Stephen J. Humphrey

Pfizer (United States)

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Robert B. McCall

University of Pittsburgh

Michael P. Smith

University of Manchester

Gerald R. Zins

W.E. Upjohn Institute for Employment Research

James H. Ludens

W.E. Upjohn Institute for Employment Research

J. M. MCCALL

CNS Research (United States)

William F. Jackson

Michigan State University

Gabrielle L. McLemore

Morgan State University

Domenica Altavilla

University of Messina

Muhittin Yürekli

Inonu University

Patrizia Canale

University of Messina

Cooperative Institutions

W.E. Upjohn Institute for Employment Research

Pfizer (United States)

University of Messina

Institute of Pharmacology

CNS Research (United States)

Azienda Ospedaliera Universitaria Policlinico "G. Martino"

National Institutes of Health

University of Florida

University of Maryland, Baltimore

University of North Carolina at Chapel Hill

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K-ATP-Blocking Diuretic PNU-37883A Reduces Plasma Renin Activity in Dogs

Journal of Cardiovascular Pharmacology (1998)

Stephen J. Humphrey James H. Ludens

We determined the effects of the K-adenosine triphosphate (ATP)-blocking diuretic PNU-37883A on plasma renin activity (PRA) in conscious and anesthetized dogs. In conscious dogs, oral PNU-37883A (6-60 mg/kg) was less potent than hydrochlorothiazide (0.15-1.5 mg/kg) and furosemide (FURO; 0.3-3.0 mg/kg) but exhibited high natriuretic efficacy with little kaliuresis. Unlike the standard diuretics, PNU-37883A reduced PRA by 46-76%, and its high dose minimally affected 24-h urinary aldosterone excretion. PNU-37883A, 1 mg/kg i.v., also blunted the hyperreninemia induced by 1 mg/kg i.v. FURO. In cannulated dogs, 10 mg/kg i.v. PNU-37883A maximally increased fractional Na+ clearance 140% and reduced PRA 76%, but these effects were accompanied by a mean 13 mm Hg pressor effect. In anesthetized dogs, renal artery-infused PNU-37883A (3 mg/kg/h i.r.a.) increased Na+ excretion and reduced renal venous PRA independent of hemodynamics, whereas half this dosage selectively reduced renal venous PRA and renin release, independent of hemodynamics and natriuresis. These data demonstrate that the K-ATP blocker diuretic PNU-37883A reduces PRA in dogs after oral, i.v., and i.r.a. administration and could be a useful pharmacologic agent for exploring the role of K-ATP channels in regulating renin release.

Kaliuresis

Plasma renin activity

10.1097/00005344-199806000-00013

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Citations (5)

Cardiovascular effects of the R- and S-enantiomers of ibutilide in conscious beagle dogs

Methods and Findings in Experimental and Clinical Pharmacology (2001)

Stephen J. Humphrey M. P. SMITH Chung Y. Hsu Rodney R. Walters

To support its class III antiarrhythmic candidacy, we examined the acute cardiovascular effects of ibutilide and its R- and S-enantiomers in conscious beagle dogs. Eight dogs were given stepped i.v. doses (0.01, 0.1, and 1.0 mg/kg) of these agents while monitoring changes in mean arterial pressure (MAP), heart rate (HR), and lead II ECG QTc length (index of class III activity). None of the treatments affected MAP and only R-ibutilide slightly increased HR. The R-isomer was also slightly more potent in prolonging QTc at the lowest dose, but its mean peak QTc change (+44 msec) overlapped those achieved with racemic (+37 msec) and S-ibutilide (+41 msec). Plasma drug analyses showed that total drug levels (sum of enantiomers) were similar with each agent, averaging 1, 12, and 170 ng/ml at 30 min after the low, middle, and high doses, respectively. Nearly equal enantiomer proportions were seen after racemic ibutilide, and no chiral inversion was seen after enantiomer administration. All treatments were well tolerated without enhanced ventricular ectopy. These data demonstrate that in conscious dogs, racemic, R-, and S-ibutilide similarly prolong QTc independent of appreciable cardiovascular changes, differential pharmacokinetics, or dysrhythmias, thereby helping to establish racemic ibutilide as the optimal developmental candidate.

