Biomedical subjects

S F Vatner

Publications and source records attributed to S F Vatner.

At least 163 records · Page 9Linked to original sources

PubMed1986

Cardiovascular responses to the stimulation of alpha-1 and alpha-2 adrenoceptors in the conscious dog.

Hemodynamic responses to the selective stimulation of alpha-1 and alpha-2 adrenoceptors were examined in chronically instrumented, conscious dogs. Norepinephrine (0.02-0.1 micrograms/kg/min), a mixed alpha-1/alpha-2 adrenoceptor agonist, phenylephrine (0.2-1.0 micrograms/kg/min), a selective alpha-adrenoceptor agonist and B-HT 920 (0.5-2.0 micrograms/kg/min), a selective alpha-2 adrenoceptor agonist, were infused i.v. after ganglionic (hexamethonium, 30 mg/kg i.v.), beta adrenoceptor (propranolol, 1, mg/kg i.v.) and muscarinic receptor (atropine methylbromide, 0.1 mg/kg i.v.) antagonism. Each of the alpha adrenoceptor agonists increased mean arterial pressure and total peripheral resistance but had no significant effect on cardiac output, stroke volume or heart rate. Equipressor doses of the alpha adrenoceptor agonists caused similar increases in left ventricular systolic and end-diastolic pressure, but there were no significant changes in left ventricular dP/dt or heart rate with any of the alpha adrenoceptor agonists. Selective antagonism of alpha-1 adrenoceptors with prazosin (1 mg/kg i.v.) abolished the pressor and vasoconstrictor responses to phenylephrine but had a lesser effect on the response to B-HT 920. Antagonism of alpha-2 adrenoceptors with rauwolscine (0.1 mg/kg i.v.) caused a significantly greater attenuation of the pressor and vasoconstrictor responses to B-HT 920 than to phenylephrine. The responses to norepinephrine were significantly attenuated by antagonism of either alpha-1 or alpha-2 adrenoceptors. Thus, in the conscious dog with reflex pathways blocked, selective stimulation of either postsynaptic alpha-1 or alpha-2 adrenoceptors increases arterial pressure and total peripheral resistance but does not significantly change heart rate, left ventricular dP/dt, stroke volume or cardiac output.

Adrenergic alpha-Agonists↗

PubMed1986

Nifedipine attenuates both alpha-1 and alpha-2 adrenoceptor-mediated pressor and vasoconstrictor responses in conscious dogs and primates.

Effects of the calcium channel blocker, nifedipine, were examined on the pressor and vasoconstrictor responses to stimulation of alpha-1 and alpha-2-adrenoceptors in chronically instrumented conscious dogs and Rhesus monkeys. Norepinephrine (NE), a mixed alpha-1 and alpha-2 adrenoceptor agonist, phenylephrine (PE) and methoxamine (M), selective alpha-1 adrenoceptor agonists, and B-HT 920, a selective alpha-2 adrenoceptor agonist, were injected i.v. after ganglionic (hexamethonium), beta adrenoceptor (propranolol) and muscarinic receptor (atropine methyl bromide) blockade. In the dog, NE (0.1 microgram/kg i.v.), PE (1 microgram/kg i.v.), M (20 micrograms/kg i.v.) and B-HT 920 (1 microgram/kg i.v.) produced similar increases in mean arterial pressure (NE, 52 +/- 4 mmHg; PE, 42 +/- 4 mm Hg; M, 43 +/- 7 mm Hg; B-HT 920, 45 +/- 6 mm Hg) and total peripheral resistance (NE, 20.8 +/- 5.8 mm Hg/l/min; PE, 23.1 +/- 4.2 mm Hg/l/min; M, 18.2 +/- 2.1 mm Hg/l/min; B-HT 920, 24.8 +/- 7.1 mm Hg/l/min). Nifedipine (0.5 microgram/kg/min i.v.) caused a similar attenuation of the pressor (NE, -54 +/- 8%; PE, -43 +/- 8%; M, -49 +/- 6%; B-HT 920, -56 +/- 8%) and vasoconstrictor (NE, -66 +/- 11%; PE, -52 +/- 9%; M, -60 +/- 13%; B-HT 920, -57 +/- 10%) responses to each of the alpha-adrenoceptor agonists. Nifedipine also attenuated pressor responses to alpha-1 and alpha-2 adrenoceptor agonists similarly in conscious monkeys. Thus, in conscious dogs and monkeys, calcium channel blockade attenuates similarly both alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction.

