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ABSTRACT: Statin drugs can upregulate endothelial nitric oxide (NO) synthase (eNOS) in isolated endothelial cells independent of lipid-lowering effects. We investigated the effect of short-term simvastatin administration on coronary vascular eNOS and NO production in conscious dogs and canine tissues. Mongrel dogs were instrumented under general anesthesia to measure coronary blood flow (CBF). Simvastatin (20 mg. kg(-1). day(-1)) was administered orally for 2 wk; afterward, resting CBF was found to be higher compared with control (P < 0.05) and veratrine- (activator of reflex cholinergic NO-dependent coronary vasodilation) and ACh-mediated coronary vasodilation were enhanced (P < 0.05). Response to endothelium-independent vasodilators, adenosine and nitroglycerin, was not potentiated. After simvastatin administration, plasma nitrate and nitrite (NO(x)) levels increased from 5.22 +/- 1.2 to 7. 79 +/- 1.3 microM (P < 0.05); baseline and agonist-stimulated NO production in isolated coronary microvessels were augmented (P < 0.05); resting in vivo myocardial oxygen consumption (MVO(2)) decreased from 6.8 +/- 0.6 to 5.9 +/- 0.4 ml/min (P < 0.05); NO-dependent regulation of MVO(2) in response to NO agonists was augmented in isolated myocardial segments (P < 0.05); and eNOS protein increased 29% and eNOS mRNA decreased 50% in aortas and coronary vascular endothelium. Short-term administration of simvastatin in dogs increases coronary endothelial NO production to enhance NO-dependent coronary vasodilation and NO-mediated regulation of MVO(2).
AJP Heart and Circulatory Physiology 12/2000; 279(6):H2649-57. · 3.71 Impact Factor
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ABSTRACT: Our previous study indicated that nitric oxide (NO)-dependent coronary vasodilation was impaired in conscious dogs with diabetes. Our goal was to determine whether modulation of O(2) consumption by NO is depressed in canine cardiac muscle after diabetes. Diabetes was induced by injection of alloxan (40-60 mg/kg iv), dogs were killed after diabetes was induced (4-5 wk), and the cardiac muscle from the left ventricle was cut into 15- to 30-mg slices. O(2) uptake by the muscle slices was measured polarographically with a Clark-type O(2) electrode. S-nitroso-N-acetylpenicillamine decreased O(2) consumption in normal and diabetic tissues (10(-4) M, 61 +/- 7 vs. 61 +/- 8%, P > 0.05). Bradykinin (10(-4) M)- or carbachol (CCh, 10(-4) M)-induced inhibition of O(2) consumption was impaired in diabetic tissues (51 +/- 6 vs. 17 +/- 4% or 48 +/- 4 vs. 19 +/- 3%, respectively, both P < 0.05 compared with normal). The inhibition of O(2) consumption by kininogen or kallikrein was depressed in diabetic tissues as well. In coronary microvessels from diabetic dogs, bradykinin or ACh (10(-5) M) caused smaller increases in NO production than those from normal dogs. Our results indicate that the modulation of O(2) consumption by endogenous, but not exogenous, NO is depressed in cardiac muscle from diabetic dogs, most likely because of decreased release of NO from the vascular endothelium.
AJP Heart and Circulatory Physiology 08/2000; 279(2):H520-7. · 3.71 Impact Factor
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ABSTRACT: Our previous studies uncovered an inhibitory effect of nitric oxide (NO) on leg skeletal muscle respiration in dogs at rest. The role of NO in the modulation of O2 consumption and O2 extraction in hindlimb muscle during elevated metabolic states was investigated in chronically instrumented dogs while walking and at three exercise intensities which markedly increased hindlimb blood flow. Walking resulted in increased O2 consumption by 17 +/- 4 mL min-1 and O2 extraction from 24 +/- 1 to 37 +/- 8%, with no alteration in hindlimb blood flow (BFLeg) and vascular resistance (VRLeg). Running at the highest speed (9.1 mph) resulted in an increase in BFLeg from 0.67 +/- 0.05 to 2.2 +/- 0.1 L min-1, a reduction of VRLeg and elevation of hindlimb O2 consumption from 33 +/- 3 to 226 +/- 21 mL min-1 and O2 extraction from 29 +/- 2 to 61 +/- 5%, with a decrease in leg venous PO2 from 38 +/- 1 to 25 +/- 1 mmHg. After nitro-L-arginine (NLA) (35 mg kg-1, i.v.) to inhibit endogenous NO synthesis, walking caused greater increases in hindlimb O2 consumption (29 +/- 5 mL min-1) and O2 extraction (43 +/- 1 to 60 +/- 3%) (both P < 0.05), with no significant change in BFLeg. During running at the highest speed, BFLeg was 1.9 +/- 0.1 L min-1 (P < 0. 05) and VRLeg was higher, accompanied by increases in hindlimb O2 consumption from 49 +/- 7 to 318 +/- 24 mL min-1 and O2 extraction from 41 +/- 2 to 79 +/- 4% (both P < 0.05), with a greater decrease in leg venous PO2 from 33 +/- 1 to 20 +/- 1 mmHg (P < 0.05). Similar results were found for intermediate levels of exercise. Our results indicate that NO modulates hindlimb skeletal muscle O2 extraction and O2 usage whether blood flow increased or not during exercise.
