Search PubMed⌕ Search

Biomedical subjects

R R Ruffolo

Publications and source records attributed to R R Ruffolo.

At least 181 records · Page 10Linked to original sources
PubMed1985

Evaluation of the alpha-1 and alpha-2 adrenoceptor-mediated effects of a series of dimethoxy-substituted tolazoline derivatives in the cardiovascular system of the pithed rat.

The alpha-1 and alpha-2 adrenoceptor-mediated effects of a series of dimethoxy-substituted tolazoline derivatives were investigated in the cardiovascular system of the pithed rat. The 2,5- and 3,5-dimethoxy-substituted tolazoline derivatives produced vasopressor responses that were inhibited by the alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.), and were not affected by the alpha-2 adrenoceptor antagonist, yohimbine (1 mg/kg i.v.), suggesting that these derivatives selectively activate postsynaptic vascular alpha-1 adrenoceptors. The 2,5- and 3,5-dimethoxy-substituted derivatives of tolazoline did not produce an alpha-2 adrenoceptor-mediated inhibition of neurogenic tachycardia in cord-stimulated pithed rats and were therefore presumed to be devoid of alpha-2 adrenoceptor agonist activity. In contrast, 2,3-dimethoxytolazoline produced a vasopressor effect that was inhibited by yohimbine but not by prazosin, suggesting selective activation of postsynaptic vascular alpha-2 adrenoceptors. Consistent with this observation is the fact that 2,3-dimethoxytolazoline elicited a dose-dependent, alpha-2 adrenoceptor-mediated inhibition of neurogenic tachycardia in cord-stimulated pithed rat. 3,4-Dimethoxytolazoline was a weak alpha-1 adrenoceptor agonist in the vasculature of the pithed rat and was devoid of agonist activity at alpha-2 adrenoceptors. However, 3,4-dimethoxytolazoline was found to be an alpha-2 adrenoceptor antagonist of similar potency as yohimbine. The results of the present study indicate that dimethoxy-substituted derivatives of tolazoline possess different activities and selectivities at alpha-1 and alpha-2 adrenoceptors depending upon the positions of substitution.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Effects of dopamine, (+/-)-dobutamine and the (+)- and (-)-enantiomers of dobutamine on cardiac function in pithed rats.

The effects of dopamine, (+/-)-dobutamine (racemic mixture) and the (+)- and (-)-enantiomers of dobutamine on myocardial function were evaluated in pithed rats. Dopamine and (+/-)-dobutamine produced effects on cardiac function in pithed rats that were qualitatively similar to those reported for these compounds in humans. The increase in cardiac output produced by dopamine and (+/-)-dobutamine was due mainly to an increase in stroke volume, with increases in heart rate contributing to a significant but lesser degree. For both dopamine and (+/-)-dobutamine, the increase in stroke volume appears to result from an increase in myocardial contractility as assessed by increases in left ventricular (LV) dp/dt. Dopamine produced a marked increase in mean arterial blood pressure, whereas (+/-)-dobutamine only modestly increased blood pressure. The (-)-enantiomer of dobutamine, which possesses mainly alpha-1 adrenoceptor agonist activity, produced dose-dependent increases in cardiac output, stroke volume, LVdp/dt and mean arterial blood pressure, but did not significantly increase heart rate except at high doses. Thus, the increase in cardiac output produced by (-)-dobutamine was derived almost exclusively from an augmentation in stroke volume resulting from an increase in myocardial contractility. In contrast, (+)-dobutamine, which possesses predominantly beta-1 and beta-2 adrenoceptor agonist activity, elicited only a modest increase in cardiac output which was due both to an increase in heart rate and stroke volume. Mean arterial blood pressure was not significantly affected by (+)-dobutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Evaluation of a novel antihypertensive agent, LY127210, in anesthetized and conscious spontaneously hypertensive rats.

