Biomedical subjects

S F Vatner

Publications and source records attributed to S F Vatner.

At least 145 records · Page 8Linked to original sources

PubMed1988

Decreased stimulatory guanosine triphosphate binding protein in dogs with pressure-overload left ventricular failure.

Alterations in the level and function of the stimulatory guanyl nucleotide binding protein (Gs) from the cardiac sarcolemma were examined in a canine model of heart failure. The present study is based on our previous investigations that demonstrated both a loss of beta-adrenergic agonist high-affinity binding sites and a decreased adenylate cyclase activity in sarcolemma from failing hearts. Using cholera toxin and [32P]NAD, we labeled the alpha subunit of Gs (Gs alpha) and found a 59% reduction in the level of this protein. Further, a 50% reduction in Gs activity was noted in a reconstitution assay utilizing membranes from the mouse S49 lymphoma cell line cyc-, which is deficient in Gs. These data suggest that, in this model of pressure-overload left ventricular failure, the acquired defect in the beta-adrenergic receptor/adenylate cyclase system involves a deficiency in the coupling protein Gs. Such an abnormality may explain the decreased adrenergic responsiveness of the failing left ventricle.

Animals↗

PubMed1988

Impaired cardiac muscarinic receptor function in dogs with heart failure.

Prior physiological studies have suggested that parasympathetic control is altered in heart failure. The goal of our studies was to investigate the influence of heart failure on the muscarinic receptor, and its coupling to adenylate cyclase. Ligand binding studies using [3H]quinuclidinyl benzilate and enriched left ventricular (LV) sarcolemma, demonstrated that muscarinic receptor density in heart failure declined 36% from a control of 5.6 +/- 0.6 pmol/mg, with no change in antagonist affinity. However, agonist competition studies with both carbachol and oxotremorine showed that it was a loss of high affinity agonist binding sites in the sarcolemma from failing LV that accounted for this difference. The functional efficacy of the muscarinic receptor was also examined. When 1 microM methacholine was added to 0.1 mM GTP and 0.1 mM isoproterenol, adenylate cyclase stimulated activity was inhibited by 15% in normal LV but only 5% in LV sarcolemma from animals with heart failure even when the reduced adenylate cyclase in these heart failure animals was taken into account. Even at 100-fold greater concentrations of methacholine, significantly less inhibition of adenylate cyclase activity was observed in LV failure as compared with normal LV sarcolemma. Levels of the GTP-inhibitory protein known to couple the muscarinic receptor to adenylate cyclase, as measured with pertussis toxin labeling, were not depressed in LV failure. Thus, the inhibitory pathway regulating LV adenylate cyclase activity is defective in heart failure. The decrease in muscarinic receptor density, and in particular the specific loss of the high affinity agonist binding component of this receptor population, appears to be the major factor underlying this abnormality.

Adenylyl Cyclases↗

PubMed1987

Effects of myocardial ischemia on regional function and stiffness in conscious dogs.

The extent to which cardiac nerves influence responses of regional ventricular function to acute myocardial ischemia was investigated in conscious dogs with intact cardiac innervation (N) and dogs with chronic cardiac denervation (D). Following coronary artery occlusion (CAO) left ventricular (LV) end-diastolic pressure increased more (P less than 0.01) in D (18 +/- 3.2 mmHg) than in N dogs (3.4 +/- 0.7 mmHg), whereas heart rate increased more in N (32 +/- 4.8 beats/min) than in D dogs (16 +/- 3.0 beats/min). In nonischemic zones of D dogs there were greater increases, P less than 0.05, in end-diastolic segment length, systolic segment shortening, and velocity of shortening than in N dogs. In ischemic zones, significantly greater increases in end-diastolic segment length were also observed in the D group, but similar reductions in segmental shortening occurred in both N (-116 +/- 2.8%) and D (-108 +/- 5.2%) dogs. The time constant of isovolumic relaxation was not different in the two groups. However, in ischemic zones of N dogs myocardial stiffness constant (k) increased by 109 +/- 24 from 33 +/- 4.9 and end-diastolic stiffness (Eed) rose by 1527 +/- 310 from 253 +/- 34 mmHg, whereas k increased significantly less (P less than 0.05) in D dogs. Eed of ischemic zones also rose significantly less (P less than 0.05) in D dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Effects of left circumflex coronary flow transducer implantation on posterior wall innervation.