Ibutilide

Beagle

10.1358/mf.2001.23.8.662135

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Citations (2)

ChemInform Abstract: Chiral Spirocyclic Benzopyran Potassium Channel Openers: Evidence for the Active Conformation of Levcromakalim.

ChemInform (1996)

Robert C. Gadwood Lisa M. Thomasco V E Groppi Bonnie‐Ann Burnett Stephen J. Humphrey

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Benzopyrans

10.1002/chin.199602170

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Receptor binding characterization in kidney membrane of [3H]U-37883, a novel ATP-sensitive K+ channel blocker with diuretic/natriuretic properties.

Molecular Pharmacology (1995)

Kaushik D. Meisheri Michel Fosset Stephen J. Humphrey M Lazdunski

U-37883 (4-morpholinecarboximidine-N-1-adamantyl-N-cyclohexyl), a known blocker of ATP-sensitive K+ (KATP) channels, produces natriuresis/diuresis in vivo by a direct effect on the kidney. In the present study, the binding characteristics of the U-37883 receptor were investigated using pig kidney cortex microsomes. [3H]U-37883 (0.5-5 nM, 50 Ci/mmol) exhibited specific binding, which was reversible, increased linearly with protein concentration (50-500 micrograms/ml), and was destroyed after treatment with proteases. Scatchard plots derived from the competition experiments suggested the presence of a single class of low affinity binding sites, with a Kd of 225 nM and a Bmax of 7.8 pmol/mg of protein. A similar Kd value was derived from complementary studies dealing with association and dissociation kinetics. The binding of [3H]U-37883 was tissue specific, because very little specific binding could be detected in microsomes from rat insulinoma cells (RINm5F) and brain. In contrast, these membranes displayed high affinity specific binding of [3H]glyburide, another KATP channel blocker. Finally, analogs of U-37883 that were found to be active KATP channel blockers in isolated rabbit mesenteric artery and active in vivo as diuretics/natriuretics were also found to be active in displacing specific binding of [3H]U-37883, whereas the inactive analogs (no vascular KATP channel-blocking activity and no in vivo diuresis/natriuresis) were inactive in this binding assay. We suggest that the U-37883 binding site represents a functional receptor that mediates the KATP channel antagonism and natriuresis observed with this class of compounds.

10.1016/s0026-895x(25)08514-1

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Citations (12)

Diuretic activity of N'-disubstituted morpholinoguanidine analogs of U-37883A in rats and dogs.

PubMed (1995)

Stephen J. Humphrey James H. Ludens Sam C. Perricone Louis L. Skaletzky Boyd E. Graham

U-37883A is a K+ sparing diuretic which selectively blocks openers of vascular ATP-sensitive K channels. Many N'-disubstituted morpholinoguanidine (N'-DMG) analogs of U-37883A were synthesized and tested for diuretic activity. In conscious rats, 10-100 mg/kg orally of the most active N'-DMGs increased urine volume (V) and Na+ excretion by up to 4-fold with little kaliuresis. The N'-DMGs U-37997A and U-38658A were less potent than standard diuretics, but did not induce the K+ loss seen with hydrochlorothiazide and furosemide or the K+ retention of amiloride and triamterene. In conscious dogs, 10 mg/kg i.v. of the N'-DMGs U-40389A and U-52090 increased V and Na+ excretion by over 7-fold with little kaliuresis. Despite their attractive diuresis, all of the N'-DMGs had narrow margins of safety. Reflecting their direct myocardial depressant action, in isolated rat hearts, bolus intracoronary U-37883A, U-18177A, and U-38658A (0.25-10 mumol) severely reduced the rate (-10 to -100%) and force (-9 to -100%) of contraction. These studies characterize the eukalemic diuretic activity of N'-DMG analogs of U-37883A, and demonstrate the marked cardiac depression characteristic of the morpholinoguanidine diuretic series.

Kaliuresis

Amiloride

Triamterene

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Involvement of serotonin in the central regulation of blood pressure: evidence for a facilitating effect on sympathetic nerve activity.

