Effects of subtype-selective and balanced angiotensin II receptor antagonists in a porcine coronary artery model of vascular restenosis.

Background: Numerous studies have demonstrated the ability of angiotensin II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors to inhibit intimal hyperplasia after balloon dilation of noncoronary arteries in small-animal models, suggesting an important role for Ang II in the response to injury. Although ACE inhibitors have not been similarly effective in nonhuman coronary models or in human restenosis trials, questions remain regarding the efficacy ACE inhibitors against tissue ACE and the contributions of ACE-independent pathways of Ang II generation. Unlike ACE inhibitors, Ang II receptor antagonists have the potential to inhibit responses to Ang II independent of its biosynthetic origin.

Vampire bat salivary plasminogen activator evokes minimal bleeding relative to tissue-type plasminogen activator as assessed by a rabbit cuticle bleeding time model.

Cuticle bleeding time (CBT) measurements in anesthetized rabbits were performed to assess the potential bleeding risks which may accompany the administration of tissue-type plasminogen activator (tPA) or vampire bat salivary plasminogen activator (BatPA). The dose of BatPA or tPA used in this study, 42 nmol/kg, was previously shown to be efficacious using a rabbit femoral artery thrombosis model (Gardell et al, Circulation 84:244, 1991). CBT was determined by severing the apex of the nail cuticle and monitoring the time to cessation of blood flow.

Nonpeptide glycoprotein IIb/IIIa inhibitors. 5. Antithrombotic effects of MK-0383.

The antiaggregatory and antithrombotic actions of MK-0383, a low molecular weight, nonpeptide antagonist of the platelet glycoprotein IIb/IIIa, were evaluated in a variety of canine models. Inhibition of ex vivo platelet aggregation responses to ADP and collagen were observed after the acute sequential i.v.

Intravenous administration of the endothelin-1 antagonist BQ-123 does not ameliorate myocardial ischaemic injury following acute coronary artery occlusion in the dog.

Objective: It has been proposed that myocardial ischaemic injury is modulated in part by the release of endothelin-1 from the coronary endothelium either during ischaemia or following reperfusion. Release of sufficient amounts of endothelin-1 would result in coronary vasoconstriction and could potentiate ischaemic damage. An endothelin-1 antagonist, BQ-123, was given intravenously to evaluate the role of endothelin-1 in postischaemic injury and determine whether blockade of the ETA receptor would afford protection from ischaemia/reperfusion injury.

Antithrombotic effects of MK-0852, a platelet fibrinogen receptor antagonist, in canine models of thrombosis.

The antiaggregatory and antithrombotic actions of MK-0852, a cyclic heptapeptide antagonist of the platelet GP IIb/IIIa, were evaluated in a variety of canine models. In vitro, MK-0852 inhibited the aggregation of canine platelet-rich plasma induced by 10 microM ADP in the presence of 1 microM epinephrine with an IC50 value of 0.10 microM.

Effect of E-4031, a class III antiarrhythmic agent, on experimental infarct size in a canine model of myocardial ischemia-reperfusion injury.

Class III antiarrhythmic agents such as E-4031 have demonstrated efficacy in preventing and/or terminating malignant ventricular arrhythmias in experimental models. It has recently been suggested that Class III agents might possess additional antiischemic properties that may translate into a reduction in the frequency or severity of arrhythmia. The potential for the Class III antiarrhythmic agent E-4031 to limit the extent of developing myocardial infarction was assessed in a barbiturate-anesthetized canine model of ischemic-reperfusion injury.

Conjunctive enhancement of enzymatic thrombolysis and prevention of thrombotic reocclusion with the selective factor Xa inhibitor, tick anticoagulant peptide. Comparison to hirudin and heparin in a canine model of acute coronary artery thrombosis.

Background: Effective thrombolytic recanalization of an occluded coronary vessel is often limited by acute thrombotic reocclusion, which has galvanized the search for effective adjunctive or conjunctive antithrombotic agents.