To determine whether dissection around a coronary artery and implantation of a flow transducer resulted in partial regional denervation of the heart, the effects of bilateral stimulation of the ansae subclaviae were evaluated on regional left ventricular (LV) wall thickening (WT) and tissue norepinephrine content in four groups of dogs following 1) sham operations (n = 6),2) implantation of a Doppler flow transducer on the left circumflex coronary artery (n = 6), 3) selective circumflex coronary artery denervation with topical phenol application (n = 5), and 4) selective denervation of the posterior LV wall by extensive surgical stripping of the left circumflex coronary artery and local application of phenol (n = 6). One week later after anesthesia (chloralose 100 mg/kg) and a second thoracotomy for implantation of ultrasonic WT crystals, stimulation of the ansae subclaviae increased posterior WT by 67 +/- 9% in the sham group, 71 +/- 14% in the flow probe group, and did not increase systolic WT in the denervated group. In the posterior LV wall, norepinephrine levels were reduced (P less than 0.01) in the denervated group (6 +/- 4 pg/mg) but not in the flow probe group (629 +/- 4 pg/mg) compared with the sham group (589 +/- 88 pg/mg). Selective left circumflex coronary artery denervation did not result in either diminished norepinephrine levels in the posterior LV wall nor diminished response of WT to sympathetic nerve stimulation. Thus chronic instrumentation applied properly to the left circumflex coronary artery does not result in significant regional denervation of the posterior myocardium.

Animals↗

PubMed1987

Coronary vasoconstriction mediated by alpha 1- and alpha 2-adrenoceptors in conscious dogs.

Coronary vasoconstriction was examined in response to the selective stimulation of alpha 1- and alpha 2-adrenoceptors in chronically instrumented conscious dogs. Norepinephrine (NE, 0.05 and 0.1 micrograms X kg-1 X min-1), a mixed alpha 1- to alpha 2-adrenoceptor agonist, phenylephrine (PE, 0.5 and 1.0 micrograms X kg-1 X min-1), a preferential alpha 1-adrenoceptor agonist, and B-HT 920 (1.0 micrograms X kg-1 X min-1), a preferential alpha 2-adrenoceptor agonist, were infused intravenously after ganglionic (hexamethonium, 30 mg/kg iv), beta-adrenoceptor (propranolol, 1.0 mg/kg iv), and muscarinic receptor (atropine methylbromide, 0.1 mg/kg iv) antagonism. Equipressor doses of the alpha-adrenoceptor agonists caused similar increases in calculated late diastolic coronary resistance (NE, 0.57 +/- 0.10 mmHg X ml-1 X min; PE, 0.61 +/- 0.13 mmHg X ml-1 X min; B-HT 920, 0.64 +/- 0.09 mmHg X ml-1 X min). Mechanically increasing aortic root pressure to levels similar to those observed in response to alpha-adrenoceptor stimulation did not increase coronary resistance. Preferential antagonism of alpha 1-adrenoceptors with prazosin (1 mg/kg iv) abolished the vasoconstrictor response to PE but had a lesser effect on the response to B-HT 920. Antagonism of alpha 2-adrenoceptors with rauwolscine (alpha-yohimbine, 0.1 mg/kg iv) abolished the vasoconstrictor response to B-HT 920 but had a lesser effect on the response to PE. The response to NE was reduced to a similar degree by either alpha 1- or alpha 2-adrenoceptor antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1987

Calcium channel blockers induce preferential coronary vasodilation by an alpha 1-mechanism.

