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Biomedical subjects

J W Constantine

Publications and source records attributed to J W Constantine.

At least 19 recordsLinked to original sources
PubMed1994

Cardiovascular effects of CP-96,345, a non-peptide blocker of tachykinin NK1 receptors.

CP-96,345, a non-peptide, selective tachykinin NK1 receptor blocker and its inactive enantiomer, CP-96,344, inhibit ligand binding of phenylalkylamine but not dihydropyridine Ca2+ channel antagonists. Whether these Ca2+ channel antagonist properties of CP-96,345 and CP-96,344 can be expressed as cardiovascular effects in vitro and in vivo is unknown. The cardiovascular effects of CP-96,345 and CP-96,344 in isolated vascular smooth muscle and in anesthetized dogs were compared to those of verapamil and nifedipine, phenylalkylamine and dihydropyridine Ca2+ channel antagonists, respectively. CP-96,345, CP-96,344, verapamil and nifedipine inhibited Ca(2+)-induced contractions in rat isolated portal vein with pD2' values of 5.9, 5.8, 6.8 and 8.1, respectively. In closed chest, anesthetized, spinal-pithed dogs, CP-96,345 caused dose-related hypotension and depressed heart rate. In open chest, anesthetized beagles at equihypotensive doses, CP-96,345, 1 mg/kg, CP-96,344, 1 mg/kg and verapamil, 0.5 mg/kg caused significant negative chronotropic, dromotropic and inotropic effects that were not observed with nifedipine, 0.01 mg/kg or nitroglycerin, 0.02 mg/kg. We conclude that the cardiovascular effects of CP-96,345 and its isomer are due to 'verapamil-like' Ca2+ channel antagonism and are not related to blockade of NK1 receptors.

Animals↗
PubMed1991

A potent nonpeptide antagonist of the substance P (NK1) receptor.

CP-96,345 [(2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)- methyl]-1-azabicyclo[2.2.2]octan-3-amine] is a potent nonpeptide antagonist of the substance P (NK1) receptor. CP-96,345 inhibited 3H-labeled substance P binding and was a classical competitive antagonist in the NK1 monoreceptor dog carotid artery preparation. CP-96,345 inhibited substance P-induced salivation in the rat, a classical in vivo bioassay, but did not inhibit NK2, NK3, or numerous other receptors; it is thus a selective NK1 antagonist. This compound may prove to be a powerful tool for investigation of the physiological properties of substance P and exploration of its role in diseases.

Animals↗
PubMed1991

Inhibition of tachykinin-induced hypotension in dogs by CP-96,345, a selective blocker of NK-1 receptors.

The effects of substance P, neurokinin A, neurokinin B, [Sar9, Met(O2)11]-substance P, [Nle10]-neurokinin A (4-10) and senktide (succinyl-[Asp6, MePhe8]-substance P (6-11)) on blood pressure and heart rate were studied in anesthetized dogs. Dose-dependent decreases in blood pressure and increases in heart rate were caused by each peptide except senktide. The latter elicited weak hypotensive or hypertensive responses at high doses. The order or potency was as follows: [Sar9, Met(O2)11]-substance P greater than or equal to substance P greater than neurokinin A greater than neurokinin B greater than [Nle10]-neurokinin A (4-10) much greater than senktide. CP-96,345, [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine] a selective NK-1 tachykinin receptor blocker, inhibited substance P-induced hypotension in a dose-related manner. Responses to each of the other peptides were inhibited by CP-96,345, 1.0 mg/kg (excluding senktide against which CP-96,345 was not tested). CP-96,344 (1.0 mg/kg i.v.) the 2R-3R enantiomer of CP-96,345 which does not block NK-1 receptors, had no effect on substance P-induced hypotension. We conclude that tachykinin-induced hypotension in dogs is mediated by NK-1 tachykinin receptors.

Animals↗
PubMed1990

Smooth muscle of rabbit isolated aorta contains the NK-2 tachykinin receptor.

Neurokinin A, neurokinin B and substance P caused concentration-related contractions of rabbit isolated aorta with pD2 values of 8.1, 6.9, and 6.0, respectively. [D-Pro2, D-Trp7, 9]-substance P, a competitive tachykinin antagonist, had pA2 values of 5.3 against neurokinin A, 5.1 against neurokinin B and 5.2 against substance P indicating that tachykinin receptors mediated responses to the agonists. [pGlu5,MePhe8,-MeGly9]-substance P 5 - 11 (DiMe-C7), senktide and septide did not contract the aorta. It is concluded that of the known tachykinin receptors smooth muscle of the rabbit isolated aorta contains only the NK-2 type.

