Reduced Mean Systemic Arterial Pressure Research Articles

Pulmonary Hemodynamic Responses to Intravenous Prostaglandin E2 in Broiler Chickens

Prostaglandin E(2) (PGE(2)) affects pulmonary arterial pressure (PAP), pulmonary vascular resistance (PVR), and respiratory rate (RR) in mammals, but no information previously was available regarding avian pulmonary responses to PGE(2). Two experiments were conducted in which 45- to 55-d-old male broiler chickens were infused i.v. with PGE(2) at the lowest rate (30 mug/min for 4 min) that reliably reduced PAP during pilot studies. When compared with preinfusion (control) values in experiment 1, PGE(2) reduced PAP from 19 +/- 1 to 16 +/- 1 mmHg (P < 0.001) and reduced mean systemic arterial pressure from 111 +/- 6 to 81 +/- 5 mmHg (P < 0.001) but did not significantly reduce heart rate (HR; control: 338 +/- 9 beats/min; PGE(2): 320 +/- 12 beats/min; P > 0.05). Infusing PGE(2) also reduced the RR from 57 +/- 2 to 46 +/- 4 breaths/min (P < 0.001) and reduced the percentage saturation of hemoglobin with oxygen (%HbO(2)) from 85 +/- 2 to 77 +/- 3%HbO(2) (P < 0.001). After the PGE(2) infusion ceased, the PAP, mean systemic arterial pressure, RR, and %HbO(2) recovered within 8 min to levels that did not differ from preinfusion control values. In experiment 2, an ultrasonic flow probe was surgically implanted on 1 pulmonary artery to measure cardiac output (CO). When compared with preinfusion control values, PGE(2) reduced CO from 140 +/- 6 to 111 +/- 5 mL/kg of BW x min (P < 0.001), reduced PAP from 25 +/- 2 to 21 +/- 1 mmHg (P < 0.001), and reduced RR from 49 +/- 4 to 35 +/- 4 breaths/min (P < 0.001). The reduction in CO was caused by a reduction in HR from 305 +/- 9 to 260 +/- 9 beats/min without a significant reduction in stroke volume (control: 0.46 +/- 0.02 mL/kg of BW x beat; PGE(2): 0.43 +/- 0.02 mL/kg of BW x beat; P = 0.158). After the PGE(2) infusion ceased the CO, PAP, RR, and HR recovered within 9 min to levels that did not differ from preinfusion control values. The PVR, calculated as PAP/CO, was not altered by PGE(2) (control: 0.18 +/- 0.01 relative resistance units; PGE(2): 0.20 +/- 0.02 relative resistance units; P > 0.723). These results indicate that in broilers PGE(2) reduced PAP by reducing CO rather than by acting as a pulmonary vasodilator to lower PVR. The PGE(2)-induced reductions in PAP would benefit broilers that are susceptible to pulmonary hypertension syndrome by reducing their right ventricular overload; however, the reductions in CO and RR combined with the onset of systemic arterial hypoxemia would accelerate the pathophysiological progression leading to terminal pulmonary hypertension syndrome.

Effects of zaprinast and dissolved nitric oxide on the pulmonary circulation of fetal sheep.

This study was designed to determine indirectly if the changes in ovine fetal pulmonary vascular tone caused by i.v. injections of nitric oxide-containing solutions are mediated by cGMP. We first characterized the dose-response relationship of bolus intrapulmonary injections of zaprinast (a cGMP-selective phosphodiesterase inhibitor) and nitric oxide solutions. Injections of nitric oxide solutions as well as zaprinast solutions resulted in dose-dependent decreases in pulmonary arterial pressure that were greater than reductions in systemic arterial pressure. We also evaluated the effects of simultaneous infusions of zaprinast and U46619 (a thromboxane mimetic) on the response to bolus injections of 1.0 micrograms of acetylcholine, 100 ng of endothelin-1, and 10.0 microL of ethanol saturated with nitric oxide. Zaprinast was infused at a rate of 1.5 mg/min, and the concentration of U46619 was titrated to raise mean left pulmonary arterial pressure (LPAP) to the steady state level that was present before infusing zaprinast. All bolus injections reduced left pulmonary arterial pressure more than they reduced mean systemic arterial pressure. However, neither the response magnitudes nor the response durations were affected by simultaneous infusions of zaprinast and U46619. We therefore suggest that modulation of fetal pulmonary vascular tone by endogenously produced nitric oxide may involve mechanisms other than raising smooth muscle cytoplasmic cGMP concentrations.