Acta Physiologica Scandinavica 04/2000; 168(4):675-86. · 2.55 Impact Factor
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ABSTRACT: Our previous studies have suggested that there is reduced nitric oxide (NO) production in canine coronary blood vessels after the development of pacing-induced heart failure. The goal of these studies was to determine whether flow-induced NO-mediated dilation is altered in coronary arterioles during the development of heart failure. Subepicardial coronary arterioles (basal diameter 80 microm) were isolated from normal canine hearts, from hearts with dysfunction but no heart failure, and from hearts with severe cardiac decompensation. Arterioles were perfused at increasing flow or administered agonists with no flow in vitro. In arterioles from normal hearts, flow increased arteriolar diameter, with one-half of the response being NO dependent and one-half prostaglandin dependent. Shear stress-induced dilation was eliminated by removing the endothelium. Arterioles from normal hearts and hearts with dysfunction but no failure responded to increasing shear stress with dilation that reached a maximum at a shear stress of 20 dyn/cm(2). In contrast, arterioles from failing hearts showed a reduced dilation, reaching only 55% of the dilation seen in vessels of normal hearts at a shear stress of 100 dyn/cm(2). This remaining dilation was eliminated by indomethacin, suggesting that the NO-dependent component was absent in coronary microvessels after the development of heart failure. Similarly, agonist-induced NO-dependent coronary arteriolar dilation was markedly attenuated after the development of heart failure. After the development of severe dilated cardiomyopathy and heart failure, the NO-dependent component of both shear stress- and agonist-induced arteriolar dilation is reduced or entirely absent.
AJP Heart and Circulatory Physiology 03/2000; 278(2):H461-8. · 3.71 Impact Factor
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ABSTRACT: In addition to regulating vascular tone, there is increasing evidence for the involvement of NO in the modulation of oxygen consumption. Our in-vitro studies indicated that exogenous and endogenous NO reduces the consumption of oxygen in isolated canine skeletal and cardiac muscle, which is probably related to its direct effect on mitochondria, i.e. cytochrome oxidase. In resting, conscious dogs, the blockade of NO synthesis results in an increase in total oxygen consumption. During exercise, there is a significant increase in the release of NO from the coronary circulation in conscious dogs, and there are greater increases in total oxygen consumption, and oxygen consumption in skeletal muscle and in the heart when NO synthesis is blocked. Our results suggest that NO plays a role in matching blood flow to tissue metabolism at rest and during exercise. The modulation of the consumption of O2 by endogenous NO in skeletal or cardiac muscle is blunted after the development of heart failure or diabetes. After heart failure, the heart switches from fatty acid to glucose metabolism, suggesting that NO also plays a role in the regulation of metabolism in the heart.