The effects of nitrendipine were evaluated on coronary and systemic dynamics in conscious dogs. Nitrendipine (8 micrograms X kg-1 X min-1) decreased late diastolic left circumflex coronary resistance (62 +/- 1.3%) significantly more (P less than 0.01) than total peripheral resistance (54 +/- 1.8%). After propranolol (1 mg/kg) and atropine methyl bromide (0.1 mg/kg) to eliminate reflex increases in myocardial metabolic demand, nitrendipine still reduced late diastolic coronary resistance (56 +/- 1.5%) significantly more (P less than 0.01) than total peripheral resistance (46 +/- 1.4%). However, after adding alpha 1-adrenergic receptor blockade with prazosin (1 mg/kg) to beta-adrenergic and cholinergic receptor blockades, nitrendipine no longer reduced late diastolic coronary resistance (40 +/- 2.7%) more than total peripheral resistance (45 +/- 2.1%) and, in fact, reduced late diastolic coronary resistance less than prior to prazosin. Nifedipine and diltiazem also reduced late diastolic coronary resistance more than total peripheral resistance prior to, but not after, alpha 1-adrenergic receptor blockade. In contrast, sodium nitroprusside reduced late diastolic coronary resistance more (P less than 0.01) than total peripheral resistance both before and after alpha 1-adrenergic receptor blockade. Thus calcium channel blockers preferentially dilate the coronary bed in comparison with the systemic circulation. Since the preferential effects were abolished by prazosin, an alpha 1-adrenergic mechanism is implicated.

Animals↗

PubMed1987

Baroreflex mechanisms buffering alpha-adrenergic agonists in conscious dogs.

To determine the relative importance of the mechanisms utilized by the arterial baroreflex in buffering the pressor and vasoconstrictor responses to alpha-adrenergic receptor agonists, we studied responses to norepinephrine and phenylephrine in conscious dogs. The dogs were studied 2-8 wk after instrumentation with aortic catheters and aortic electromagnetic flow probes to measure arterial pressure and cardiac output. Total peripheral resistance was calculated on-line by a digital computer. The dogs were studied after beta-adrenergic receptor blockade (propranolol 1.0 mg/kg) to eliminate the complicating inotropic effects of the agonists studied. Norepinephrine (0.2 microgram/kg bolus) increased mean arterial pressure by 30 +/- 3 mmHg, total peripheral resistance by 51 +/- 4 mmHg . l-1 . min-1, and decreased heart rate by 26 +/- 3 beats/min. After arterial baroreceptor denervation, norepinephrine increased mean arterial pressure by 69 +/- 8 mmHg, total peripheral resistance by 48 +/- 6 mmHg . l-1 . min-1, and heart rate did not change. After ganglionic blockade (hexamethonium 40 mg/kg), norepinephrine increased mean arterial pressure by 76 +/- 3 mmHg, total peripheral resistance by 47 +/- 4 mmHg X l-1 X min-1, and heart rate did not change. Only after elimination of the buffering by heart rate by use of cholinergic receptor blockade (atropine 0.1 mg/kg) or ventricular pacing could buffering of the vasoconstrictor responses to alpha-adrenergic receptor agonists be demonstrated. Thus in conscious dogs the primary mechanism for buffering increases in arterial pressure induced by alpha-adrenergic receptor agonists is compensatory changes in heart rate and cardiac output with little buffering of total peripheral resistance.

Adrenergic alpha-Agonists↗

PubMed1987

Enhanced responsiveness to carotid baroreceptor unloading in conscious dogs during development of perinephritic hypertension.

The effects of unloading the carotid sinus baroreceptors before and during the development of perinephritic hypertension were studied in conscious dogs instrumented with aortic catheters to measure arterial pressure and heart rate, and electromagnetic flow probes to measure cardiac output and calculate total peripheral resistance. Prior to hypertension, bilateral carotid occlusion (BCO) increased mean arterial pressure by 38 +/- 2 from 101 +/- 2 mm Hg and total peripheral resistance by 19 +/- 2 from 46 +/- 3 mm Hg/l/min, while cardiac output and heart rate did not change from 2,299 +/- 128 ml/min and 84 +/- 4 beats/min, respectively. At 2 weeks after renal wrapping, there were significant increases in baseline mean arterial pressure, cardiac output, and total peripheral resistance and decreases in heart rate; BCO increased mean arterial pressure by 59 +/- 5 from 130 +/- 4 mm Hg, heart rate by 36 +/- 5 beats/min from 69 +/- 3 beats/min, and cardiac output by 458 +/- 103 from 2,711 +/- 239 ml/min. By 4 weeks after renal wrapping, heart rate and mean arterial pressure responses to BCO were approaching baseline levels. After beta-adrenergic receptor blockade, responses to BCO of mean arterial pressure, cardiac output, and heart rate were no longer significantly enhanced during the development of hypertension. Thus, in conscious dogs, reflex pressor responses to baroreceptor unloading via BCO were enhanced during the development of hypertension but no longer present 3 weeks later. The augmented mean arterial pressor responses to BCO were mediated by increases in cardiac output and heart rate, which in turn, appeared to be controlled by beta-adrenergic receptor mechanisms.

