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Biomedical subjects

R J Gorczynski

Publications and source records attributed to R J Gorczynski.

At least 37 records · Page 2Linked to original sources
PubMed1982

Ultra-short-acting beta-adrenergic receptor blocking agents. 1. (Aryloxy)propanolamines containing esters in the nitrogen substituent.

In an attempt to produce short-acting beta-adrenergic receptor blocking agents, we prepared several (aryloxy)propanolamines with ester functions incorporated into the nitrogen substituent. Many of these compounds exhibited a short duration of blocking activity after their continuous intravenous infusion for 40 min. However, their durations were found to increase considerably upon longer intravenous infusion.

Adrenergic beta-Antagonists↗
PubMed1982

Ultra-short-acting beta-adrenergic receptor blocking agents. 2. (Aryloxy)propanolamines containing esters on the aryl function.

Several short-acting beta-adrenergic receptor blocking agents have been prepared by incorporating ester functions into the aryl portion of certain (aryloxy)propanolamine systems. In particular, methyl 3-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]propionate hydrochloride (ASL-8052) was found to be a moderately potent, cardioselective compound with a short duration of action when determined in in vivo canine models.

Adrenergic beta-Antagonists↗
PubMed1982

Augmented tissue oxygen supply during striated muscle contraction in the hamster. Relative contributions of capillary recruitment, functional dilation, and reduced tissue PO2.

To investigate the relative contributions of alterations in blood flow, capillary density, and tissue PO2 to elevated oxygen delivery in working muscle, we conducted experiments on the suffused hamster cremaster muscle, using in vivo microscopic techniques. Muscle PO2 was measured during striated muscle twitch contraction at 1 Hz. Tissue oxygenation was changed by using suffusion solutions equilibrated with 0%, 5%, 10%, 21%, or 50% oxygen. Contraction caused an increase in capillary density (capillary recruitment), whose magnitude was related to the equilibration gas and, thus, to the suffusate PO2. Capillary recruitment first increased as the oxygen content was raised, peaked with 10% oxygen, and then diminished with higher oxygen content. Arteriolar functional dilation was also observed; when oxygen was raised above 21%, dilation was decreased. The data suggest that oxygen supply is increased primarily by arteriolar conductance changes with low suffusion solution oxygen (0% to 5%), and by capillary recruitment and increased PO2 gradients above 10% oxygen. When vasomotor tone was increased by addition of norepinephrine to the suffusion medium, the changes observed were similar to those observed when oxygen was increased. Therefore, we propose that the altered microvascular responses during vasoconstriction are a function of vascular tone rather than the levels of tissue PO2. A model is proposed which may partially explain the relations among vascular tone, functional dilation, and capillary recruitment. Our data also suggest that tissue PO2 may not be precisely regulated about a narrowly defined set point in this striated muscle but that, instead, tissue PO2 is a dependent variable controlled by the integrated effects of capillary recruitment, functional vasodilation, and altered metabolism.

Animals↗
PubMed1982

Cardiovascular pharmacology of ASL-7022. II. Mechanisms of inotropic selectivity.

The effect of ganglionic blockade (GB, hexamethonium, 10 mg/kg i.v.) upon the inotropic/chronotropic actions of ASL-7022 (2-[2-(3,4-dihydroxyphenyl)-1-methylethyl]-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene) was examined in anesthetized, vagotomized, open chest dogs instrumented for measurement of blood pressure, heart rate (HR) and right ventricular contractile force (strain-gauge). In a separate series of experiments, the effect of ASL-7022 upon sympathetic neurotransmission to the sinoatrial node was also examined. ASL-7022 preferentially increased contractile force at doses which were smaller than required to increase HR. HR decreased slightly over most of the inotropic dose range. The compound also caused a marked decline in blood pressure. GB converted the negative chronotropic effect to positive chronotropic action but had no effect on the inotropic dose-response relation. Thus, the inotropic selectivity of the compound was reduced by GB, but was still similar to that of dobutamine under conditions of GB. ASL-7022 also produced a dose-dependent inhibition of the positive chronotropic effect of sympathetic nerve stimulation and this action was blocked by phentolamine. These results demonstrate that the inotropic selectivity of ASL-7022 is related in part to the negative chronotropic action of the compound. However, the compound does possess intrinsic inotropic selectivity in the absence of its negative chronotropic action, i.e., in the presence of GB. The HR lowering effect is most likely due to sympathoinhibition due to action at inhibitory alpha adrenergic receptors located at ganglionic and/or presynaptic sites.

Animals↗
PubMed1982

Cardiovascular pharmacology of ASL-7022, a novel catecholamine. I. Inotropic, chronotropic and pressor actions.