Methods And Results: Recombinant versions of tick anticoagulant peptide (rTAP) and hirudin (rHIR) are highly selective and potent polypeptide inhibitors of factor Xa and thrombin, respectively. The comparative antithrombotic efficacies of rTAP, rHIR, and heparin, administered conjunctively with recombinant tissue-type plasminogen activator (rt-PA), on thrombolytic reperfusion and reocclusion, were determined in a canine model of occlusive coronary artery thrombosis with a superimposed critical stenosis.

Vampire bat salivary plasminogen activator promotes rapid and sustained reperfusion without concomitant systemic plasminogen activation in a canine model of arterial thrombosis.

The efficacy of recombinant vampire bat salivary plasminogen activator (bat-PA) as a thrombolytic agent was compared with that of human tissue-type plasminogen activator (t-PA) in a canine model of arterial thrombosis. An occlusive thrombus was formed in the femoral artery by insertion of a thrombogenic copper coil; femoral arterial blood flow was monitored with a Doppler flow meter. Bat-PA and t-PA, when administered by 5-minute intravenous infusion (14 nmol/kg), reperfused seven out of eight and four out of eight dogs, respectively.

Effective thrombolysis without marked plasminemia after bolus intravenous administration of vampire bat salivary plasminogen activator in rabbits.

Background: The use of recombinant tissue-type plasminogen activator (t-PA) in thrombolytic therapy is frequently associated with significant fibrinogenolysis. In contrast, recombinant vampire bat salivary plasminogen activator (Bat-PA) displays strict fibrin specificity, an attribute that could be desirable in a fibrinolytic agent.

Methods And Results: The efficacy and fibrin selectivity of Bat-PA was evaluated and compared with that of t-PA using a rabbit model of femoral arterial thrombosis.

Acceleration of recombinant tissue-type plasminogen activator-induced thrombolysis and prevention of reocclusion by the combination of heparin and the Arg-Gly-Asp-containing peptide bitistatin in a canine model of coronary thrombosis.

The effect of tissue-type plasminogen activator (t-PA) alone or in combination with heparin, the Arg-Gly-Asp-containing peptide bitistatin, or both heparin and bitistatin was evaluated on thrombolysis time and acute reocclusion in a canine model of coronary thrombosis. Thrombus formation was elicited by electrolytic injury with a needle electrode to the endothelial surface of the circumflex coronary artery in the open-chest, anesthetized dog in the presence of a flow-limiting critical stenosis. Thirty minutes after spontaneous coronary artery occlusion, t-PA (1 mg/kg i.

Cardiac and noncardiac atrial natriuretic factor (ANF) biosynthesis and storage and plasma ANF in the rat model of chronic ventricular dysfunction.

To evaluate the role of atrial natriuretic factor (ANF) in chronic heart failure (HF), the biosynthesis and storage of ANF in cardiac and noncardiac tissues and the level of plasma ANF were measured in rats exhibiting minimal [2-fold rise in left ventricular end diastolic pressure; myocardial infarct (MI) scar length, 25% left ventricle (LV)] and moderate-severe (3-fold rise in left ventricular end diastolic pressure; decreased contractility (dp/dtmax); MI scar length, 47% LV) chronic HF 30 and 60 days after coronary arterial ligation. In rats with moderate-severe HF (30 days post-MI), the cardiac ANF mRNA concentration (determined by dot blot analysis) increased in three heart chambers [LV, 6-fold; left atria (LA), 3-fold; right ventricle (RV), 2-fold], cardiac immunoreactive ANF (IRANF; determined by RIA) concentration increased on the left side (LV, 7-fold; LA, 33%), but was unchanged (RV) or reduced on the right side (right atria, 33%), and plasma IRANF increased 3-fold above sham control values. Excluding the LV (used for MI scar length), the pattern and magnitude of change in ANF mRNA concentration in moderate-severe HF at 60 days were similar to those at 30 days; the cardiac IRANF concentration at this time was the same (LA) or less than (RV, 66%) sham values, and plasma IRANF increased 6-fold above respective sham values.

Beneficial effects of milrinone and enalapril on long-term survival of rats with healed myocardial infarction.

