Cardiovascular responses to an isosterically modified prostaglandin analog in conscious dogs

The cardiovascular effects of oral and intravenous administration of 0.05 and 0.1 mg/kg of the isosterically modified prostaglandin (PG) analog, (+)- 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-thiazolidinyl] propyl) benzoic acid were ascertained in conscious mongrels. After 0.05 mg/kg p.o., mean arterial pressure (MAP), obtained from indwelling catheters, fell from 105 +/- 1 to 100 +/- 4 mm Hg and total peripheral resistance (TPR) decreased from 0.062 +/- 0.006 to 0.039 +/- 0.002 mm Hg/ml/min. Cardiac output (CO), measured via electromagnetic flow probes, rose from 1.8 +/- 0.2 to 2.6 +/- 0.1 l/min and heart rate from 109 +/- 13 to 128 +/- 8 beats/min. The 0.1 mg/kg p.o. dose produced similar results. Intravenous injection of 0.1 mg/kg immediately dropped MAP from 103 +/- 6 to 58 +/- 3 mm Hg and TPR from 0.049 +/- .006 to .014 +/- .002 mm Hg/ml/min. CO climbed from 2.3 +/- 0.2 to 5.3 +/- 0.5 l/min and HR increased from 126 +/- 9 to 254 +/- 14 beats/min. Stroke volume was not affected by either oral or intravenous administration of the PG analog. Pretreatment with 100 micrograms/kg timolol blunted the CO and HR responses to 0.1 mg/kg iv of the PG analog without affecting the depressor response. Metaraminol infused during injection of 0.1 mg/kg iv of the PG analog diminished all responses. When compared to the cardiovascular effects of hydralazine and nitroprusside, the profile of the PG analog activity closely resembled that produced by the arterial vasodilator, hydralazine; in contrast, nitroprusside (which also dilates veins) reduced stroke volume, but did not significantly affect HR. In conclusion, dilation of the resistance vessels by the PG analog decreased MAP and TPR and reflexly elevated CO and HR in conscious dogs.     

Comparison of haemodynamic responses to dobutamine and salbutamol in cardiogenic shock after acute myocardial infarction.

Nine patients with critically reduced cardiac output after acute myocardial infarction underwent a single cross-over comparison of dobutamine and salbutamol to compare the haemodynamic effects of these drugs, which have, respectively, predominantly beta 1-adrenergic and beta 2-adrenergic agonist activity. The responses were used to select the more appropriate treatment for individual patients. Only relatively small responses were obtained: those with poorest baseline measurements tended to show the least effect. When the results from the series were averaged, dobutamine (250-750 microgram/min) caused a small but progressive increase in cardiac index (1.8 to 2.2 1/min/m2) throughout the dose range. Systemic blood pressure was not increased, and calculated systemic vascular resistance fell from 25 to 19 units. Heart rate rose from 107 to 118 beats/min and stroke index from 17 to 19 ml/beat/m2. Pulmonary artery end-diastolic pressure fell from 18 to 15 mm Hg. Salbutamol (10-40 microgram/min) produced a similar progressive increase in cardiac index, from 1.6 to 2.21/min/m2. Systemic blood pressure was not altered, and systemic vascular resistance fell from 25 to 20 units. Heart rate rose from 105 to 119 beats/min and stroke index from 16 to 19 ml/beat/m2. Pulmonary artery end-diastolic pressure did not fall. Dobutamine and salbutamol have closely similar haemodynamic effects when used in cardiogenic shock after acute myocardial infarction. Both drugs increase cardiac index but heart rate also rises, and the increase in stroke index is relatively small. Mean arterial pressure is altered little by either agent, but dobutamine (in contrast with dopamine) tends to reduce pulmonary artery end-diastolic pressure, which may be beneficial.     

Comparison of haemodynamic responses to dopamine and salbutamol in severe cardiogenic shock complicating acute myocardial infarction.