LY127210 (7,8-dimethoxy-1H-3-benzazepin-2-amine, hydrochloride) is a novel peripheral arterial vasodilator that reduces mean arterial blood pressure in anesthetized and conscious spontaneously hypertensive rats by all conventional routes of administration. The antihypertensive activity of LY127210 results predominantly from a decrease in total peripheral vascular resistance, and the degree of reflex tachycardia produced by LY127210 in conscious spontaneously hypertensive rats is significantly less than that produced by hydralazine at equivalent antihypertensive doses. The relative lack of reflex tachycardia produced by LY127210 appears to result from a direct bradycardic effect of the compound that occurs at the level of the myocardium at doses similar to those required to produce peripheral arteriolar vasodilation. It is proposed that the direct bradycardic effect of LY127210 serves to offset, at least in part, the tachycardia resulting from reflex stimulation of sympathetic outflow that occurs upon activation of the baroreflex loop as blood pressure is lowered. The results indicate that LY127210 may provide adequate control of blood pressure and may not require the concomitant administration of a beta-adrenoceptor antagonist to control reflex tachycardia, as is commonly necessary with hydralazine.

Angiotensin II↗
PubMed1985

Inotropic selectivity of dobutamine enantiomers in the pithed rat.

The inotropic selectivities of the (-)- and (+)-enantiomers of dobutamine were assessed in pithed rat by comparing the relative ability of each enantiomer to increase left ventricular contractility (left ventricular dp/dt) and heart rate. The (-)-enantiomer of dobutamine, which is predominantly an alpha-1 adrenoceptor agonist, displayed greater inotropic selectivity than the (+)-enantiomer, which is predominantly a beta-1 and beta-2 adrenoceptor agonist. Pretreatment with the alpha-1 adrenoceptor antagonist prazosin significantly inhibited the effect of (-)-dobutamine on left ventricular dp/dt, but did not affect the chronotropic activity of this enantiomer. As such, pretreatment with prazosin decreased the inotropic selectivity of (-)-dobutamine. In contrast, the inotropic activity and selectivity of (+)-dobutamine were not affected by prazosin pretreatment. These results indicate that the inotropic effects of (-)-dobutamine are mediated, at least in part, by alpha-1 adrenoceptors. We conclude, based on the marked inotropic activity of (-)-dobutamine and the greater inotropic selectivity of (-)-dobutamine over (+)-dobutamine, that alpha-1 adrenoceptors may play a role in the inotropic activity and selectivity of racemic dobutamine used clinically. The possible involvement of both myocardial alpha-1 and beta-1 adrenoceptors in the inotropic activity of dobutamine must be considered.

Animals↗
PubMed1984

Interactions of three inotropic agents, ASL-7022, dobutamine and dopamine, with alpha- and beta-adrenoceptors in vitro.

Three inotropic agents, ASL-7022, dobutamine and dopamine, were evaluated for their alpha- and beta-adrenoceptor mediated effects in vitro in a variety of isolated organs and in radioligand binding studies. All compounds were alpha 1-adrenoceptor agonists in rat and guinea pig aortae, but the rank orders of potency were exactly opposite in these two tissues. Only the rank potency order of dobutamine greater than ASL-7022 greater than dopamine obtained in rat aorta was consistent with the results obtained in radioligand binding studies to alpha 1-adrenoceptors in rat cerebral cortex and to previous results obtained in vivo in the pithed rat. The results obtained in guinea pig aorta did not parallel the radioligand binding studies in rat brain or our previous results in pithed rat, and suggests that species differences exist between postsynaptic vascular alpha 1-adrenoceptors in rat and guinea pig aorta, consistent with previous conclusions. ASL-7022 was found to be a potent alpha 2-adrenoceptor agonist in field-stimulated guinea pig ileum, and was approximately 10-fold more potent than dobutamine in this respect, which was also confirmed by radioligand binding studies to alpha 2-adrenoceptors in rat cerebral cortex. The beta 1-adrenoceptor mediated effects of these compounds were evaluated in guinea pig atria, where the rank order of potency was dobutamine greater than ASL-7022 greater than dopamine. An identical rank order of affinity was established for these compounds by displacement of 3H-dihydroalprenolol from beta 1-adrenoceptors in rat cerebral cortex. The beta 1-adrenoceptor mediated effects of dobutamine and ASL-7022 in guinea pig atria were completely direct in nature and not secondary to the release of endogenous catecholamines. In contrast, a major component of the beta 1-adrenoceptor mediated tachycardia produced by dopamine in guinea pig atria was indirect in nature as evidenced by the marked attenuation in potency that occurred following catecholamine depletion with reserpine. All three compounds elicited beta 2-adrenoceptor mediated inhibition of tone in rat uterus, with the rank order of potency being ASL-7022 greater than dobutamine greater than dopamine. Again, this rank order of beta 2-adrenoceptor potency was also reflected in beta 2-adrenoceptor affinity as assessed by displacement of 3H-dihydroalprenolol from beta 2-adrenoceptors in rat cerebellum. Based on these results, it may be concluded that for alpha-adrenoceptors, dobutamine is a selective alpha 1-adrenoceptor agonist, ASL-7022 is a selective alpha 2-adrenoceptor agonist, and dopamine is a nonselective alpha-adrenoceptor agonist.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