Journal of Pharmacology and Experimental Therapeutics (1982)

Robert B. McCall Stephen J. Humphrey

The effects of serotonin (5-HT) receptor agonists and antagonists on sympathetic nervous discharge (SND) recorded from the external carotid and splanchnic nerves were studied in baroreceptor-denervated cats. Intravenous administration of the 5-HT antagonists methysergide (0.025-1.6 mg/kg), metergoline (0.01-0.32 mg/kg), cyproheptadine (0.05-1.6 mg/kg) and cinanserin (0.2-6.4 mg/Kg) was associated with a prolonged dose-related inhibition of SND. Maximum reductions in SND produced by methysergide, metergoline, cyproheptadine and cinanserin were 90, 72, 71 and 50%, respectively. In contrast, a progressive increase in SND was observed in vehicle control animals. Methysergide, metergoline and cyproheptadine failed to reduce SND in cats pretreated with the 5-HT synthesis inhibitor p-chlorophenylalanine. Clonidine (20 micrograms/kg i.v.) significantly inhibited SND (-73%) in p-chlorophenylalanine-treated cats. The selective 5-HT agonists 5-methoxydimethyltryptamine and lisuride also reduced SND in a dose-dependent manner. The time course of the depressor effects of 5-methoxydimethyltryptamine and lisuride correlate well to their ability to inhibit 5-HT cell firing. These data indicate that 5-HT agonists which act presynaptically to inhibit 5-HT cell firing and antagonists which act postsynaptically to block the effect of synaptically released 5-HT both mediate a central reduction in SND. It is concluded that central 5-HT neurons facilitate transmission in central sympathetic pathways.

Metergoline

Methysergide

Cyproheptadine

Lisuride

Idazoxan

10.1016/s0022-3565(25)33158-7

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Citations (49)

Pathogenesis of Cardiovascular Alterations in Dogs Treated with Minoxidil

Toxicologic Pathology (1989)

G. M. Mesfin R. C. Piper Donald W. DuCharme Robert G. Carlson Stephen J. Humphrey

Minoxidil and other potent vasodilators cause coronary arterial injury, right atrial hemorrhagic lesions, and subendocardial necrosis in dogs. This paper discusses the pathogenesis of coronary arterial and right atrial lesions associated with minoxidil in the dog. Acute coronary vascular injury characterized by segmental medial hemorrhage and necrosis and perivascular inflammation occurred only during the first few days of treatment, after which tolerance to further acute injury developed. At 30 d or more of treatment, coronary vascular injury was characterized by perivascular fibrosis rarely attended by medial distortion or hyperplasia and subintimal thickening, changes consistent with responses to previous injury. Right atrial hemorrhagic lesions, unlike coronary vascular injury, often became progressively more extensive with continued treatment. At 3 d, atrial hemorrhage and inflammation were confined to the subepicardium of the right atrium, evidently around affected subepicardial branches of the right coronary artery. At 30 d, fibrovascular proliferative right atrial lesions (granulation tissue with evidence of continual hemorrhage) extended from the epicardium to the myocardium, with eventual replacement of the atrial wall by mature connective tissue at 1 yr of treatment. Minoxidil-induced cardiovascular lesions were not prevented by treatment with a β-blocker (propranolol), or an α-blocker (dibenzylene), or by sympathetic neural activity suppression (surgical sympathectomy or constant carotid sinus nerve stimulation), suggesting that the sympathetic response to the pharmacologic activity of minoxidil was not responsible for the induction of the cardiovascular lesions. Minoxidil-related vascular lesions were confined to the most pharmacologically responsive segment of the arterial system, the coronary arteries, suggesting that medial injury may have been associated with tensile changes in the arterial wall.

