Effect of the thromboxane A2 receptor antagonist SQ 30,741 on ultimate myocardial infarct size, reperfusion injury and coronary flow reserve

We determined if the thromboxane A2 antagonist SQ 30,741 can reduce ultimate myocardial infarct size and reperfusion injury. Anesthetized dogs were subjected to left circumflex coronary artery occlusion for 90 min at which time reperfusion was instituted. In one study, SQ 30,741 (1 mg/kg + 1 mg/kg/hr) was given either 10 min postocclusion (n = 7) or 2 min (n = 9) before reperfusion along with their appropriate vehicle controls in a model of 90 min of occlusion and 5 hr of reperfusion. Infarct size was reduced 50% (P less than .05) when SQ 30,741 was given 10 min postocclusion and 30% (P less than .05) when given only during reperfusion. Flow reserve using maximally dilating doses of adenosine was determined 3 hr postreperfusion in vehicle (10 min postocclusion, n = 10), SQ 30,741 (10 min postocclusion, n = 6) and nonischemic (n = 5) animals. Maximal subendocardial flow was reduced during reperfusion in ischemic animals, but SQ 30,741 improved this compared to vehicle animals (400 +/- 95, 88 +/- 25 and 208 +/- 48 ml/min/100 g; nonischemic, vehicle, SQ 30,741 groups, respectively). To determine if myocardial salvage can be observed 24 hr postocclusion with SQ 30,741 or the cyclooxygenase inhibitor aspirin, dogs were given vehicle (n = 9), SQ 30,741 (10 min postocclusion up to 4 hr postreperfusion) or aspirin (n = 9, 40 mg/kg 30 min preocclusion) and infarct size was determined 24 hr postocclusion (90 min left circumflex coronary artery occlusion + reperfusion).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of the cardioprotective actions of WEB-2170, bepafant, a platelet activating factor antagonist, in myocardial ischemia and reperfusion.

The cardioprotective effects of WEB-2170, a specific platelet activating factor (PAF) receptor antagonist, were investigated in a feline model of myocardial ischemia (MI) and reperfusion. Either WEB-2170 (1-mg/kg bolus plus 2 mg/kg/hr) or its vehicle (0.9% NaCl) was administered 1 hr after left anterior descending coronary artery occlusion (i.e., 30 min before reperfusion). The cardiac area-at-risk (AAR) was similar in MI-reperfused (MI + R) cats given either WEB-2170 (31.5 +/- 3.6%) or vehicle (27.8 +/- 2.8%). However, in cats receiving only the vehicle, 1.5 hr of ischemia plus 4.5 hr of reperfusion resulted in significant myocardial injury (necrotic tissue/AAR, 37.7 +/- 4.5%), high plasma creatine kinase activity (29.4 +/- 4.1 I.U./micrograms of protein) and a marked decrease in endothelium-dependent relaxation in isolated left anterior descending coronary arteries to acetylcholine (33 +/- 4% of U-46619-induced vasocontraction) with no change in endothelium-independent relaxation to NaNO2 (91 +/- 1%). In contrast, MI + R cats treated with WEB-2170 developed significantly less myocardial necrosis (necrotic tissue/AAR, 12.0 +/- 2.8%, P less than .001), lower plasma creatine kinase activity (16.5 +/- 4.1 I.U./micrograms of protein, P less than .01) and enhanced vascular relaxation to acetylcholine (53 +/- 4.1%, P less than .01) compared to MI + R cats given only the vehicle. Furthermore, the addition of WEB-2170 to PMN suspensions in vitro significantly inhibited (P less than .01) PAF-induced polymorphonuclear leukocyte (PMN) adherence to endothelial cells (12 +/- 2.4 cells/field vs. 27 +/- 2.6 in the control group).(ABSTRACT TRUNCATED AT 250 WORDS)     

Probenecid impairment of acetaminophen and lorazepam clearance: direct inhibition of ether glucuronide formation

