Endogenous methyl palmitate modulates nicotinic receptor-mediated transmission in the superior cervical ganglion

Nitric oxide (NO) is identified as the endothelium-derived relaxing factor and a neurotransmitter with a superfusion bioassay cascade technique. By using a similar technique with rat superior cervical ganglion (SCG) as donor tissue and rabbit endothelium-denuded aortic ring as detector tissue, we report here that a vasodilator, which is more potent than NO, is released in the SCG upon field electrical stimulation (FES) or addition of nicotine. Release of this vasodilator was enhanced by arginine analogs, including N^ω-nitro-l-arginine (a NO synthase inhibitor), suggesting that it is not NO. Analysis by gas chromatography/mass spectrometry identified 2 saturated fatty acids, palmitic acid methyl ester (PAME) and stearic acid methyl ester (SAME), being released from the SCG upon FES in the presence of arginine analogs. Exogenous PAME but not SAME induced significant aortic dilation (EC₅₀ = 0.19 nM), indicating that PAME is the potent vasodilator. Release of PAME and SAME was significantly diminished in chronically decentralized SCG but not denervated SCG, suggesting the preganglionic origin. Furthermore, release of both fatty acids was calcium- and myosin light chain kinase-dependent, suggesting that both were released from axoplasmic vesicular stores. Electrophysiological studies further demonstrated that PAME but not SAME inhibited nicotine-induced inward currents in cultured SCG and the α7-nicotinic acetylcholine receptor-expressing Xenopus oocytes. Endogenous PAME appears to play a role in modulation of the autonomic ganglionic transmission and to complement the vasodilator effect of NO.     

Hemodynamic assessment of prenalterol: A cardioselective beta agonist in patients with impaired left ventricular function

The hemodynamic effects of a new cardioselective beta agonist, prenalterol, were evaluated in 12 patients with moderate or severe impairment of left ventricular function due to coronary heart disease or primary cardiomyopathy. In doses up to 7 mg the drug led to a substantial increase of left ventricular pressure rise (+55%) and mean circumferential fiber shortening (+59%) and a decrease of left ventricular end-diastolic pressure (–52%), mean pulmonary artery pressure (–24%) and pulmonary vascular resistance (–37%) indicating augmented myocardial contractility and reduced left ventricular preload. Cardiac output was increased only in 4 of 12 patients, heart rate, left ventricular systolic and mean right atrial pressures and the pressure-rate product as an index for myocardial oxygen demand remained essentially unchanged. The same is true for stroke index, stroke work index, total peripheral resistance, left ventricular end-diastolic and end-systolic volume and ejection fraction. The positive inotropic effect was achieved with good tolerance and without arrhythmogenic or other side effects. Prenalterol may be especially useful in patients with low sympathetic activity and hypotension. In patients with diffuse congestive cardiomyopathy, high sympathetic activity, pronounced peripheral vasoconstriction and normal blood pressure, vasodilator therapy alone or in combination with prenalterol should be considered.     

Reverse remodeling in heart failure with intensification of vasodilator therapy

Background: Heart failure therapy with beta-receptor blockade has been shown to effect a partial reversal of left ventricular (LV) remodeling in heart failure. Hypothesis: We tested the hypothesis that, in the absence of beta blockade, uptitration of angiotensin-converting enzyme (ACE) inhibitor and nitrate therapy over conventional dosages would improve symptoms as well as LV function in patients with severe heart failure. Methods: For patients with nonischemic or ischemic cardiomyopathy, intensive high-dose angiotensin-converting enzyme inhibitor and nitrate therapy was uptitrated. Echocardiograms were obtained semiannually and evaluated in a blinded fashion. Of 99 patients in the study, aged 55 ± 13 years, with heart failure for 5.2 ± 3.1 years, 74 were men, 69 were Caucasian, and 34 had ischemic cardiomyopathy. The final dosage of enalapril was 40 ± 23 mg/day and of isosorbide dinitrate it was 153 ±127 mg/day. Results: Initial New York Heart Association classification improved from 2.8 ± 0.9 to 1.7 ± 0.9 (p<0.001) in 2.7 years of follow-up. Of the 99 patients, 72 further improved their ejection fraction. For the whole group, ejection fraction increased from 21 ± 9% to 30 ± 13% in 6 months (p>0.001), with are-duction in LV end-diastolic size from 6.6 ± 0.9 to 6.3 ± 1.0 cm (p = 0.002), and a decrease in the severity of mitral regurgitation from mild/moderate to only mild. Resting heart rate declined with no change over time in systemic systolic blood pressure. Final ejection fraction for nonischemic patients (n = 65) was 36 ± 16% versus 23 ± 9% for the ischemic population. Conclusion: Uptitration of high-dose ACE inhibitor and nitrate therapy to higher doses is well tolerated in severe heart failure, further improves both clinical status and LV systolic function, and is more effective in nonischemic than in ischemic cardiomyopathy.     