Coronary Artery Disease 08/1999; 10(5):315-20. · 1.24 Impact Factor
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ABSTRACT: The role of nitric oxide (NO) in the control of coronary blood flow (CBF) during the development of diabetes is unknown. To study this, mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and CBF. With heart rate controlled (150 beats/min), veratrine (1-10 micrograms/kg) caused dose-dependent increases in CBF; e.g., 5 mirograms/kg of veratrine increased CBF by 57 +/- 7% from 41 +/- 1.3 ml/min (P < 0.05). The dogs developed diabetes 4-5 wk after injection of alloxan (40-60 mg/kg iv, blood glucose levels were 384 +/- 18 mg/dl). After diabetes the same doses of veratrine caused smaller increases in CBF; i.e., 5 micrograms/kg of veratrine increased CBF by 32 +/- 2% (P < 0.05 compared with control) from 28 +/- 4 ml/min. ACh- and adenosine-induced coronary vasodilation were reduced after diabetes as well. In anesthetized dogs after diabetes, vagal stimulation caused smaller increases in CBF. ACh and bradykinin caused smaller increases in NO(-)(2) production in coronary microvessels from diabetic dogs. Furthermore, despite the fact that mRNA for endothelial cell NO synthase from the aorta was increased twofold with the use of Northern blotting, the protein for aortic endothelial constitutive NO synthase was reduced by 66% after diabetes, as determined by Western blotting. Our results indicate that the NO-dependent coronary vasodilation by the Bezold-Jarisch reflex is impaired in conscious dogs after diabetes. The mechanism responsible for the impaired endothelium-dependent coronary vasodilation is most likely the decreased release of NO from the endothelium.
The American journal of physiology 07/1999; 277(1 Pt 2):H268-78.
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ABSTRACT: The goal of this study was to understand the mechanisms behind the changes in plasma NOx during heart failure. Heart failure is associated with an increase in plasma nitrate levels, and yet most experimental evidence demonstrates a reduction in endothelial nitric oxide production during heart failure. Dogs were chronically instrumented for measurement of systemic hemodynamics and left ventricular (LV) dimensions. Hearts were paced at 210 bpm for 3 weeks (n = 14) and then 240 bpm for 1 week (n = 7). Hemodynamics, arterial blood gases, plasma NOx, and creatinine levels were monitored weekly. Heart failure was evidenced by cachexia, ascites, and hemodynamic alterations. Resting heart rate rose (94 +/- 6 to 135 +/- 9 bpm), and LV dP/dt fell (2810 +/- 82 to 1471 +/- 99 mm Hg/s), while LV end diastolic pressure quadrupled (5.8 +/- 0.7 to 25 +/- 0.8 mm Hg), and diastolic wall stress quadrupled (11 +/- 1.3 to 43 +/- 6.0 g/cm2, all P < 0.05). These changes occurred during a doubling in plasma NOx (5.5 +/- 1.5 to 10 +/- 1.6 microM, P < 0.05). There were no changes in plasma NOx through 3 weeks of pacing. Plasma creatinine levels increased 450% (from 0.27 +/- 0.32 to 1.21 +/- 0.63 mg%). Stimulated nitrite production by agonists in sieved coronary microvessels was unchanged after 3 weeks of pacing but was reduced after heart failure. Plasma NOx did not correlate with LV dP/dt or systolic wall stress but correlated directly with LV EDP or diastolic wall stress and inversely with cardiac work. Plasma NOx rose in direct relation to plasma creatinine levels (Y = 4.8X + 2.8, r2 = 0.84), suggesting that the rise in plasma NOx during heart failure is due to decreased renal function not increased NO production.
Nitric Oxide 10/1997; 1(5):386-96. · 3.55 Impact Factor
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ABSTRACT: The effects of exercise training on the coronary vasodilation following activation of the Bezold-Jarisch reflex were examined in conscious dogs. Mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and left circumflex coronary blood flow (CBF). With the heart rate controlled (150 bpm), veratrine (0.5 to 20 micrograms/kg) caused dose-dependent increases in CBF; eg, 5 micrograms/kg of veratrine increased CBF by 61 +/- 6% from 31 +/- 1.3 mL/min (P < .05). After exercise training, the dose-response curve of CBF in response to veratrine was shifted to the left; eg, 5 micrograms/kg of veratrine increased CBF by 101 +/- 12% (P < .05 compared with control) from 34 +/- 2.3 mL/min. The enhanced coronary vasodilation was blunted by nitro-L-arginine (NLA, 35 mg/kg). In anesthetized dogs after exercise training, electrical stimulation of the left vagus nerve caused greater increases in CBF, and NLA inhibited increases in CBF. Acetylcholine, norepinephrine, angiotensin II, and bradykinin caused greater increases in NO2- production in coronary microvessels from exercise-trained dogs compared with those from normal dogs. Our results indicate that the coronary vasodilation following activation of the Bezold-Jarisch reflex is enhanced in conscious dogs after exercise training. Since electrical stimulation of the vagus nerve caused greater coronary vasodilation and since the agonists resulted in greater increases in NO production in coronary microvessels from exercise-trained dogs, the mechanism responsible for the enhanced coronary vasodilation following activation of the Bezold-Jarisch reflex is most likely due to the increased release of NO from the endothelial cells.
