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J D Kohli

Publications and source records attributed to J D Kohli.

At least 37 records · Page 2Linked to original sources
PubMed1986

Relative activities of SCH 23390 and its analogs in three tests for D1/DA1 dopamine receptor antagonism.

Inhibitory activities of a series of analogs of SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) in which the 7-chloro group was substituted by bromo, fluoro, methyl and methoxy groups, respectively, were compared in three tests for D1 and DA1 dopamine (DA) receptor antagonism: inhibition of DA-induced renal vasodilation in the anesthetized dog (DA1 receptor model), inhibition of DA-stimulated adenylate cyclase in the striatum of adult female rats (D1 receptor model) and displacement of [3H]SCH 23390 in the striatal homogenates of male rats. In addition the D2 receptor affinity of each of the compounds chosen was assessed via displacement of [3H]spiperone binding from rat striatum. S-enantiomers of the Cl and CH3 analogs were 200- to 700-fold weaker than the respective R-enantiomers in all three tests. The activity of all the R-enantiomers was in the nanomolar range and varied no more than 8-fold in all three tests. The F analog in the ligand binding test was the only exception, which was 30-fold weaker than the C1 analog. All of the R-enantiomers studied showed much weaker affinity for the D2 receptor, as assessed by displacement of [3H]spiperone binding. Similar enantiomer selectivity and parallel affinities of the R-enantiomers in the prototype models for D1 and DA1 receptors strengthen the evidence in support of identity between the D1 and DA1 dopamine receptors. These results further indicate that displacement of SCH 23390 in the ligand binding test reflects affinity of a compound for D1 and DA1 dopamine receptors.

Adenylyl Cyclases↗
PubMed1986

Alpha-adrenoceptor blocking activity of fenoldopam (SK&F 82526), a selective DA1 agonist.

The alpha-adrenoceptor blocking activity of fenoldopam (SK&F 82526), a selective dopamine vascular receptor (DA1) agonist, was evaluated in isolated segmental preparations of rabbit aorta, dog mesenteric and rabbit splenic arteries. Fenoldopam, in concentrations ranging from 10(-6) to 10(-4) M, produced parallel, dextral shifts of concentration-contractile response curves to noradrenaline. Slopes of the Schild regression lines were not significantly different from unity in the three vessels. pA2 values for fenoldopam in the rabbit aorta, dog mesenteric and rabbit splenic arteries were 5.48 +/- 0.08, 5.78 +/- 0.05, and 5.20 +/- 0.05, respectively. In experiments where the drug was added to the bathing medium before exposing the vascular segments to the irreversible alpha-adrenoceptor antagonist, phenoxybenzamine, fenoldopam provided nearly complete protection against alpha-adrenoceptor blockade. These results demonstrate that fenoldopam possesses alpha-adrenoceptor antagonist activity and competes with alpha-phenoxybenzamine, for occupancy at the same receptor site.

Adrenergic alpha-Antagonists↗
PubMed1986

Bulbocapnine is not a selective DA1 receptor antagonist.

Antagonist activity of bulbocapnine on DA1 versus DA2 dopamine receptors was studied simultaneously in a dog under pentobarbitone anaesthesia and without phenoxybenzamine pretreatment. Fenoldopam (SK&F 82526) injected into the renal artery was the DA1 agonist and dipropyl dopamine or piribedil injected into the femoral artery were the DA2 agonists. Both at 0.5 and 1 mg kg-1 doses intravenous bulbocapnine caused nearly equal inhibition of DA1 and DA2 dopamine receptor-mediated responses. Our results show that under these experimental conditions bulbocapnine is not a selective DA1 dopamine antagonist.

Animals↗
PubMed1985

Effects of the enantiomers of 3-PPP on DA1 and DA2 dopamine receptors in the dog.

The (+)- and (-)-enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) were studied for their effects on DA1 and DA2 dopamine receptors in pentobarbital anesthetized dogs. 3-PPP enantiomers were administered into the renal artery after phenoxybenzamine pretreatment to determine possible DA1 activity; dopamine was also injected for comparison. DA2 activity was determined by injection of the enantiomers into the femoral vascular bed with intact nerve supply and without phenoxybenzamine; dipropyl dopamine (DPDA) or apomorphine were used as standard DA2 agonists. Antagonist activity of the enantiomers on DA1 or DA2 receptors was determined by simultaneous administration of the enantiomer with DA in the renal vascular bed and with DPDA or apomorphine in the femoral vascular bed. Neither enantiomer was active as a DA1 agonist, but both exhibited antagonist activity. Both enantiomers were found to be agonists of the DA2 receptor; in addition, both showed DA2 antagonist activity. In all actions the (-)-enantiomer was approximately 4 times more potent than the (+)-enantiomer.