Eleven subjects received acetaminophen (650 mg i.v.) on two occasions in random sequence, with and without concurrent administration of probenecid (500 mg) every 6 hr. Nine subjects similarly received lorazepam (2 mg. i.v.) with and without concurrent probenecid. Acetaminophen half-life was prolonged during probenecid treatment (mean +/- S.E., 4.30 +/- 0.23 vs. 2.51 +/- 0.16 hr; P less than .001) due to markedly decreased clearance (178 +/- 13 vs. 329 +/- 24 ml/min; P less than .001) with no change in volume of distribution (65 +/- 4 vs. 69 +/- 3 l; NS). Urinary excretion of acetaminophen glucuronide during 24 hr was decreased (84 +/- 9 vs. 260 +/- 21 mg of acetaminophen as glucuronide; P less than .001) and acetaminophen sulfate excretion was increased (323 +/- 25 vs. 217 +/- 17 mg of acetaminophen as sulfate; P less than .005) during concurrent probenecid treatment. However, the sum of the two conjugated metabolites was not significantly different (407 +/- 28 vs. 476 +/- 20 mg of acetaminophen as glucuronide plus sulfate excreted per 24 hr; NS). Lorazepam half-life was also prolonged during probenecid treatment (33.0 +/- 3.9 vs. 14.3 +/- 1.08 hr; P less than .001) due to decreased clearance (44.7 +/- 5.4 vs. 80.3 +/- 13.2 ml/min; P less than .001) with no change in volume of distribution (111 +/- 5 vs. 111 +/- 7 l; NS). Formation of the ether glucuronides of acetaminophen and lorazepam is impaired markedly by therapeutic doses of probenecid. Sulfate conjugation is not affected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiarrhythmic and antifibrillatory actions of the beta adrenergic receptor antagonist, dl-sotalol

The antiarrhythmic and antifibrillatory actions of the beta adrenergic receptor antagonist, dl-sotalol, were examined in the canine heart subjected to myocardial ischemic injury. Programmed electrical stimulation of the heart was done 4 to 7 days after a 2-hr occlusion followed by reperfusion of the left anterior descending coronary artery. The resulting dysrhythmias consisted of nonsustained ventricular tachycardia (n = 1), sustained ventricular tachycardia (n = 5) or polymorphous ventricular tachycardia degenerating to ventricular fibrillation (n = 3). After dl-sotalol (8 mg/kg), programmed stimulation failed to produce ventricular arrhythmias in five animals with only nonsustained ventricular tachycardia observed in the other animals. Epicardial activation delays produced in ischemically injured myocardium by premature ventricular stimuli were not altered by treatment with sotalol. However, the increase in ventricular refractoriness (156 +/- 5 msec predrug vs. 191 +/- 7 msec post 8 mg/kg of sotalol, P less than .01) prevented the introduction of premature ventricular stimuli at coupling intervals previously producing ventricular tachyarrhythmias despite the presence of continuous diastolic electrical activity recorded with epicardial composite electrodes over the region of chronic myocardial injury. In a conscious canine model which spontaneously develops ventricular fibrillation, dl-sotalol (2 mg/kg, n = 7; 8 mg/kg, n = 13) decreased the incidence of ventricular fibrillation and increased survival at 24 hr (13 of 20, 65% vs. control, 1 of 15, 7%; P less than .001). Composite electrograms recorded from the anterior and posteriorlateral surfaces of the heart demonstrated the rapid development of activation delays on the posteriorlateral surface with the appearance of ischemic ST segment changes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Value of myocardial contrast echocardiography for predicting left ventricular remodeling and segmental functional recovery after anterior wall acute myocardial infarction.

OBJECTIVE: We sought to study the value of microvascular perfusion assessed by myocardial contrast echocardiography in predicting left ventricular remodeling after anterior wall acute myocardial infarction. METHODS: In 31 patients myocardial contrast echocardiography was performed up to 48 hours after acute myocardial infarction with determination of end-diastolic and end-systolic volumes, wall-motion score index, and myocardial perfusion score index (MPSI) at rest and under dobutamine stress at 6 months. Patients were classified into remodeling group (RG) (n = 19) and non-RG (n = 12), and, according to number of segments without opacification, reflow (< or =2 segments, n = 15) and no-reflow (>2 segments, n = 16) groups. RESULTS: Wall-motion score index (1.84 +/- 0.22 vs 1.64 +/- 0.3; P =.049), MPSI (1.53 +/- 0.25 vs 1.26 +/- 0.17; P =.006), and number of segments without contrast (3.11 +/- 2.23 vs 1.08 +/- 1.38; P =.018) were higher in RG than in non-RG. End-diastolic and end-systolic volumes, and wall-motion score index, increased significantly in RG at 6 months and decreased in non-RG. MPSI increased in RG (1.53 +/- 0.25-1.66 +/- 0.21; P =.011) and was the only independent predictor of left ventricular remodeling (odds ratio = 1.8; 95% confidence interval = 1.15-2.82; P =.010). No-reflow group presented 27.8 +/- 19.9% of segments with resting functional recovery or contractile reserve, and reflow group presented 69.9 +/- 31.2% (P <.001). CONCLUSION: MPSI obtained 48 hours after acute myocardial infarction is an independent predictor of left ventricular remodeling. Patients with two or fewer segments without opacification revealed a better prognosis of resting ventricular function and contractile reserve.     