Circulation Research 07/1997; 80(6):868-76. · 9.49 Impact Factor
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ABSTRACT: Our goal was to determine the role of nitric oxide (NO) on the coronary vasodilation induced by prostacyclin (PGI2) in conscious dogs.
Dogs were chronically instrumented for the measurements of coronary blood flow (CBF), left ventricular pressure (LVP), mean arterial pressure (MAP) and heart rate (HR).
Intravenous injections of PGI2 caused dose-dependent increases in CBF, and decreases in MAP and late diastolic coronary resistance (LDCR). For instance, CBF increased by 128 +/- 19% (P < 0.05) from 30 +/- 3.5 ml/min and LDCR decreased by 73 +/- 3% (P < 0.05) from 2.57 +/- 0.20 mmHg/ml/min following injection of PGI2 (1.0 microgram/kg). After infusion of nitro-L-arginine (NLA, 35 mg/kg) intravenously, the coronary vasodilation induced by PGI2 was partially attenuated. PGI2 (1.0 microgram/kg) increased CBF by 55 +/- 15% from 33 +/- 5.3 ml/min and decreased LDCR by 42 +/- 9% (both P < 0.05, compared with before NLA) from 3.29 +/- 0.39 mmHg/ml/min. Infusion of L-arginine (100 mg/kg) reversed the action of NLA. For example, PGI2 (1.0 microgram/kg) increased CBF by 115 +/- 15% from 36 +/- 6 ml/min and decreased LDCR by 68 +/- 3% from 3.02 +/- 0.36 mmHg/ml/min (both P > 0.05, compared with before NLA). Atropine (0.1 mg/kg) partially attenuated the coronary vasodilation induced by PGI2 the magnitude of which was almost identical to that by NLA. NLA or atropine also blunted the coronary vasodilation induced by acetylcholine, while the coronary vasodilation induced by nitroglycerin was not affected by NLA.
Our results indicate that the coronary vasodilation induced by PGI2 was partially attenuated by NLA or atropine, suggesting that the coronary vasodilation induced by PGI2 is due to two components: a reflex parasympathetic cholinergic vasodilation mediated by NO and a direct action of PGI2.
Cardiovascular Research 11/1996; 32(5):940-8. · 6.06 Impact Factor
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ABSTRACT: The mechanism responsible for the regulation of cardiac function by endogenous nitric oxide (NO) remains unclear. In this investigation, O2 consumption by freshly isolated myocardial muscle segments from the left ventricular free wall of canine hearts was quantified by a Clark-type O2 electrode at 37 degrees C. S-nitroso-N-acetylpenicillamine (SNAP, 9 +/- 3% to 50 +/- 8%), bradykinin (BK, 14 +/- 3% to 30 +/- 5%), or carbachol (CCh, 15 +/- 4% to 29 +/- 4%) significantly attenuated tissue O2 consumption at doses of 10(-7) to 10(-4) mol/L (mean +/- SE, P < .05). The effects of BK and CCh, but not SNAP, were blocked by 10(-4) mol/L NG-nitro-L-arginine, consistent with both BK and CCh stimulating NO biosynthesis and with SNAP decomposing to release NO, respectively. Similar doses of 8-Br-cGMP caused a respiratory inhibition, but to a lesser extent (9 +/- 2% to 14 +/- 6%). A mitochondrial uncoupler, 2,4-dinitrophenol (at 1 mmol/L), blocked the effects of 8-Br-cGMP, but not those of SNAP, BK, or CCh, suggesting that the major site of action of NO is on mitochondrial electron transport. Myocardial muscle from dogs with pacing-induced heart failure had a basal O2 consumption rate of 251 +/- 21 nmol.min-1.g-1, which was 54% higher than the rate seen in muscle from normal healthy canine hearts. The inhibitory effects of BK and CCh on O2 consumption were not observed in failing cardiac tissue, but SNAP showed an unaltered inhibitory effect. Therefore, our results indicate that NO released from microvascular endothelium by BK, stimulation of muscarinic receptors, and perhaps flow velocity may play an important physiological role in the control of cardiac mitochondrial respiration, and the loss of this regulatory function may contribute to the development of heart failure.