Animals↗
PubMed1986

Nifedipine attenuates both alpha-1 and alpha-2 adrenoceptor-mediated pressor and vasoconstrictor responses in conscious dogs and primates.

Effects of the calcium channel blocker, nifedipine, were examined on the pressor and vasoconstrictor responses to stimulation of alpha-1 and alpha-2-adrenoceptors in chronically instrumented conscious dogs and Rhesus monkeys. Norepinephrine (NE), a mixed alpha-1 and alpha-2 adrenoceptor agonist, phenylephrine (PE) and methoxamine (M), selective alpha-1 adrenoceptor agonists, and B-HT 920, a selective alpha-2 adrenoceptor agonist, were injected i.v. after ganglionic (hexamethonium), beta adrenoceptor (propranolol) and muscarinic receptor (atropine methyl bromide) blockade. In the dog, NE (0.1 microgram/kg i.v.), PE (1 microgram/kg i.v.), M (20 micrograms/kg i.v.) and B-HT 920 (1 microgram/kg i.v.) produced similar increases in mean arterial pressure (NE, 52 +/- 4 mmHg; PE, 42 +/- 4 mm Hg; M, 43 +/- 7 mm Hg; B-HT 920, 45 +/- 6 mm Hg) and total peripheral resistance (NE, 20.8 +/- 5.8 mm Hg/l/min; PE, 23.1 +/- 4.2 mm Hg/l/min; M, 18.2 +/- 2.1 mm Hg/l/min; B-HT 920, 24.8 +/- 7.1 mm Hg/l/min). Nifedipine (0.5 microgram/kg/min i.v.) caused a similar attenuation of the pressor (NE, -54 +/- 8%; PE, -43 +/- 8%; M, -49 +/- 6%; B-HT 920, -56 +/- 8%) and vasoconstrictor (NE, -66 +/- 11%; PE, -52 +/- 9%; M, -60 +/- 13%; B-HT 920, -57 +/- 10%) responses to each of the alpha-adrenoceptor agonists. Nifedipine also attenuated pressor responses to alpha-1 and alpha-2 adrenoceptor agonists similarly in conscious monkeys. Thus, in conscious dogs and monkeys, calcium channel blockade attenuates similarly both alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction.

Animals↗
PubMed1983

Effects of trimazosin and prazosin on blood pressure and on pressor responses to phenylephrine in rats.

As part of an ongoing investigation into the cardiovascular properties of trimazosin, 99 male Sprague-Dawley rats were anesthetized and cannulas were placed in jugular veins for administration of drugs. The rats were injected with phenylephrine and then treated with either solvent, diazoxide, prazosin, or trimazosin. Blood pressure and heart rate were measured by a pressure transducer and a biotachometer, respectively; both were recorded continuously. Preliminary results indicate that trimazosin was less potent but more efficacious in lowering blood pressure than was prazosin and caused less blockade of the alpha-1-adrenoceptors even when its hypotensive effect exceeded that of prazosin. The differences in hypotensive potency and in alpha-1-receptor blockade are consistent with the fact that trimazosin has less affinity than does prazosin for alpha-1-receptors in vitro. The greater efficacy of trimazosin, compared to prazosin, is further evidence that in addition to alpha-1-receptor blockade, another mechanism contributes to the hypotensive effect of trimazosin. This mechanism has yet to be elucidated.

Animals↗
PubMed1983

Structure-activity studies of configurationally rigid arylprostaglandins.

Potent, albeit nonselective, smooth-muscle stimulant activity has been previously reported for 16-phenoxy- and 17-phenylprostaglandins, a finding that led to the design and development of the tissue-selective uterine stimulant sulprostone. As an extension of this work, analogues incorporating the 16-phenoxy and 17-phenyl substituents into the rigid indanyl, tetrahydronaphthyl, dihydrobenzofuryl, and dihydrobenzopyranyl ring systems were prepared and evaluated for uterine stimulant activity in vitro and diarrheal effects in vivo. Since these cyclic groups, with the exception of the indanyl, contain a chiral center, both optical antipodes were prepared. These studies demonstrate that ring size, heteroatom, and absolute configuration at C-16 are important determinants for potency and selectivity.