Improvement of exercise capacity after nifedipine in patients with Eisenmenger syndrome complicating ventricular septal defect.

We investigated the potential benefit of a preferential pulmonary vasodilatory effect of nifedipine in 4 patients with Eisenmenger syndrome complicating ventricular septal defect. First-pass radionuclide scan was performed at rest to measure intracardiac shunting before and after nifedipine. Two hours after 20 mg sublingual nifedipine, right-to-left shunt increased from 16.3 +/- 1.4 to 20.4 +/- 1.5% (p less than 0.05), but systemic arterial oxygen saturation (SAO2) remained steady. With 4 weeks of maintenance nifedipine therapy, resting intracardiac shunting and SAO2 were unchanged from baseline. Symptom-limited cycle ergometry was performed before and after maintenance nifedipine with placebo control. Exercise duration was prolonged (8.7 +/- 0.6 vs. 6.8 +/- 0.9 min; p less than 0.02) and SAO2 at each stage of exercise was consistently increased in all patients after nifedipine. Cardiac output and the SAO2 at peak exercise were similar. Thus, chronic nifedipine therapy increases SAO2 on exercise and improves maximal exercise capacity in patients with Eisenmenger syndrome, which is not predicted by study of resting intracardiac shunting after acute therapy.     

Effect of Xiongshao Capsule（芎芍胶囊）on the Function of Vascular Endothelium of Patients with Cervical Atherosclerosis

Objective: To study the effect of Xiongshao Capsule (芎芍胶囊, XSC), a TCM herb that can promote blood circulation to remove blood stasis, on the endothelial dependent relaxation function, serum nitric oxide (NO), and plasma endothelin-1 (ET-1) of the patients with cervical atherosclerosis. Methods: Forty patients were randomly divided into two groups: XSC group and Probucol group (western medicine control).In addition, 20 healthy people were set as a normal control group. Plasma ET-1, serum NO, the internal diameter of basal brachial artery, endothelial dependent flow mediated dilation (FMD) and non-endothelial dependent nitroglycerin induced dilation (NID) to the trial group before and after therapy and to the healthy control group were determined respectively. Results: Compared to the healthy control group, FMD of patients with atherosclerosis was damaged obviously, the serum NO level decreased, plasma ET-1 increased (P＜0.01), NID also decreased (P＜0.05), the internal diameter of basal brachial artery has no obvious difference (P＞0.05). After the patients with atherosclerosis were treated with Xiongshao Capsule for 12 weeks,FMD increased evidently, plasma ET-1 decreased, serum NO and the ratio of NO/ET-1 increased, compared with the level before therapy and Probucol group, the difference was significant (P＜0.05, P＜0.01), NIDdidn′t change obviously (P＞0.05). Conclusion: XSC could regulate vascular activity factor and improve the function of endothelial dependent vascular dilation of patients with atherosclerosis.     

Changes in plasma renin activity and haemodynamics during vasodilator therapy in conscious dogs with myocardial infarction or chronic volume overload

The aim of the study was to compare the changes in plasma renin activity induced by a vasodilator in normal dogs and in dogs with an impaired cardiac reserve. In normal conscious dogs, a 60-min nitroprusside infusion increased plasma renin activity from 1.05 +/- 0.26 to 8.35 +/- 1.20 ng, angiotensin I ml-1 h-1 (P less than 0.002) and heart rate from 83 +/- 6 to 149 +/- 15 beats/min (P less than 0.002). In five dogs in which a aortocaval fistula had been created 4 weeks earlier, the same infusion still increased plasma renin activity but significantly less than in normal dogs (0.90 +/- 0.29 to 4.44 +/- 0.64 ng ml-1 h-1; P less than 0.01) and the heart rate was unchanged (134 +/- 4 to 139 +/- 7 beats/min; NS). Similarly, in five dogs with a previous myocardial infarction, the heart rats response to nitroprusside was blunted (108 to 107 beats/min;NS) and plasma renin activity increased less than in normal dogs. Plasma renin activity also increased acutely after hydralazine administration in dogs which myocardial infarction (1.05 +/- 0.26 to 8.99 +/- 0.79 ng ml-1 h-1; P less than 0.05); after 1 week of hydralazine, plasma volume had increased from 54.9 +/- 0.9 ml kg-1 to 74.5 +/- 4.9 ml kg-1 (P less than 0.05) and plasma renin activity remained higher than control (4.66 +/- 0.66 ng ml-1 h-1; P less than 0.01). In conclusion, vasodilator therapy rapidly activates vasoconstrictor forces and fluid retention even in dogs with limited cardiac reserve. Although the regulation of plasma renin secretion appears altered in these models of heart disease, the renin response remains sufficient to seriously limit the beneficial effects of vasodilator therapy.     