Coronary Vascular Effects of Endothelin-1 During Arterial Hypotension

Endothelin-1 (ET-1) effects on left circumflex coronary artery (LCCA) flow, systemic arterial pressure, heart rate, and left ventricle (LV) pressure and dP/dt were recorded in five anesthetized goats under control conditions and during arterial hypotension. Hypotension, induced by mechanical constriction of the inferior vena cava, reduced mean systemic arterial pressure from 92 +/- 4 to 59 +/- 4 mm Hg (p < 0.002), LCCA flow from 26 +/- 4 to 17 +/- 3 ml/min (p < 0.01), systolic LV pressure from 108 +/- 2.5 to 79 +/- 2 mm Hg (p < 0.002), and peak systolic LV dP/dt from 1,500 +/- 106 to 990 +2- 130 mm Hg/s (p < 0.02). Heart rate did not change (p > 0.05). ET-1 (0.01-0.1 nmol) injected into LCCA reduced LCCA flow in a dose-dependent manner without affecting the other variables recorded during control periods (C) and hypotension (H). The percentage reductions of LCCA flow by ET-1 were: for 0.01 nmol, 4.5 +/- 2 (C) vs. 11 +/- 2 (H) (p < 0.05); for 0.03 nmol, 15 +/- 2 (C) vs. 32 +/- 4 (H) (p < 0.05); and for 0.1 nmol, 44 +/- 5 (C) vs. 67 +/- 5 (H) (p < 0.05). This indicates that the coronary vasoconstrictor effects of ET-1 are increased during hypotension. Therefore, heart ischemia may be aggravated in situations of arterial hypotension with increased plasma concentrations of ET-1.

Coronary Vascular Effects of Endothelin-1 During Arterial Hypotension

Summary: Endothelin-1 (ET-1) effects on left circumflex coronary artery (LCCA) flow, systemic arterial pressure, heart rate, and left ventricle (LV) pressure and dP/dt were recorded in five anesthetized goats under control conditions and during arterial hypotension. Hypotension, induced by mechanical constriction of the inferior vena cava, reduced mean systemic arterial pressure from 92 ± 4 to 59 ± 4 mm Hg (p < 0.002), LCCA flow from 26 ± 4 to 17 ± 3 ml/min (p < 0.01), systolic LV pressure from 108 ± 2.5 to 79 ± 2 mm Hg (p < 0.002), and peak systolic LV dP/dt from 1,500 ± 106 to 990 ± 130 mm Hg/s (p < 0.02). Heart rate did not change (p > 0.05). ET-1 (0.01–0.1 nmol) injected into LCCA reduced LCCA flow in a dose-dependent manner without affecting the other variables recorded during control periods (C) and hypotension (H). The percentage reductions of LCCA flow by ET-1 were: for 0.01 nmol, 4.5 ± 2 (C) vs. 11 ± 2 (H) (p < 0.05); for 0.03 nmol, 15 ± 2 (C) vs. 32 ± 4 (H) (p < 0.05); and for 0.1 nmol, 44 ± 5 (C) vs. 67 ± 5 (H) (p < 0.05). This indicates that the coronary vasoconstrictor effects of ET-1 are increased during hypotension. Therefore, heart ischemia may be aggravated in situations of arterial hypotension with increased plasma concentrations of ET-1.

Analysis of responses to substance P in the pulmonary vascular bed of the cat.

Responses to substance P were investigated in the pulmonary vascular bed of the cat with controlled pulmonary blood flow and constant left atrial pressure. Under baseline conditions, intralobar injections of substance P caused small, inconsistent reductions in lobar arterial pressure (AP) and significant reductions in mean systemic AP without affecting left atrial pressure. Decreases in lobar AP were significant and dose related when lobar vascular resistance was increased with U-46619, a thromboxane A2 mimetic. When compared with other vasodilator agents, the order of potency was substance P approximately bradykinin > pituitary adenylate cyclase activating polypeptide (PACAP) > acetylcholine (in nmol). Pulmonary vasodilator responses to substance P were unchanged by administration of atropine, glibenclamide, or sodium meclofenamate or when airflow to the left lower lung lobe was interrupted by bronchial occlusion. The NO synthesis inhibitor, N omega-nitro-L-argininemethyl ester (L-NAME), and the soluble guanylate cyclase inhibitor, methylene blue (MB), selectively inhibited pulmonary vasodilator responses to substance P and to acetylcholine. MB or L-NAME had no significant effect on pulmonary vasodilator responses to albuterol, lemakalim, or PACAP, whereas MB inhibited and L-NAME enhanced vasodilator responses to NO and sodium nitroprusside. The present investigation demonstrates that, when tone is increased experimentally, substance P has potent pulmonary vasodilator activity, and responses are not dependent on changes in bronchomotor tone, on the activation of muscarinic receptors or ATP-sensitive K+ channels, or on the release of a dilator prostaglandin but do involve, at least in part, endothelium-derived NO release and soluble guanylate cyclase activation.