Animals↗
PubMed1985

Comparison of the cardiovascular actions of dopamine and epinine in the dog.

The effects of i.v. infusions of 3 and 6 micrograms/kg/min of dopamine (DA) and epinine on heart rate, arterial blood pressure, regional blood flows and vascular resistances in the renal, mesenteric and femoral vascular beds were compared in pentobarbital-anesthetized dogs. At the 3 micrograms/kg/min infusion rate, neither DA nor epinine changed blood pressure, whereas at the higher infusion rate both increased blood pressure by about 20 mm Hg. DA increased renal blood flow significantly at both infusion rates; whereas, epinine did not change renal blood flow. After administration of phenoxybenzamine, both epinine and DA decreased blood pressure; upon adding propranolol, the vasodepressor effect of epinine, but not of DA, was abolished. However, propranolol did not inhibit epinine-mediated vasodilation in the renal or mesenteric vascular beds, but a marked increase in femoral vascular resistance was observed. The addition of (R)-sulpiride, a DA antagonist, abolished DA and epinine-induced vasodilation in the mesenteric and renal vascular beds. Experiments in animals treated with hexamethonium to block ganglion transmission and propranolol to block beta adrenoceptors revealed that both selective alpha-1 (terazosin) and alpha-2 (rauwolscine) adrenoceptor antagonists inhibited the vasopressor response to DA to a greater degree than the responses to epinine. Thus, although DA and epinine possess significant DA1 activity, the consistent increase in renal blood flow observed with DA is not seen with epinine because of the more potent alpha adrenoceptor activity of the latter, which is mediated by both alpha-1 and alpha-2 adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1984

C(2)-Methylation abolishes DA1 dopamine agonist activity of 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN): steric intolerance by the receptor.

The synthesis of 2-amino-2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene is reported. This compound did not produce vasodilation in the dog renal artery and was inactive as a DA1-type dopamine agonist. This is in contrast to the 2-nonmethylated homologue 6,7-ADTN, which is a potent DA1 agonist. High-field 1H NMR studies of the O,O-dimethyl ethers for both compounds as their free bases in chloroform-d revealed that the 2-methyl homologue probably exists as a rapidly equilibrating mixture of conformers; it seems likely that it can adopt the active conformation proposed to be required by the dopamine receptor. The lack of activity is therefore attributed to the steric effect of the 2-methyl group, consistent with explanations offered by others that the dopamine receptor cannot tolerate alkylation at the alpha side-chain carbon.

Animals↗
PubMed1983

Selective DA2 versus DA1 antagonist activity of domperidone in the periphery.

Relative activity of domperidone as an antagonist of the two peripheral dopamine (DA) receptors, DA1 and DA2, was studied in pentobarbital-anesthetized dogs. Renal vasodilation produced by intra-arterial injection of DA into the phenoxybenzamine-pretreated renal vascular bed was the DA1-mediated response, while femoral vasodilation induced by dipropyl dopamine injected into the femoral artery with intact nerve supply was the DA2-mediated response. Domperidone, 0.5-5 micrograms/kg intravenously, inhibited the DA2 response by 15-75%. In contrast, doses up to 5 mg/kg had no effect on DA1-mediated or bradykinin-induced renal vasodilation. Domperidone has thus proved to be more selective than other DA2 antagonists, differentiating between the two peripheral DA receptors by a margin of greater than 10(4). Furthermore, domperidone was found to be selective as a DA2 versus alpha 2-adrenergic antagonist as studied on the dog cardioaccelerator nerve, thus, enhancing its value as a selective DA2 antagonist.

Animals↗
PubMed1982

Modification of cardiovascular actions of 2-amino-5,6-dihydroxytetralin by N,N-di-n-propyl substitution.