The 3,4-catechol derivative of propranolol, a minor dihydroxylated metabolite.

The O,O-dibenzyl ether of the 3,4-catechol derivative of propranolol (11) was prepared to determine whether the catechol is a product of metabolic hydroxylation. 4-(Allyloxy)-1,2-naphthoquinone (5) was reduced with sodium dithionite and alkylated with benzyl chloride to produce ether 7. Osmium tetroxide oxidation of 7 afforded glycol 8. Subsequent monotosylation, oxirane formation with KOH, and opening with isopropylamine afforded benzyl ether 11. Although hydrogenolysis was successful, catechol 3 was rapidly oxidized to the corresponding o-quinone (12). Reduction of 12 with sodium bisulfite afforded 3, which was derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) to serve as a standard for the metabolic experiments. Gas chromatography-mass spectrometry of the Me3Si ethers of the products of metabolism of pseudoracemic propranolol (made up of equal molar (2R)-propranolol-d0/(2S)-propranolol-3',3'-d2) in the presence of the rat liver 9000g supernatant fraction showed four dihydroxylated metabolites, of which catechol 3 was in smallest amount, approximately 9% of the sum of dihydroxylated metabolites. Each of the four dihydroxylated propranolols arises stereoselectively from the 2R enantiomer of propranolol (by 1.15- to 2-fold), as determined by parent ion intensities at m/z 507 vs. 509. Quinone 12 was a nonselective competitive beta-adrenoceptor antagonist, being about 16-fold less potent than propranolol in both beta 1 and beta 2 assays.

Animals↗
PubMed1984

Possible relationship between receptor reserve and the differential antagonism of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses by calcium channel antagonists in the pithed rat.

The effect of the calcium channel antagonist diltiazem was investigated on the alpha-1 and alpha-2 adrenoceptor-mediated pressor responses elicited by cirazoline and B-HT 933, respectively, in pithed rat. Diltiazem (3 mg/kg i.v.) selectively inhibited the alpha-2 adrenoceptor-mediated pressor effect of B-HT 933 but did not affect the alpha-1 adrenoceptor-mediated pressor effect of cirazoline. However, after removal of spare postsynaptic vascular alpha-1 adrenoceptors by treatment with the irreversible alpha adrenoceptor antagonist phenoxybenzamine, the alpha-1 adrenoceptor-mediated pressor response of cirazoline became highly sensitive to antagonism by diltiazem and resembled in this regard alpha-2 adrenoceptor-mediated vasoconstriction for which no receptor reserve exists. In addition, as the alpha-1 adrenoceptor reserve was progressively reduced by treatment with increasing doses of phenoxybenzamine, the alpha-1 adrenoceptor-mediated pressor response of cirazoline became progressively more sensitive to inhibition by diltiazem, such that there was a high inverse correlation between the magnitude of the alpha-1 adrenoceptor reserve and the degree to which this response was antagonized by diltiazem. There was also a high inverse correlation between the intrinsic activity of alpha-1 adrenoceptor selective agonists and the degree to which their pressor responses were inhibited by diltiazem. Thus, pressor responses of agonists with high intrinsic activities (large receptor reserve) were resistant to antagonism by diltiazem, whereas the alpha-1 adrenoceptor-mediated pressor responses of partial agonists with low intrinsic activities (no receptor reserve) were highly sensitive to antagonism by diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Effects of structure-activity relationships of alpha-adrenergic compounds on electrolyte transport in the rabbit ileum and rat colon.

