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Biomedical subjects

R E Purdy

Publications and source records attributed to R E Purdy.

At least 55 records · Page 3Linked to original sources
PubMed1989

Evidence for allosteric blockade of serotonergic receptors in rabbit thoracic aorta.

2-Brom-d-lysergic acid diethylamide (BOL) appeared to behave as either a reversible competitive or noncompetitive antagonist of vascular serotonergic (5-HT2) receptors depending on experimental conditions. This was explored using rabbit thoracic aorta rings mounted in tissue baths for the measurement of isometric contraction. BOL caused concentration-dependent parallel rightward shifts of the 5-HT dose-response curve in untreated aortas but, in addition, caused a marked reduction of maximal response in aortas pretreated with benextramine to inactivate alpha adrenoceptors. Ketanserin behaved as a reversible competitive antagonist in both untreated and benextramine-pretreated aortas. The respective ketanserin pA2 values were 9.08 +/- 0.09 (S.E.M.) and 9.01 +/- 0.04. Ketanserin, 1 x 10(-7) M, reversed completely the reduction of maximal response caused by 1 x 10(-9) M BOL and partially reversed those caused by 1 x 10(-8) and 1 x 10(-7) M BOL. Furthermore, the 5-HT dose-response curve in the presence of 1 x 10(-7) M ketanserin and that in the presence of 1 x 10(-7) M ketanserin plus 1 x 10(-9) M BOL were superimposed. These results are consistent with the conclusion that BOL is a noncompetitive 5-HT2 receptor antagonist. We propose that BOL acts at an allosteric site to convert the 5-HT2 receptor to a low activity state, thus, reducing the maximal response. BOL does not act at the 5-HT2 receptor itself. Ketanserin competes with 5-HT at the 5-HT2 receptor and with BOL at the allosteric site.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1988

Angiotensin II amplification of alpha-adrenergic vasoconstriction: role of receptor reserve.

Angiotensin II (Ang II) is known to enhance the vasoconstrictor response to norepinephrine (NE). In the present study, this interaction was investigated using isolated rabbit femoral artery rings mounted in tissue baths for the measurement of isometric contraction. Exposure to 3 x 10(-10) M Ang II caused a contraction that was less than 5% of the maximal response to NE. In the presence of Ang II, the NE dose-response curve shifted to the left twofold and the maximal response was not changed. The calcium channel antagonist nifedipine, 1 x 10(-7) M, caused a modest inhibition of the response to NE in either the presence or absence of Ang II. In contrast, nifedipine abolished the leftward shift of the NE dose-response curve caused by Ang II. Femoral arteries were pretreated with benextramine to cause partial alpha-adrenoceptor inactivation. The maximal contractile response to NE in these tissues was between 20% and 40% of that in control vessels, indicating that alpha-adrenoceptor reserve had been eliminated. In benextramine-pretreated vessels, the presence of 3 x 10(-10) M Ang II caused a modest leftward shift of the NE dose-response curve but increased the maximal responses to all NE concentrations by 200% to 800%. Nifedipine caused a modest inhibition of the response to NE in the absence of Ang II. In contrast, the enhanced response to NE in the presence of Ang II was nearly abolished. These results support our conclusions that 1) Ang II enhances the vasoconstrictor response to alpha-adrenergic stimulation, 2) the magnitude of enhancement is greater under conditions of reduced alpha-receptor reserve, and 3) calcium channel activation plays a major role in the amplified response.

Angiotensin II↗
PubMed1988

Further evidence for a homogeneous population of beta-1-adrenoceptors in bovine coronary artery.

