A5001582950- Nitric Oxide and Endothelin Effects
- Cardiac Arrhythmias and Treatments
- Heart Rate Variability and Autonomic Control
- Inflammatory mediators and NSAID effects
- Cardiac Imaging and Diagnostics
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Hormonal and reproductive studies
- Cardiac electrophysiology and arrhythmias
- Heart Failure Treatment and Management
- Renin-Angiotensin System Studies
- Pulmonary Hypertension Research and Treatments
- Advanced MRI Techniques and Applications
- Renal function and acid-base balance
- Eicosanoids and Hypertension Pharmacology
- Adipose Tissue and Metabolism
- Adenosine and Purinergic Signaling
- Cardiovascular Disease and Adiposity
- Mitochondrial Function and Pathology
- Receptor Mechanisms and Signaling
- Pharmacology and Obesity Treatment
- Neuroscience of respiration and sleep
- Neuropeptides and Animal Physiology
- Pharmacological Effects and Assays
- Ion channel regulation and function
- Redox biology and oxidative stress
Merck & Co., Inc., Rahway, NJ, USA (United States)
2008-2024
New York Medical College
1992-2011
Henry Ford Hospital
1999
Sapienza University of Rome
1984
University of Messina
1975
New York University
1967-1970
Columbia University Irving Medical Center
1970
Memorial Hospital
1967
Background and purpose: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated increased blood pressure. In a phase 3 clinical study, evaluating the effects atherosclerosis, there was an excess deaths adverse cardiovascular events patients taking torcetrapib. The studies reported herein sought to evaluate off‐target Experimental approach: Cardiovascular CETP inhibitors anacetrapib...
The mechanism of modulation cyclic GMP-associated vascular responses by methylene blue, an agent employed to inhibit the activation soluble guanylate cyclase in tissues, was investigated cremaster muscle microcirculation pentobarbital-anesthetized rats. effect topically applied agents on diameter third-order arterioles (15-20 microns diameter) determined vivo television microscopy. Topical application (100 microliters) acetylcholine (0.01 microgram) or nitric oxide (0.06-6 micrograms) caused...
The aims of the present study were to determine response rat cremaster muscle first-order arterioles hypoxia and role endothelium-derived prostaglandins in response. Isolated cannulated, pressurized 65 mm Hg, studied a no-flow condition bath containing Krebs' bicarbonate solution, pH 7.4, equilibrated with 21% O2-5% CO2-74% N2 (PO2, 150 Hg) or 95% N2-5% CO2 15 Hg [hypoxia]). Responses vasoactive substances before after removal endothelium blockade prostaglandin synthesis by administration...
Recent reports have indicated that vascular responsiveness can be altered by exogenously administered or endogenously released prostaglandins. Furthermore, in certain tissues inhibitors of prostaglandin synthesis been shown to limit the increase blood flow response bradykinin and enhance reduction angiotensin norepinephrine. These findings suggest an important local circulatory role for We attempted implicate further prostaglandins regulation examining effects indomethacin (IND)...
We investigated the role of nitric oxide (NO) in control myocardial O 2 consumption Fischer 344 rats. In rats at 4, 14, and 23 mo age, we examined cardiac function using echocardiography, regulation vitro, endothelial NO synthase (eNOS) protein levels, potential mechanisms that regulate superoxide. Aging was associated with a reduced ejection fraction [from 75 ± 2%at4moto66 3% ( P < 0.05) mo] an increased diastolic volume 0.60 0.04 to 1.00 0.10 ml 0.01)] heart weight (from 0.70 0.02 0.90...
Responses to changes in intravascular pressure of isolated rat mesenteric arterioles were investigated under no-flow conditions. First-, second-, third-, and fourth-generation cannulated. Vascular diameters measured with an image-shearing device recorded. The (except for the first-generation vessels) developed spontaneous tone, corresponding step increases (from 20 160 mmHg, by 20-mmHg steps). For example, at 80 mmHg mean first-, vessels 286.9 +/- 5.0, 203.4 8.2, 92.5 4.6, 35.6 4.8 microns,...