Twelve patients with severe persistent cardiogenic shock complicating acute myocardial infarction underwent single crossover treatment with intravenous dopamine and salbutamol to determine the more beneficial therapy. Salbutamol (10 to 40 microgram/min) reduced systemic vascular resistance and progressively increased both cardiac index and stroke index. Heart rate increased from 95 to 104 beats/min. Changes in mean arterial pressure and pulmonary artery end-diastolic pressure were small and insignificant. Dopamine infusion at rates of 200 and 400 micrograms/min also increased cardiac index and stroke index. Systemic vascular resistance fell slightly but mean arterial pressure rose from 57 to 65 mm Hg. Heart rate increased from 95 to 105 beats/min. Changes in pulmonary artery end-diastolic pressure were again small and insignificant. Dopamine infusion at 800 micrograms/min caused an appreciable increase in systemic vascular resistance; a further increment in mean arterial pressure was observed, though cardiac index fell slightly. Heart rate and pulmonary artery end-diastolic pressure rose steeply. Salbutamol, a vasodilator, increased cardiac output in patients with cardiogenic shock complicating acute myocardial infarction but did not influence blood pressure. If correction of hypotension is essential dopamine in low doses may be the preferred agent. Doses of 800 microgram/min, which is within the therapeutic range, worsen other manifestations of left ventricular dysfunction.     

Cardiac and hemodynamic responses to synthetic atrial natriuretic factor in rats

To determine the hemodynamic effects of a hypotensive dose of atrial natriuretic factor (ANF), a synthetic peptide containing 26 amino acids of endogenous rat ANF (Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly -Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-COOH) was studied in two groups of barbiturate anesthetized rats. In the first experiment, a 20-minute infusion of a hypotensive dose, 95 pmole/min i.v., of the synthetic ANF decreased mean arterial pressure (MAP) by 40 +/- 3 mm Hg from a baseline of 128 +/- 5 mm Hg, and cardiac output (CO) (microsphere method) by 7.8 +/- 1.8 ml/min/100 gm from a baseline of 23.5 +/- 1.3 ml/min/100 gm. Synthetic ANF did not significantly affect the total peripheral resistance (TPR) measured at the end of the 20-minute infusion. Sodium nitroprusside (SNP), infused at an equihypotensive dose of 20 micrograms/kg/min i.v., produced the same hemodynamic profile in seven other animals; in contrast, 0.3 mg/kg i.v. of hydralazine (n = 7) lowered MAP by 56 +/- 6 mm Hg and reduced TPR index by 3.0 +/- 0.6 mm Hg/ml/min/100 gm, but did not change CO. Other than an increase in coronary blood during SNF infusion, there were no significant changes in the distribution of cardiac output. Infusion of the saline vehicle had no significant effects on any of these parameters. The results of the second experiment in anesthetized rats confirmed that hypotensive doses of 40 and 100 pmole/kg/min i.v. lowered CO (dye dilution method) from a baseline of 33 +/- 6 to a minimum of 24 +/- 2 ml/min/100 gm (p less than 0.05) without affecting TPR. In addition, synthetic ANF did not significantly affect heart rate (HR) but it slightly reduced cardiac contractility (dp/dt50). These results suggest that the hypotensive dose of synthetic ANF reduced cardiac output, partially by diminishing stroke volume, and perhaps contractility.     

Effects of calcitonin gene-related peptide on renal blood flow in the rat

The effects of alpha-rat calcitonin gene-related peptide (alpha-rCGRP) on systemic and renal hemodynamics and on renal electrolyte excretion were examined in normal anesthetized rats. In one group of rats (n = 7), infusions of alpha-rCGRP at doses of 10, 50, 100, and 500 ng/kg/min for 15 min each produced dose-related and significant decreases in mean arterial pressure from a control of 130 +/- 3 mm Hg to a maximal depressor response of 91 +/- 2 mm Hg. During the first three doses of alpha-rCGRP, renal blood flow progressively and significantly increased from a control of 5.0 +/- 0.3 ml/min to a peak level of 6.3 +/- 0.3 ml/min achieved during the 100 ng/kg/min infusion. With the highest infusion rate of 500 ng/kg/min, renal blood flow fell below the control level to 4.5 +/- 0.2 ml/min (P less than 0.05). The responses in renal blood flow and mean arterial pressure were associated with reductions in renal vascular resistance. After cessation of alpha-rCGRP infusions, arterial pressure, renal blood flow, and renal vascular resistance gradually returned toward the baseline values. In another group of rats (n = 9), infusion of alpha-rCGRP for 30 min at 100 ng/kg/min produced a significant reduction in urinary sodium excretion from 0.28 +/- 0.06 to 0.14 +/- 0.5 muEq/min (P less than 0.05). Urine flow and urinary potassium excretion also appeared to decrease, but the changes were not significantly different (P greater than 0.05) from their respective baselines. These results demonstrate that alpha-rCGRP is a potent and reversible hypotensive and renal vasodilatory agent in the anesthetized rat. The data also suggest that alpha-rCGRP may have significant effects on the excretory function of the kidney.     