Animals↗

PubMed1986

Effects of brief periods of myocardial ischemia on regional myocardial function and creatine kinase release in conscious dogs and baboons.

The effects of 15 min periods of coronary occlusion on global and regional myocardial function, plasma creatine kinase (CK) and isoenzyme MB CK activity and subsequent myocardial necrosis were studied in 15 conscious dogs and 9 conscious baboons. Overall left ventricular (LV) function was assessed with measurements of LV systolic and diastolic pressures, rate of change of LV pressure, LV dP/dt. Regional LV function was assessed with measurements of regional segment length and velocity of shortening and/or regional LV wall thickening. An implanted hydraulic occluder on either the left anterior descending or circumflex coronary artery was inflated for 15 min. This induced complete loss of segment length shortening and systolic wall thickening (ultrasonic transit time technique). With release of the occlusion and reperfusion, recovery of regional mechanical function was delayed, but did occur after 6 hrs. Serial plasma enzyme activity revealed a significant increase in total CK as well as MB CK. At autopsy, neither gross pathological evidence (TTC-technique) nor histological evidence of myocyte necrosis was observed. Thus, in the conscious dog as well as in the conscious baboon, short episodes of intense myocardial ischemia do not result in a permanent deficit of myocardial function or necrosis. However, during the early phase of reperfusion, significant depression of regional mechanical function is observed associated with significant appearance of total CK and MB CK in the blood.

Animals↗

PubMed1985

Regulation of coronary resistance vessels and large coronary arteries.

There is now considerable evidence for alpha-adrenergic regulation of coronary resistance vessels and large coronary arteries based on studies of chronically instrumented, conscious animals. Infusion of norepinephrine at low doses causes reduction of coronary blood flow with a slight increase in arterial pressure, indicating intense coronary vasoconstriction. This coronary constrictor response was reversed to coronary vasodilation with infusion of norepinephrine after alpha-adrenergic blockade. Stimulation of alpha 1- and alpha 2-adrenergic receptors with phenylephrine and B-HT 920, respectively, also increased calculated coronary vascular resistance in the conscious animal. These effects were eliminated by selective alpha 1-adrenergic blockade with prazosin and by selective alpha 2-adrenergic blockade with rauwolscine. Stimulation of the carotid chemoreceptor reflex elicits a period of intense coronary vasoconstriction, characterized by a decrease in coronary blood flow despite increased arterial driving pressure. This response was eliminated by prior alpha-adrenergic blockade or a combination of cardiac sympathetic denervation and adrenalectomy. Using chronically implanted ultrasonic crystals to measure the epicardial coronary diameter instantaneously and continuously in conscious dogs, marked vasodilation of the large coronary arteries was observed with administration of nitroglycerin or calcium-channel antagonists; in contrast, activation of alpha-adrenergic receptors with methoxamine induced substantial constriction, characterized by a reduction in coronary artery diameter in the face of elevated distending pressure. The regulation of large coronary arteries is further complicated by the fact that these vessels are responsive to changes in myocardial metabolic demands and coronary blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1985

Autonomic mechanisms regulating myocardial contractility in conscious animals.