Isolated rings from the proximal and distal ends of the bovine epicardial anterior descending coronary artery and guinea pig tracheal rings were mounted in tissue baths for the measurement of isometric contraction and relaxation, and spontaneously beating rabbit atria were prepared for measurement of chronotropic response. All tissues were exposed to phenoxybenzamine to block tissue uptake of catecholamines and alpha adrenoceptors. The arterial and tracheal rings were contracted with 25 mM K+ in order to observe agonist-induced relaxation. Beta adrenergic agonist dose-response curves were obtained in all tissues in the presence and absence of the beta-2 selective antagonist, ICI 118,551. The orders of agonist potencies in the proximal and distal coronary arteries and the rabbit atria were the same: namely, isoproterenol (ISO) greater than norepinephrine (NE) much greater than procaterol. In contrast, that in the guinea pig trachea was procaterol greater than ISO greater than NE. Procaterol was a weak, partial agonist in the bovine coronary artery and rabbit atria and a potent, full agonist in the guinea pig trachea. The ICI 118,551 pA2 values in the proximal segment of the bovine coronary artery were the same against both NE and fenoterol, 7.38. In the distal segment, the values were 7.33 and 7.14, respectively. ICI 118,551 -log KB values in the rabbit atria, 6.81 and 6.83 for NE and ISO, respectively, were slightly below those in the coronary artery segments, whereas -log KB values in the guinea pig trachea were substantially higher, 8.19 and 8.81 for fenoterol and procaterol, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Vasoreactivity in isolated perfused atherosclerotic human coronary arteries.

Atherosclerosis may be important in the modulation of arterial vasoreactivity and coronary artery flow. Since the endothelium is reduced or absent in atherosclerosis, drug effects are enhanced or modulated. To examine this hypothesis, vasoreactivity induced by serotonin (5-HT) was studied in isolated, perfused, and pharmacologically responsive normal and atherosclerotic human coronary arteries obtained within five hours post mortem. In this model, flow was maintained through the vessels and the effects of vasospasm and vasorelaxation on decreasing and increasing flow respectively were measured. Vessels 3 cm long and approximately 1.5 mm in internal diameter were dissected free and perfused at constant pressure (30 mm Hg) with oxygenated Krebs bicarbonate solution. 5-HT was introduced in the perfusate at 10(-5) M final concentration as a pulse of 100 ml followed by a 1-l washout with drug-free solution. Flow rate and total flow were measured. Normal and atherosclerotic coronary arteries showed peak reductions in flow rate of 22% and 92% respectively, while the times to peak reduction of flow averaged 6 and 4 min and the times to 50% relaxation averaged 13 and 24 min. Ultrasound imaging showed that heavily atherosclerotic regions with extensive focal plaque maintained the induced spasm for a longer period than regions with less disease within the same vessel. Silver nitrate staining showed that these heavily atherosclerotic regions were devoid of endothelium. Thus, atherosclerotic human coronary arteries show a larger magnitude of spasm which persists for a longer period of time as compared to normal coronaries.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Artery Disease↗
PubMed1987

Receptors for 5-hydroxytryptamine in rabbit blood vessels: activation of alpha adrenoceptors in rabbit thoracic aorta.

Experiments were carried out to identify the receptors mediating the contraction of the rabbit thoracic aorta to 5-hydroxytryptamine (5-HT). Isolated aortic rings were mounted in tissue baths for the measurement of isometric contraction and 5-HT dose-response curves were obtained in the presence and absence of receptor antagonists. Prazosin, 1 X 10(-7) M, or 30-min pretreatment with 1 X 10(-5) M benextramine had no effect on the contractile response of aorta to 5-HT up to 1 X 10(-5) M, whereas 2 brom-D-lysergic acid diethylamide, 1 X 10(-7) M, shifted the 5-HT dose-response curve far to the right. Alpha receptor blockade with either prazosin or benextramine in the presence of 2 brom-D-lysergic acid diethylamide produced a greater blockade than that caused by 2 brom-D-lysergic acid diethylamide alone. When 5-HT dose-response curves were extended to 1 X 10(-3) M, three phases were identified. The first, a dose-related contraction, was mediated exclusively by serotonergic receptors. The second, a relaxation to approximately 40% of maximum, occurred at 1 X 10(-5) M and appeared to result from the rapid development of tachyphylaxis. The third phase was a dose-related contraction to concentrations of 5-HT above 1 X 10(-5) M and was inhibited by either prazosin or pretreatment with benextramine. Similar results were obtained in aortic rings from reserpine-pretreated rabbits. It is concluded that the contractile response to concentrations of 5-HT below 1 X 10(-5) M is mediated exclusively by serotonergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Bovine anterior descending coronary artery possesses a homogeneous population of beta-1 adrenergic receptors.