Abortion, Induced↗
PubMed1982

Functional postsynaptic alpha 2- but not alpha 1-adrenoceptors in dog saphenous vein exposed to phenoxybenzamine.

Phenoxybenzamine greatly attenuated phenylephrine-induced contractions of dog saphenous vein in vitro, but had less effect on contractions induced by clonidine. The phenoxybenzamine-resistant responses to clonidine were not affected by prazosin or by corynanthine but were competitively antagonized by yohimbine (pA2 8.2). It is concluded that exposure of saphenous vein to phenoxybenzamine resulted in blockade of alpha 1-adrenoceptors to the extent that there remained a virtually homogeneous population of postsynaptic alpha 2-adrenoceptors. The effects of agents at postsynaptic alpha 2-adrenoceptors can be studied on this preparation without the complications caused by the presence of functional alpha 1-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1982

Blockade of central alpha 2-adrenoceptors enhances the carotid occlusion response in dogs.

Intravertebral artery injection of yohimbine at total doses of 10, 50, 100 and 200 micrograms caused dose-related enhancement of the systemic pressor response to bilateral carotid artery occlusion (BCO) in dogs; the response was depressed by 5000 micrograms yohimbine. Basal blood pressure was increased by 100 and 200 micrograms yohimbine, and decreased by 5000 micrograms. Intravertebral artery injection of rauwolscine, 5 micrograms enhanced the BCO response but had no effect on basal blood pressure. Corynanthine, 200 or 500 micrograms was ineffective. The pressor response to intravenously administered noradrenaline was not affected by any of the drugs. It is concluded that enhancement of the BCO response by yohimbine and rauwolscine is caused by blockade of central alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1981

The cardiovascular effects of trimazosin.

Trimazosin, a quinazoline related to the antihypertensive agent prazosin, was studied in anesthetized animals and isolated tissue preparations for effects related to cardiovascular activity. In cats, there was no evidence for ganglion-, adrenergic neurons-, or beta -adrenoceptor blockade, but the pressor effect of epinephrine was reversed. In dogs, the hypotensive effect to trimazosin was due to selective blockade of vascular alpha 1-adrenoceptors. Trimazosin competitively antagonized norepinephrine-induced contraction of rabbit aorta, and in rabbit pulmonary artery it selectively blocked postsynaptic alpha 1-adrenoceptors. In spinal-pithed dogs and rats trimazosin lowered blood pressure, in contrast to the lack of such activity reported for prazosin in pithed rats. It is concluded that trimazosin lowers blood pressure by selective blockade of alpha 1-adrenoceptors, and has, in addition, a hypotensive effect in pithed animals which is not due to alpha -adrenoceptor blockade.

Adrenergic alpha-Antagonists↗
PubMed1981

Smooth muscle of rabbit aorta contains alpha 1-but not alpha 2-adrenoceptors.

We have investigated the residual contractile response to noradrenaline remaining after phenoxybenzamine (3 x 10(-7) mol/l) in rabbit aorta, since it has been reported that phenoxybenzamine at low doses completely and irreversibly blocks alpha 1-but not alpha 2-adrenoceptors. The contraction elicited by noradrenaline slowly recovered with time after it had been almost abolished by phenoxybenzamine. This residual response was blocked by the alpha 1-selective antagonist prazosin (3 x 10(-8) mol/l) but not by the alpha 2-selective antagonist rauwolscine (3 x 10(-7) mol/l). The results confirm that the smooth muscle of rabbit aorta contains alpha 2-but not alpha 2-adrenoceptors.

Animals↗
PubMed1981

Comparative pharmacology and clinical efficacy of newer agents in treatment of heart failure.

The animal and human pharmacology of several new drugs (prazosin, trimazosin, pirbuterol, and carbazeran) useful in the treatment of congestive heart failure (CHF) is delineated in relation to the pharmacology of other agents employed for CHF management. Prazosin and trimazosin are selective alpha 1-blockers that cause a balanced increase in cardiac output (CO) and reduction in left ventricular filling pressure (LVFP); the reduction in diastolic blood pressure with these drugs is significantly related to increase in treadmill exercise, fall in LVFP, and increase in CO. Pirbuterol is a relatively selective beta 2-agonist with somewhat greater effects on CO than on LVFP. Early promise in CHF therapy is being shown by a novel series of cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitors with combined direct inotropic and vasodilator effects. Double-blind long-term studies demonstrate persistent efficacy of prazosin and trimazosin in CHF as measured by improvement in New York Heart Association functional class, treadmill exercise performance, and noninvasive measures of cardiac function; these data are supported by studies in which repeat cardiac catheterization has been performed after several months of therapy. Double-blind studies of other CHF drugs are in progress.