In this review some of the issues and controversies involved in the neural control of the myocardial inotropic response to stress have been discussed. For example, it is surprising that either direct or reflex activation of the sympathetic nerves induces a relatively small increase (20-40%) in the left ventricular inotropic state when compared with the three-five-fold increase associated with maximal dynamic exercise. Studies contrasting the levels of circulating catecholamines with the left ventricular inotropic responses induced by hemorrhage, exercise and exogenously administered catecholamines, suggest that the catecholamine concentration at the synaptic cleft is the primary determinant of the left ventricular inotropic response. Although parasympathetic neural activation alone appears to have little direct influence on the left ventricular inotropic state and central nervous system integration of the autonomic nervous system usually insures there is a reciprocal relationship between sympathetic and parasympathetic neural activity, the potential for parasympathetic inhibition of the response to sympathetic or sympathomimetic augmentation of the intropic response exists. The importance of sympathetic-parasympathetic nervous system interaction in physiologic and pathologic conditions has yet to be defined. It is this type of knowledge of the interactions of reflex pathways which will be critical to the full understanding of autonomic reflex control of myocardial performance under physiologic and pathologic conditions.

Anesthesia↗

PubMed1985

Creatine kinase release not associated with myocardial necrosis after short periods of coronary artery occlusion in conscious baboons.

The effects of 15 minute periods of coronary artery occlusion on plasma creatine kinase (CK) and CK-MB isoenzyme activity, regional myocardial function and subsequent myocardial necrosis were studied in six conscious baboons 2 to 3 weeks after recovery from instrumentation. Mid left anterior descending coronary artery occlusion induced complete loss of systolic wall thickening (ultrasound transit time technique) and decreases in epicardial (-93%) and endocardial (-96%) blood flows (microsphere technique). Reperfusion after 15 minutes resulted in complete recovery of regional function 24 hours later. Serial plasma enzyme activity revealed a significant increase in total CK from 71 +/- 11 to 976 +/- 158 U/liter and in CK-MB from levels that were too low to measure to 21.4 +/- 2.9 U/liter. At autopsy, neither gross pathologic evidence (triphenyltetrazolium chloride staining technique) nor histologic evidence of myocardial necrosis was observed. Thus, in the conscious baboon short episodes of myocardial ischemia are associated with a significant appearance of CK and CK-MB in the blood in the absence of cellular necrosis.

Animals↗

PubMed1985

Correlation between cardiac performance and plasma catecholamine levels in conscious dogs.

We correlated levels of circulating norepinephrine (NE) and epinephrine (Epi) induced by 1) infusions, 2) treadmill exercise, and 3) hemorrhage with left ventricular (LV) function in conscious dogs instrumented for the measurement of LV and arterial pressures, LV diameter, and calculations of indexes of myocardial contractility. With infusions of NE, significant hemodynamic changes were observed only when plasma levels of NE exceeded 1,000 pg/ml. While statistically significant, the increase in rate of rise of LV pressure (LV dP/dt) at these levels was relatively slight, i.e., 8 +/- 2.3%. With further increases in catecholamines (greater than 1,000 pg/ml) good correlations were observed with increases in arterial pressure and myocardial contractility. Similar results occurred with infusions of Epi. Moderate treadmill exercise doubled LV dP/dt, while NE and Epi rose by only 563 +/- 128 and 292 +/- 50 pg/ml, respectively. Hemorrhage (30 ml/kg) decreased all indexes of contractility but increased plasma NE by 1,108 +/- 206 pg/ml and Epi by 1,475 +/- 266 pg/ml. Despite arterial NE and Epi levels 10-20 times those during exercise, infusions were unable to reproduce the peak changes in contractility seen with exercise. Infusions of NE or Epi to equal the plasma levels during exercise increased contractility by only 5-10%. In view of the marked disparity between levels of circulating catecholamines and LV function during exercise, hemorrhage, and catecholamine infusion, we conclude that circulating catecholamines do not adequately reflect the degree of inotropic stimulation to the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Norepinephrine-induced beta 1-adrenergic peripheral vasodilation in conscious dogs.