Isolated vessel rings from the proximal and distal ends of the bovine anterior descending coronary artery were mounted in tissue baths for the measurement of isometric contraction. These rings were pre-exposed to phenoxybenzamine to block tissue catecholamine uptake and alpha adrenoceptors. They were then contracted with high potassium, and beta adrenergic agonist dose-relaxation response curves were obtained in the presence and absence of beta antagonists. The orders of agonist potency in the arterial rings were the same as that in spontaneously beating guinea pig atria: isoproterenol (ISO) greater than norepinephrine (NE) greater than fenoterol (FE) greater than salbutamol (SA) and differed from that in the guinea pig trachea: ISO greater than FE greater than SA greater than NE. Schild analysis yielded propranolol pA2 values in the coronary artery rings which did not differ between the four agonists studied or between the proximal and distal ends of the coronary artery. Similar results were obtained with practolol and butoxamine with the exception that in the case of butoxamine, a higher pA2 value was obtained against ISO in the distal ring preparations. The practolol and butoxamine pA2 values in the artery rings matched the respective--log KB values obtained in the guinea pig atria using NE as the agonist but were the reverse of those obtained in the guinea pig trachea using either FE or SA as the agonist. It is concluded that the proximal and distal ends of the bovine anterior descending coronary artery possess a homogeneous population of beta-1 adrenergic receptors.

Adrenergic beta-Agonists↗
PubMed1986

Vasoconstrictor threshold synergism and potentiation in the rabbit isolated thoracic aorta.

Isolated rings of rabbit thoracic aorta were mounted in tissue baths for the measurement of isometric contraction, and the effects of combinations of two agonists were studied. Concentrations of methoxamine, clonidine, norepinephrine (NE), 5-hydroxytryptamine (5-HT) and potassium causing threshold contraction (0.1 g) were determined. Combinations of any two of these or of two doses of the same agonist elicited far greater than additive contractions ranging from 0.5 to 2.7 g. When dose-response curves to an alpha adrenergic agonist were obtained in the presence of a threshold concentration of the same or another alpha agonist, the curve was shifted to the left at threshold but converged with the control curve between ED10 and ED70. When 5-HT dose-response curves were obtained in the presence of either NE or methoxamine, the curve was shifted to the left in a parallel fashion. Both NE and methoxamine dose-response curves were also shifted to the left in a parallel fashion in the presence of 5-HT. The threshold concentration of potassium caused leftward parallel shifts of the dose-response curves for all agonists studied. These observations are consistent with the conclusion that the resting state of the rabbit thoracic aorta differs from the threshold contractile state and that this accounts for the far greater than additive contraction caused by combinations of two threshold doses of the same or different agonists. The first dose delivers sufficient stimulus to move the tissue from resting to threshold contractile state whereas the stimulus delivered by the second dose manifests entirely as contraction. This phenomenon affects primarily the threshold response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Enhancement of the pressor response to norepinephrine by angiotensin in the conscious rabbit.

The pressor interactions between angiotensin II and norepinephrine were investigated in conscious New Zealand white rabbits receiving a low sodium diet. Angiotensin II was administered continuously by intraperitoneal osmotic pumps in a subpressor dose so as to avoid the potentially confounding effects of experimentally-induced hypertension. Norepinephrine challenges were given as a series of graded intravenous boluses. During the 3 days of study the baseline blood pressure in the angiotensin-treated rabbits (n=10) did not differ from that in controls (n=10) whose intraperitoneal pumps contained only diluent. After 24 hours the systolic and diastolic blood pressure responses to norepinephrine in the angiotensin-treated group were, on average, 45% and 30% higher than in the controls; after 72 hours, they were 46% and 34% higher. Although the pressor amplitudes were increased by angiotensin II, they were not prolonged. Thus, facilitation by the subpressor angiotensin II of the blood pressure responses to norepinephrine did not seem dependent upon alterations in endogenous sympathetic mechanisms or the uptake of norepinephrine; nor could it be explained by sodium retention. It is possible that angiotensin II exhibits its effect by enhancing contractile responsiveness to norepinephrine at the postreceptor level.

Angiotensin II↗