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D E Vatner

Publications and source records attributed to D E Vatner.

At least 55 records · Page 3Linked to original sources
PubMed1995

Decreased adenylate cyclase activity and expression of Gs alpha in human myocardium after orthotopic cardiac transplantation.

We studied several aspects of guanine nucleotide-stimulated adenylate cyclase function in patients after orthotopic cardiac transplantation. In 28 patients, adenylate cyclase activity was measured in endomyocardial biopsy samples obtained just before and at monthly intervals after cardiac transplantation. In biopsies obtained > or = 6 months after transplantation, basal adenylate cyclase activity was decreased by 67% (n = 12; P < .05), GTP gamma S-stimulated adenylate cyclase activity was decreased by 78% (n = 12; P < .05), Mn+2+forskolin-stimulated adenylate cyclase activity was decreased by 80% (n = 8; P < .05), and Mn+2-stimulated adenylate cyclase activity (a measure of activity of the catalytic subunit of adenylate cyclase) was decreased by 83% (n = 8, P < .05). Western blot analysis demonstrated that 6 months after cardiac transplantation, the level of Gs alpha protein was decreased by 61 +/- 12% (n = 8; P < .001). There was no change in the level of Gi alpha as assessed by pertussis toxin-catalyzed ADP-ribosylation (n = 4; P = NS). With the use of the quantitative polymerase chain reaction, a 50 +/- 10% (n = 6; P < .001) reduction in the steady-state level of Gs alpha mRNA was observed. There was no change in the level of mRNA for Gi-3 alpha. Thus, after orthotopic cardiac transplantation in humans, guanine nucleotide-stimulated adenylate cyclase activity is decreased in parallel with decreased levels of Gs alpha protein and mRNA.

Adenylyl Cyclases↗
PubMed1995

Overexpression of Gs alpha protein in the hearts of transgenic mice.

Alterations in beta-adrenergic receptor-Gs-adenylyl cyclase coupling underlie the reduced catecholamine responsiveness that is a hallmark of human and animal models of heart failure. To study the effect of altered expression of Gs alpha, we overexpressed the short isoform of Gs alpha in the hearts of transgenic mice, using a rat alpha-myosin heavy chain promoter. Gs alpha mRNA levels were increased selectively in the hearts of transgenic mice, with a level 38 times the control. Despite this marked increase in mRNA, Western blotting identified only a 2.8-fold increase in the content of the Gs alpha short isoform, whereas Gs activity was increased by 88%. The discrepancy between Gs alpha mRNA and Gs alpha protein levels suggests that the membrane content of Gs alpha is posttranscriptionally regulated. The steady-state adenylyl cyclase catalytic activity was not altered under either basal or stimulated conditions (GTP + isoproterenol, GTP gamma S, NaF, or forskolin). However, progress curve studies did show a significant decrease in the lag period necessary for GppNHp to stimulate adenylyl cyclase activity. Furthermore, the relative number of beta-adrenergic receptors binding agonist with high affinity was significantly increased. Our data demonstrate that a relatively small increase in the amount of the coupling protein Gs alpha can modify the rate of catalyst activation and the formation of agonist high affinity receptors.

Adenylyl Cyclases↗
PubMed1994

Mechanisms mediating responsiveness to beta-adrenergic stimulation after coronary reperfusion in conscious dogs.

The goal of this study was to assess beta-adrenergic receptor (beta-AR) signaling mechanisms in mediating physiological responses to sympathomimetic amines after 45 min coronary artery occlusion followed by 45 min reperfusion. At this time, isoproterenol (Iso) infusion (0.1 microgram/kg-1.min-1, n = 5) increased percent wall thickening in previously ischemic subendocardium (Endo) more than in nonischemic Endo (12.6 +/- 1.2 vs. 7.2 +/- 0.6%, P < 0.05), whereas forskolin (25 nmol.kg-1.min-1, n = 6) elicited the opposite effect (3.6 +/- 0.6 vs. 10.4 +/- 2.8%, P < 0.05). During Iso and forskolin infusions increases in regional myocardial blood flow in the previously ischemic zone were similar to the nonischemic zone. In all groups, total beta-AR density was depressed in previously ischemic Endo compared with nonischemic Endo (65 +/- 7 vs. 82 +/- 8 fmol/mg, P < 0.05), but the fraction of beta-AR binding agonist with high affinity increased (82 +/- 4 vs. 49 +/- 1%, P < 0.05). The changes in beta-AR were associated with a decrease in Iso-stimulated adenylyl cyclase (22 +/- 8%), a decrease in guanosine 5'-triphosphate (GTP)-stimulatory protein (Gs) (23 +/- 6%), and a decrease in inhibitory G proteins (16 +/- 4%). However, regional Endo functional responsiveness to beta-AR stimulation was enhanced in reperfused myocardium in response to Iso but not to forskolin. Thus the mechanism of increased number of beta-AR binding agonist with high affinity in previously ischemic myocardium predominated over persistent downregulation of total beta-AR density and reductions in Gs and adenylyl cyclase activity and correlated best with the physiological response to beta-AR stimulation. These data may also suggest that Iso exerts an action distal to adenylyl cyclase in previously ischemic myocardium.