Effect of Systemic Vasodilators on Internal Mammary Flow During Coronary Bypass Grafting

Background. The effect of vasodilators on acute flow in the internal mammary (IMA) is unclear. Topical vasodilators show no effect on acute flow when the distal segment of the IMA is resected. The purpose of this study was to evaluate the effect of systemic vasodilators when this segment is resected.

Methods. We studied 60 patients with proximal anterior descending coronary artery lesions in whom the left IMA was harvested for grafting to the left anterior descending coronary artery. The patients were divided into six groups (n = 10), based on which of the following agents were studied: normal saline solution, nitroglycerin, nitroprusside, dobutamine, dopexamine, and amrinone. After harvesting, the IMA was trimmed as proximally as possible (and at least 3 cm proximal to the bifurcation), and free flow was measured before any pharmacologic intervention (flow 1). Systemic infusion of one of the six agents commenced. A mean of 17 ± 3.4 minutes after infusion began, with a comparable cardiac index, a second measurement of IMA flow was taken (flow 2). Hemodynamic measurements for each flow, including blood pressure, heart rate, and cardiac output, were taken.

Results. A significant increase in IMA flow was noted for those patients receiving nitroglycerin (93.5 versus 106.8 mL/min; p = 0.025), and a significant decrease in flow was noted for those receiving nitroprusside (91.0 versus 78.2 mL/min; p = 0.042). The effects remained significant when corrected for cardiac index and compared with the normal saline solution group. No other systemic agents tested significantly affected the IMA flow (dobutamine, 83.8 versus 85.0 mL/min; dopexamine, 101.8 versus 91.4 mL/min; amrinone, 75.4 versus 79 mL/min; normal saline solution, 85.8 versus 84.6 mL/min).

Conclusions. Resection of the distal segment of the IMA and the use of intravenous nitroglycerin optimizes the flow in IMA grafts.     

DIFFERING EFFECTS OF THE VASODILATOR DRUGS, PRAZOSIN AND DIAZOXIDE ON PLASMA RENIN ACTIVITY IN THE DOG

1. The effects of intravenous (i.v.) administration of the vasodilator drugs prazosin or diazoxide on blood pressure and plasma renin activity were evaluated in the anaesthetized dog. 2. Prazosin and diazoxide both induced a rapid reduction in the mean arterial pressure to 73% and 75% of control values respectively. 3. Prazosin Iowered plasma renin activity to 62% (P < 0.025) of the control value whereas diazoxide raised plasma renin activity to 178% (P < 0.05) of the control value. 4. The combination of vasodilatation and low renin activity observed following the administration of prazosin is unique, and may have clinical significance if these factors reduce the vascular complications of hypertension.     

Antihypertensive,vasodilating, and sympatholytic activities of ofornine® in spontaneously hypertensive rats

This study of spontaneously hypertensive (SH) rats documents oral antihypertensive activity of the vasodilator Ofornine®, an anthranilamide whose effect was sustained, at least in part, by suppression of compensatory renal and neurohumoral responses. Doses of 2.5 to 100 μg/kg p.0. reduced systolic blood pressure (BP) by up to 75 mm Hg. Effect lasted 6-24 hr and did not diminish during a 16 day (25 μg/kg/day) regimen. Metoclopramide (10.0 μg/kg)and haloperidol (3.0 μg/kg) antagonized the antihypertensive effect. Antihypertensive activity was confirmed by direct (arterial cannula) monitoring where 0.001-1.O μg/kg i.v. reduced mean BP by 6-47% without tachycardia. Doses of 1-10 ag/kg i.a. reduced perfusion pressure of the SH rat hindquarters by 35-74 mm Hg. A dose of 5.0 μg/kg p.0. reduced BP and urine norepinephrine levels of SH rats by 58 mm Hg and approximately 50% without raising plasma renin activity or causing sodium retention. How- ever, Ofornine® (25 μg/kg p.0. daily for 6 days) did not affect reflex bradycardic or tachy- cardic effects of phenylephrine and sodium nitroprusside in SH rats. These and other results indicate that Ofornine@ reduces SH rat blood pressure through vasodilating and presynaptic adrenolytic activities, and that a dopaminergic mechanism may be involved.