Norepinephrine (NE) elicits alpha-adrenergic vasoconstriction and beta 1-adrenergic increases in heart rate and myocardial contractility. To determine whether NE can also elicit peripheral beta 1-adrenergic vasodilation, conscious dogs were studied after recovery from instrumentation for the measurement of cardiac output, arterial pressure, and left ventricular (LV) pressure and calculations of LV dP/dt and total peripheral resistance (TPR). NE, after pretreatment with hexamethonium and phentolamine, reduced mean arterial pressure 40 +/- 5% from 117 +/- 9 mmHg and TPR 60 +/- 5% from 0.058 +/- 0.007 mmHg X ml-1 X min and increased cardiac output 55 +/- 11% from 2,159 +/- 188 ml/min. beta 1-Adrenergic blockade with atenolol reversed the vasodilation induced by NE completely, while at this time isoproterenol was still able to reduce peripheral resistance further, by 67 +/- 7%, indicating that beta 2-adrenergic receptors were not blocked. Administration of phentolamine to intact dogs caused a fall in mean arterial pressure (23 +/- 5%) and TPR (34 +/- 5.4%) and an endogenous increase in plasma NE (2,987 +/- 905 pg/ml) and epinephrine (584 +/- 92 pg/ml). These increases in cardiac output and decreases in TPR were also reversed by atenolol (0.5 mg/kg). Moreover, this dose of atenolol blocked the increases in iliac blood flow induced by local injection of NE in the limb. Thus, in the presence of alpha-adrenergic receptor blockade, either administration of NE or release of endogenous NE elicits potent peripheral vasodilation, which appears to involve a beta 1-adrenergic receptor mechanism.

Adrenergic beta-Agonists↗

PubMed1985

Effects of volume expansion on renal nerve activity, renal blood flow, and sodium and water excretion in conscious dogs.

Effects of acute volume expansion with isotonic isoncotic 3% dextran in saline were examined on renal nerve activity (RNA), renal blood flow, vascular resistance, and sodium and water excretion in conscious dogs. In intact dogs, acute volume expansion increased mean arterial pressure 15 +/- 3 mmHg, left atrial pressure 5.5 +/- 0.6 mmHg, and decreased RNA 88 +/- 2%, whereas renal blood flow did not change and renal vascular resistance increased slightly. When renal perfusion pressure was maintained at control levels, volume expansion decreased RNA 87 +/- 2% and renal vascular resistance 15 +/- 4%. During the 80-min period after volume expansion, urine flow rate increased 0.66 +/- 0.13 ml/min and sodium excretion rose 3.89 +/- 0.54 mueq X min-1 X kg-1, whereas RNA remained depressed. Arterial baroreceptor denervation (ABD) did not diminish responses of RNA, renal blood flow, renal vascular resistance, or sodium and water excretion to volume expansion. After ABD plus bilateral cervical vagotomy, volume expansion did not decrease RNA, and diuretic and natriuretic responses were significantly attenuated (P less than 0.025). However, responses of renal blood flow to volume expansion were not altered significantly. In conscious dogs with renal denervation, responses of renal blood flow to volume expansion were not impaired, whereas diuretic and natriuretic responses were attenuated (P less than 0.025). Thus, in intact conscious dogs, vagally mediated reflex decreases in RNA induced by acute volume expansion exerted a significant effect on sodium and water excretion but little control of renal blood flow and renal vascular resistance.

Animals↗

PubMed1985

Effects of altered site of electrical activation on myocardial performance during inotropic stimulation.