Amino Acid Sequence↗
PubMed1994

Decrease in myocardial ryanodine receptors and altered excitation-contraction coupling early in the development of heart failure.

BACKGROUND: Rapid ventricular pacing for 1 day reduced myocardial contractile function without inducing heart failure in conscious, chronically instrumented dogs. After 4 to 7 weeks of pacing, myocardial contractility was depressed further and overt signs of congestive heart failure, eg, ascites, dyspnea, and edema, were evident. METHODS AND RESULTS: The mechanical restitution response, a physiological index of calcium release, was depressed at 1 day of rapid ventricular pacing. Postextrasystolic potentiation was also depressed by a similar amount, 14 +/- 3%, at 1 day after pacing. The response to isoproterenol 0.2 microgram/kg per minute was depressed by a significantly greater amount (P < .05), 52 +/- 7%, at 1 day after pacing. 3H-ryanodine receptor binding fell from 1013 +/- 25 to 808 +/- 42 fmol/mg after 1 day of pacing and remained depressed at similar levels (782 +/- 61 fmol/mg) at 4 to 7 weeks when heart failure was manifest. Ryanodine receptor affinity was unchanged from control values. Neither dihydropyridine binding nor affinity for 3H-PN200-110 was changed from control levels. Within 5 days after recovery from 1 day of pacing, physiological responses to isoproterenol, postextrasystolic potentiation, and mechanical restitution recovered, as did 3H-ryanodine binding density. CONCLUSIONS: These findings suggest that the changes in excitation-contraction coupling and potentially the sarcoplasmic reticulum calcium release channel occur early in the development of heart failure and therefore may be important in the pathogenesis of the contractile abnormalities in this disease state.

Animals↗
PubMed1994

Downregulation of adenylylcyclase types V and VI mRNA levels in pacing-induced heart failure in dogs.

We have shown that the heart expresses two distinct forms of adenylylcyclase mRNA, types V and VI. In this study we have characterized the expression of these two mRNA species in heart failure generated by overdrive pacing at a rate of 240 beats/min. After 4 wk, left ventricular end-diastolic pressure and heart rate increased significantly with the appearance of signs of heart failure, i.e., edema, ascites, and exercise intolerance. Basal as well as forskolin-stimulated adenylylcyclase activities decreased significantly, which was accompanied by a reduction in the steady state mRNA levels of adenylylcyclase types V and VI. These data suggest that in this model of cardiomyopathy, the downregulation of adenylylcyclase catalytic activity results, at least in part, from a reduction in the steady state levels of types V and VI adenylylcyclase mRNA levels.

Adenylyl Cyclases↗
PubMed1993

Effects of coronary arterial reperfusion on beta-adrenergic receptor-adenylyl cyclase coupling.