Circulation Research 10/1996; 79(3):381-7. · 9.49 Impact Factor
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ABSTRACT: 1. The aims of our study were to determine the role of nitric oxide (NO) in cholinergic reflex dilation of the coronary circulation in normal healthy conscious dogs and after the development of pacing-induced dilated cardiac myopathy and overt congestive heart failure. 2. Dogs were instrumented using sterile surgical techniques under general anaesthesia and allowed to fully recover. The Bezold-Jarisch reflex was stimulated by the intra-atrial injection of veratrine or the intravenous injection of PGI2, while the carotid chemoreflex was stimulated by the intracarotid injection of nicotine. Experiments were performed before and after the development of overt congestive heart failure (HF) caused by rapid left ventricular pacing for 4 weeks. 3. The release of NO, or NO-mediated vascular relaxation following administration of acetylcholine (ACh) may have little physiological significance since as ACh is released from nerve endings in vivo. Stimulation of the Bezold-Jarisch or carotid chemoreflex resulted in typical vagal cholinergic reflex coronary vasodilation, an increase in coronary blood flow and a decrease in coronary vascular resistance, which was substantially reduced following NO synthesis inhibition with nitro-L-arginine. 4. After the development of severe congestive HF, the production of NO by sieved coronary microvessels from the heart was markedly reduced accompanied by a 60-80% reduction in both the mRNA (northern blot) and protein (western blot) for endothelial NO synthase in the aorta. 5. After the development of severe pacing-induced HF, activation of the Bezold-Jarisch or carotid chemoreflex no longer resulted in coronary vasodilation due to the disappearance of NO production from the coronary circulation. 6. Therefore, cholinergic reflex coronary vasodilation is mediated by NO. Because coronary blood vessels lose the ability to produce NO after the development of HF, reflex cholinergic coronary vasodilation is markedly altered, uncovering a previously undiscovered specific defect in the integrated control of the coronary circulation in the failing heart.
Clinical and Experimental Pharmacology and Physiology 09/1996; 23(8):715-21. · 1.85 Impact Factor
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ABSTRACT: A number of reflexes participate in the control of coronary vascular resistance through activation of the sympathetic or parasympathetic nervous system. Classically, activation of vagal efferent fibers to the heart results in vasodilation due to the release of acetylcholine and activation of muscarinic receptors. Recently, we have found that activation of a number of reflexes in conscious dogs, the Bezold-Jarisch reflex and the carotid chemoreflex in particular, results in cholinergic coronary vasodilation which is blocked by an inhibitor of nitric oxide synthesis, nitro-L-arginine. After the development of pacing-induced heart failure, the cholinergic dilation subsequent to activation of the Bezold-Jarisch or carotid chemoreflex is essentially abolished, since coronary blood vessels no longer produce nitric oxide. In contrast, after brief exercise training, there is a potentiation of Bezold-Jarisch reflex-induced coronary vasodilation since exercise upregulates nitric oxide production by coronary blood vessels. Since the Bezold-Jarisch reflex may be important as a compensatory mechanism during acute myocardial infarction, and the carotid chemoreflex is the acute mechanisms responsible for ameliorating systemic hypoxemia, the role of nitric oxide in reflex cholinergic coronary vasodilation may be essential in the compensatory vascular adjustments evoked by these and other reflexes.
EXS 02/1996; 76:1-19.
