 5. Thus, dilator responses of the rat basilar artery to NO appear to be mediated by activation of soluble guanylate cyclase and partially by activation of a 4-aminopyridine-sensitive mechanism. The most likely mechanism would appear to be activation of voltage-dependent K+ channels by NO/cyclic GMP. (+info)
Renal hemodynamic effects of L-arginine and sodium nitroprusside in heart transplant recipients.
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BACKGROUND: Long-term treatment with cyclosporine A (CsA) induces vasoconstriction in the kidney and causes renal impairment. An altered L-arginine (L-Arg)/nitric oxide (NO) pathway may play a key role in CsA nephrotoxicity. METHODS: We studied the effect of L-Arg (dosage, 17 mg/kg/min over 30 min), the precursor of NO synthesis, and sodium nitroprusside (SNP; dosage, 1.0 microgram/kg/min over 30 min) on renal hemodynamics in a double-blind, placebo-controlled, randomized, three-way cross-over study comprising 12 stable cardiac transplant recipients on long-term CsA treatment, 10 patients with chronic nephropathy not receiving CsA, and 13 healthy controls. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured by paraaminohippurate (PAH) and the inulin clearance method, respectively. RESULTS: In healthy subjects, L-Arg induced an increase in RPF (P = 0.009) and GFR (P = 0.001). By contrast, L-Arg did not induce renal hemodynamic effects in heart transplant patients or patients with chronic nephropathy. SNP reduced RPF (P = 0.050) and GFR (P = 0.005) in patients with chronic nephropathy but did not affect renal hemodynamics in heart transplant recipients or in healthy subjects. CONCLUSIONS: These data indicate that L-Arg cannot be used to reverse CsA-induced renal vasoconstriction in heart transplant recipients under long-term CsA treatment, although these patients have a normal renal response to SNP. (+info)
Exercise training does not alter acetylcholine-induced responses in isolated pulmonary artery from rat.
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In chronic exercise-trained animals, acetylcholine (ACh)-stimulated endothelial nitric oxide (NO) release is enhanced in the systemic circulation. The purpose of the present study was to determine whether chronic exercise training also enhances NO-mediated relaxation in rat pulmonary artery. Sprague-Dawley rats were randomly divided into groups of exercise-trained and sedentary control rats. The exercise-trained rats ran on a motor-driven treadmill at 30 m x min(-1) up a 15 degree incline 10-60 min x day(-1), 5 days per week for 10 weeks, and had less body weight, lower serum total cholesterol and triglyceride levels than sedentary rats. Contraction induced by potassium chloride and prostaglandin (PG)F2alpha were similar between isolated conduit pulmonary arterial rings from sedentary and exercise-trained rats. There were no differences between PGF2alpha-precontracted rings from sedentary and exercise trained rats in both ACh and sodium nitroprusside-induced relaxations. The NO synthase inhibitor, nitro-L-arginine, suppressed ACh-induced relaxation in both sedentary and exercise-trained rats. These results suggested chronic exercise training did not alter the acetylcholine-induced endothelial NO production and release and the sensitivity of vascular smooth muscle cell to NO in isolated conduit pulmonary artery of rat. (+info)