The effects of 1 h of coronary arterial occlusion (CAO) followed by 15 min reperfusion (CAR) were examined in nine conscious dogs. Ischemia was verified by decreased regional blood flow (radioactive microspheres) and loss of systolic regional wall motion in the ischemic zone. beta-Adrenergic receptor density assessed by 125I-labeled cyanopindolol binding in a crude membrane fraction tended to decrease but was not significantly different. However, adenylyl cyclase activity and the guanine nucleotide stimulatory protein (Gs) were reduced in ischemic subendocardium compared with nonischemic subendocardium. The fraction of beta-adrenergic receptors binding agonist with high affinity increased in ischemic subendocardial and subepicardial layers. Compared with prior data in experiments with 1 h CAO without CAR, the increase in beta-adrenergic receptor density that occurs with myocardial ischemia is rapidly reversed with CAR of 15 min duration, while the decreased fraction of receptors binding agonist with high affinity was reversed to an increase in high-affinity receptors. The global decreases in adenylyl cyclase and Gs, which have been observed with simple CAO, persist but are observed selectively in the previously ischemic subendocardium after CAR. Thus both CAO and CAR affect beta-adrenergic receptors and adenylyl cyclase differently. During CAR, increased numbers of beta-adrenergic receptors binding agonist with high affinity occur potentially as a compensatory mechanism in the face of persistent reductions in adenylyl cyclase activity and Gs.

Adenylyl Cyclases↗
PubMed1993

Increased alpha 1-adrenergic vascular sensitivity during development of hypertension in conscious dogs.

The goal of this study was to determine whether enhanced vascular responsiveness during the development of perinephritic hypertension is selective or nonspecific. The effects of graded infusions of norepinephrine (NE), phenylephrine (PE), angiotensin II (ANG II), and vasopressin (VP) were examined on mean arterial pressure, total peripheral resistance (TPR), and aortic pressure-diameter relationships in conscious dogs. NE increased TPR significantly greater (P < 0.01) in hypertension than normotension, as did PE infusion, whereas ANG II and VP increased TPR similarly before and after hypertension. Analysis of aortic pressure-diameter relationships also demonstrated significant (P < 0.05) shifts in response to NE and PE, but not ANG II and VP, during the development of hypertension. In normotensive dogs, low doses of ANG II infusion also enhanced the vasoconstrictor response not only to NE and PE but also to VP. In contrast to what was observed in hypertension, in the presence of ANG II infusion after ganglionic blockade, enhanced responses to PE and NE were no longer observed. The alpha 1-adrenergic receptor density in membrane preparations from aortic tissue, as determined by [3H]prazosin binding, was higher (P < 0.05) in hypertensive dogs than control dogs. Thus the vascular responsiveness in the aorta and resistance vessels is enhanced to alpha 1-adrenergic stimulation, but not to all vasoconstrictors, during developing perinephritic hypertension. The mechanism appears to involve increased alpha 1-adrenergic receptor density.

Angiotensin II↗
PubMed1993

Depressed beta-adrenergic receptor- and endothelium-mediated vasodilation in conscious dogs with heart failure.

Peripheral vasodilator responsiveness was examined in pacing-induced heart failure (HF) in 11 conscious dogs chronically instrumented for measurement of systemic (total peripheral resistance [TPR]) and local (iliac blood flow) vascular resistance. Dose responses to isoproterenol (ISO), acetylcholine (ACh), and nitroglycerin (NTG) were examined in the same dogs before pacing (control) and after 4 to 7 weeks of rapid ventricular pacing, which induced congestive HF, characterized by increased left ventricular end-diastolic pressure (6.7 +/- 0.4 [control] versus 28 +/- 1.5 [HF] mm Hg) and decreased cardiac output (-30 +/- 5%) and left ventricular dP/dt (-53 +/- 3%), as well as ascites and peripheral edema. In the control state, TPR fell by 57 +/- 2% in response to ISO (100 ng/kg), by 61 +/- 3% in response to ACh (3 micrograms/kg), and by 55 +/- 2% in response to NTG (10 micrograms/kg). In HF, smaller decreases (P < .05) in TPR were observed with the same doses of ISO (-50 +/- 2%) and ACh (-49 +/- 2%) but not with NTG (-58 +/- 3%). Depressed responses to systemic ISO and ACh, but not NTG, were observed in HF in the presence of ganglionic blockade and also after local administration of smaller doses of the drugs in the absence of ganglionic blockade, but where systemic effects were not elicited. Inhibition of nitric oxide synthase increased TPR to a greater degree before HF (+154 +/- 28% [control]) than after (+80 +/- 22% [HF]) and eliminated the depressed responses to ACh but not to ISO. beta-Adrenergic receptor density, as determined by 125I-cyanopindolol binding in membrane preparations from mesenteric vessels was significantly decreased after HF (130 +/- 3 [control] versus 100 +/- 8 [HF] fmol/mg, P < .05) without any change in affinity. Thus, peripheral vascular beta-adrenergic receptor downregulation occurs in HF, independent of altered endothelium-mediated peripheral vasodilation.