Role of medullary plasma flow in the attenuated furosemide response in indomethacin-treated rats

To determine the role of medullary hemodynamics in the attenuated furosemide response observed during prostaglandin synthesis inhibition, medullary plasma flow was measured by the albumin accumulation technique in nondiuretic rats and during furosemide administration (4 mg/kg b.wt./hr) in indomethacin- or indomethacin vehicle-treated rats. As in previous studies indomethacin attenuated furosemide chloruresis (FeCl: 11.4 +/- 1.1 vs. 5.0 +/- 0.9%, P less than .001) without altering mean arterial pressure, inulin clearance or total renal blood flow. Medullary plasma flow was not different between nondiuretic rats and furosemide-treated rats (41.4 +/- 4.3 vs. 41.3 +/- 3.4 ml/min/100 g of tissue). Medullary plasma flow was reduced (P less than .05) during indomethacin antagonism of furosemide chloruresis (41.3 +/- 3.4 vs. 29.1 +/- 2.8 ml/min/100 g of tissue). Angiotensin II blockade with saralasin (2 micrograms/kg/min) prevented the fall in medullary plasma flow in indomethacin-treated rats during furosemide infusion but did not alter mean arterial pressure, inulin clearance or total renal blood flow. However, furosemide's chloruretic response in rats treated with both indomethacin and saralasin remained lower (P less than .001) than that in vehicle-treated rats (FeCl 4.7 +/- .94 vs. 11.4 +/- 1.1%) and was not different from that in indomethacin-treated rats. These data demonstrate that although medullary plasma flow is reduced during indomethacin antagonism of furosemide response this change does not contribute to the attenuated chloruresis. Additionally, the dissociation of the antichloruretic and hemodynamic effects of indomethacin observed during saralasin administration suggest that hemodynamic mechanisms are not involved in the attenuated response to furosemide observed during prostaglandin synthesis inhibition.     

The ischemia-modified albumin in relation to pacemaker and defibrillator implantation

BACKGROUND: Ischemia-modified albumin (IMA) is considered a marker of myocardial ischemia whereas cardiac enzymes are released when cardiac necrosis occurs. It has previously been shown that permanent pacemaker-defibrillator insertion is associated with myocardial injury expressed as cardiac enzyme rise. OBJECTIVE: We assessed whether pacemaker-defibrillator implantation also induces changes in IMA plasma levels and whether, therefore, myocardial ischemia precedes necrosis. METHODS: We studied 64 consecutive patients undergoing pacemaker or defibrillator implantation; 43 were men and 21 women and their age was 70 +/- 11 years (range 23-84 years). Blood samples were collected at baseline, six hours and 48 hours following the procedure. IMA measured by the albumin cobalt binding test (ACB, Integra 800 analyzer), as well as creatine kinase (CK), the MB isoenzyme of creatine kinase (CK-MB) and cardiac troponin I (Tn-I) were evaluated. RESULTS: Data analysis showed that compared to baseline measurements, IMA increased at six hours (P = 0.015) and at 48 hours (P = 0.003)[97.6 +/- 10.2 vs 101.4 +/- 10.7 vs 102.1 +/- 9.2 U/mL at baseline, six hours and 48 hours, respectively]; similarly, CK increased at six hours (P = 0.0001) and remained high at 48 hours (P = 0.0001) [74.9 +/- 49.9 vs 136.1+/-186.7 vs 115.2 +/- 63.9 mIU/mL], while CK-MB increased at six hours (P = 0.0001), but returned to baseline values at 48 hours (P = 0.05) [0.90 +/- 0.89 vs 1.27 +/- 134 vs 0.71 +/- 0.63 ng/mL] and Tn-I increased at six hours (P = 0.0001) and returned to baseline levels at 48 hours (P = 0.32) [0.057 +/- 0.23 vs 0.16 +/- 0.36 vs 0.03 +/- 0.045 ng/mL]. CONCLUSION: Permanent pacemaker-defibrillator insertion is associated with myocardial ischemia and necrosis.     