The effects of altering the site of electrical activation on responses to isoproterenol (ISO) and treadmill exercise were examined in mongrel dogs instrumented for long-term measurement of left ventricular pressure, left ventricular dP/dt, coronary blood flow, cardiac output, left ventricular diameters, and mean arterial pressure and O2 content in the coronary sinus and aorta. During spontaneous rhythm, 0.2 micrograms/kg/min ISO increased heart rate by 90 +/- 7 beats/min, left ventricular dP/dt by 2479 +/- 301 mm Hg/sec, cardiac output by 3.5 +/- 0.9 liters/min, coronary blood flow by 30.4 +/- 3.9 ml/min, and myocardial oxygen consumption (MVO2) by 3.91 +/- 0.84 ml/min. During right atrial pacing at 193 +/- 7 beats/min, the effects of ISO were not different from the effects during spontaneous rhythm, with the exception of a lesser increase in coronary blood flow and lesser reductions in coronary resistance and left ventricular end-diastolic diameter and pressure. During right ventricular pacing at an identical rate, ISO increased left ventricular dP/dt (1140 +/- 158 mm Hg/sec) and cardiac output (2.2 +/- 0.5 liters/min) significantly less (p less than .025) than during either sinus rhythm or right atrial pacing, while MVO2 rose to a higher value. During right ventricular pacing the changes in mean arterial pressure and left ventricular end-diastolic diameters with ISO were not significantly different from those during right atrial pacing. Treadmill exercise induced significantly smaller (p less than .025) increases in left ventricular dP/dt during right ventricular pacing as compared with during either right atrial pacing or sinus rhythm, while MVO2 rose to a higher value.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Effects of coronary artery reperfusion on regional myocardial blood flow and function in conscious baboons.

The effects of coronary artery reperfusion initiated 1 hr and 3 hr after coronary artery occlusion were evaluated on measurements of overall and regional left ventricular function and on regional myocardial blood flow. These experiments were conducted in conscious baboons 2 to 3 weeks after recovery from instrumentation with a solid state left ventricular pressure gauge, aortic and left atrial catheters, a hydraulic occluder around the mid left anterior descending coronary artery, and pairs of ultrasonic transducers implanted in the endocardium of the left ventricular free wall or across the free wall to measure endocardial segment shortening and wall thickening, respectively. Coronary artery occlusion induced similar effects in both groups. At 1 hr after occlusion, the ischemic zone was characterized by severe and equal reductions in both endocardial (-97 +/- 1%) and epicardial (-95 +/- 4%) blood flows and complete loss of regional systolic function, which was replaced by paradoxical wall motion. Reperfusion initiated after 1 hr of ischemia was associated with a marked transient increase in endocardial (+386 +/- 51%) and epicardial (+544 +/- 79%) blood flows. During the subsequent 4 weeks, segment shortening and wall thickening tended to improve. However, at 4 weeks after reperfusion, segment shortening was still depressed by 45 +/- 12% and wall thickening by 58 +/- 14%. In contrast, reperfusion initiated after 3 hr of ischemia was not associated with a significant hyperemic response, and systolic segment shortening and wall thickening did not recover during the subsequent 4 week period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Mechanisms of supersensitivity to sympathomimetic amines in the chronically denervated heart of the conscious dog.