Impaired vascular dynamics in normotensive diabetic rats induced by streptozotocin: tapered T-tube model analysis

This study is to explore the changes of arterial mechanical properties in streptozotocin (STZ)-diabetic rats, based on the exponentially tapered T-tube model. Rats given STZ 65 mg kg(-1)i.v. are compared with untreated weight- and age-matched controls. A high-fidelity pressure sensor and electromagnetic flow probe measured pulsatile pressure and flow waves in the ascending aorta, respectively. Diabetic rats exhibit isobaric vasodilatation that is characterized by an increase in cardiac output and no significant changes in aortic pressure. Total peripheral resistance of diabetic rats is lower than that of weight- and age-matched controls. Diabetic rats have higher total peripheral compliance (2.86+/-0.70 microl mm Hg(-1)) than do weight- (1.77+/-0.34 microl mm Hg(-1)) and age-matched (1.87+/-0.69 microl mm Hg(-1)) controls. Aortic characteristic impedance is reduced from 0.017+/-0.003 mm Hg min kg ml(-1)in weight- and 0.020+/-0.004 mm Hg min kg ml(-1)in age-matched controls to 0.010+/-0.004 mm Hg min kg ml(-1)in diabetic rats. Moreover, diabetic rats show shorter wave transit time in lower body circulation (17.86+/-1.91 ms) than do weight- (20.45+/-1.91) and age-matched (23.05+/-2.04 ms) controls. Under isobaric vasodilatation, the decreased resistance and increased compliance in peripheral circulation suggest that the contractile dysfunction of the smooth muscle cells may occur in resistance arterioles in diabetes. With unaltered aortic pressure, an impairment in aortic distensibility of STZ-diabetic rats is manifest on the reduced wave transit time rather than on the diminished aortic characteristic impedance.     

Fluid extravasation from spleen reduces blood volume in endotoxemia

We recently demonstrated that fluid is filtered out of the splenic circulation and into the lymphatic system. The current experiments were designed to investigate the importance of this route of fluid extravasation in endotoxemia. Lipopolysaccharide (LPS) was infused into conscious intact and splenectomized rats (150 microg x kg(-1). h(-1) i.v. for 18 h). In the intact rats, mean arterial pressure (MAP) fell from 101+/-2.4 to 88+/-3.9 mm Hg (n = 7) and then stabilized at about 90 mm Hg. Hematocrit rose from 41+/-0.9 to 45+/-0.4% at 40 min, at which time plasma volume had fallen from 4.7+/-0.12 to 4.0+/-0.05 ml/100 g body wt. In the splenectomized rats MAP did not fall and hematocrit did not rise. There also was no change in plasma volume, i.e., splenectomy prevented the hypotension and hemoconcentration customarily induced by LPS. In a second series of experiments, splenic arterial and venous blood flows were simultaneously measured in anesthetized rats infused with LPS (150 microg x kg(-1) x h(-1)). LPS increased splenic fluid efflux. We conclude that during endotoxemia the initial fall in circulating blood volume may be attributed to fluid extravasation from the splenic vasculature.     

Pulmonary vascular response to prostacyclin in fetal lambs.

Eighteen prostacyclin injections (19.4 +/- 1.5 micrograms/kg) were performed in five chronically instrumented, intact fetal lambs in order to study the effects on pulmonary blood flow. These resulted in a brief period of bradycardia followed by a more prolonged period of increased pulmonary blood flow. In this latter phase, pulmonary blood flow increased from a baseline value of 49 +/- 4 ml/(kg min) to 122 +/- 10 ml/(kg min). Systolic/diastolic pulmonary arterial pressure simultaneously fell from 73 +/- 2/48 +/- 1 to 68 +/- 2/42 +/- 1 mm Hg. Flow through the ductus arteriosus was unchanged and right ventricular output increased to account for the increased pulmonary blood flow. Thus, prostacyclin causes pulmonary vasodilation in intact fetal lambs and may participate in the control of fetal pulmonary blood flow and the circulatory adjustments to extra-uterine life.     