Deferoxamine pretreatment reduces canine infarct size and oxidative injury

To test whether iron-catalyzed processes contribute to myocardial necrosis during ischemia and reperfusion, we administered the iron chelator, deferoxamine, to chloralose-anesthetized dogs subjected to 90 min of left anterior descending artery occlusion followed by 360 min of reperfusion. Deferoxamine blocks iron-catalyzed hydroxyl radical formation in vitro. Groups of dogs received either pretreatment with deferoxamine or iron-loaded deferoxamine (15 mg/kg over 30 min preocclusion and 2.5 mg/kg/hr during the first 120 min of reperfusion), equal volumes of saline or deferoxamine treatment during reperfusion (15 mg/kg over 30 min beginning at 75 min of occlusion followed by 2.5 mg/kg/hr during the remainder of the first 120 min of reperfusion). Infarct size as a percentage of area at risk was reduced (P less than .05) by deferoxamine pretreatment (29.8 +/- 4.8%, n = 7, +/- S.E.) compared to saline control (46.8 +/- 4.7%, n = 8), deferoxamine reperfusion (50.5 +/- 6.7%, n = 8) or iron-loaded deferoxamine (60.2 +/- 8.6%, n = 3)-treated dogs. Deferoxamine pretreatment also decreased (P less than .05) the release of oxidized glutathione into the coronary sinus during early reperfusion compared to the other groups. There were no differences between groups in area at risk, risk zone blood flow during ischemia or in heart rate-blood pressure product. Deferoxamine did not decrease hydrogen peroxide concentration, neutrophil superoxide anion production or neutrophil adherence in vitro. We conclude that iron-mediated processes, possibly including iron-catalyzed hydroxyl radical formation, contribute to myocardial necrosis during regional ischemia and reperfusion.     

Pharmacokinetics and dynamics of (+/-)-verapamil in lean and obese Zucker rats

To evaluate the mechanism of obesity-induced changes in pharmacokinetics and pharmacodynamics of verapamil observed in humans, single-dose and steady-state kinetic/dynamic studies in obese Zucker rats were done. Seven lean and five obese Zucker rats received a single dose of verapamil (2 mg/kg) and plasma samples were obtained for verapamil concentrations over the following 7 hr. Terminal elimination half-life was significantly prolonged in obese animals compared to lean (mean +/- S.D., 2.68 +/- 0.87 hr obese vs. 1.39 +/- 0.35 hr lean; P less than .01) due to the significantly increased total volume of distribution observed in the obese animals (1.62 +/- 0.28 liters obese vs. 0.83 +/- 0.14 liters lean; P less than .001). There was no significant difference in the total clearance (0.45 +/- 0.16 liters/hr obese vs. 0.43 +/- 0.10 liters/hr lean; NS) between lean and obese animals. A physiological explanation for the increased volume of distribution was evaluated by determining actual distribution of verapamil into tissue during steady-state infusion. Six lean and six obese animals received a loading infusion of verapamil (25 micrograms/min) for 1.2 hr in lean and 1.6 hr in obese rats followed by a constant infusion of 5 micrograms/min for the next 2.5 to 3 hr. Steady-state clearance was similar between groups (0.349 +/- 0.095 liters/hr obese vs. 0.244 +/- 0.066 liters/hr lean; NS). Plasma verapamil concentration at the termination of steady-state infusion was similar between lean and obese rats (0.91 +/- 0.24 microgram/ml obese vs. 1.26 +/- 0.33 microgram/ml lean).(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduction in the incidence of thrombosis by the thromboxane synthetase inhibitor CGS 13080 in a canine model of coronary artery injury