Mechanisms of denervation supersensitivity to sympathomimetic amines were studied in conscious animals. Norepinephrine, 0.1 micrograms/kg, increased left ventricular dP/dt significantly more (4208 +/- 828 mm Hg/sec) in dogs with cardiac denervation than in intact dogs (1029 +/- 280 mm Hg/sec), P less than 0.01, whereas responses to isoproterenol were similar in both groups. Denervation supersensitivity to isoproterenol could be demonstrated only after opposing reflex effects were blocked. After ganglionic blockade, norepinephrine still induced 2- to 3-fold greater increases in left ventricular dP/dt and 3- to 7-fold greater increases in heart rate in cardiac-denervated dogs, whereas isoproterenol and prenalterol, not taken up by presynaptic nerve endings, elicited only 40%-50% greater increases in left ventricular dP/dt and heart rate in dogs with cardiac denervation. The density of beta-adrenergic receptors [( 3H]dihydroalprenolol) was elevated (P less than 0.01) in denervated left ventricles (105 +/- 6.9 fmol/mg protein, n = 8) compared to normal left ventricles (70 +/- 6.3 fmol/mg protein, n = 12). This was accompanied by enhanced isoproterenol-mediated adenylate cyclase activity. However, muscarinic cholinergic receptor density, [( 3H]quinuclidinyl benzilate), decreased from control levels of 251 +/- 11 fmol/mg protein (n = 7) to 193 +/- 14 fmol/mg protein (n = 6). Thus, chronic cardiac denervation results in upregulation of the beta-adrenergic receptor and down-regulation of the muscarinic receptor. The increased beta-adrenergic receptor density and adenylate cyclase stimulation correlated well with the amount of denervation supersensitivity to isoproterenol and prenalterol, but accounted for only a minor fraction of denervation supersensitivity to norepinephrine. The major mechanism of denervation supersensitivity to norepinephrine appears to involve lack of the norepinephrine reuptake.

Adenylyl Cyclases↗

PubMed1985

Adverse effects of chronic cardiac denervation in conscious dogs with myocardial ischemia.

The extent to which total chronic cardiac denervation protects the ischemic myocardium was investigated in conscious dogs. The major hemodynamic difference after coronary artery occlusion was that left ventricular end-diastolic pressure rose significantly more, P less than 0.01, in the denervated group (12 +/- 1.5 mm Hg) than in the normal group (4.4 +/- 1.4 mm Hg). Blood flow (radioactive microspheres) in the ischemic endo- and epicardium fell to similar levels at 3-5 minutes after coronary occlusion, but was significantly less (P less than 0.01) in denervated dogs at 3 hours after occlusion in the endo- (0.05 +/- 0.01) and epicardium (0.30 +/- 0.02 ml/min per g), than in the endo- (0.13 +/- 0.03) and epicardium (0.42 +/- 0.05 ml/min per g) in the normal group. A subgroup of normal dogs was also studied, with left ventricular end-diastolic pressure increased by volume loading to levels similar to those observed in the denervated group after coronary occlusion; in these dogs, blood flow was similar to that in the other two groups 3-5 minutes after coronary artery occlusion, but, at 3 hours, was significantly more depressed (P less than 0.01) than that observed in normal dogs without volume loading in both endo- (0.03 +/- 0.01) and epicardial (0.25 +/- 0.03 ml/min per g) layers. Infarct size, as a fraction of the area at risk, was significantly greater (P less than 0.05) in the denervated group (60 +/- 4.3%) and in the subgroup of normal dogs with elevated left ventricular end-diastolic pressure (73 +/- 5.8%), compared with the normal group without volume loading (37 +/- 8.1%). Thus, in conscious dogs, total chronic cardiac denervation exerts an adverse effect on infarct size which may be related to the sustained elevation in left ventricular end-diastolic pressure and consequent impairment of collateral perfusion.

Animals↗

PubMed1985

Effects of hemorrhage on renal nerve activity in conscious dogs.

We studied the effects of slow continuous hemorrhage (0.5 ml/kg per min) on measurements of arterial and left atrial pressures, and renal nerve activity in conscious dogs with all reflexes intact, or after sinoaortic baroreceptor denervation, cardiac denervation, or sinoaortic baroreceptor denervation plus vagal denervation. In intact dogs, mean arterial pressure remained relatively constant at 101 +/- 4 mm Hg until 20 +/- 4 ml/kg of hemorrhage, when renal nerve activity increased by 211 +/- 53%. At 39 +/- 2 ml/kg hemorrhage, mean arterial pressure fell by 48 +/- 3 mm Hg, and renal nerve activity returned to the prehemorrhage control level. Cardiac denervation did not affect the response of mean arterial pressure to hemorrhage, whereas, after sinoaortic baroreceptor denervation and sinoaortic baroreceptor plus vagal denervation, mean arterial pressure remained at its control level only through 8 +/- 1 and 4 +/- 1 ml/kg hemorrhage, respectively. The increases in renal nerve activity during nonhypotensive hemorrhage were significantly attenuated by either sinoaortic baroreceptor or cardiac denervation, and were completely blocked by sinoaortic baroreceptor plus vagal denervation. However, the decline in renal nerve activity with hypotensive hemorrhage was not blocked by either cardiac or sinoaortic baroreceptor denervation, and was enhanced after sinoaortic baroreceptor plus vagal denervation. Our data indicate that nonhypotensive hemorrhage in the conscious dog elicits a striking increase in renal nerve activity, which then returns to control levels during hypotensive hemorrhage. Both sinoaortic and cardiopulmonary baroreceptors are involved in mediating the increase in renal nerve activity, whereas the decline in renal nerve activity is not due to either of these baroreflexes.