ASL-7022 (2-[3-(3,4-dihydroxy-phenyl)-1-methylethyl]-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene) was examined for inotropic, chronotropic and blood pressure activity in pentobarbital anesthetized, vagotomized dogs instrumented for measurement of right ventricular contractile force, blood pressure and heart rate. The compound produced a dose-dependent increases in contractile force accompanied by bradycardia and hypotension. At high doses, the compound increased heart rate. At doses which increased contractile force by 100%, ASL-7022 produced no significant increase in heart rate, whereas dopamine and dobutamine produced small but significant increase in cardiac rate, ASL-7022 was therefore found to be more inotropic selective with respect to cardiac action than dopamine or dobutamine. Beta blockade reduced the positive inotropic, positive chronotropic and depressor action of the compound and also eliminated the negative chronotropic effect. ASL-7022 appears to be a beta adrenergic receptor agonist which possesses a unique spectrum of cardiovascular action.

Animals↗
PubMed1981

N-Aralkyl substitution of 2-amino-5,6- and -6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenes. 1. Cardiac and pressor/depressor activities.

Amino substitution o rigid forms of dopamine [2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-5,6-DTN) and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN)] with aralkyl functionalities was carried out to investigate the role of such structural modifications upon cardiac inotropic/chronotropic and blood pressure activity. Derivatives of A-5,6-DTN were strong vasodepressor agents devoid action was associated with the dihydroxyphenyl-1-methylethyl derivative, which was also an inotropic selective compound. The amino substituent of dobutamine was ineffective in reducing peripheral vascular action when combined with the rigid forms of dopamine. It was also ineffective in imparting inotropic selectivity when combined with A-5,6-DTN. An analysis of these observations in light of existing structure-activity relationships of aminoaralkyl substitution of other catecholamine structure is presented.

Animals↗
PubMed1981

Effects of propranolol on myocardial infarct size with and without coronary artery reperfusion in the dog.

The ability of propranolol to limit myocardial infarct size (IS) following coronary artery occlusion with and without reperfusion into a critical stenosis was assessed in the dog. IS was determined by the nitrobluetetrazolium staining method and expressed as percent of the left ventricle (free wall plus septum). In Series 1 dogs the left circumflex coronary artery (LCX) was ligated at its origin. IS at 6 h was similar in groups pretreated with saline (36.0 +/- 1.3%) or propranolol (0.2 mg . kg-1, 34.7 +/- 1.7%; 1.0 mg . kg-1, 36.7 +/- 1.5%; 4.4 mg . kg-1, 34.8 +/- 0.3%). In Series 2 dogs a relatively small infarction was produced by ligating the largest branch of the LCX between the left anterior descending and posterior descending arteries. IS at 6 h was not significantly different in dogs pretreated with saline (8.1 +/- 1.7%) or propranolol (0.2 mg . kg-1, 7.1 +/- 2.5%; 1.0 mg . kg-1, 4.6 +/- 1.2%). In Series 3 dogs the LCX was ligated approximately 10 mm from its origin for 60 min followed by reperfusion into a critical stenosis. IS determined at 24 h was significantly less in dogs treated with propranolol (1.0 mg . kg-1) before LCX occlusion (4.6 +/- 0.6%) or 5 min after LCX reperfusion (9.5 +/- 1.8%) than in dogs treated with saline (22.6 +/- 2.8%). In Series 4 dogs treatment was exactly as in Series 3 except that reperfusion was not instituted. IS was similar in dogs pretreated with saline (29.0 +/- 1.5%) or propranolol (31.1 +/- 3.0%). Thus, in the present study, propranolol limited IS in the presence but not in the absence of reperfusion. In the reperfusion model propranolol was effective when administered before coronary occlusion or after initiation of reperfusion.

Animals↗
PubMed1980

Comparison of the autonomic effects of procainamide and N-acetylprocainamide in the dog.

The autonomic effects of procainamide (PA) and N-acetylprocainamide (NAPA) were studied in anesthetized dogs. High plasma concentrations of PA (31 +/- 1.3--64 +/- 3.4 micrograms/ml) and NAPA (64 +/- 3.4--127 +/- 8.3 micrograms/ml)) reduced base-line mean arterial pressure and heart rate and attenuated the pressor and positive chronotropic responses to bilateral carotid occlusion and the negative chronotropic response to vagal stimulation. Neither drug reduced the pressor or positive chronotropic responses to catecholamines (epinephrine, phenylphrine, isoproterenol), however. In fact, at some doses PA and NAPA accentuated the pressor and positive chronotropic effects of epinephrine. Similarly, the depressor response to acetylcholine was not reduced by these drugs; it was significantly increased at some doses. In the isolated hindlimb (constant flow) PA and NAPA reduced the pressor response to preganglionic (sympathetic chain) stimulation but not to postganglionic (femoral and sciatic nerves) stimulation. We conclude that NAPA, like PA, at high plasma levels is vagolytic and attenuates baroreceptor-mediated reflexes associated with reduced arterial pressure. These effects appear to be due to ganglionic blockade.