The antithrombotic potential of the thromboxane (TX) synthetase inhibitor CGS 13080 (CGS) was studied in an anesthetized open-chest canine model of coronary artery intimal wall injury induced by the local application of a low amperage electrical current (100 microA for 6 hr). CGS was administered by i.v. infusion (1 mg/kg/min) beginning 30 min before applying the direct current to the intimal wall of the vessel. CGS did not alter basal values for heart rate, blood pressure or coronary blood flow. After 6 hr of current application to the vessel, 1 of 10 CGS-treated dogs exhibited complete thrombotic occlusion of the circumflex coronary artery compared to 8 of 10 nontreated control dogs (P less than .01). Thrombus masses within the injured left circumflex coronary artery were: Control, 25.9 +/- 4.5 mg (n = 10) and CGS, 11.0 +/- 2.8 mg (n = 10); P less than .01. The concentration of TXB2 determined ex vivo in serum from thrombin-activated whole blood was decreased by CGS administration: Control, 43.15 +/- 16.08 ng/ml (n = 9) vs. CGS, 1.72 +/- .69 ng/ml (n = 10); P less than .001. Ex vivo platelet aggregometry demonstrated that arachidonic acid (0.65 mM)-induced aggregation was reduced from a control value of 82.3 +/- 7.8% (n = 10) to 45.0 +/- 11.3% (n = 10) (P less than .05), whereas aggregation in response to ADP (5 micrograms/ml) or collagen (156 and 312 micrograms/ml) was unaffected. CGS was compared with two other TX synthetase inhibitors, U63557A and OKY1581, for the ability to divert cyclic endoperoxide metabolism to the synthesis of prostaglandin (PG) E2 and prostacyclin in response to stimulation of whole blood in vitro with collagen (25 micrograms/ml). CGS, U63557A and OKY 1581 were found to be equally effective with respect to PGE2 and 6-keto PGF1 alpha production in vitro. The data demonstrate that CGS is an effective antithrombotic agent in vivo and that it selectively inhibits arachidonic acid-induced platelet aggregation ex vivo and the formation of TXA2 in thrombin-activated whole blood.     

Myocardial performance index in female rats with myocardial infarction: relationship with ventricular function parameters by Doppler echocardiography.

BACKGROUND: The aim of the study was to analyze the myocardial performance index (MPI), its relationship with the standard variables of systolic and diastolic functions, and the influence of time intervals in an experimental model of female rats with myocardial infarction (MI). METHODS: Forty-one Wistar female rats were submitted to surgery to induce MI. Six weeks later, Doppler echocardiography was performed to assess infarct size (IS,%), fractional area change (FAC,%), ejection fraction biplane Simpson (EF), E/A ratio of mitral inflow, MPI and its time intervals: isovolumetric contraction (IVCT, ms) and relaxation (IVRT, ms) times, and ejection time (ET, ms); MPI = IVCT + IVRT/ET. RESULTS: EF and FAC were progressively lower in rats with small, medium and large-size MI ( P < .001). E/A ratio was higher only in rats with large-size MI (6.25 +/- 2.69; P < .001). MPI was not different between control rats and small-size MI (0.37 +/- 0.03 vs 0.34 +/- 0.06, P = .87), but different between large and medium-size MI (0.69 +/- 0.08 vs 0.47 +/- 0.07; P < .001) and between these two compared to small-size MI. MPI correlated with IS (r = 0.85; P < .001), EF (r = -0.86; P < .001), FAC (r = -0.77; P < .001) and E/A ratio (r = 0.77; P < .001, non-linear). IVCT was longer in large size MI compared to medium-size MI (31.87 +/- 7.99 vs 15.92 +/- 5.88; P < .001) and correlated with IS (r = 0.85; P < .001) and MPI (r = 0.92; P < .001). ET was shorter only in large-size MI (81.07 +/- 7.23; P < .001), and correlated with IS (r = -0.70; P < .001) and MPI (r = -0.85; P < .001). IVRT was shorter only in large-size compared to medium-size MI (24.40 +/- 5.38 vs 29.69 +/- 5.92; P < .037), had borderline correlation with MPI (r = 0.34; P = .0534) and no correlation with IS (r = 0.26; p = 0.144). CONCLUSIONS: The MPI increased with IS, correlated inversely with systolic function parameters and had a non-linear relationship with diastolic function. These changes were due to the increase of IVCT and a decrease of ET, without significant influence of IVRT.     

Insulin and losartan reduce proteinuria and renal hypertrophy in the pregnant diabetic rat