Effects of dopamine (DA) and the N,N-di-n-propyl derivative of 2-amino-5,6-dihydroxytetralin (dipropyl-A-5,6-DTN) were compared on renal blood flow in phenoxybenzamine pretreated dogs. Equivalent increments in renal blood flow were observed in the dose range of 12-190 nmol (ED50 of DA, 1.4 x 10(-8) mol; ED50 of dipropyl-A-5,6-DTN, 1.2 x 10(-8) mol, n = 7). Effects of 47 nmol of DA and dipropyl-A-5,6-DTN were reduced equally by simultaneous injections of 0.5 mg sulpiride (76 +/- 4 and 59 +/- 6%, respectively, n = 5). Intravenous injections of dipropyl-A-5,6-DTN in doses of 4-16 micrograms/kg elevated arterial blood pressure and decreased heart rate and cardiac contractility in open chest, vagotomized dogs, confirming its neuronal inhibitory effect mediated by DA2-presynaptic receptors. Dipropyl-A-5,6-DTN also caused dose-related femoral artery vasoconstriction in the hexamethonium pretreated dog. The hypertensive effect of intravenous dipropyl-A-5,6-DTN and its femoral vasoconstrictor effect were abolished by phenoxybenzamine. These results show that dipropyl-A-5,6-DTN possesses DA1-, DA2- and alpha-adrenergic activities. It is significant that by introducing di-n-propyl substitution on the nitrogen of 5,6-dihydroxy-2-aminotetralin, potent DA1-agonist activity can be conferred upon a molecule which is inactive in that respect. Further, beta-adrenergic activity of the primary amine is replaced by potent alpha-adrenergic activity by this substitution.

Adrenergic alpha-Agonists↗
PubMed1982

Synthesis of 2-(alkylamino)-5,6- and -6,7-dihydroxy-3,4-dihydroquinazolines and evaluation as potential dopamine agonists.

Based upon the known dopaminergic properties of 2-aminodihydroxy-1,2,3,4-tetrahydronaphthalenes (ADTN's), heterocyclic congeners were prepared. Several 2-(alkylamino)-5,6- and -6,7-dihydroxy-3,4-dihydroquinazolines were synthesized and tested for a dopamine-like vasodilatory action in the canine renal artery. The 6,7-disubstituted series had a weak antagonist effect against dopamine. Neither 5,6- nor 6,7-dihydroxy substitution gave dopamine agonists. Measured pKa values confirmed the expectation that the dihydroquinazolines were more basic than dopamine, one possible reason for the lack of dopamine-like action.

Animals↗
PubMed1982

Influence of sex hormones on parathion toxicity in rats: antiacetylcholinesterase activity of parathion and paraoxon in plasma, erythrocytes, and brain.

Administration of parathion resulted in a greater inhibition of acetylcholinesterase (AChE) activity of plasma, erythrocytes, and brain in female rats than in male rats. No sex-related difference was observed in the antiacetylcholinesterase activity of paraoxon, an active metabolite of parathion. Gonadectomy increased the susceptibility of males but had no perceptible effect on females, resulting in comparable inhibition of AChE by parathion in both sexes. Administration of testosterone led to recovery from increased sensitivity to the antiacetylcholinesterase activity of parathion in castrated males and afforded partial protection to ovariectomized females. On the other hand, administration of estradiol further enhanced the enzyme inhibition by parathion in castrated males but had no significant effect on that in ovariectomized females. Alterations in the status of sex hormones did not affect the antiacetylcholinesterase activity of paraoxon in plasma and erythrocytes. However, inhibition of AChE activity by paraoxon was significantly higher in brains of gonadectomized rats than those of normal rats and the effect was reversible on administration of the respective sex hormones. The results indicate that testosterone plays an important role in determining parathion toxicity (as reflected by its antiacetylcholinesterase activity), probably by activating the oxidative cleavage of the insecticide into nontoxic metabolites.

Animals↗
PubMed1982

Contractile actions of racemic and d-propranolol on isolated canine mesenteric and coronary arteries.

