Capsaicin-induced inhibition of platelet aggregation is not mediated by transient receptor potential vanilloid type 1.

Capsaicin is an agonist of transient receptor potential vanilloid type 1 (TRPV1), in which it can act as a neuronal stimulant and result in nociception. Capsaicin also affects a variety of nonneuronal tissues, in which its mechanisms of action are less certain. The present study investigated whether the inhibitory effects of capsaicin on platelet aggregation are mediated via TRPV1. Venous whole blood obtained from beagle dogs (n = 6) was preincubated with capsaicin and/or the potent and selective competitive TRPV1 antagonist, A-993610 and then exposed to collagen (2 µg/ml). An aggregometer was used to quantify the platelet response. Capsaicin exposure inhibited collagen-induced platelet aggregation in a concentration-dependent manner, with significant effects at 10 and 30 µg capsaicin per millilitre. A-993610 alone (0.1-1.0 µg/ml) had no effects on collagen-induced platelet aggregation, nor did it have any effects on capsaicin's ability to inhibit platelet aggregation. The current results agree with previous findings that capsaicin can inhibit platelet aggregation. In addition, the present study demonstrates that capsaicin's inhibitory effect on collagen-induced canine platelet aggregation is not mediated by TRPV1.

N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as acetyl-coA carboxylase inhibitors--improvement of cardiovascular and neurological liabilities via structural modifications.

A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.

Hemodynamic effects of potent and selective JNK inhibitors in anesthetized rats: implication for targeting protein kinases in metabolic diseases.

The hemodynamic effects of a series of potent and selective 4-aminopyridine carboxamide-based pan-JNK inhibitors were assessed in an anesthetized rat model. The effects of these agents on mean arterial pressure, heart rate, cardiac contractility, and peripheral vascular resistance are described, and the implication for targeting protein kinases in metabolic diseases is discussed.

Postischemic administration of CGX-1051, a peptide from cone snail venom, reduces infarct size in both rat and dog models of myocardial ischemia and reperfusion.

CGX-1051 is a synthetic version of a peptide originally isolated from the venom of cone snails. In the present studies, we tested the potential cardioprotective effect of CGX-1051 in a rat and dog model of myocardial ischemia/reperfusion. CGX-1051 was administered 5 minutes before reperfusion as intravenous bolus doses of 30, 100, and 300 microg/kg. Infarct size (IS) is reported as IS/area at risk (AAR). In the rat, the vehicle control group had an IS/AAR of 59.8+/-2.1%. Postischemic administration of CGX-1051 at doses of 30, 100, and 300 microg/kg resulted in an IS/AAR of 52.6+/-4.2%, 34.6+/-5.6% (P<0.05), and 40.8+/-5.2% (P<0.05), respectively. In the dog, the vehicle control group had an IS/AAR of 18.8+/-1.7%. Postischemic administration of CGX-1051 at doses of 30, 100, and 300 microg/kg resulted in an IS/AAR of 16.9+/-2.5%, 8.4+/-2.9% (P<0.05) and 9.9+/-2.4% (P<0.05), respectively. These results demonstrate that administration of CGX-1051 at a clinically relevant time point results in a dose-dependent reduction in IS in both rats and dogs.

Preischemic and postischemic administration of AEOL10113 reduces infarct size in a rat model of myocardial ischemia and reperfusion.

Reactive oxygen species (ROS) have been implicated as important mediators of cellular damage during ischemia/reperfusion. AEOL10113 is a low-molecular-weight superoxide dismutase mimetic that has dismutase activity against ROS. The objective of this study was to test the cardioprotective efficacy of postischemic administration of AEOL10113 in a rat model of left ventricular ischemia and reperfusion. Left ventricular infarction was produced by 25 min of left coronary artery occlusion followed by 3 h of reperfusion. Infarct size (IS) is reported as IS/area at risk (AAR). The control group had an IS/AAR of 67.5 +/- 2.6%. Postischemic administration of AEOL10113 beginning 5 min prior to reperfusion at doses of 0.03, 0.1, and 0.3 mg/kg resulted in an IS/AAR of 69.3 +/- 3.4%, 57.8 +/- 3.3% (P < 0.05), and 55.0 +/- 2.9% (P < 0.05), respectively. Preischemic administration of AEOL10113 beginning 5 min prior to occlusion at a dose of 0.3 mg/kg resulted in an IS/AAR of 44.2 +/- 5.9% (P < 0.0125). AAR as a percentage of the left ventricle and rate-pressure product were unaffected by any dose tested. The data from this study demonstrate that pre- and postischemic administration of AEOL10113 reduces IS in a rat model of myocardial ischemia and reperfusion.

K-ATP opener-mediated attenuation of spontaneous bladder contractions in ligature-intact, partial bladder outlet obstructed rats.

Symptoms of urinary frequency and urgency secondary to benign prostatic obstruction are common in elderly men. In many patients, these symptoms correspond to the urodynamic finding of involuntary detrusor contractions during filling cystometry (i.e., detrusor instability). Spontaneous non-voiding contractions during filling can be modeled in animals by subchronic, partial urethral obstruction. However, many investigators remove the obstructive ligature a few days prior to cystometrical evaluation (which may not be an ideal representation of the clinical situation where obstruction is still present), and all perform cystometry within 3 days post-bladder catheterization surgery (i.e., while considerable wound healing is present). In the current study, we evaluated the effects, after oral dosing, of three structurally diverse ATP-sensitive potassium channel openers (KCOs) on spontaneous contractions secondary to obstruction in rats with an intact obstructive ligature at the time of testing and 2 weeks post-bladder catheterization. ZD6169, WAY-133537 and a novel dihydropyridine KCO, A-278637, all significantly decreased spontaneous bladder contractions at 30 min post-dosing (p.o.). However, only ZD6169 (10 micromol/kg) and A-278637 (3 micromol/kg) attenuated such bladder contractions at doses that did not concurrently, significantly affect mean arterial blood pressure and heart rate. These data confirm the efficacy of KCOs to inhibit unstable contractions in obstructed rats, and they further demonstrate the positive effect of a novel, bladder-selective KCO, A-278637, in an animal model with potentially less artifact than in previous such models.

Oral bimoclomol elevates heat shock protein 70 and reduces myocardial infarct size in rats.

Bimoclomol has been shown to increase an inducible member of the heat shock protein 70 family (HSP70) and cytoprotect in vitro. Here, we addressed whether oral pretreatment of rats with bimoclomol could elevate myocardial HSP70 and reduce infarct size in a rat model of ischemia and reperfusion. Rats were pretreated with bimoclomol at 3, 6 or 18 h or with 42 degrees thermal stress 24 h before ischemia. Infarct size was significantly decreased 6 h after oral administration of bimoclomol and 24 h after thermal stress. Left ventricles from a separate group of rats were examined for HSP70 levels. Western blots showed a significant increase in HSP70 6 h after oral administration of bimoclomol and 24 h after thermal stress. There was a significant correlation (P<0.05) between HSP70 induction and infarct size reduction, whether produced by thermal stress or oral administration of bimoclomol. Thus, bimoclomol can increase HSP70 and reduce infarct size in a rat model of ischemia and reperfusion.