Acetylcholine↗
PubMed1993

Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure.

The development of pacing-induced heart failure was studied in chronically instrumented, conscious dogs paced at a rate of 240 beats/min for 1 d (n = 6), 1 wk (n = 6), and 3-4 wk (n = 7). Left ventricular (LV) dP/dt was decreased (P < 0.0125) at 1 d, LV end-diastolic pressure and heart rate were increased (P < 0.0125) at 1 wk, but clinical signs of heart failure were only observed after 3-4 wk of pacing. Plasma norepinephrine rose (P < 0.0125) after 1 d of pacing, whereas LV norepinephrine was reduced (P < 0.0125) only after 3-4 wk of pacing. Both the fraction of beta-adrenergic receptors binding agonist with high affinity and adenylyl cyclase activity decreased (P < 0.0125) after 1 d of pacing. Total beta-adrenergic receptor density was not changed at any time point, but beta 1-adrenergic receptor density was decreased (P < 0.0125) after 1 wk. The functional activity of the guanine nucleotide binding protein, Gs, was not reduced, but the Gi alpha 2 isoform of the alpha subunit of the GTP-inhibitory protein rose after 3-4 wk of pacing. Thus, myocardial beta-adrenergic signal transduction undergoes change shortly (1d) after the initiation of pacing, before heart failure develops. The mechanism of beta-adrenergic receptor dysfunction in pacing-induced heart failure is characterized initially by elevated plasma levels of catecholamines, uncoupling of beta-adrenergic receptors, and a defect in the adenylyl cyclase catalytic unit. Selective down-regulation of beta 1-adrenergic receptors, increases in Gi alpha 2, and decreases in myocardial catecholamine levels occur as later events.

Adenylyl Cyclases↗
PubMed1992

Mechanisms of alpha 1-adrenergic vascular desensitization in conscious dogs.

To investigate the mechanisms of alpha 1-adrenergic vascular desensitization, osmotic minipumps containing either saline (n = 9) or amidephrine mesylate (AMD) (n = 9), a selective alpha 1-adrenergic receptor agonist, were implanted subcutaneously in dogs with chronically implanted arterial and right atrial pressure catheters and aortic flow probes. After chronic alpha 1-adrenergic receptor stimulation, significant physiological desensitization to acute AMD challenges was observed, i.e., pressor and vasoconstrictor responses to the alpha 1-adrenergic agonist were significantly depressed (p < 0.01) compared with responses in the same dogs studied in the conscious state before pump implantation. However, physiological desensitization to acute challenges of the neurotransmitter norepinephrine (NE) (0.1 micrograms/kg per minute) in the presence of beta-adrenergic receptor blockade was not observed for either mean arterial pressure (MAP) (30 +/- 7 versus 28 +/- 5 mm Hg) or total peripheral resistance (TPR) (29.8 +/- 4.9 versus 28.9 +/- 7.3 mm Hg/l per minute). In the presence of beta-adrenergic receptor plus ganglionic blockade after AMD pump implantation, physiological desensitization to NE was unmasked since the control responses to NE (0.1 micrograms/kg per minute) before the AMD pumps were now greater (p < 0.01) than after chronic AMD administration for both MAP (66 +/- 5 versus 32 +/- 2 mm Hg) and TPR (42.6 +/- 10.3 versus 23.9 +/- 4.4 mm Hg/l per minute). In the presence of beta-adrenergic receptor, ganglionic, plus NE-uptake blockade after AMD pump implantation, desensitization was even more apparent, since NE (0.1 micrograms/kg per minute) induced even greater differences in MAP (33 +/- 5 versus 109 +/- 6 mm Hg) and TPR (28.1 +/- 1.8 versus 111.8 +/- 14.7 mm Hg/l per minute). The maximal force of contraction induced by NE in the presence or absence of endothelium was significantly decreased (p < 0.05) in vitro in mesenteric artery rings from AMD pump dogs compared with saline control dogs. Furthermore, alpha 1-adrenergic receptor density, as determined by [3H]prazosin binding in membrane preparations from vessels in the mesentery, was decreased (8.2 +/- 1.0 versus 18.4 +/- 1.4 fmol/mg protein, p < 0.001) without any change in Kd in the AMD pump dogs compared with the saline pump dogs.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Agonists↗
PubMed1991

Inotropic response to norepinephrine is augmented early and maintained late in conscious dogs with perinephritic hypertension.