Clonidine, an alpha 2-adrenergic agonist, increases electrolyte absorption in the intestine and inhibits diarrhea. In an attempt to develop a gut-specific alpha 2-adrenergic compound for the treatment of diarrhea, we tested several imidazoline derivatives to determine which aspects of the molecule are gut specific. The potency of each compound in the stimulation of electrolyte transport in the rabbit ileum and rat colon was determined using a modified Ussing chamber technique. These results were then compared with the ability of these drugs to lower blood pressure following intracisternal injection in spontaneously hypertensive rats, as well as with other alpha 2-adrenergic properties that have been defined in previous studies. Results indicate that all imidazoline derivatives interact with alpha 2-adrenergic receptors in the gut preparation but activate the ion transport processes to a variable extent; i.e., all analogs tested are either agonist or antagonist for ion transport. Structure activity relationships were derived; for the agonist property in the gut, the imidazoline derivative required (a) substitution (in order of potency) with halide greater than CH3 or C2H5 greater than CH3O or greater than OH at position 2 or 6 of the phenyl ring, or a simultaneous substitution at positions 3 and 4 with hydroxy groups, or certain other groups that independently enhance the agonist properties and (b) the presence of a proper bridging unit between the phenyl and imidazoline rings, NH greater than or equal to CH2. In addition, it was found that certain compounds with a methoxy substitution of the phenyl ring displayed a dissociation between the intestinal ion transport potency and central hypotensive activities. 2-Methoxytolazoline, which was relatively active in the gut as compared with other methoxy-substituted compounds, had little effect in lowering blood pressure. However, 3,5- or 2,5-dimethoxytolazoline had no effect on intestinal ion transport but lowered blood pressure in spontaneous hypertensive rats. These results indicate that the alpha 2-adrenergic receptors in the gut and brain may be different. Further modification of the imidazoline molecule could result in analogs with selective ion transport action in the intestine.

Adrenergic alpha-Agonists↗
PubMed1984

alpha-Adrenoceptors.

Explore the source record for details and available documents.

Adrenergic alpha-Agonists↗
PubMed1984

A study of the selectivity and potency of rauwolscine, RX 781094 and RS 21361 as antagonists of alpha-1 and alpha-2 adrenoceptors.

In a comparative study using various in vivo and in vitro models, the alpha-1/alpha-2 adrenoceptor blocking potencies and selectivities were quantitatively assessed for the purported alpha-2 adrenoceptor selective antagonists rauwolscine, RX 781094 and RS 21361. In pithed normotensive rats, RX 781094 showed direct agonist activity at postjunctional alpha-1 and alpha-2 adrenoceptors and had an indirect tachycardic effect. RS 21361 exhibited but minor actions on diastolic pressure and did not influence heart rate. Rauwolscine, RX 781094 and RS 21361 caused rightward parallel displacements of the log dose-response curve to the increase in diastolic pressure of methoxamine (alpha-1 agonist) and B-HT 920 (alpha-2 agonist) as well as to the B-HT 920-induced reduction in stimulation-evoked tachycardia. Schild plots afforded straight lines with slopes not significantly different from unity. Rauwolscine was more potent than RX 781094 in blocking these alpha-2 adrenoceptors in vivo, whereas both compounds were equipotent at alpha-1 adrenoceptors. RS 21361 possessed moderate in vivo blocking potencies at either subtype. All three antagonists had high blocking selectivity for alpha-2 adrenoceptors in vivo. Rauwolscine was found about 25 times more selective than RX 781094 and 2 times more selective than RS 21361. RX 781094 was approximately 3 times more effective than rauwolscine in antagonizing the centrally mediated alpha-2 adrenoceptor-induced hypotension and sedation of clonidine in rats and mice, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1984

Interactions of agonists with peripheral alpha-adrenergic receptors.