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C J Smith,
D Sun,
C Hoegler,
B S Roth,
X Zhang, G Zhao,
X B Xu,
Y Kobari,
K Pritchard,
W C Sessa,
T H Hintze
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ABSTRACT: Endothelium-dependent responses are depressed in coronary and peripheral blood vessels after the onset of pacing-induced heart failure in dogs and heart failure of various etiologies in humans. The present study was designed to examine whether these responses were due to decreases in the expression of endothelial cell NO synthase (ecNOS) and cyclooxygenase-1 (COX-1). After 1 month of left ventricular pacing, 8 mongrel dogs were monitored for heart failure as defined by clinical signs and left ventricular end diastolic pressures > 25 mm Hg. Total RNA and protein were isolated from endothelial cells scraped from the thoracic aorta and analyzed by Northern and Western blotting, respectively. Blots probed with 32P-labeled cDNAs for ecNOS and COX-1 were quantified densitometrically, and results were normalized against GAPDH or von Willebrand factor (vWF). In arbitrary units, the ratios of ecNOS to GAPDH were 2.66 +/- 0.77 (mean +/- SEM, n = 17) and 1.12 +/- 0.37 (n = 6 and the ratios of COX-1 to GAPDH were 1.52 +/- 0.52 and 0.56 +/- 0.15 before and after heart failure, respectively. These represent 56% to 64% (P < .05) reductions in ecNOS and COX-1 gene expression. There was no change in the ratios of either COX-1 or ecNOS to vWF. There was also a marked reduction in ecNOS protein after heart failure, estimated at 70%. A marked reduction in nitrite production, a measure of enzyme activity, from thoracic aortas in response to stimulation by either acetylcholine or bradykinin also occurred. To determine whether ecNOS and COX-1 could be independently regulated, an orally active NO-releasing agent, CAS 936, was given to 7 normal dogs for 7 days, and aortic ecNOS and COX-1 mRNAs were analyzed. The ratio of ecNOS to GAPDH was depressed by 52% (P < .05) in aortas from these dogs, whereas the ratio of COX-1 to GAPDH was unchanged. Similar results were found when data were normalized to vWF. These results suggest that at least two endothelial vasodilator gene products are reduced in heart failure, as opposed to a selective defect in NO synthase gene expression.
Circulation Research 02/1996; 78(1):58-64. · 9.49 Impact Factor
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ABSTRACT: Nitric oxide (NO) is a vasodilator produced under normal physiologic conditions primarily by the vascular endothelium lining all blood vessels. The primary stimulus for the production of nitric oxide by the constitutive endothelial nitric oxide synthase (ECNOS, Type II) found in blood vessels is most likely the shear stress, the frictional force, caused by blood flowing through blood vessels. During exercise there is an increase in cardiac output and redistribution of blood flow to increase blood flow in skeletal muscle and in the coronary circulation. These adjustments provide increased oxygen delivery to support aerobic energy production and to sustain the exercise response. NO may be involved in the regulation of vascular tone in exercising skeletal and cardiac muscle by promoting, enhancing the metabolic vasodilation. In addition, the production of NO by capillary endothelium may regulate oxygen consumption by mitochondria through chemical interactions between NO and the iron-sulfur center of these enzymes. Finally, brief exercise training may alter the gene expression for the enzyme, the constitutive endothelial NO synthase, which forms NO and may be part of the vascular adaptation seen after aerobic exercise training. Furthermore, if there is a genetic predisposition to produce NO, as in world class athletes or animals bred to race, NO may contribute to spectacular exercise performance. These three potential roles of NO will be discussed and data presented to support each of these in our review.
Medicine & Science in Sports & Exercise 09/1995; 27(8):1125-34. · 4.43 Impact Factor
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ABSTRACT: Activation in conscious dogs of the carotid chemoreflex or cardiac receptors results in coronary vasodilation that is mediated by a vagal cholinergic mechanism. Our previous study showed that the coronary vasodilation following activation of carotid chemoreflex is also mediated by nitric oxide (NO). In addition, NO production is depressed after the development of heart failure. Therefore, we hypothesized that the coronary vasodilation after activation of reflexes that elicit efferent vagal coronary vasodilation would be blunted in conscious dogs after pacing-induced heart failure due to the disappearance of NO.
Mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and left circumflex coronary blood flow (CBF). Without the heart rate controlled, intra-atrial injection of veratrine (4 micrograms/kg) caused bradycardia (-36 +/- 3 beats per minute). With the heart rate controlled, veratrine increased CBF in a dose-dependent manner: for example, 4 micrograms/kg of veratrine increased CBF by 54 +/- 5% from 38 +/- 4.9 mL/min (P < .05). The increases in CBF induced by veratrine were markedly blunted by nitro-L-arginine (NLA). Activation of carotid chemoreflex by nicotine increased CBF by 121 +/- 9% from 32 +/- 4 mL++/min (P < .05) with the heart rate controlled and caused bradycardia (-32 +/- 5 beats per minute) without the heart rate controlled. After the development of heart failure, in response to activation of carotid chemoreflex or cardiac receptors the coronary vasodilation was almost abolished (CBF increased by only 23 +/- 8% or 11 +/- 3%, P < .05 compared with control). There still was a marked bradycardia after injections of nicotine or veratrine (-50 +/- 11 or -48 +/- 7 beats per minute).