We studied the inotropic responses to intravenous infusions of norepinephrine in nine conscious chronically instrumented dogs before and early (2-4 weeks) in the development of perinephritic hypertension; seven conscious dogs were studied later (approximately 14 weeks), during a more stable phase of hypertension. perinephritic hypertension was associated with a 24% increase in left ventricular (LV) mass during developing hypertension; no further increase was seen during the stable hypertension phase. LV end-systolic stress was increased early (p less than 0.01) but was normalized later. The LV end-systolic stress-volume relation demonstrated an enhanced contractile response to norepinephrine during developing hypertension, which returned toward control later in the course of stable hypertension. The LV dP/dt responses to norepinephrine (0.4 microgram/kg/min) were significantly greater during developing hypertension (7,509 +/- 337 mm Hg/sec, p less than 0.05) compared with the control period (4,737 +/- 286 mm Hg/sec) and returned toward the control value during stable hypertension (5,168 +/- 465 mm Hg/sec). The enhanced inotropic responses to norepinephrine in developing hypertension were preserved in the presence of ganglionic blockade, suggesting that the augmentation was not mediated via reflex mechanisms. These physiological responses were associated with an increase in beta-adrenergic receptor density, but no significant change in basal or maximal adenylate cyclase stimulation occurred during developing hypertension. Thus, in contrast to prior studies in anesthetized animals, the inotropic response to beta-adrenergic stimulation is not depressed in conscious dogs but is enhanced selectively during the development of hypertension and maintained during stable hypertension.

Animals↗
PubMed1991

Decreased Gs alpha mRNA levels accompany the fall in Gs and adenylyl cyclase activities in compensated left ventricular hypertrophy. In heart failure, only the impairment in adenylyl cyclase activation progresses.

We have previously reported that there is a global reduction in adenylyl cyclase associated with a decrement in Gs functional activity in cardiac sarcolemma from animals with pressure overload-induced hypertrophy and heart failure. This study was performed to determine whether hypertrophy alone in the absence of heart failure is sufficient to promote these changes and whether the superimposition of heart failure intensified these changes. Basal and stimulated adenylyl cyclase and Gs activity, as determined in the S49 cyc- reconstitution assay, were measured in sarcolemma from normal (NL), left ventricular hypertrophy (LVH) and heart failure (HF) animals. Simultaneously, we measured the mRNA level encoding for the Gs alpha subunit. These studies indicate that Gs activity and Gs alpha mRNA are decreased by approximately 30% both in the failing heart and even in the heart with compensated hypertrophy before heart failure develops (Gs activity, pmol cyclic AMP/10 min per microgram, NL 4.2 +/- 0.4, LVH 3.0 +/- 0.2, HF 3.2 +/- 0.3; Gs alpha mRNA, pg/10 micrograms RNA, NL 131 +/- 9.0, LVH 104 +/- 7.4, HF 97.4 +/- 9.1; P less than 0.05 as compared with NL for LVH and HF). Accompanying this decrement in Gs activity is a fall in adenylyl cyclase, both basal and stimulated. However, we also identified a further decrease in adenylyl cyclase without any additional change in Gs or in its alpha subunit mRNA level. This is seen only in the sarcolemma from animals with heart failure as compared with those with compensated LV hypertrophy (e.g., NaF-stimulated activity, pmol cyclic AMP/min per mg, NL 420.2 +/- 17.5, LVH 347.1 +/- 29.6, HF 244.2 +/- 27.3; P less than 0.05 compared with NL for LVH and HF, P less than 0.05 compared with LVH for HF). In summary, these studies indicate that both Gs and adenylyl cyclase activities fall in parallel with the development of LV hypertrophy followed by a further decrement in adenylyl cyclase, independent of Gs, in the setting of heart failure.

Adenylyl Cyclases↗
PubMed1990

Alpha- and beta-adrenergic control of large coronary arteries in conscious calves.