Animals↗
PubMed1981

N-(Methanesulfonyl)-16-phenoxyprostaglandincarboxamides: tissue-selective, uterine stimulants.

In an effort to develop tissue-selective prostaglandin analogues resistant to the metabolic inactivating pathways of the natural materials, hybrid compounds modified both at C-1 with a sulfonimide moiety and in the n-amylcarbinol side chain with substituted phenoxy groups were synthesized and evaluated in a variety of in vitro models. Several of these analogues exhibited potent, tissue-selective, uterine stimulant activity, a finding subsequently confirmed in clinical studies with one member of this series, N-(methanesulfonyl)-16-phenoxy-omega-tetranor-PGE2-carboxamide (CP-34089/ZK-57671, sulprostone).

Abortifacient Agents, Nonsteroidal↗
PubMed1980

alpha 1- and alpha 2-vascular adrenoceptors in the dog.

Prazosin inhibited contractions of isolated electrically stimulated dog pulmonary artery preincubated with (-)-7-3H-norepinephrine, but had no effect on 3H-overflow, whereas yohimbine enhanced both responses. In pithed dogs the cumulative doses of yohimbine required for 50% inhibition of the pressor effects of clonidine, phenylephrine and norepinephrine were 23, 188 and 35 micrograms/kg i.v., and those for prazosin were 9, 1.5 and 5 micrograms/kg i.v., respectively. The agonists could be ranked in pairs depending on the extent to which the antagonists discriminated members of the pair: clonidine-phenylephrine > phenylephrine-norepinephrine > clonidine-norepinephrine. The results suggest that pressor effects in dogs are mediated by both alpha 1- and alpha 2-vascular (i.e. postsynaptic) adrenoceptors.

Animals↗
PubMed1980

Complete blockade by phenoxybenzamine of alpha 1- but not of alpha 2-vascular receptors in dogs and the effects of propranolol.

In pithed dogs pressor responses to phenylephrine were completely inhibited 1 h after phenoxybenzamine 20 mg/kg i.v., but those to norepinephrine were only partially inhibited. The pressor effects of norepinephrine in phenoxybenzamine-treated animals were inhibited by yohimbine, 2.0 mg/kg i.v., but not by prazosin, 0.5 mg/kg i.v. In animals treated with phenoxybenzamine, 20 mg/kg i.v., plus propranolol, 5.0 mg/kg i.v., the partially restored pressor response to epinephrine, and the responses to norepinephrine, were completely inhibited by yohimbine, 2.0 mg/kg i.v., partially inhibited by corynanthine, 5.0 mg/kg i.v., but not affected by prazosin, 0.5 mg/kg i.v. In additional animals treated with phenoxybenzamine plus propranolol, yohimbine, 10, 50, 200 and 500 microgram/kg i.v., caused dose-related inhibition of both the partially restored pressor response to epinephrine, and the pressor responses to norepinephrine. It is concluded that: 1) phenoxybenzamine completely blocks alpha 1, but not alpha 2 vascular receptors; 2) the pressor effect of norepinephrine in phenoxybenzamine-treated animals, and the partially restored pressor effect of epinephrine in phenoxybenzamine-propranolol-treated animals, are both mediated by alpha 2 vascular receptors which are resistant to blockade by phenoxybenzamine.

Animals↗
PubMed1980

Structure activity studies leading to a tissue-selective hypotensive prostaglandin analog, 13,14-dihydro-16-phenyl-omega-tetranor PGE2.

During our systematic search for prostaglandins with improved tissue selectivity and metabolic stability, we synthesized a series of PGE2 analogs in which the n-amyl carbinol side chain was systematically substituted by a phenyl ring, based on structural considerations incorporating the 17,18-cis-double bond of PGE1 into an aromatic ring. These compounds were evaluated for uterine stimulant, bronchodilator and hypotensive activity. Among the divergent biological profiles exhibited by these analogs, noteworthy was the tissue-selective hypotensive profile displayed by 13,14-dihydro-16-phenyl-omega-tetranor PGE2.

Animals↗