Animals↗

PubMed1985

Loss of high affinity cardiac beta adrenergic receptors in dogs with heart failure.

We studied the alterations in myocardial beta-adrenergic receptor-adenylate cyclase activity and muscarinic receptor density in a canine model of left ventricular (LV) failure. LV failure was characterized by a doubling of LV weight/body weight ratio (3.3 +/- 0.1 to 6.9 +/- 0.4 g/kg) and an elevation of LV end-diastolic pressure, 32 +/- 4.5 mmHg, compared with 7.7 +/- 0.6 mmHg in normal dogs. Despite a 44% increase in receptor density as measured by antagonist binding studies with [3H]dihydroalprenolol, there was a twofold decrease in receptor affinity, i.e., an increase in the dissociation constant (Kd) (5.6 +/- 0.7 to 12 +/- 1.6 nM) in heart failure. Agonist displacement of [3H]dihydroalprenolol binding with isoproterenol in the presence and absence of 5'-guanylylimidodiphosphate [Gpp(NH)p] demonstrated a striking loss of high affinity binding sites in heart failure (51 +/- 16 to 11 +/- 5%). Beta-Adrenergic receptor-mediated stimulation of adenylate cyclase and maximal stimulation with Gpp(NH)p or sodium fluoride was reduced in heart failure. There was a concomitant marked, P less than 0.01, reduction in muscarinic receptor density (242 +/- 19 vs. 111 +/- 20 fmol/mg). Thus, while muscarinic receptor density fell, beta-adrenergic receptor density actually increased in LV failure. However, a larger portion of the beta-adrenergic receptors are not functionally coupled to the GTP-stimulatory protein (Ns), as evidenced by a decrease in the fraction of receptors that bind agonist with high affinity.

Adenylyl Cyclases↗

PubMed1984

Measurement of arterial pressure-dimension relationships in conscious animals.

Currently, considerable clinical interest exists in the vasoactivity of large coronary arteries due to the prevalence of coronary vasospasm in mediating angina pectoris and even myocardial infarction. Although arterial elastic properties have been studied extensively in acute, anesthetized animal experiments and in vitro preparations, few data are available on these properties in conscious, chronically instrumented animals, where the complicating influences of anesthesia, recent surgery, and acute manipulation of the vessel are minimized. To study vascular smooth muscle in the conscious animal we modified the transit-time dimension measurement technique by designing smaller, higher frequency (7 MHz) transducers, and introducing electronic refinements to accurately measure smaller dimensions (2 mm minimum). We applied this technique to the left circumflex coronary (LCC) artery, along with arterial pressure measurements from either chronically implantable strain-gauge manometers, or microtip catheter manometers, to study dynamic compliance and vascular control mechanisms of these arteries for periods of months in conscious, chronically instrumented animals. Infusion of an alpha-adrenergic vasoconstrictor, methoxamine (50 micrograms/kg/min), caused sustained reduction in LCC diameter (9% +/- 2%) at a time when mean arterial pressure rose by 65% +/- 5% and heart rate and mean coronary blood flow (electromagnetic flow probe) were returned to control levels. Methoxamine induced a marked leftward shift in the pressure-diameter and stress-radius relationships, reducing vascular caliber for any given stress and pressure level. Moreover, smooth-muscle activation raised the effective incremental modulus (Einc) of the coronary arterial wall when compared at similar radii, but it reduced Einc when compared at similar stress or pressure levels. Thus, for any given arterial pressure level the Einc of the LCC artery wall can be reduced considerably by the enhanced smooth-muscle activation elicited by methoxamine. Nitroglycerin (25 micrograms/kg) induced an initial decrease in LCC diameter as pressure fell and LCC blood flow rose. However, dimensions then increased, reaching a maximum 5 minutes later, when LCC blood flow was reduced, and heart rate and left ventricular dP/dt were at control levels. The calcium-channel antagonist, nifedipine, caused similar early changes, with the increase in LCC caliber persisting for 46 +/- 5 minutes while LCC blood flow returned to control in 15 +/- 3 minutes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1984