Animals↗

PubMed1987

Altered adrenergic control in hypercholesterolemia.

Vascular reactivity is altered by hypercholesterolemia and atherosclerosis. Animal studies have shown that serotonergic mechanisms of vasoconstriction are enhanced, while the changes with adrenergic mechanisms are still equivocal. Serum lipids are increased with beta-blocker and diuretic therapy for hypertension. Thus, the increase in serum lipids may be responsible for both structural and functional abnormalities of the vascular system in hypertensive patients. In contrast, recent reports have suggested that alpha 1-adrenergic receptor inhibition, useful in hypertension therapy, may exert a beneficial effect on plasma lipids. We have also collected preliminary data in our laboratory examining the effects of alpha 1-adrenergic receptor inhibition with prazosin on plasma cholesterol levels and vascular reactivity in monkeys with hypercholesterolemia. We observed large reductions in both total cholesterol and the very-low-density lipoprotein (VLDL) + low-density lipoprotein (LDL) fraction of cholesterol in these animals during treatment with prazosin. Thus, in addition to its sympatholytic action on the vasculature, alpha 1-adrenergic receptor inhibition appears to exert a beneficial effect in reducing total cholesterol levels.

Adrenergic alpha-Antagonists↗

PubMed1987

Blood flow- and endothelium-mediated vasomotion of iliac arteries in conscious dogs.

The effects of removal of endothelium and changes in blood flow in conscious dogs on the responses of large iliac artery diameter to local infusion of nitroglycerin, acetylcholine, epinephrine, and norepinephrine into the iliac artery were studied. Infusion of agonists did not change mean arterial pressure or heart rate. In vessels with intact endothelium, iliac diameter increased with nitroglycerin (5.1 +/- 0.5%), acetylcholine (4.5 +/- 0.5%), and epinephrine (3.5 +/- 0.9%) and decreased with norepinephrine (-6.7 +/- 1.7%). Preventing increases in blood flow during infusions of agonists abolished the dilation with epinephrine but not with nitroglycerin or acetylcholine. When blood flow was completely stopped by occlusion of the iliac artery, local injection of nitroglycerin (5.7 +/- 0.7%) and acetylcholine (3.0 +/- 0.6%) dilated, but epinephrine constricted (-9.1 +/- 1.7%), the iliac artery. Removal of the iliac artery endothelium did not change the dilation with nitroglycerin (4.6 +/- 0.5%), abolished the dilation with acetylcholine (0.0 +/- 0.3%), reversed the dilation with epinephrine to constriction (-3.3 +/- 0.7%), and enhanced the constriction with norepinephrine (-13.6 +/- 1.6%). These results indicate that epinephrine and acetylcholine dilate the iliac artery via a mechanism mediated by the endothelium. The endothelium-dependent dilation observed with epinephrine is mediated by an increase in iliac blood flow, while that observed with acetylcholine is due partially to a direct effect on the endothelium as well as an effect of blood flow superimposed on the direct effect. The results further indicate that the endothelium attenuates vasoconstriction produced by the alpha-adrenergic agonists, norepinephrine and epinephrine.

Acetylcholine↗

PubMed1987

Vasomotor control: functional hyperemia and beyond.

Historically, functional hyperemia has been viewed largely as an interaction between a parenchymal cell and its associated microvasculature. Locally released metabolites have been thought to produce relaxation of the smooth muscle and a vasodilation that increases blood flow in proportion to metabolic need. This symposium report presents evidence from a variety of disciplines and a number of different types of biological preparations that demonstrates that functional hyperemia is a complex process involving several classes of microvessels including capillaries, arterioles, and small arteries. These vessels do not function independently but are coordinated by a complex set of interrelations involving at least three different modes of interaction between parenchymal cells and the various segments of the vascular bed. These are local metabolic effects, propagated effects extending over long segments of the vasculature, and flow-dependent vasodilation induced by local changes in blood flow. In addition to these acute responses to metabolic demand it appears that tissues may be capable of more long-term structural alterations of the arterial and arteriolar network in response to sustained changes in the relationship between supply and demand. The vascular bed appears to be able to adapt either by increasing the maximal anatomic diameter of the large arteries or by inserting new arterioles into the parenchyma. Thus, classical functional hyperemia appears to be but one manifestation of a multifaceted process leading to highly coordinated responses of many vascular elements, resulting finally in vascular patterns that are optimized to meet parenchymal cell demands.