The alpha adrenoceptors may be subdivided based on their anatomical distribution within the synapse. Presynaptic alpha adrenoceptors are generally of the alpha 2 subtype and modulate neurotransmitter liberation via a negative feedback mechanism. Postsynaptic alpha adrenoceptors are usually of the alpha 1 subtype and mediate the response of the effector organ. Although this anatomical subclassification is generally applicable, many exceptions are now known. A more useful classification of alpha-adrenoceptor subtypes is based on a pharmacological characterization in which selective agonists and antagonists are used. Two major classes of alpha-adrenoceptor agonists are known: the phenethylamines, which are structurally related to norepinephrine, and the imidazolines, which are structurally related to clonidine. A number of important differences between these two classes of agonists have been observed and have led to the conclusion that the phenethylamines and imidazolines interact differently with alpha adrenoceptors. Many developments have recently been made in regard to peripheral alpha adrenoceptors in the cardiovascular system. Postsynaptic alpha adrenoceptors in the vasculature represent a mixed population of alpha 1 and alpha 2 adrenoceptors. Both alpha-adrenoceptor subtypes mediate vasoconstriction, but appear to do so through different mechanisms. alpha 1 adrenoceptors also exist in the heart and mediate a positive inotropic response. Renal alpha 1 and alpha 2 adrenoceptors have been identified and subserve a variety of functions such as regulation of renal blood flow, gluconeogenesis, renin release, and sodium and water reabsorption.

Adrenergic alpha-Agonists↗
PubMed1984

Characterization of the alpha adrenoceptor-mediated effects and antihypertensive activity of ICI 106270: comparison with clonidine.

Clonidine and ICI 106270 are centrally acting antihypertensive agents which act through stimulation of medullary alpha-2 adrenoceptors. Both compounds are equipotent agonists at alpha-2 adrenoceptors as assessed in functional studies in isolated organs and in radioligand binding studies. In addition, clonidine and ICI 106270 possess the same degree of selectivity for alpha-2 adrenoceptors over alpha-1 adrenoceptors. Clonidine and ICI 106270 are equipotent antihypertensive agents after intracisternal administration to spontaneously hypertensive rats, consistent with the observations made in vitro that both compounds are equipotent alpha-2 adrenoceptor agonists. Both compounds were less potent in lowering blood pressure after i.v. administration than after intracisternal administration, thus confirming a central mechanism of action. Interestingly, clonidine was a more potent antihypertensive agent than ICI 106270 after i.v. administration, which, in view of the equal potencies observed after intracisternal administration, suggests that diffusion of ICI 106270 into the central nervous system is selectively retarded, relative to clonidine, by the blood-brain barrier. The differences observed in the rate of penetration of the blood-brain barrier are consistent with the higher pka and corresponding higher extent of ionization (at physiological pH) and lower lipophilicity of ICI 106270 relative to clonidine. A relatively large difference between the i.v. and p.o. antihypertensive potencies was observed for ICI 106270 which indicates poor p.o. absorption of ICI 106270 relative to clonidine, again likely resulting from the greater proportion of ICI 106270 existing in the ionized species.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Interaction of the novel inotropic agent, ASL-7022, with alpha and beta adrenoceptors in the cardiovascular system of the pithed rat: comparison with dobutamine and dopamine.