Separate hemodynamic roles for chloride and sodium in deoxycorticosterone acetate-salt hypertension

It has been reported that both sodium and chloride ions must be ingested to induce the elevated blood pressure of deoxycorticosterone acetate (DOCA)-salt-sensitive hypertension. This study was designed to determine the separate roles of the sodium and chloride ions in the altered hemodynamics underlying the high blood pressure. DOCA pellets (75 mg) were implanted in uninephrectomized rats and the animals were then fed one of four diets: (i) high sodium chloride, (ii) high sodium-low chloride, (iii) high chloride-low sodium, or (iv) low sodium chloride. Blood pressures were measured weekly by tail-cuff plethysmography for 5 weeks and the animals were then subjected to a terminal experiment to measure cardiac output by thermodilution technique, renal blood flow by electromagnetic flow probe, and direct arterial pressure. Blood pressure in the DOCA-high NaCl group was significantly greater (P less than 0.05) compared with that of the DOCA-low NaCl group (160 +/- 3 mm Hg vs 124 +/- 2 mm Hg, respectively) at 5 weeks after treatment; all other groups were not significantly different from the DOCA-low NaCl group. Cardiac output was significantly greater in DOCA-treated rats consuming diets high in sodium (44 +/- 2 ml/min/100 g) or sodium chloride (40 +/- 2 ml/min/100 g) compared with animals consuming low sodium chloride (31 +/- 2 ml/min/100 g; P less than 0.01 for each comparison). Direct intraarterial blood pressure and renal blood flow were used to calculate renal vascular resistance. Renal vascular resistance was increased in those DOCA-treated rats consuming diets high in chloride (42 +/- 3 mm Hg/ml/min/100 g) and high sodium chloride (54 +/- 3 mm Hg/ml/min/100 g) compared with rats consuming low sodium chloride (30 +/- 3 mm Hg/ml/min/100 g; P less than 0.01 for each). It appears that elevations in cardiac output are associated with increased dietary sodium and act in synergy with the elevations in renal vascular resistance associated with increased dietary chloride. Increases in both cardiac output and renal vascular resistance are involved in the maintenance of elevated blood pressure in the DOCA-salt-sensitive model of hypertension.     

Reference cardiopulmonary values in normal dogs

The purpose of this project was to collate canine cardiopulmonary measurements from published and unpublished studies in our laboratory in 97 instrumented, unsedated, normovolemic dogs. Body weight; arterial and mixed-venous pH and blood gases; mean arterial, pulmonary arterial, pulmonary artery occlusion, and central venous blood pressures; cardiac output; heart rate; hemoglobin; and core temperature were measured. Body surface area; bicarbonate concentration; base deficit; cardiac index; stroke volume index, systemic and pulmonary vascular resistance indices; left and right cardiac work indices; alveolar partial pressure of oxygen (pO2) ; alveolar-arterial pO2 gradient (A-apO2); arterial, mixed-venous, and pulmonary capillary oxygen content; oxygen delivery; oxygen consumption; oxygen extraction; venous admixture; arterial and mixed-venous blood CO2 contents; and CO2 production were calculated. In the 97 normal, resting dogs, mean arterial and mixed-venous pH were 7.38 and 7.36, respectively; partial pressure of carbon dioxide (pCO2), 40.2 and 44.1 mm Hg, respectively; base-deficit, -2.1 and -1.9 mEq/liter, respectively; pO2, 99.5 and 49.3 mm Hg, respectively; oxygen content, 17.8 and 14.2 ml/dl, respectively; A-a pO2 was 6.3 mm Hg; and venous admixture was 3.6%. The mean arterial blood pressure (ABPm), mean pulmonary arterial blood pressure (PAPm), pulmonary artery occlusion pressure (PAOP) were 103, 14, and 5.5 mm Hg, respectively; heart rate was 87 beats/min; cardiac index (CI) was 4.42 liters/min/m2; systemic and pulmonary vascular resistances were 1931 and 194 dynes.sec.cm-5, respectively; oxygen delivery, consumption and extraction were 790 and 164 ml/min/m2 and 20.5%, respectively. This study represents a collation of cardiopulmonary values obtained from a large number of dogs (97) from a single laboratory using the same measurement techniques.     