Large and small coronary arteries are subject to control by alpha- and beta-adrenergic mechanisms. However, controversy exists as to the distribution and physiological effects of alpha- and beta-adrenergic receptor subtypes in large coronary arteries. Studies in our laboratory have addressed these questions in conscious calves, chronically instrumented to measure large coronary artery diameter and coronary blood flow. Additionally, adrenergic receptor subtype distribution was determined using ligand binding assays in membrane preparations isolated from large coronary arteries of calves. Physiological results demonstrate, in contrast to the results of most previous studies, that both alpha 1- and alpha 2-adrenergic receptors elicit constriction of the large coronary artery. Studies with ganglionic blockade indicate that the constriction was unaltered by autonomic reflexes or presynaptic release of neurotransmitters. Selective beta-adrenergic receptor activation demonstrated that both beta 1- and beta 2-adrenergic receptors elicit dilation of large coronary arteries, and that the vasodilation was direct, i.e., it was not mediated by increases in coronary blood flow. Biochemical characterization of adrenergic subtype density indicated the presence of both alpha 1- and alpha 2-, as well as beta 1- and beta 2-adrenergic receptor subtypes. Thus, both biochemical and physiological data support the concept that large coronary arteries are regulated by both alpha 1- and alpha 2-, as well as beta 1- and beta 2-adrenergic receptor subtypes.

Adrenergic alpha-Agonists↗
PubMed1990

Characterization of subfractions from purified sarcolemma of canine left ventricle.

Three membrane fractions were studied from canine myocardial left ventricle (LV); crude, light vesicle, and enriched sarcolemma. The percent of the total yield of membrane protein was 99.3 +/- 0.2% for the crude fraction, 0.4 +/- 0.1% for the light vesicle fraction, and 0.3 +/- 0.03% for the purified fraction. Sodium, potassium-ATPase activity in the purified fraction (100 +/- 10.8 mumol Pi/h/mg) was five fold more concentrated than in the light vesicle fraction (18.5 +/- 1.85 mumol Pi/h/mg), and nineteen fold more than in the crude fraction (5.29 +/- 0.57 mumol Pi/h/mg). beta-Adrenergic receptors were 8-fold enriched in the purified fraction (1006 +/- 219 vs 132 +/- 13 fmol/mg in the crude fraction) and 4-fold enriched in the light vesicle fraction (497 +/- 152 fmol/mg). Adenylate cyclase activity was enriched by only 13 to 17-fold in the purified fraction, and only 2 to 4-fold in the light vesicle fraction. The percent of the total beta-adrenergic receptors per gram wet weight was 94 +/- 20% for the crude fraction, 2.1 +/- 0.4% for the light vesicle fraction, and 3.8 +/- 0.7% for the purified fraction. When alamethicin was used to uncover latent enzyme activity, beta-adrenergic receptor density was not affected, but Na+,K(+)-ATPase and adenylate cyclase activity were enhanced in each membrane fraction studied. The surprising finding was that Na+,K(+)-ATPase activity was enriched to the same extent as the beta-adrenergic receptor density in the light vesicle fraction. One potential explanation is that the light vesicle fraction is located in a specialized region of the plasma membrane.

Adenylyl Cyclases↗
PubMed1990

Beta-receptors and adenylate cyclase: comparison of nonischemic, ischemic, and postmortem tissue.

We compared the effects of myocardial ischemia and postmortem changes on beta-adrenergic receptors and their coupling to adenylate cyclase activity. The effects of 1 h of left circumflex coronary artery occlusion were examined in eight conscious calves, which were then anesthetized with pentobarbital sodium, and the left ventricle was divided into nonischemic and ischemic regions. A crude membrane fraction was prepared from each region and from the nonischemic tissue 1 h postmortem. beta-Adrenergic receptor density increased (152 +/- 55%) and decreases in basal (-21 +/- 6.1%), isoproterenol-stimulated (-25 +/- 8.0%), 5'-guanylylimidodiphosphate [Gpp(NH)p]-stimulated (-17 +/- 5.8%), fluoride-stimulated (-26 +/- 5.8%), and forskolin-stimulated (-31 +/- 8.4%) adenylate cyclase activities were observed in the ischemic myocardium compared with nonischemic myocardium. Similarly, in postmortem samples, beta-adrenergic receptor density rose 58 +/- 16%, whereas decreases in basal (-48 +/- 8.7%), isoproterenol-stimulated (-61 +/- 7.8%), Gpp(NH)p-stimulated (-58 +/- 7.0%), fluoride-stimulated (-64 +/- 6.1%), and forskolin-stimulated (-52 +/- 6.2%) adenylate cyclase activities were observed. Agonist-binding competition curves with isoproterenol were shifted, indicating that beta-adrenergic receptors were binding agonists with low affinity in both the ischemic and postmortem myocardium. The marked, but directionally opposite, changes in receptor density and adenylate cyclase that occur postmortem indicate the importance of prompt processing of tissues. The striking similarity in response of beta-adrenergic receptor agonist and antagonist binding and adenylate cyclase activity in ischemic and postmortem tissue raises the speculation that similar mechanisms may operate under both conditions.