Acecainide↗
PubMed1979

Synthesis and pharmacology of potential beta-blockers.

Several 1-(4-substituted phenoxyl)-2-hydroxy-3-isopropylaminopropanes and 1-(4-substituted phenoxy)-2-hydroxy-3-[3,4-dimethoxyphenethyl]aminopropanes were synthesized for possible beta-adrenergic receptor blockage. The compounds were synthesized by reaction of the 4-substituted phenol with epichlorohydrin and subsequent opening of the resulting epoxide with either N-isopropylamine or N-3,4-dimethoxyphenethylamine. Preliminary biological testing indicated a decrease in the beta-blocking potency and the duration of action.

Adrenergic beta-Antagonists↗
PubMed1979

Conformational analogues of dopamine. Synthesis and pharmacological activity of (E)- and (Z)-2-(3,4-dihydroxyphenyl)cyclopropylamine hydrochlorides.

(E)- and (Z)-(+/-)-2-(3,4-dihydroxyphenyl)cyclopropylamine hydrochlorides were synthesized as part of a program to assess the importance of conformational isomerism with respect to the various peripheral biological actions of dopamine. Although neither of the compounds possessed dopaminergic activity in the canine renal blood-flow model, both agents were weak alpha-adrenergic agonists and exhibited cardiostimulatory properties similar to dopamine. The E isomer was apprxoximately 5 times more potent than the Z isomer in its alpha-adrenergic activity and approximately 15 times as potent in its cardiac effects. Possible reasons for the lack of renal dopaminergic activity exhibited by the E isomer are presented.

Adrenergic alpha-Agonists↗
PubMed1978

Interrelations between contracting striated muscle and precapillary microvessels.

Arterioles and capillaries in the hamster cremaster muscle were observed during electrical stimulation of striated muscle fibers in order to characterize the microcirculatory basis of functional hyperemia. When contraction was restricted to single muscle fibers, responses were variable and frequently transient. Stimulation of either small bundles of muscle fibers or the entire cremaster muscle resulted in reproducible responses typified by: 1) a latency period, 2) an early, often transient phase of dilation, and 3) a second, slower phase of dilation. The latency varied inversely with contraction frequency, and the magnitude of the dilation varied directly with contraction frequency over the range 1--8/s. With stimulation of single fibers and small groups of fibers, arteriolar vasodilation was highly localized to regions of the arterioles that were in close apposition to the stimulated fibers. The number of capillaries with red blood cell flow increased during contraction, and the increase was graded with contraction frequency. The changes observed suggest that the vascular response during functional hyperemia is a two-part process and that the control processes are influenced by contraction frequency.

Animals↗
PubMed1978

Role of oxygen in arteriolar functional vasodilation in hamster striated muscle.

Small isolated groups of striated muscle cells were stimulated in the hamster cremaster muscle. During and after stimulation, oxygen microelectrodes were employed to determine the relationships among arteriolar vasodilation, tissue Po2, and periarteriolar Po2. Localized contraction produced a biphasic arteriolar vasodilation without associated alteration of Po2 on the surface of the arterioles (vascular smooth muscle Po2). In contrast, muscle contraction produced a decline in muscle tissue Po2 that was proportional to the contraction frequency over the range of 1--4 contractions per second. An increase in contraction frequency also produced a graded increase in arteriolar diameter, the magnitude of which was statistically correlated with the steady-state change in tissue Po2. However, arteriolar diameter changes preceded tissue Po2 changes, both with the initiation of functional dilation and during the recovery period. Tissue Po2 was manipulated at rest and during contraction by increasing the Po2 of the superfusion solution. Increasing the tissue Po2 caused a decrease in vascular diameter under both conditions and a reduction in the magnitude of the arteriolar vasodilation during contraction. Restoration of tissue Po2 to resting levels during muscle contraction produced only partial restoration of vascular diameters. The results are consistent with the hypothesis that at least three components are involved in the vascular control process during muscular activity: an early component independent of tissue oxygen levels, a late component independent of oxygen, and a late component associated with a decrease in muscle Po2, without an effect on vascular smooth muscle Po2. The evidence indicated that Po2 of the smooth muscle of the arterioles had no role in the dilation observed.

Animals↗