Our results indicate that vagally mediated coronary vasodilation is selectively attenuated in conscious dogs after pacing-induced heart failure, whereas the vagally mediated bradycardia is preserved. Since muscarinic receptor-induced coronary vasodilation is mediated by NO, the disappearance of NO from blood vessels leads to a defect in the integrated neural regulation of coronary blood flow and myocardial function during heart failure.
Circulation 05/1995; 91(10):2655-63. · 14.74 Impact Factor
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ABSTRACT: The role of nitric oxide (NO) in the regulation of O2 consumption was studied in chronically instrumented conscious dogs. A specific NO synthesis inhibitor, nitro-L-arginine (NLA, 30 mg/kg i.v.), significantly increased mean arterial pressure from 100 +/- 4 to 134 +/- 5 mm Hg (mean +/- SEM) and total peripheral resistance by 157 +/- 16% and reduced cardiac output by 47 +/- 3% and heart rate by 34 +/- 6% after 120 minutes. Changes in arterial blood gases were not observed. There were significant changes in PO2 (-14 +/- 2 mm Hg), O2 saturation (-21 +/- 2%), the percentage of hemoglobin as oxyhemoglobin (-21 +/- 2%), and O2 content (-3.0 +/- 0.9 vol%) and a significant increase in percent reduced hemoglobin (21 +/- 1%) in mixed venous blood, associated with an increase in O2 extraction (5.1 +/- 0.2 vol%) (all P < .01). O2 consumption was increased from 124 +/- 6 to 155 +/- 9 mL/min (P < .05). Methoxamine, titrated to have hemodynamic effects similar to those of NLA (eg, mean arterial pressure increased from 97 +/- 4 to 131 +/- 5 mm Hg), had much smaller effects on venous blood gases, hemoglobin, and O2 extraction (2.3 +/- 0.7 vol%) and no significant effect on O2 consumption. NLA also caused an increase in O2 consumption of 37 +/- 8% (P < .01) in quietly resting conscious dogs that had undergone pretreatment with hexamethonium and atropine, but no significant change in O2 consumption in dogs anesthetized with barbiturate.(ABSTRACT TRUNCATED AT 250 WORDS)
Circulation Research 01/1995; 75(6):1086-95. · 9.49 Impact Factor
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ABSTRACT: The mechanism of action of nitrates, compounds that have been used classically in the treatment of heart failure, appears to be the stimulation of guanylate cyclase in vascular smooth muscle, perhaps the same physiologic action as endothelium-derived relaxing factor, now thought to be synonymous with nitric oxide (NO). Drugs that release NO either inside cells or in plasma have been developed recently. One such compound, CAS 936, when taken orally, is converted to an active metabolite, 3754. The goal of our studies was to determine the effects of CAS 936 and 3754 on cardiovascular function in conscious dogs before and after the development of pacing-induced heart failure. CAS 936 (10 mg/kg, p.o.) increased large coronary artery diameter 9.1 +/- 1.2% and reduced left ventricular end diastolic pressure (LVEDP) 2.5 +/- 0.5 mm Hg, but had no significant effects on coronary blood flow or vascular resistance. The metabolite 3754 caused dose-related increases in coronary artery diameter, and large reductions in LVEDP. The effect of these compounds on large coronary artery diameter was significantly greater (p < 0.05) than that of nitroglycerin (25 micrograms/kg). After heart failure, both CAS 936 and 3754 caused significant increases in large coronary artery diameter (10%) and a reduction in preload, up to 10 mm Hg, which was even larger than in normal dogs. Thus, these NO-releasing agents are potent selective large-vessel dilators that also reduce preload and maintain this unique vasodilator profile even in the failing heart.
Journal of Cardiovascular Pharmacology 01/1993; 22 Suppl 7:S51-8. · 2.29 Impact Factor