METABOLIC EFFECTS OF SODIUM NITROPRUSSIDE ON THE PIG KIDNEY IN VIVO: STUDIES BY PHOSPHORUS-31 MAGNETIC RESONANCE SPECTROSCOPY

Phosphorus-31 magnetic resonance spectroscopy was applied to the pig kidney in vivo to determine the metabolic effects of infusion of sodium nitroprusside, and of more severe hypotension produced by venesection or halothane. Sodium nitroprusside 7-20 micrograms kg-1 min-1 reduced mean systemic arterial pressure (AP) of the pig from 89 to 46 mm Hg. Glomerular filtration rate and total sodium reabsorption were reduced proportionally. Renal metabolism, assessed by the ratio [ATP]: [Pi] (inorganic phosphate), did not change. Adding halothane or venesection to nitroprusside hypotension caused a further reduction in systemic AP to 42 and 39 mm Hg, respectively. Renal [ATP] decreased in direct proportion to mean AP. It is concluded that sodium nitroprusside, even in high doses, does not reduce renal oxygen delivery as assessed by the ability of the kidney to maintain normal ATP content. However, haemorrhage or an increase in halothane dosage results in irreversible damage to the energy producing processes of the kidney. This may be relevant to the clinical use of the drug.

Effects of nicorandil on left ventricular hemodynamics and volume at rest and during exercise-induced angina pectoris

The hemodynamic effects of nicorandil (20 mg) were compared with placebo in a double-blind study of 20 patients with angiographically proved coronary artery disease at rest before and 7, 15, 30 and 60 minutes after oral dosing. The impact of the drug on left ventricular (LV) hemodynamics and volume during exercise-induced angina was determined by repeating exercise 60 minutes after drug administration, at the same work load that reliably induced angina during control predrug exercise. At rest, nicorandil reduced all components of systemic arterial pressure without change in cardiac or stroke volume indexes or heart rate. Pulmonary artery occluded pressure was reduced without change in LV ejection fraction or systemic vascular resistance index. Effects were evident at 7 minutes and peaked at 30 minutes with attenuation at 60 minutes. Compared with control supine bicycle exercise, the drug (at 60 minutes) reduced mean systemic arterial pressure and LV filling pressure without change in cardiac stroke volume indexes and heart rate. There was a smaller increase in LV ejection fraction. These data suggested greatest impact on LV function during exercise when substantial decreases in filling pressure occurred at maintained cardiac pumping indexes.

Kinetics of pulmonary platelet deposition and clearance during thrombin-induced microembolism in rabbits.

Using 111In-labeled autologous platelets, we studied the kinetics of pulmonary platelet deposition and clearance in relation to hemodynamic and structural events during thrombin-induced pulmonary microembolism in rabbits. Autologous platelets were radiolabeled and returned to animals prior to infusion of thrombin (100 units/kg over 15 min) (n = 20) or saline (n = 6). All animals were pretreated with tranexamic acid, an inhibitor of fibrinolysis. Thrombin-treated animals manifested progressive increases in mean pulmonary platelet activity, reaching a maximum of 38% above baseline (p less than .0001), whereas no change was observed in saline-treated controls. Animals that died during, or immediately following, thrombin infusion manifested significantly greater increases in pulmonary platelet uptake (mean 1.55 +/- 0.47 times baseline), compared to surviving animals (1.14 +/- 0.16; p less than .05 survivors vs. nonsurvivors). In surviving animals, following cessation of thrombin, pulmonary platelet activity cleared gradually, with a half-time of approximately 12 min. Thrombin reduced circulating platelet counts (p less than .001), increased mean pulmonary artery pressure (13 +/- 3 mm Hg to 18 +/- 6 mm Hg; p less than .0001), and reduced mean systemic arterial pressure (55 +/- 10 mm Hg to 44 +/- 7 mm Hg; p less than .001). The time courses of these events approximated that of thrombin-induced pulmonary platelet uptake. Furthermore, the increase in pulmonary artery pressure occurred predominantly in the group of animals in which the increase in pulmonary radiolabeled platelet activity exceeded the median value of 20%. Postmortem histology showed extensive pulmonary thrombus extending from small arterial to capillary levels in animals that died during, or immediately following, thrombin infusion, but not in surviving animals. Our findings suggest that platelet aggregation plays an important role in the pathogenesis of hemodynamic change following thrombin-induced pulmonary embolization.