This study was designed to investigate the effect of hyperglycemia and angiotensin II (AngII) on renal hypertrophy and proteinuria in the pregnant diabetic rat. Secondary objectives were to evaluate changes in components of the renin-angiotensin axis and the effects of administration of losartan on pregnancy outcome. Fifty-three pregnant rats were allocated to 6 groups (1) nondiabetic controls (n = 12), (2) nondiabetic controls administered losartan (70-80 mg/kg/day; n = 10), (3) rats in which intravenous streptozotocin (STZ) was used to induce diabetes (55 mg/kg on day 10 of pregnancy; n = 10), (4) diabetic rats treated with losartan (n = 7), (5) diabetic rats treated with insulin (4 U/day; n = 7), and (6) diabetic rats treated with insulin and losartan (n = 7). Urinary protein excretion measured 4 days after STZ was 4 times greater in the rats with STZ-induced diabetes and significantly less in diabetic rats given losartan, insulin, or both. Postpartum kidney weight was greater in the rats with STZ-induced diabetes (2.04 +/- 0.21 g) than in the controls (1.37 +/- 0.14 g; P <.05) and reduced in the diabetic rats given losartan, insulin, or both (1.57 +/- 0.22, 1.73 +/- 0.13, and 1.51 +/- 0.14 g, respectively; P <.05). Plasma levels of angiotensin II in rats given losartan were more than 3.5 times greater than those in controls (749 +/- 436, 596 +/- 323, 567 +/- 349, and 159 +/- 28 pg/mL; P <.001). Postpartum activity of angiotensin-converting enzyme was increased in the untreated diabetic rats compared with that in control rats (162 +/- 12 vs 117 +/- 16 nmol/mL/min; P <.05). This increase was abolished by treatment with losartan or insulin. The number of newborns and mean weight of each newborn was similar in all groups. In summary, administration of losartan or insulin prevented, in part, kidney hypertrophy and protein excretion in the diabetic pregnant rat. Losartan did not affect the number or weight of newborns. Because angiotensin II receptor-blockers are contraindicated in pregnancy, good control of diabetes through the use of insulin should be advantageous.     

Effects of diphenyl-phenylenediamine on gentamicin-induced lipid peroxidation and toxicity in rat renal cortex

The hypothesis that lipid peroxidation is linked causally to the pathogenesis of aminoglycoside nephrotoxicity was tested by determining whether administration of the antioxidant, diphenyl-phenylenediamine (DPPD) would inhibit lipid peroxidation and ameliorate gentamicin-induced proximal tubular cell injury. Rats were injected with saline, gentamicin or gentamicin plus DPPD for 4 days and were sacrificed 48 hr later. Gentamicin increased malondialdehyde in renal cortex from a control level of 0.65 +/- 0.04 to 1.01 +/- 0.03 nmol/mg of protein, P less than .01; it was reduced to 0.20 +/- 0.03 by DPPD, P less than .01 compared to control. Arachidonic acid comprised 27.6 +/- 0.5% of the fatty acid in renal cortical phospholipid of control rats. Gentamicin lowered arachidonic acid to 16.7 +/- 0.9%, P less than .01, and promoted a shift toward saturated fatty acids. DPPD reversed these changes. Gentamicin depressed catalase activity from a control value of 0.211 k/min to 0.154 +/- 0.008 k/min, P less than .01. DPPD depressed catalase further to 0.095 +/- 0.066 k/min, P less than .01. Total glutathione and reduced glutathione were depressed whereas the fraction of total glutathione in the oxidized state was augmented by gentamicin. These changes were prevented by DPPD. The renal cortical phospholipidosis induced by gentamicin was not altered by DPPD. The increased urinary excretions of alanine aminopeptidase and N-acetyl-beta-glucosaminidase induced by gentamicin were augmented further by DPPD. In DPPD rats serum creatinine (0.45 +/- 0.04 mg/dl) was higher (P less than .01) than that of gentamicin rats (0.35 +/- 0.01 mg/dl), which was higher (P less than .01) than that of control rats (0.26 +/- 0.01 gm/dl).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acid cholesteryl ester hydrolase activity of mononuclear leukocyte in type 2 (non-insulin-dependent) diabetic patients

Acid cholesteryl ester hydrolase activity of mononuclear leukocytes was measured in 52 Type 2 (non-insulin-dependent) diabetic patients. Enzyme activity was significantly lower in the diabetic patients than in 14 age-matched control subjects (0.89 +/- 0.08 (mean +/- S.E.) vs. 2.20 +/- 0.17 nmol/mg protein/hr, p less than 0.01). In diabetic patients undergoing diet treatment only, the enzyme activity was significantly lower in poorly controlled patients than in well controlled patients (0.43 +/- 0.03 vs. 1.15 +/- 0.24 nmol/mg protein/hr, p less than 0.01). In the diabetic patients, there was a significant negative correlation between the enzyme activity and serum total cholesterol or low density lipoprotein cholesterol level (r = -0.361, p less than 0.01, n = 52 or r = -0.630, p less than 0.01, n = 28). These results suggest that a low level of acid cholesteryl ester hydrolase activity in mononuclear leukocyte might play an important role in the progression of atherosclerosis in Type 2 diabetes.     