Animals↗

PubMed1986

Augmented catecholamine uptake by the heart during hemorrhage in the conscious dog.

Changes in arterial and coronary sinus concentrations of norepinephrine (NE) and epinephrine (E) in response to hemorrhage were examined in conscious dogs. Hemorrhage (45 +/- 3.2 ml/kg) decreased mean arterial pressure by 47 +/- 6%, left ventricular (LV) dP/dt by 38 +/- 6%, and mean left circumflex coronary blood flow by 47 +/- 6%, while heart rate increased by 44 +/- 13%. Increases in concentrations of arterial NE (5,050 +/- 1,080 from 190 +/- 20 pg/ml) and E (12,700 +/- 3,280 from 110 +/- 20 pg/ml) were far greater than increases in coronary sinus NE (1,700 +/- 780 from 270 +/- 50 pg/ml) and E (4,300 +/- 2,590 from 90 +/- 10 pg/ml). Net release of NE from the heart at rest was converted to a fractional extraction of 66 +/- 9% after hemorrhage. Fractional extraction of E increased from 16 +/- 6% at rest to 73 +/- 8% after hemorrhage. In cardiac-denervated dogs, hemorrhage (46 +/- 2.8 ml/kg) decreased mean arterial pressure by 39 +/- 15%, LV dP/dt by 36 +/- 10%, and mean left circumflex coronary blood flow by 36 +/- 13%, while heart rate increased by 24 +/- 10%. Hemorrhage increased arterial NE (1,740 +/- 150 from 210 +/- 30 pg/ml) and E (3,050 +/- 880 from 140 +/- 20 pg/ml) more than it increased coronary sinus NE (460 +/- 50 from 150 +/- 30 pg/ml) and E (660 +/- 160 from 90 +/- 20 pg/ml) but significantly less (P less than 0.05) than observed in intact dogs. These experiments indicate that hemorrhage, unlike exercise and sympathetic nerve stimulation, does not induce net overflow of NE from the heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Vagally mediated regulation of renal function in conscious primates.

The effects of vagal denervation (VD) were examined on responses of Na+ and water excretion to acute volume expansion (18 ml/kg of 6% dextran in saline) in six conscious rhesus monkeys with chronic sinoaortic denervation (SAD). After SAD, volume expansion increased mean arterial pressure (from 95 +/- 6.6 to 119 +/- 7.5 mmHg), right atrial pressure (from 1.3 +/- 0.7 to 5.9 +/- 1.8 mmHg), urine flow (from 0.08 +/- 0.01 to 0.68 +/- 0.20 ml/min), and Na+ excretion (from 1.30 +/- 0.45 to 29.51 +/- 10.40 mueq/min). After VD, volume expansion increased mean arterial and right atrial pressures similarly, but induced significantly lower (P less than 0.05) increases in urine flow (from 0.05 +/- 0.01 to 0.19 +/- 0.03 ml/min) and Na+ excretion (from 0.87 +/- 0.27 to 11.50 +/- 6.13 mueq/min). Thus vagal mechanisms appear to play an important role in mediating excretion of Na+ and water in response to acute volume expansion in the conscious primate.

Animals↗

PubMed1986

Enhanced adrenergic constriction of iliac artery with removal of endothelium in conscious dogs.