Studies in humans and animals have shown that insulin administration increases cardiac output both forearm hindlimb blood flow. In this study we tested the hypothesis dilates skeletal muscle arterioles dilation is endothelium dependent. First-order (77 microns) from rat cremaster were isolated, pressurized (65 mmHg), equilibrated a Krebs bicarbonate-buffered solution (pH 7.4) gassed with 10% O2 (5% CO2-85% N2), studied no-flow state. Cumulative concentration-response curves to (10...
Purpose: This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated COPD (PH-COPD). Methods: Eligible were 40– 80 years old (FEV /FVC < 0.7; FEV > 30% predicted) PH (mean arterial pressure ≥ 25 mmHg). Participants randomized 2:1 to or placebo via dry-powder inhaler once daily for 7 days Part (360 μg) 28 2 (380 μg). Safety was assessed by adverse events (AEs) blood oxygenation. Part-2 had...
Effects of ranolazine alone and in the presence phenylephrine (PE) or isoproterenol (ISO) on hemodynamics, coronary blood flow heart rate (HR) absence hexamethonium (a ganglionic blocker) were studied conscious dogs. Ranolazine (0.4, 1.2, 3.6, 6 mg/kg, intravenous) caused transient (<1 minute) reversible hemodynamic changes. PE (0.3-10 μg/kg) a dose-dependent increase pressure decrease HR. ISO (0.01-0.3 an at high (11-13 mM), but not moderate (4-5 mM) concentrations partially attenuated...
Several studies implicate endogenously synthesized prostaglandins in the mediation of reactive hyperemic responses coronary, renal, and skeletal muscle circulations. We sought additional evidence to involve locally released hyperemia at level microcirculation. The cremaster pentobarbital-anesthetized Wistar-strain rats was prepared for direct vivo observation measurement postocclusive single arterioles. Responses individual arterioles were reproducible over a 3-h test period. postocclusion...
Our laboratory has demonstrated previously that prostaglandins are partially responsible for the vasodilation of rat cremaster muscle arterioles in vivo to a brief occlusion or hydrogen peroxide (H2O2). In present study, pentobarbital-anesthetized rats, we investigated mechanism prostaglandin-independent portion dilation these stimuli by measurement changes diameter third order cremasteric (approximately 15 microns) video microscopy. presence indomethacin suffusion (10 micrograms/ml),...
Pharmacological probes were used to assess the possible roles of guanosine 3',5'-cyclic monophosphate (cGMP)-associated endothelium-derived relaxing factor (EDRF) in mediating microvascular responses endogenous and exogenous agents vivo. Pentobarbital-anesthetized rats (Wistar, 6 wk old) prepared for vivo microscopic observation quantification changes diameter third-order arterioles (15-25 microns) cremaster muscle topical application all agents. In indomethacin-pretreated preparations,...
SummaryAdministration of the vasode-pressor prostaglandins, PGE1 and PGE2, nitroprusside, an agent whose direct vascular activity is similar to resulted in a reduction systemic arterial blood pressure accompanied by expected reflex increase heart rate. Injection pros-tacyclin (PGI2) prostaglandin precursor, arachidonic acid, into femoral vein, pulmonary artery, left atrium, ventricle dog elicited fall concomitant rate both open- closed-chest anesthetized dogs. Bilateral vagal section...
In this study we tested the hypothesis that lactate, independent of changes in pH, can affect skeletal muscle blood flow through arteriolar dilation may be mediated by guanosine 3',5'-cyclic monophosphate. Isolated, cannulated, and pressurized first-order rat cremaster arterioles were studied a chamber containing Krebs-bicarbonate buffer under no-flow conditions. At pH 7.4 PO2 65 Torr, neutralized lactic acid (lactate) pyruvic (pyruvate) caused over 1-10 mM concentration range. This response...
With in vivo television microscopy, changes arteriolar diameter to topical administration of various vasoactive agents were examined the absence or presence NG-monomethyl-L-arginine (L-NMMA, 100 microM) NG-nitro-L-arginine (L-NNA, 2.5 microM, 20 microliters/min ia), specific inhibitors endothelium-derived relaxing factor (EDRF) biosynthesis. In cremaster muscle arterioles (15-22 microns) rats (n = 6-11), dilations acetylcholine (1-100 ng) significantly inhibited (60-70%) by either arginine...