Protection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy.

STUDY OBJECTIVE--To assess whether long term inhibition of angiotensin converting enzyme with captopril and frusemide or bendrofluazide protects kidney function in diabetic nephropathy. DESIGN--Non-randomised controlled before-after trial of matched hypertensive insulin dependent diabetics with nephropathy treated with captopril and frusemide or bendrofluazide. SETTING--Outpatient diabetic clinic in tertiary referral centre. PATIENTS--Treatment group of 18 hypertensive insulin dependent diabetics with nephropathy (mean age 33), who had not been treated previously. Control group of 13 patients (mean age 32) fulfilling the same entry criteria from a prospective study. INTERVENTIONS--Treatment group was given daily captopril 37.5-100.0 mg and frusemide (mean) 98 mg (10 patients) or bendrofluazide (mean) 4 mg (seven). Treatment was continued for about two and a half years. Controls were not treated. END POINT--Measurement of arterial blood pressure, albuminuria, and glomerular filtration. MEASUREMENTS AND MAIN RESULTS--Baseline values were identical in treated and untreated groups respectively: mean blood pressure 146/93 (SE 3/1) mm Hg v 137/95 (2/1) mm Hg; geometric mean albuminuria 982 (antilog SE 1.2) micrograms/min v 936 (1.2) micrograms/min; and mean glomerular filtration rate 98 (SE 5) ml/min/1.73 m2 v 96 (6) ml/min/1.73 m2. Mean arterial blood pressure fell by 8.7 (1.3) mm Hg with captopril and rose by 6.6 (1.5) mm Hg in controls, (p less than 0.001); Albumin excretion decreased to 390 (1.1) micrograms/min with captopril and rose to 1367 (1.3) micrograms/min in controls (p less than 0.001). The rate of decrease in glomerular filtration rate was lower with captopril (5.8 (0.7) ml/year v 10.0 (1.3) ml/year) (p less than 0.01). Rate of fall in glomerular filtration rate and mean arterial blood pressure were significantly correlated (n = 31, r = 0.37, p less than 0.05). CONCLUSIONS--Captopril is a valuable new drug for treating hypertension in insulin dependent diabetics with nephropathy.     

Blood pressure of sinoaortic-denervated dogs is not increased by cardiac denervation

Although blood pressure rises markedly after acute sinoaortic denervation, animals with chronic sinoaortic denervation have normal or only slightly elevated mean arterial pressures. The present study was performed to determine whether reflexes from cardiac receptors exert antihypertensive effects and thereby lower blood pressure in animals with chronic sinoaortic denervation. We made multiple measurements of blood pressures in dogs with chronic sinoaortic denervation before and after their hearts were denervated surgically. Mean arterial pressure after cardiac denervation (100.3 +/- 4.2 mm Hg) was not significantly different from the mean pressures recorded before cardiac denervation in these sinoaortic-denervated dogs (104.8 +/- 3.1 mm Hg). Also, mean heart rate after cardiac denervation (107.4 +/- 5.5 beats/min) did not differ significantly from the mean heart rate recorded before cardiac denervation (107.2 +/- 5.9 beats/min). Cardiac denervation did, however, appear to reduce the lability of both blood pressure and heart rate in sinoaortic-denervated dogs. We conclude that cardiac receptors are not responsible for maintaining arterial pressure within essentially normal limits in animals with chronic sinoaortic denervation.     

Distribution of respiratory muscle and organ blood flow during endotoxic shock in dogs

Respiratory muscle blood flow and organ blood flow during endotoxic shock were studied in spontaneously breathing dogs (SB, n = 6) and mechanically ventilated dogs (MV, n = 5) with radiolabeled microspheres. Shock was produced by a 5-min intravenous injection of Escherichia coli endotoxin (0.55:B5, Difco, 10 mg/kg) suspended in saline. Mean arterial blood pressure and cardiac output in the SB group dropped to 59 and 45% of control values, respectively. There was a similar reduction in arterial blood pressure and cardiac output in the MV group. Total respiratory muscle blood flow in the SB group increased significantly from the control value of 51 +/- 4 ml/min (mean +/- SE) to 101 +/- 22 ml/min at 60 min of shock. In the MV group, respiratory muscle perfusion fell from control values of 43 +/- 12 ml/min to 25 +/- 3 ml/min at 60 min of shock. In the SB group, 8.8% of the cardiac output was received by the respiratory muscle during shock in comparison with 1.9% in the MV group. In both groups of dogs, blood flow to most organs was compromised during shock; however, blood flow to the brain, gut, and skeletal muscles was higher in the MV group than in the SB group. Thus by mechanical ventilation a fraction of the cardiac output used by the working respiratory muscles can be made available for perfusion of other organs during endotoxic shock.     