Comparison of beta adrenergic receptor binding characteristics and coupling to adenylate cyclase in rat pulmonary artery versus aorta

In an effort to define the mechanisms regulating pulmonary vasodilatation and explain the greater in vitro response to iso-proterenol in the pulmonary artery (PA) vs. aorta (AO), we compared beta adrenergic receptor binding characteristics and coupling to adenylate cyclase in PA and AO obtained from adult male rats. Beta adrenergic receptor binding characteristics and affinity for agonists were determined with [125I]-iodocyanopindolol. Agonist displacement studies were characteristic of a beta-2 adrenergic receptor subtype. Receptor density (44.7 +/- 7.3 vs. 39.6 +/- 0.8 fmol/mg of protein means +/- S.E.M., PA vs. AO) and the dissociation constant for the radioligand (10.3 +/- 2.6 vs. 13.4 +/- 3.5 pM) were similar in the two arteries. However, affinity for l-isoproterenol was greater (the inhibition constant was lower) in PA compared to AO (0.08 +/- 0.03 vs. 1.20 +/- 0.18 microM, P less than .05), as was affinity for l-epinephrine (0.89 +/- 0.20 vs. 3.87 +/- 0.62 microM, P less than .05). Affinity was similar for l-norepinephrine (18.93 +/- 3.63 vs. 13.49 +/- 3.12 microM). Base-line cyclic AMP (cAMP) content, basal adenylate cyclase activity and adenylate cyclase activity stimulated by GTP, isoproterenol plus GTP and forskolin were measured by radioimmunoassay for cAMP. Base-line cAMP content was greater in PA than in AO (513.5 +/- 46.9 vs. 125.5 +/- 19.1 pmol of cAMP per mg of protein, P less than .001), as was basal adenylate cyclase activity (10.8 +/- 1.2 vs. 5.7 +/- 1.3 pmol of cAMP per mg of protein per min, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of antihypertensive treatment on the left ventricular isomyosin profile in one-clip, two kidney hypertensive rats

In order to investigate the cardiac effects of antihypertensive therapies in one-clip two-kidney hypertension in rats, we compared the consequences on myosin isoenzyme profile and on left ventricular hypertrophy of two treatments: one was a new converting enzyme inhibitor (S9490), the second a more standard tripletherapy associating clonidine, dihydralazine and furosemide. The two treatments were initiated 4 weeks after clipping and administered during 5 weeks. During the treatment period average systolic blood pressure was 215 +/- 32 mmHg in the hypertensive untreated group (HC2, n = 12) and 144 +/- 13 mm Hg in the CEI group (HT1, n = 13), which is not significantly different from the value found in the sham-operated group (139 +/- 4 mm Hg, C2, n = 13). Blood pressure was lowered only to 173 +/- 18 mm Hg in the group treated with tripletherapy (HT2, n = 12). The left ventricular weight decreased significantly in the CEI-treated group toward values similar to those of the sham-operated animals (2.2 +/- 0.13 mg/g vs. 1.9 +/- 10 mg/g, respectively NS), whereas it did not change in the tripletherapy group when compared to the untreated hypertensive animals despite the fall in blood pressure. In the hypertensive untreated rats the percentage of V1 isoenzyme of cardiac myosin was lower than in the sham-operated group (42.8 +/- 9.0% vs. 57.5 +/- 7.6% P less than .001). In parallel the V3 form of cardiac myosin increased (24.1 +/- 7.4% vs. 15.7 +/- 4.3%, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)     

On the mechanism of renin release during experimental myocardial ischaemia

An increase in plasma renin activity (PRA) following experimental coronary occlusion has previously been demonstrated in anaesthetized and conscious dogs. The purpose of the present study was to analyse the mechanism of this renin release. In two distinct models of myocardial ischaemia in anaesthetized dogs--i.e. occlusion of the left-anterior descending coronary artery (model A, n = 21) and atrial pacing in the presence of stenosis of the left-anterior descending coronary artery (model B, n = 23), an increase in arterial PRA was found from 1.68 +/- 0.43 to 3.06 +/- 0.63 ng ml-1 h-1 (model A, mean +/- SEM, P less than 0.025) and from 9.87 +/- 3.59 to 14.96 +/- 4.06 ng ml-1 h-1 (model B, P less than 0.05), respectively. The increase in PRA following coronary occlusion was not blunted by adrenergic beta-receptor blockade with propranolol (3 mg kg-1 i.v.; n = 4). Coronary sinus PRA was lower than arterial PRA and the increase in PRA did not occur in nephrectomized dogs (n = 5). The data suggest that myocardial ischaemia induces a release of renin from the kidney which is not mediated by adrenergic beta receptors.     