Three selective inotropic agents, ASL-7022, dobutamine and dopamine, were evaluated for their effects at alpha and beta adrenoceptors in the cardiovascular system of the pithed rat. ASL-7022, dobutamine and dopamine were equipotent as pressor agents in propranolol- and reserpine-pretreated pithed rats; however, the mechanisms involved in their alpha adrenoceptor-mediated pressor effects were markedly different. The pressor response of ASL-7022 was mediated entirely by postsynaptic vascular alpha-2 adrenoceptors, whereas the pressor response of dobutamine was mediated exclusively by postsynaptic vascular alpha-1 adrenoceptors. The pressor response of dopamine was mediated by both postsynaptic vascular alpha-1 and alpha-2 adrenoceptors. All three compounds elicited beta-2 adrenoceptor-mediated vasodepressor responses in pithed rats when vascular tone was elevated by a constant infusion of angiotensin II. In contrast to the equal vasopressor potencies of these compounds, the vasodepressor activities varied by more than two orders of magnitude with ASL-7022 being the most potent and dopamine the least potent. Based on ratios of relative potencies for alpha adrenoceptor-mediated vasopressor effects and beta-2 adrenoceptor-mediated vasodepressor effects, it appears that dobutamine possesses an equal balance between its vasopressor and vasodepressor potencies, such that the net effect in the vasculature is a physiological antagonism with little or no change in blood pressure, consistent with clinical observations and experiments in animals. In contrast, the vasopressor potency of dopamine exceeds its potency as a depressor agent, such that the net effect is vasoconstriction, consistent with clinical and animal studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Interactions of epinephrine, norepinephrine, dopamine and their corresponding alpha-methyl-substituted derivatives with alpha and beta adrenoceptors in the pithed rat.

The effects of alpha-methyl substitution of epinephrine, norepinephrine and dopamine were investigated at alpha-1, alpha-2, beta-1 and beta-2 adrenoceptors in the pithed rat. alpha-Methyl substitution of these three phenethylamines variably altered their capacity to elicit alpha adrenoceptor-mediated vasoconstriction, with slightly enhanced potency being observed for alpha-methyl substitution of norepinephrine and dopamine and a marked reduction in potency for alpha-methyl substitution of epinephrine. However, in all instances, alpha-methyl substitution resulted in a higher selectivity for alpha-2 adrenoceptors (over alpha-1 adrenoceptors). Thus, while epinephrine, norepinephrine and dopamine all produced vasoconstriction that was mediated equally by postsynaptic vascular alpha-1 and alpha-2 adrenoceptors, their corresponding alpha-methyl-substituted derivatives produced vasoconstriction exclusively by activation of postsynaptic vascular alpha-2 adrenoceptors. The beta-1 adrenoceptor-mediated chronotropic effects of these phenethylamines were inconsistently affected by alpha-methyl substitution, with an increase in potency being observed for alpha-methyl substitution of norepinephrine and decreases in potency being observed for alpha-methyl substitution of epinephrine and dopamine. In marked contrast, alpha-methyl substitution of epinephrine, norepinephrine and dopamine was associated with consistent and dramatic increases in potency for beta-2 adrenoceptor-mediated vasodepressor activity. These results indicate that alpha-2 and beta-2 adrenoceptors possess the unique ability to recognize and/or accept alpha-methyl substituents on phenethylamines and that this ability is not shared by their respective receptor subtypes, the alpha-1 and beta-1 adrenoceptors. Furthermore, the results show that alpha-methylepinephrine is a potent beta adrenoceptor agonist, with an apparent 500-fold selectivity for beta-2 adrenoceptors over beta-1 adrenoceptors.

Animals↗
PubMed1983

Selective alpha 2-adrenoceptor agonist activity of the novel inotropic agent, ASL-7022: comparison with dobutamine.

ASL-7022 is a novel inotropic agent capable of increasing the force of myocardial contraction at doses which produce little effect on heart rate. The inotropic selectivity of ASL-7022, like that of dobutamine, has been proposed to result, in part, from agonist activity at alpha-adrenoceptors. Following beta-adrenoceptor blockade, ASL-7022 and dobutamine increase diastolic blood pressure in pithed rat, with both compounds being equal in potency. The pressor activity of ASL-7022 was selectively antagonized by yohimbine (1 mg/kg i.v.) and was unaffected by prazosin (0.1 mg/kg i.v.), whereas the converse was true for dobutamine. These results indicate that the pressor effects of ASL-7022 and dobutamine are mediated by different populations of postjunctional vascular alpha-adrenoceptors in pithed rat, with ASL-7022 selectively stimulating alpha 2-adrenoceptors and dobutamine selectively activating alpha 1-adrenoceptors.

Adrenergic beta-Agonists↗