Effect of alpha-adrenergic blockade on the cardiovascular responses to hypoxemia and hypercapnic acidosis in conscious dogs

In order to evaluate the role of the alpha-adrenergic system in the systemic and renal hemodynamic changes of the acute combined blood gas derangement, seven conscious mongrel dogs in careful sodium balance (80 mEq/day for 4 days) were evaluated. Each animal was evaluated during combined acute hypoxemia (PaO2 = 35 +/- 1 mm Hg) and hypercapnic acidosis (PaCO2 = 56 +/- 2 mm Hg; pH = 7.18 +/- 0.01) with (i) vehicle (D5W) alone and (ii) alpha 1-adrenergic blockade with prazosin, 0.1 mg/kg iv. Mean arterial pressure increased during the combined blood gas derangement with vehicle. In contrast, mean arterial pressure fell during combined acute hypoxemia and hypercapnic acidosis with alpha 1-adrenergic blockade. The mechanism for abrogation of the rise in mean arterial pressure during the combined blood gas derangement by alpha 1-adrenergic blockade appeared to be through attenuation of the rise in cardiac output rather than an exaggerated fall in total peripheral resistance. These observations suggest that the alpha-adrenergic system is important in circulatory homeostasis during the combined blood gas derangement.     

Cardiovascular effects of training for a marathon run in unfit middle aged men.

The effects of a 30 week exercise programme on serum lipid values, blood pressure, and cardiac function were assessed in a group of sedentary men aged 35-50 training for their first marathon. Mean serum cholesterol concentration (n = 33) fell by 12% from 6.54 (SE 0.18) to 5.76 (0.15) mmol/l (mean fall 0.78 mmol/l; 95% confidence interval 0.52 to 1.04 mmol/l), serum triglyceride concentration (n = 33) by 22% from 1.56 (0.17) to 1.21 (0.09) mmol/l (mean fall 0.34 mmol/l; 95% confidence interval 0.12 to 0.56 mmol/l), and mean blood pressure (n = 27) by 10% from 102 (2) to 92 (2) mm Hg (mean fall 10 mm Hg; 95% confidence interval 7 to 13 mm Hg). These changes were not explained by changes in body composition. Peak exercise left ventricular end diastolic volume (n = 16) increased with training; as a result of this and an increased exercise left ventricular ejection fraction peak exercise cardiac output increased from 19.9 (1.2) to 23.1 (3.0) l/min (mean rise 3.2 l/min; 95% confidence interval 1.5 to 5.0 l/min). Maximum oxygen consumption increased from 33.9 (1.6) to 39.0 (1.3) ml/kg/min (mean rise 5.0 ml/kg/min; 95% confidence interval 1.8 to 8.2 ml/kg/min). This study showed favourable effects on coronary risk factors and cardiac function and supports the place of regular exercise in coronary prevention programmes.     

Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy.

OBJECTIVE--To assess whether inhibition of angiotensin converting enzyme protects kidney function in diabetic nephropathy. DESIGN--Open, randomised follow up study of normotensive insulin dependent diabetics with nephropathy either treated or not with captopril for one year. SETTING--Outpatient diabetic clinic in a tertiary referral centre. PATIENTS--32 Normotensive patients with insulin dependent diabetes complicated by nephropathy who were randomised either to the treatment group (n = 15) or to the control group (n = 17). INTERVENTIONS--The treatment group was given captopril (25-100 mg/day) for 12 months, the average dose during the second six months of the study being 40 mg daily. Controls were not treated. MAIN OUTCOME MEASURES--Albuminuria, arterial blood pressure, and the glomerular filtration rate. RESULTS--Mean arterial blood pressure fell by 3 (SE 2) mm Hg in the captopril treated group and rose by 6 (1) mm Hg in the controls. In addition, albuminuria declined by 11% in the captopril treated group and rose by 55% in the controls, fractional albumin clearance fell by 17% in the captopril treated group and increased by 66% in the controls, and the glomerular filtration rate declined by 3.1 (2.8)ml/min/1.73 m2 with captopril and by 6.4 (3.1) ml/min/1.73 m2 in the controls. CONCLUSION--Inhibition of angiotensin converting enzyme arrests the progressive rise in albuminuria in normotensive insulin dependent diabetics with nephropathy.     