Adenylyl Cyclases↗
PubMed1990

Role of intact cardiac nerves and reflex mechanisms in desensitization to catecholamines in conscious dogs.

To study chronic catecholamine desensitization, mini-osmotic pumps were implanted subcutaneously to deliver NE, (0.5 micrograms/kg/min) or saline over 3-4 wk in dogs instrumented with left ventricular (LV) pressure gauges and arterial and left atrial pressure catheters. An acute challenge to NE (0.4 micrograms/kg/min) in intact, conscious dogs increased LV dP/dt by 1,531 +/- 208 mmHg/s before NE pumps, and by a similar amount, 1,340 +/- 166 mmHg/s, 3-4 wk after NE pumps. In contrast, an acute challenge to isoproterenol (ISO, 0.4 micrograms/kg/min) increased LV dP/dt by 5,344 +/- 532 mmHg/s before NE pumps, and significantly less (P less than 0.05; 2,425 +/- 175 mmHg/s) after NE pumps. In the presence of ganglionic and alpha 1-adrenergic blockades, NE (0.4 micrograms/kg/min) increased LV dP/dt by 3,656 +/- 468 mmHg/s before NE pumps and significantly less (P less than 0.01; 1,459 +/- 200 mmHg/s) after NE pumps. Confirming this, an acute challenge to NE (0.4 micrograms/kg/min) in dogs with arterial baroreceptor denervation increased LV dP/dt by 3,732 +/- 896 mmHg/s before NE pumps, and significantly less (P less than 0.05, 1,725 +/- 408 mmHg/s) after NE pumps. In addition, in cardiac denervated dogs, NE (0.4 micrograms/kg/min) increased LV dP/dt by 9,901 +/- 1,404 mmHg/s before NE pumps and significantly less (P less than 0.01, 2,690 +/- 306 mmHg/s) after NE pumps. Desensitization of heart rate responses to NE challenge was also more apparent in the absence of reflex mechanisms. Thus, neural reflex mechanisms play a major role in physiological expression of cardiac desensitization to catecholamines in conscious dogs.

Animals↗
PubMed1989

Species differences in regulation of alpha-adrenergic receptor function.

The effects of alpha-adrenergic receptor stimulation with norepinephrine and phenylephrine after beta-adrenergic and muscarinic receptor blockades were compared in conscious baboons, calves, dogs, and rats in which left ventricular (LV) pressure. LV maximum rate of pressure development (dP/dt), and heart rate were measured. Autonomic receptor density was examined in crude sarcolemmal preparations from the hearts. The major physiological differences were observed in rats, where alpha 1-adrenergic receptor stimulation resulted in the greatest (P less than 0.05) increases in LV dP/dt (29 +/- 2%) in response to phenylephrine, 5.0 micrograms/kg, in comparison with responses in dogs (12 +/- 4%), calves (3 +/- 3%), and baboons (1 +/- 2%). This was associated with the greatest (P less than 0.05) alpha 1-adrenergic receptor density in the rat heart (73 +/- 5 fmol/mg) compared with values in the baboon (6 +/- 1 fmol/mg), calf (21 +/- 3 fmol/mg), or dog (10 +/- 3 fmol/mg) myocardium. Thus there are major differences among mammalian species in alpha-adrenergic receptor density and physiological responsiveness to alpha-adrenergic agonists.

Adrenergic alpha-Agonists↗