This investigation was undertaken to determine whether propranolol exerts a direct vasoconstriction action which contributes to the increased systemic and regional vascular resistance observed after its acute administration. Helically cut strips of canine mesenteric and coronary arteries were exposed to cumulative concentrations of racemic propranolol, d-propranolol, metoprolol and sotalol. Racemic and d-propranolol were equipotent in eliciting concentration-related increments in tension in the mesenteric (3 x 10(-6)-3 x 10(-5) M) and coronary (3 x 10(-7)-3 x 10(-5) M) arterial strips. Metoprolol and sotalol did not cause contractions in concentrations up to 10(-4) M. Phenoxybenzamine, 10-(-6) M, did not alter the contractile responses elicited by racemic and d-propranolol. Upon exposure of mesenteric strips to calcium-free media or 10(-6) M verapamil, the contractile responses to propranolol (3 x 10(-5) M) and KCl (30 mM) were markedly reduced (not significantly different), whereas norepinephrine (10(-6) M)-induced responses were inhibited to a significantly lesser degree. In coronary arteries exposed to calcium-free media or 10(-6) M verapamil, the responses to propranolol, KCl and methoxamine (10(-5) M) were all extensively decreased (not significantly different). These results indicate that propranolol exerts a direct contractile effect on canine mesenteric and coronary arteries, which is unrelated to its beta adrenergic blocking activity and is not mediated through action on alpha adrenergic receptors. The propranolol-induced contraction appears to be associated predominantly with an influx of calcium ion.

Adrenergic beta-Antagonists↗
PubMed1982

Facilitation of ganglionic transmission by sulpiride: evidence for an inhibitory role of dopamine in the canine sympathetic ganglion.

Effects of the (R) and (S) enantiomers of sulpiride, a potent dopamine (DA) antagonist, on ganglionic transmission were studied in anesthetized dogs. The pre- and postganglionic nerves of cardiac sympathetic ganglia were stimulated electrically, and heart rate was monitored as a measure of ganglionic transmission and sympathetic nerve activity. The heart rate was free from influence of the central nervous system. (R)- And (S)-sulpiride injected i.a. close to the blood supply of the ganglia did not alter basal heart rate, but facilitated ganglionic transmission as demonstrated by an increase in the tachycardia induced by preganglionic nerve stimulation. The (R) enantiomer was 4 times more active than the (S) enantiomer in this respect. Neither enantiomer affected the tachycardia induced by postganglionic nerve stimulation. Norepinephrine and DA injected i.a. caused inhibition of the tachycardia induced by preganglionic nerve stimulation. The inhibitory effect of both catecholamines was antagonized by the sulpiride enantiomers (R)-sulpiride was about 4-fold more potent than (S)-sulpiride in antagonizing DA, whereas (S)-sulpiride was more active against norepinephrine. The sulpiride enantiomers affected neither the tachycardia induced by i.a. administration of acetylcholine nor the bradycardia induced by vagal nerve stimulation. Thus, cholinesterase inhibition and ganglionic stimulation were excluded. These data are, therefore, consistent with the hypothesis that the facilitatory action of the sulpiride enantiomers is related to the antagonism of catecholamines. Positive correlation between the activity of the (R) enantiomer to facilitate ganglionic transmission and to antagonize DA suggests that DA is a physiologically released catecholamine modulating transmission in the cardiac sympathetic ganglia of the dog.

Animals↗
PubMed1981

Relative contracting and relaxing potencies of a series of prostaglandins on isolated canine mesenteric artery strips.

The contracting and relaxing potencies of and interactions between a number of prostaglandins (PGs) were studied in vitro on spiral strips of small canine mesenteric arteries (outside diameter less than 1 mm). PGF2 alpha and PGE2, the most potent contracting PGs, were nearly equal in potency (EC50 4 x 10(-7) M) and did not cause relaxation under our experimental conditions. PGI2 and PGE1 were equal and the most potent relaxing PGs (EC50 3 x 10(-9) M). PGE1 also caused contraction, but this effect was not consistent. PGI2 did not cause contraction in concentrations up to 3 x 10(-6) M. In higher concentrations, however, it caused abrupt and near maximal contraction. PGD2 was weak in both respects, causing incomplete relaxation and contraction or biphasic effects. Interaction studies showed that PGE1 and PGI2 mutually excluded the relaxing effects of each other. PGE1 also reversed the relaxing effect of isoproterenol. However, pre-exposure to PGD2 did not attenuate the relaxing effect of PGE1 or PGI2 nor was the relaxing effect of PGD2 changed by pre-exposure to PGE1. Two different orders of potency of PGs suggest two PG receptors subserving contraction and relaxation, respectively. Further, it appears that several PGs can act upon both receptors which may explain unusual interactions between the PGs and some of their atypical effects. Finally, the data also suggest that there may be subtypes of the PG receptors subserving contraction and relaxation.

Animals↗