Indoramin in heart failure: possible adverse effects on hemodynamics and exercise capacity.

Indoramin is an alpha 1-adrenergic antagonist vasodilator of potential value in heart failure. We measured hemodynamics and exercise capacity in 12 patients with heart failure, before and after 1 week of indoramin dosing, 75 mg b.i.d. Maximal hemodynamic effects 2 hours after the first dose of indoramin consisted of reduced mean systemic arterial pressure from 96.0 +/- 15.3 to 87.9 +/- 15.3 mm Hg (P less than 0.05) and pulmonary wedge pressure from 23.6 +/- 7.8 to 16.9 +/- 6.6 mm Hg (P less than 0.001). Heart rate, cardiac index, and total systemic resistance did not change acutely after indoramin, but after 1 week mean systemic arterial pressure was still reduced whereas cardiac index fell from 2.69 +/- 0.38 to 2.32 +/- 0.44 L/min/m2 (P less than 0.05) and total systemic resistance rose from 20.4 +/- 2.8 to 21.9 +/- 4.0 U (P less than 0.1). After 1 week maximal exercise oxygen uptake fell from 16.8 +/- 5.6 to 12.5 +/- 3.5 ml/min/kg (P less than 0.02). This limited observation suggests that indoramin is a predominant venodilator acutely in patients with heart failure but that despite this effect it may worsen functional capacity and hemodynamics during continuous dosing in these patients.

Effects of buccal nitrate on left ventricular haemodynamics and volume at rest and during exercise-induced angina.

A novel approach has been employed to characterize the effects of a cardioactive drug on left ventricular haemodynamics and volume by simultaneously determining cardiac stroke volume (thermodilution) and left ventricular ejection fraction (nuclear probe). The effects of glyceryl trinitrate were evaluated in 12 patients with angiographically proven coronary artery disease at rest and 3, 7, 15 and 30 min following 10 mg buccal nitroglycerin (Suscard) administration. The impact of the drug on left ventricular haemodynamics and volume during exercise-induced angina was determined by repeating exercise 30 min following drug administration, at the workload that reliably induced angina during control exercise. At rest buccal nitroglycerin reduced systemic arterial pressure, cardiac and stroke volume indices, and increased heart rate. The left ventricular ejection fraction (E.F.) increased; its filling pressure together with end-diastolic and end-systolic volumes were significantly reduced. Compared with control supine-bicycle exercise, the drug reduced mean systemic arterial pressure and left ventricular filling pressure without change in cardiac and stroke volume indices. There was a smaller increase in left ventricular volume during exercise, and the fall in E.F. was attenuated. These data demonstrated differential actions of glyceryl trinitrate on left ventricular function related to the physiological state in obstructive coronary artery disease. These techniques appear to hold promise in the evaluation of the effects of other therapies on left ventricular volume in coronary artery disease.

Hemodynamic effects of nifedipine versus hydralazine in primary pulmonary hypertension

The acute hemodynamic effects of both sublingual nifedipine (N) and intravenous hydralazine (Hy) were studied in 5 patients with primary pulmonary hypertension to ascertain whether the capacity for pulmonary vasodilatation was generalized or drug-specific, and to determine which of the 2 agents had preferential pulmonary vasodilatory effects. For the group as a whole, neither N nor Hy produced changes in heart rate, mean pulmonary capillary wedge or right atrial pressures. Both N and Hy reduced mean systemic arterial pressure (before N 90 ± 8 mm Hg, after N 76 ± 7 mm Hg, p < 0.01; before Hy 92 ± 11 mm Hg, after Hy 68 ± 8 mm Hg, p < 0.05), and decreased systemic vascular resistance (before N 1,558 ± 645 dynes s cm −5, after N 1,192 ± 430 dynes s cm −5, p < 0.05; before Hy 1,700 ± 415 dynes s cm −5, after Hy 957 ± 285 dynes s cm −5, p < 0.05). In addition, N administration resulted in an increased cardiac output (before N 4.5 ± 2.0 liters/min, after N 4.8 ± 2.0 liters/min, p < 0.01); Hy administration was associated with a more varied effect on cardiac output (before Hy 4.0 ± 1.0 liters/min, after Hy 5.3 ± 1.8 liters/min, p < 0.10, difference not significant [NS]). Although for the group neither agent decreased mean pulmonary artery pressure (PAP) (before N 51 ± 13 mm Hg, after N 44 ± 13 mm Hg, NS; before Hy 50 ± 15 mm Hg, after Hy 51 ± 15 mm Hg, NS) or pulmonary vascular resistance (before N 873 ± 458 dynes s cm −5, after N 680 ± 450 dynes s cm −5, NS; before Hy 945 ± 454 dynes s cm −5, after Hy 715 ± 309 dynes s cm −5, NS), 4 of 5 patients had a decrease in PAP after N and 1 had no change, and only 1 of 5 patients had a decreased PAP after Hy administration. Moreover, compared with the changes after Hy administration, PAP declined after N administration (δPAP after Hy 0.2 ± 9 mm Hg, after N −7 ± 9 mm Hg, p < 0.05). The PA diastolic to mean PA wedge pressure gradient tended to decrease after N administration (after N −5.0 ± 10 mm Hg, after Hy +4.7 ± 7 mm Hg, NS), suggesting more pulmonary vasodilatation after N administration. Moreover, the ratio of pulmonary to systemic vascular resistances was unchanged after N but increased after Hy administration (before N 0.55 ± 0.2, after N 0.53 ± 0.2, NS; before Hy 0.55 ± 0.2, after Hy 0.74 ± 0.3, p < 0.02), indicating the more balanced vasodilatory effect of N. Two patients were treated chronically with Hy but had intolerable adverse effects; 1 was subsequently treated successfully with N. A third patient had pulmonary edema (presumably neurogenic) 30 minutes after Hy administration; this patient later died. Another patient has symptomatically improved with chronic N therapy. Thus, N appears to be a more specific pulmonary arterial vasodilator than Hy in acute drug testing; in this small group of patients with primary pulmonary hypertension, N appears to be more efficacious when administered chronically.