Cardiovascular responses to an isosterically modified prostaglandin analog in conscious dogs

The cardiovascular effects of oral and intravenous administration of 0.05 and 0.1 mg/kg of the isosterically modified prostaglandin (PG) analog, (+)-4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-thiazolidinyl]propy} benzoic acid were ascertained in conscious mongrels. After 0.05 mg/kg p.o., mean arterial pressure (MAP), obtained from indwelling catheters, fell from 105 ± 1 to 100 ± 4 mm Hg and total peripheral resistance (TPR) decreased from 0.062 ± 0.006 to 0.039 ± 0.002 mm Hg/ml/min. Cardiac output (CO), measured via electromagnetic flow probes, rose from 1.8 ± 0.2 to 2.6 ± 0.1 l/ml and heart rate from 109 ± 13 to 128 ± 8 beats/min. The 0.1 mg/kg p.o. dose produced similar results. Intravenous injection of 0.1 mg/kg immediately dropped MAP from 103 ± 6 to 58 ± 3 mm Hg and TRP from 0.049 ± .006 to .014 ± .002 mm Hg/ml/min. CO climbed from 2.3 ± 0.2 to 0.2 to 5.3 ± 0.5 l/ml and HR increased from 126 ± 9 to 254 ± 14 beats/min. Stroke volume was not affected by either oral or intravenous administration of the PG analog. Pretreatment with 100 μg/kg timolol blunted the CO and HR responses to 0.1 mg/kg iv of the PG analog without affecting the depressor response. Metaramidol infused during injection of 0.1 mg/kg iv of the PG analog diminished all responses. When compared to the cardiovascular effects of hydralazine and nitroprusside, the profile of the PG analog activity closely resembled that produced by the arterial vasodilator, hydralazine; in contrast, nitroprusside (which also dilates veins) reduced stroke volume, but did not significantly affect HR. In conclusion, dilation of the resistance vessels by the PG analog decreased MAP and TPR and reflexly elevated CO and HR in conscious dogs.     

Effects of endogenous angiotensin II on the fetal circulation

The role of endogenous angiotensin II in the regulation of the circulation was investigated by infusion of [sar1],[ala8]-angiotensin II, a competitive antagonist of angiotensin II, into fetal sheep with chronically-maintained intravascular catheters. The thesis considered was that angiotensin II may have a greater role in the fetus than in the adult since the autonomic nervous system does not develop fully until late in gestation. Fetal cardiac output and its distribution to various organs and actual blood flows to fetal tissues were determined by the radionuclide-labelled microsphere technique. Intravenous infusion of [sar1], [ala8]-angiotensin II at a rate of 13.95-42.15 microgram/min per kg fetal body weight increased plasma renin activity from a control value of 8.9 +/- 1.6 to 18.9 +/- 3.9 ng/ml per h (SEM). Mean arterial blood pressure fell significantly from a control level of 47 +/- 1.6 to 41 +/- 1.1 mmHg. Blood flow to the unbilical-placental circulation decreased from 239 +/- 27.0 to 198 +/- 20.2 ml/min per kg, but the calculated vascular resistance in the umbilical-placental circulation did not change. Although cardiac output did not change, blood flow to the peripheral circulation, which includes the fetal skin, muscle and and bone and constitutes 75 +/- 0.9% of the total fetal body weight, increased as did flow to the thyroid and adrenal circulations. Endogenous angiotensin II appears to be important in maintaining blood flow to the umbilical-placental circulation by maintaining fetal arterial blood pressure. Angiotensin II exerts this effect by mediating a tonic vasoconstriction primarily in the peripheral circulation.     