The long-term survival of rats with healed myocardial infarction and congestive heart failure treated with milrinone, enalapril and the combination of milrinone plus enalapril, was documented. Seven days after sham or coronary ligation, 200 rats (99 sham and 101 myocardial infarcted) were randomized based on electrocardiographic criteria to receive tap water, milrinone (20-40 mg/l drinking water), enalapril (17-25 mg/l) or the combination of milrinone plus enalapril (20-40 mg/17-25 mg per l). The date of spontaneous death was recorded and heart weights and myocardial infarct size (by planimetry) were determined.

Increased survival in rats with congestive heart failure treated with enalapril.

Vasodilating drugs such as angiotensin converting enzyme (ACE) inhibitors may extend life expectancy in patients with congestive heart failure (CHF). The purpose of this study was to evaluate whether long-term therapy (365 days) with enalapril (ENAL, an ACE inhibitor), would prolong life in rats with a healed myocardial infarction (MI), an experimental model with hemodynamic characteristics of CHF. Seven days after sham or coronary ligation, when the healing phase of MI was well underway, 132 rats (75 sham, 57 MI) were randomized to receive either enalapril in the drinking water (17-25 mg/L, approximately 1.

Measurement of cardiac output in anesthetized rats by dye dilution using a fiberoptic catheter.

A method is described for the measurement of cardiac output and oxygen saturation in closed-chest rats using a small (2.4 F) commercially available fiberoptic catheter and a reflection-spectral-photometer. Positioned in the aortic arch, the catheter functions as an oxymeter for oxygen saturation and as a densitometer for measurement of indocyanine green, obviating the need for blood removal and passage through a densitometer.

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.

Acute and subacute hemodynamic effects of enalaprilat, milrinone and combination therapy in rats with chronic left ventricular dysfunction.

A model of congestive heart failure (CHF) was produced in rats approximately 76 days following surgical occlusion of the left coronary artery. In rats with healed myocardial infarction (MI size = 45% LV), hemodynamic variables were predictably elevated (LVEDP greater than 20 mm Hg) or depressed LV dP/dtmax (5200 mm Hg/sec). The hemodynamic response (MAP, HR, LVEDP, and dP/dtmax) to intravenous infusion of Mil (54 to 347 micrograms/kg) was measured on two occasions, separated by a 7-12 day period of oral treatment (2 mg/kg/day).

Synthetic atrial natriuretic factor in conscious normotensive and hypertensive rats.

Synthetic atrial natriuretic factor (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 [disulfide bond between cysteines]) was infused intravenously into conscious normotensive and deoxycorticosterone, one-kidney, one-clip, and two-kidney, one-clip hypertensive rats. Mean arterial pressure, urine volume, and electrolyte excretion rates were measured during a 20-minute infusion of a single dose (ranging from 0-1520 pmol/min) into each animal; 95 to 380 pmol/minute of synthetic atrial natriuretic factor maximally reduced mean arterial pressure by -20 +/- 4, -29 +/- 2, and -39 +/- 7 mm Hg in normotensive, one-kidney, one-clip, and two-kidney, one-clip hypertensive rats, respectively. In deoxycorticosterone rats, a dose of 760 pmol/minute was required to produce the largest depressor response (-58 +/- 12 mm Hg).

Renal and systemic effects of synthetic atrial natriuretic factor.

A synthetic peptide corresponding to a sequence of 26 amino acids contained in endogenous rat atrial natriuretic factor (ANF), was infused into one renal artery of anesthetized dogs for a comprehensive in vivo evaluation of the renal and systemic effects of pure ANF. The results proved conclusively that ANF acted directly on the kidney since urine volume and fractional excretion of sodium, potassium, chloride and calcium were elevated in a dose-related manner in the ANF-treated kidney, but were not significantly affected in the contralateral saline-infused organ. The maximum effects achieved with the synthetic ANF were higher than any reported following intravenous administration of crude extracts of rat atria and were similar to those produced by thiazide diuretics.

Novel renin inhibitors containing the amino acid statine.

The proteolytic enzyme renin (EC3.4.99.