Acute haemodynamic effects of oral prazosin in severe mitral regurgitation.

Acute haemodynamic effects of single dose oral prazosin were studied in eight patients with mitral regurgitation. Heart rate, mean systemic arterial pressure, pulmonary arterial pressure, left ventricular filling pressure, and forward cardiac output were measured in all patients. At peak effect, prazosin reduced mean systemic arterial pressure (95 +/- 4 to 86 +/- 4 mmHg), pulmonary arterial pressure (45 +/- 6 to 23 +/- 4 mmHg), and left ventricular filling pressure (30 +/- 4 to 21 +/- 3 mmHg). Pulmonary and systemic vascular resistance also fell (316 +/- 49 to 208 +/- 43 dynes s cm-5 and 2132 +/- 148 to 1491 +/- 94 dynes s cm-5, respectively). Forward cardiac index increased from 1.89 +/- 0.12 to 2.43 +/- 0.13 l/min per m2 and stroke volume from 43 +/- 5 to 57 +/- 6 ml/beat after prazosin. The onset of these changes occurred between 15 and 30 minutes, peaked between 45 and 60 minutes, and persisted for six hours. These data indicate that in patients with mitral regurgitation oral prazosin promptly improves cardiac performance (judged by increased forward cardiac output and reduced left ventricular filling pressure) as systemic and pulmonary vascular resistance are reduced.

Nitrate effects on cardiac output and left ventricular outflow resistance in chronic congestive heart failure

Nitrates have been used for long-term vasodilator therapy of left ventricular failure. Whereas left ventricular filling pressure (LVFP) consistently decreases, cardiac output does not always increase after nitrate administration, suggesting that preload reduction may be the predominant action of these agents in congestive heart failure. In 28 patients with chronic congestive heart failure due to cardlomyopathy, nitrate administration reduced mean systemic arterial pressure from 91.9 to 83.6 mm Hg, LVFP from 29.3 to 19.0 mm Hg and systemic vascular resistance from 33.2 to 24.0 U. Cardiac index increased from 1.70 to 2.09 liters/min/m 2. All changes were significant (p < 0.001). The change in cardiac index after nitrate administration correlated positively with the control LVFP (r = 0.52) and inversely with the control cardiac index (r = 0.52). In six patients, nitrate effects were compared to those of preload reduction with the application of tourniquets and outflow resistance reduction with the administration of nitroprusside. All three interventions reduced LVFP comparably and significantly, tourniquets by 6.3 mm Hg, nitroprusside by 9.3 mm Hg and nitrates by 8.7 mm Hg. The cardiac index decreased 0.16 liters/min/m 2 after tourniquets, but increased 0.50 liters/min/m 2 during nitroprusside therapy and 0.21 liters/min/m 2 after the administration of nitrates. The differences in cardiac index response between tourniquets and the two vasodilators were statistically significant, as was that between nitroprusside and nitrates. We conclude that the hemodynamic actions of nitrates in congestive heart failure are qualitatively similar to those of nitroprusside, but quantitatively less. Nitrates reduce outflow resistance as well as preload in congestive heart failure, and the magnitude of the former response is dependent upon the base line cardiac index and LVFP.