Minoxidil

Pathogenesis

10.1177/019262338901700113

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Citations (67)

Selective in vivo Antagonism of Pinacidil-lnduced Hypotension by the Guanidine U37883A in Anesthetized Rats

Pharmacology (1994)

Michael P. Smith Stephen J. Humphrey William F. Jackson

The pyridylcyanoguanidine pinacidil exerts its hypotensive effect by opening ATP-sensitive potassium channels (K+atp) in vascular smooth muscle. Direct glyburide-like antagonism of pinacidil-induced vasorelaxation by the guanidine U37883A (4-morpholinecarboximidine-N-l-adamantyl-N'-cyclohexylhydrochloride) has recently been demonstrated in isolated rabbit mesenteric artery. We herein report the first detailed in vivo cardiovascular interaction between U37883A and pinacidil in an anesthetized rat model. U37883A, administered from 0.1 to 3.0 mg/kg i.v. 10 min subsequent to pinacidil, immediately and dose-dependently reversed pinacidil's steady-state hypotensive effects by 29–100% (ED50 = 0.4 mg/kg), while reversal of pinacidil's tachycardiac effects from 10 to 79% was evident with 0.1–1.0 mg/kg i.v. U37883A (ED50 = 0.5 mg/kg). In contrast to these effects, pretreatment with 0.3-3.0 mg/kg i.v. U37883A only moderately inhibited the acute pinacidil-induced hypotension by 6-58%. Because U37883A's separate bradycardiac effects lowered basal heart rate, U37883A pretreatment precipitated a paradoxical 15–51 % augmentation of sustained pinacidil-induced tachycardia, although absolute heart rates were below those seen with pinacidil alone. Qualitatively similar K+ATP blocking effects by U37883A were also observed in rats treated with the K+ATP openers (PCOs) cromakalim (BRL 34915), RPS 49365 and minoxidil. However, U37883A-treated rats remained responsive to the hypotensive action of both i.v. sodium nitroprusside and isoproterenol and buccal nifedipine. This study corroborates prior in vitro and in vivo findings and establishes that the guanidine U37883A is an effective and relatively selective blocker of PCO-induced vasodilation in the anesthetized rat. U37883A also appears more effective at closing basally and pinacidil-opened K+Atp than preventing K+Atp opening by pinacidil in vivo.

Pinacidil

Cromakalim

ED50

10.1159/000139255

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Citations (11)

Whole Body and Regional Hemodynamic Effects of Minoxidil in the Conscious Dog

Journal of Cardiovascular Pharmacology (1984)

Stephen J. Humphrey Gerald R. Zins

Cardiovascular Diseases Research, The Upjohn Company, Kalamazoo, Michigan Received August 23, 1982; revision accepted July 6, 1984. Address correspondence and reprint requests to Dr. Humphrey at The Upjohn Company, 301 Henrietta Street, Kalamazoo, MI 49001.

Minoxidil

10.1097/00005344-198411000-00001

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Citations (1)

Whole Body and Regional Hemodynamic Effects of Minoxidil in the Conscious Dog

Journal of Cardiovascular Pharmacology (1984)

Stephen J. Humphrey Gerald R. Zins

Microsphere estimates of whole body hemodynamics and tissue blood flow were made in conscious and pentobarbital-anesthetized dogs treated orally with the peripheral vasodilator minoxidil. Under both circumstances, 1.0-30 mg/kg minoxidil significantly reduced mean arterial pressure 21-41% and total peripheral resistance 52-75% 4 h after administration. Dose-dependent increases in heart rate and cardiac output were evident under conscious conditions, with both parameters approximately doubling at 1.0 mg/kg. The near maximal vasodilation achieved with this dose of minoxidil was due to diminished vascular resistance in all major tissue beds. The enhanced cardiac output was associated with significant 50-87% increases in blood flow to the skin, skeletal muscle, bone, stomach, large intestine, and pancreas. Far more dramatic six- to 10-fold increases in regional myocardial blood flow were seen at this dose, which appeared to be only partially dependent on increased cardiac work. Comparable blood flow patterns were seen with acute minoxidil at doses greater than 1.0 mg/kg, and with chronic minoxidil at 1.0 and 30 mg/kg/day. These experiments establish minoxidil's relative vasodilation in the major tissue beds of the dog which contributes to its hypotensive activity.

Minoxidil

10.1097/00005344-198406060-00001

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Citations (40)