Regional myocardial blood flow and necrosis in primates following coronary occlusion.

The effects of acute coronary artery occlusion on regional myocardial blood flow distribution in the remote nonischemic zone, the central ischemic zone, and the lateral border zone of the infarct were evaluated in conscious primates. Prior to coronary artery occlusion, blood flow was 1.51 +/- 0.11 in endocardial (Endo) and 1.36 +/- 0.11 ml X min-1g-1 in epicardial (Epi) layers with an Endo-to-Epi ratio of 1.17 +/- 0.05. Regional blood flow in the remote nonischemic zone increased by 28.0 +/- 4.7 and 31.7 +/- 3.6% for Endo and Epi layers, respectively, following coronary occlusion and remained elevated during the subsequent 24 h. At the center of infarct, Endo and Epi blood flows were depressed by 97.9 +/- 0.7 and by 97.9 +/- 0.8%, respectively, at 5 min after coronary occlusion and remained severely depressed throughout the 24-h observation period. Blood flow at the ischemic lateral border of the infarct was severely depressed and similar to the flow at the center of the infarct, whereas the nonischemic lateral border of the infarct had blood flow levels similar to the remote, nonischemic myocardium. Microsphere loss was not a feature of the primate infarct.

Animals↗

PubMed1984

Reactive dilation of large coronary arteries in conscious dogs.

To study the response of large coronary arteries to short periods of myocardial ischemia a pair of ultrasonic dimension transducers, a flow probe and a hydraulic occluder were implanted around the left circumflex coronary artery for the instantaneous and continuous measurement of external coronary artery dimensions and coronary blood flow, respectively. At 6.1 +/- 0.4 seconds after release of a 15-second occlusion, mean coronary blood flow increased by 255 +/- 30% from a preocclusion flow of 32 +/- 4.1 ml/min. At this time, large coronary arterial cross-sectional area was unchanged but increased slowly, reaching a peak 28 +/- 4.4% above preocclusion levels 61 +/- 3.2 seconds after occlusion, i.e., reactive dilation. During maximal reactive dilation, coronary blood flow had already returned to control levels, and heart rate, mean arterial pressure, left ventricular systolic pressure, and left ventricular dP/dt were not different from control. The reactive dilation was not affected if the occlusion occurred proximal or distal to where diameter was measured, or by combined alpha- and beta-adrenergic receptor blockade, ganglionic blockade, inhibition of prostaglandin synthesis, or by aminophylline. When the reactive hyperemia was prevented by constricting the coronary artery upon release of the coronary occlusion, the reactive dilation was not observed. Thus, large coronary arteries respond to brief periods of occlusion with reactive dilation. The time course of this response is distinctly different from the accompanying reactive hyperemia, and could be eliminated by preventing the marked increase in coronary blood flow following release from the brief period of coronary artery occlusion.

Aminophylline↗