We studied, in conscious dogs, the effects of removal of endothelium on the responses of iliac artery diameter and iliac blood flow to intra-arterial infusions of adrenergic agonists. With endothelium intact, iliac diameter increased with intra-arterial infusion of nitroglycerin (4.7 +/- 0.4%), acetylcholine (4.2 +/- 0.6%), and epinephrine (4.5 +/- 1.3%), and decreased with norepinephrine (-7.5 +/- 1.7%), phenylephrine (-6.6 +/- 1.0%), and B-HT 920 (-2.1 +/- 0.6%). One- to-five days following removal of endothelium with a balloon-tipped catheter, base-line iliac diameter was unchanged, and still increased with nitroglycerin (4.6 +/- 0.5%), but not with acetyl-choline, and epinephrine actually decreased diameter (-3.5 +/- 1.3%). Removal of the endothelium also enhanced the constriction observed with norepinephrine (-12.5 +/- 2.0%) and phenylephrine (-11.4 +/- 1.6%), but not with B-HT 920 (-1.8 +/- 0.5%). The changes in arterial pressure, iliac blood flow, iliac vascular resistance, and heart rate induced by any of the agonists did not differ before and after removal of the endothelium. These results indicate that the endothelium mediates the dilation in response to epinephrine and also serves an important role in protecting against alpha 1-adrenergic vasoconstriction of large iliac arteries.

Animals↗

PubMed1986

Vagal regulation of arginine vasopressin in conscious dogs.

To determine whether removal of inhibition of arginine vasopressin (AVP) by vagal afferents results in persistent elevation of plasma AVP, effects of bilateral cervical vagal denervation (VD) on plasma AVP were examined in 10 dogs with sinoaortic baroreceptor denervation (SAD). VD increased plasma AVP levels by 98 +/- 16 from 3.8 +/- 1.0 pg/ml (P less than 0.01) at 15 min after VD. By 4 h after VD there were no significant differences from control values. Responses of plasma AVP were also examined in response to acute volume expansion in conscious dogs with all reflexes intact, SAD, and SAD plus VD. In intact and SAD dogs, when blood volume was expanded by 20% with a rapid infusion of isotonic, isooncotic 3% dextran in saline, mean left atrial pressure rose transiently and plasma AVP fell insignificantly. With more prolonged stimulation to cardiopulmonary receptors, i.e., when left atrial pressure was maintained at elevated levels for 1 h by volume loading, plasma AVP fell by 0.9 +/- 0.3 pg/ml. However, after correction for hemodilution was made, AVP did not change with volume expansion, indicating that secretion rate was unchanged. Thus acute, but not chronic, interruption of vagal pathways induces striking release of AVP, but a resetting mechanism rapidly returns plasma AVP to control levels. Furthermore, stimulation of vagally innervated receptors by means of acute volume expansion suppresses plasma AVP when the elevation in atrial pressure is sustained, but this fall in plasma AVP can be accounted for entirely by the concomitant hemodilution.

Anesthesia↗

PubMed1986

Mechanical and inotropic reserve in conscious dogs with left ventricular hypertrophy.

We studied the left ventricular (LV) responses to infusions of norepinephrine and prenalterol, a specific beta 1-adrenergic receptor agonist, in conscious, chronically instrumented adult dogs with severe LV hypertrophy. The goal of this study was to determine the extent of compensation induced by LV hypertrophy in an animal model in which the pressure overload was gradually increased, as occurs in human pathological states. One to 2 yr after banding the ascending aorta of puppies, six dogs with severe LV hypertrophy (LV free-wall weight-to-body weight ratio 7.0 +/- 0.4 g/kg), and nine sham-operated littermates (LV free-wall weight-to-body weight ratio 4.0 +/- 0.2 g/kg) were studied. The dogs were instrumented with ultrasonic dimension crystals (to measure LV short-axis diameter and wall thickness), miniature LV pressure transducers, and LV and aortic catheters. In the control dogs norepinephrine (0.4 micrograms X kg-1 X min-1) increased LV systolic/diastolic pressure from 121 +/- 2/9 +/- 1 to 177 +/- 9/20 +/- 2 mmHg, mean arterial pressure from 97 +/- 2 to 143 +/- 9 mmHg, LV dP/dt from 3,363 +/- 123 to 5,174 +/- 343 mmHg/s, and mean systolic wall stress from 194 +/- 14 to 299 +/- 22 g/cm2, while mean velocity of circumferential fiber shortening (Vcf), (dD/dt/D)max, and heart rate did not change from base line. In dogs with LV hypertrophy norepinephrine increased LV pressure from 224 +/- 16/11 +/- 1 to 305 +/- 22/19 +/- 1 mmHg, mean arterial pressure from 90 +/- 2 to 132 +/- 4 mmHg, LV dP/dt from 3,246 +/- 156 to 5,619 +/- 345 mmHg/s, and mean systolic wall stress from 224 +/- 11 to 307 +/- 24 g/cm2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Subtypes of beta-adrenergic receptors in bovine coronary arteries.