Endothelin-a receptor blockade does not debilitate the cardiovascular and hormonal adaptation to xenon or isoflurane anesthesia in dogs

The objective of this study was to investigate whether circulatory and hormonal changes during xenon plus remifentanil or isoflurane plus remifentanil anesthesia are altered by endothelin-A (ET(A)) receptor blockade. Eight beagle dogs were studied in four protocols (n = 7 each). After a 30-min awake period, anesthesia was induced with 8 mg/kg propofol, administered intravenously (iv), and maintained with either 0.8% +/- 0.01% (vol/vol) isoflurane plus 0.5 microg/kg/min remifentanil (Protocol 1) or 63% +/- 1% (vol/vol) xenon plus 0.5 microg/kg/min remifentanil (Protocol 2) for 1 hr. Protocols 3 and 4 were preceded by ET(A) blockade with ABT-627 (Atrasentan; iv bolus of 1 mg/kg, then 100 microg/kg/h continuously). Irrespective of Atrasentan administration, the mean arterial blood pressure (MAP) ranged between 92 and 96 mm Hg in the awake state and fell to 67 +/- 3 mm Hg in controls (mean +/- SEM) and to 64 +/- 2 mm Hg in the Atrasentan group during isoflurane plus remifentanil anesthesia, whereas MAP remained constant during xenon plus remifentanil anesthesia. A decrease in heart rate was observed during either kind of anesthesia, but bradycardia was most prominent during xenon plus remifentanil anesthesia. In the control groups, and in the Atrasentan-treated dogs, a decrease in cardiac output and an increase in systemic vascular resistance were more prominent during xenon plus remifentanil than during isoflurane plus remifentanil anesthesia. Hormonal alterations during anesthesia remained unaffected by ET(A) receptor blockade. Angiotensin II and vasopressin increased in all protocols, and adrenaline and noradrenaline concentrations rose only during xenon plus remifentanil anesthesia. We conclude that the hemodynamic and hormonal adaptation after xenon plus remifentanil and isoflurane plus remifentanil anesthesia does not depend on the endothelin system, because it is unaffected by ET(A) receptor inhibition. Therefore, the use of Atrasentan does not impair cardiovascular stability during xenon- or isoflurane-based anesthesia in our dog model. However, the way anesthesia is performed is of crucial importance for hemodynamic and hormonal reactions observed during research in animals because the release of vasopressin and catecholamines may be intensified by xenon plus remifentanil anesthesia.     

LTB4 mediated hypoxemia in guinea pigs: relationship to pulmonary and cardiovascular pathophysiology

LTB4 is released in the presence of lung injury and may therefore play a role in the pathophysiology of the lung damage. We therefore, administered LTB4 as an I.V. bolus or as an aerosol to guinea pigs and assessed the physiologic response and the lung histology. After 2 ug of I.V. LTB4 airway pressure (AP) rose transiently by 5 +/- 1 mmHg and at five min was back to baseline while PaO2 fell from 96 +/- 5 mmHg to 78 +/- 3 mmHg and remained low at least 45 min. Static compliance (Cstat) was unchanged. Right ventricular systolic pressure (RVSP) and mean aortic pressure (MAP) rose from 9 +/- 1 to 16 +/- 1 mmHg and 43 +/- 4 to 62 +/- 5 mmHg respectively while cardiac index (C.I.) fell from 266 to 208 ml/kg/min but all values were baseline again by 10 min. Aerosolized LTB4 raised AP by 4.6 +/- 0.2 mmHg while PaO2 fell from 90 +/- 7 to 52 +/- 5 mmHg. AP recovered by 20 min but PaO2 remained low at least for 1 hour. MAP, RVSP and CI and Cstat were unaffected. Both I.V. and inhaled LTB4 increased neutrophil infiltrate in the lung although the water aerosol control did too, preventing us from showing a significant effect with LTB4 aerosol. Indomethacin blocked the airway effects and the hypoxemia after I.V. or aerosolized LTB4 but not the neutrophil infiltrate or the rise in RVSP. It actually enhanced (p less than .05) the rise in MAP after I.V. LTB4. Thus cyclooxygenase released products likely mediated the rise in airway pressure and the prolonged fall in PaO2 after LTB4 in guinea pigs but not the pulmonary and systemic vasoconstriction.