Effects of prolonged phenylephrine infusion on cardiac adrenoceptors and calcium channels

Effects of prolonged in vivo infusion of phenylephrine upon receptor binding and cardiac contractility were studied in Sprague-Dawley rats. A 1-hr i.v. infusion of phenylephrine (3 mg/kg/hr) resulted in a sustained 50% increase in diastolic blood pressure and 5% increase in heart rate. Chronic (6-day) infusion (3 mg/kg/hr) utilizing Alzet mini-osmotic pumps maintained plasma concentrations of phenylephrine at 1.0 microgram/ml, depleted myocardial norepinephrine stores 8-fold and resulted in a modest cardiac hypertrophy. Density and affinity of myocardial adrenoceptors and calcium channels were quantified by analyzing saturation isotherms of radioligand binding. [3H]Prazosin, [3H]dihydroalprenolol and [3H]nitrendipine bound specifically and with high affinity to cardiac alpha-1 and beta adrenoceptors and calcium channels, respectively. As measured by Scatchard analyses, phenylephrine infusion significantly decreased the maximum number (Bmax) of specific [3H]prazosin binding sites by 39% (430 +/- 20 vs. 263 +/- 16 fmol/mg of protein; P less than .05). Chronic phenylephrine treatment also decreased the Bmax for [3H]dihydroalprenolol binding by 31% (124 +/- 3.3 vs. 86 +/- 6.6 fmol/mg of protein; P less than .05) and the Bmax for [3H]nitrendipine binding by 32% (342 +/- 8.8 vs. 235 +/- 6.7 fmol/mg of protein; P less than .05). Binding affinities (Kd) of [3H]prazosin, [3H]dihydroalprenolol and [3H]nitrendipine remained unchanged. Administration of vehicle alone or surgical manipulation due to osmotic pump implantation did not affect either the density or affinity of [3H]prazosin, [3H]dihydroalprenolol or [3H]nitrendipine binding. Contractile responses to phenylephrine were studied in isolated ventricular strips to determine the functional significance of alpha-1 adrenoceptor down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of parathyroid hormone activity on gentamicin nephrotoxicity

Dietary calcium (CA++) supplementation attenuates gentamicin nephrotoxicity in rats. It has been proposed that this protective effect results from the ability of Ca++ to interfere with gentamicin binding to renal cell membranes. However, calcium supplementation also suppresses parathyroid hormone (PTH) activity, which may affect gentamicin nephrotoxicity by altering renal brush border phospholipid composition or renal calcium handling. We therefore compared gentamicin nephrotoxicity in PTH-stimulated control rats and parathyroidectomized (PTX) rats. Although their pretreatment serum ionized calcium concentration was significantly higher (1.27 +/- 0.01 vs. 0.88 +/- 0.06 mmol/L; P less than 0.001), PTH-stimulated rats had higher peak renal cortical gentamicin concentrations (543 +/- 20 vs. 395 +/- 49 micrograms/gm; P less than 0.025) and serum creatinine concentrations (3.0 +/- 0.8 vs. 0.9 +/- 0.3 mg/dl; P less than 0.05). Structural injury and depression of renal cortical slice uptake of p-aminohippurate were also less severe in PTX rats. Gentamicin treatment also caused increased urinary Ca++ excretion in control rats (from 2.12 +/- 0.64 mumol/mg creatinine per day [pretreatment] to 16.86 +/- 2.07 mumol/mg creatinine per day; P less than 0.001) but not in PTX rats. Control rats ingesting chow containing a standard Ca++ content (1.2%) resembled PTX rats. These results indicate that PTH stimulation exacerbates gentamicin nephrotoxicity. Increased peak renal cortical gentamicin concentrations in PTH-stimulated rats may be caused by increased gentamicin transport across the brush border as a consequence of PTH-mediated alteration of plasma membrane phospholipid composition, turnover, or both.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of sodium fluoride on total serum protein levels and transaminase activity in rats.

Transaminase activity and serum total protein level were investigated in adult rats after oral treating with sodium fluoride at three doses, 10, 20 and 30 mg/kg daily for 90 days. After 90 days, the average total serum protein level of the rats in the treatment group decreased significantly compared with that in the control [1.9 +/- 0.1 (mean +/- S.D., n = 140) vs. 3.1 +/- 0.2] mg/dl, P< 0.05. Serum transaminase activity in the treatment group increased compared with that in the control [5.3 +/- 0.4 (mean +/- S.D., n = 140) vs. 3.2 +/- 0.3] micromol/min per ml, P < 0.05.