Whether large coronary artery dilation induced by beta-adrenergic stimulation is mediated by beta 1- or beta 2-adrenergic receptors remains controversial. This problem is particularly difficult to address in vivo due to the concomitant increase in coronary blood flow with beta-adrenergic stimulation, which by itself can dilate large coronary arteries. To reconcile this problem, 5 calves were instrumented with intraaortic and intracoronary (i.c.) catheters, ultrasonic diameter transducers, Doppler flow transducers, and hydraulic occluders on the left circumflex coronary artery. Two to six weeks following surgery, beta-adrenergic agonists were administered i.c. to avoid complicating systemic effects. Isoproterenol (0.0025 micrograms/kg, a beta 1 + beta 2-adrenergic agonist) increased coronary diameter (7.1 +/- 0.8% from 5.80 +/- 0.58 mm) (p less than 0.01). Similar increases (p less than 0.01) in coronary diameter occurred with prenalterol (0.4 micrograms/kg, beta 1-adrenergic agonist) (9.5 +/- 1.4%) and pirbuterol (0.25 micrograms/kg, beta 2-adrenergic agonist) (8.1 +/- 1.2%). When coronary blood flow was prevented from rising with the hydraulic constrictor, increases in coronary diameter to all three beta-adrenergic agonists were not attenuated. Large coronary artery dilation with prenalterol and pirbuterol was abolished with beta 1- and beta 2-adrenergic receptor blockade, respectively, while neither beta 1- nor beta 2-adrenergic blockade alone abolished the large coronary artery dilation with isoproterenol. To identify the predominant subtype of beta-adrenergic receptor, competitive inhibition curves utilizing 125I-cyanopindolol (125I-CYP) as the radiolabel versus isoproterenol, epinephrine, and norepinephrine were generated in membrane preparations from calf heart (predominant beta 1), calf lung (predominant beta 2) and calf coronary artery. The coronary artery membrane preparations demonstrated an intermediate pattern. Competition curves with selective beta 1- and beta 2-adrenergic receptor agonists and antagonists again demonstrated a pattern for coronary artery intermediate to that of heart and lung, further confirming the presence of both beta-adrenergic receptor subtypes in large coronary arteries, with a ratio of beta 1: beta 2 of 1.5-2.0:1.0. Thus, large coronary arteries of the calf contain both beta 1- and beta 2-adrenergic receptors identified utilizing ligand binding techniques, and stimulation of both receptor subtypes in the intact conscious animal results in large coronary artery dilation, independent of blood-flow-mediated vasodilation.

Adrenergic beta-Agonists↗

PubMed1986

Regulation of large coronary arteries.

The majority of studies on the control of coronary artery vasoactivity have examined changes in coronary blood flow and coronary vascular resistance, indices that primarily reflect regulation of small arterioles and precapillary vessels. With the emergence of coronary artery vasospasm as a significant cause of angina pectoris, myocardial infarction, and sudden death, the control of large coronary artery caliber has assumed more significance. It is clear that resistance coronary vessels and large coronary arteries differ in response to both pharmacologic and physiologic stimuli. Vasodilation of large coronary arteries may occur by direct action of agents on the arterial smooth muscle or by the indirect action of receptor occupation, changes in blood flow, or liberation of endothelial factors. These indirect factors appear to contribute also to responses to agents that constrict coronary smooth muscle directly or through the autonomic nervous system. Furthermore, the mechanisms responsible for control of large coronary vessels in the normal circulation are likely to be profoundly different from those in the presence of diseased vessels. For example, several factors associated with coronary artery disease--elevated plasma cholesterol levels, endothelial disruption, atherosclerosis, vascular stenosis, and aggregated platelets--all have important actions on the control of large coronary arteries.

Animals↗