The vascular actions of L-arginine (L-Arg) were studied in isolated, pressurized first-order rat cremaster muscle arterioles (93 +/- 2.9 microns) bathed a Krebs bicarbonate-buffered solution, pH 7.4, equilibrated with 21% O2-5% CO2. Arterioles before and after either the administration NG-nitro-L-arginine (L-NNA, 10(-3) M), an inhibitor synthesis endothelium-derived relaxing factor (EDRF), or removal endothelium. Acetylcholine (ACh, 10(-8) 10(-6) sodium nitroprusside (SNP, M) phenylephrine...
The role of endothelium in the vasodilation third order arterioles cremaster muscle to a variety vasoactive agents was investigated pentobarbital-anesthetized rats. Changes diameter topical administration were measured with image shearing, before and after mercury light/sodium fluorescein (light/dye) treatment 50- 100-microns segment arteriole under study recorded video microscopy. Before light/dye treatment, arachidonic acid (10(-5) M), prostaglandin E2 (5 x 10(-6) A23187 (2 acetylcholine...
Effects of caffeine on regadenoson-induced coronary vasodilation and changes in hemodynamics were examined conscious dogs. Sixteen dogs chronically instrumented for measurements blood flow (CBF), mean arterial pressure (MAP), heart rate (HR). Regadenoson (5 μg/kg, IV) increased CBF from 34 ± 2 to 191 7 mL/min. The duration the 2-fold increase was 515 71 seconds. decreased MAP by 15 2% HR 114 14%. Regadenoson-induced maximum increases not significantly lower presence at 1, 2, 4, 10 mg/kg (2...
Novel therapeutics for pulmonary arterial hypertension (PAH) with improved safety/tolerability profiles are needed to address continued high rates of morbidity/mortality.This Phase 1 study evaluated efficacy/safety inhaled single-dose MK-5475, an investigational, small-molecule stimulator soluble guanylate cyclase designed delivery via a dry-powder inhaler device, in participants PAH (Clinicaltrials.gov: NCT03744637). Eligible were 18-70 years age; body mass index ≤35 kg/m2; diagnosis (Group...
Abstract —The aim of this study was to determine whether bradykinin, the angiotensin-converting enzyme inhibitor ramiprilat, and calcium-channel antagonist amlodipine reduce myocardial oxygen consumption (MV̇ o 2 ) via a B -kinin receptor/nitric oxide–dependent mechanism. Left ventricular free wall septum were isolated from normal receptor knockout (B −/−) mice. Myocardial tissue measured in an airtight chamber with Clark-type electrode. Baseline MV̇ not significantly different between...
The effects of arginine analogues, inhibitors endothelium-derived nitric oxide synthesis, on dilation arterioles in response to various vasoactive substances were studied. At 65 mmHg intravascular pressure, isolated rat cremaster muscle developed tone spontaneously and achieved control diameters similar those observed vivo (84.1 +/- 2.0 microns vs. passive diameter: 161.3 3.4 microns). Acetylcholine (ACh, 5 x 10(-8) M), sodium nitroprusside (SNP, arachidonic acid (AA, 10(-7) prostaglandin E2...
In pentobarbital-anesthetized rats we investigated the role of endothelium in dilation third-order arterioles cremaster muscle to acetylcholine, adenosine, and sodium nitroprusside vivo. Responses topical administration these agents were measured with image shearing recorded video microscopy before after light-dye (L-D) treatment a 50- 100-microns segment arteriole under study. L-D consisted intravascular fluorescein illumination discrete area study its excitation light from mercury lamp....
The effects of oxygen metabolites (superoxide anion and hydrogen peroxide) on male Wistar rat cremasteric arterioles the involvement these species in mechanism vasodilation to arachidonic acid bradykinin were examined by vivo television microscopy. In present study, xanthine oxidase-derived from endogenous substrates elicited that was selectively almost completely inhibited catalase but not superoxide dismutase. These findings implicate peroxide as vasoactive metabolite generated. Topical...
Many commercially available biologics, previously delivered only intravenously, are being re-formulated for subcutaneous delivery to improve patient access and compliance. However, due inherent solubility limitations, large volume injections (more than 2 mL) typically required. Different strategies explored the tolerability of such injections, including co-formulation with hyaluronidase and/or implementing different needle designs. While there have been separate reports measuring injection...