Cellular and molecular biology of the cardiovascular system.
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Animals↗
Biomedical subjects
S F Vatner
Publications and source records attributed to S F Vatner.
Mechanisms of subendocardial dysfunction in response to exercise in dogs with severe left ventricular hypertrophy.
The effects of exercise on regional myocardial blood flow and function were examined in the presence and absence of beta-adrenergic receptor blockade in 10 adult conscious dogs with severe left ventricular (LV) hypertrophy induced by aortic banding in puppies, which increased the LV weight/body weight ratio by 87%. Exercise at the most intense level studied increased LV systolic (+87 +/- 8 mm Hg) and end-diastolic (+28 +/- 5 mm Hg) pressures, systolic (+85 +/- 12 g/cm2) and diastolic (+49 +/- 11 g/cm2) wall stresses, and subepicardial wall thickening (+0.18 +/- 0.05 mm) but reduced subendocardial wall thickening (-0.45 +/- 0.12 mm) and full wall thickening (-0.42 +/- 0.13 mm). This was associated with a fall in the subendocardial/subepicardial (endo/epi) blood flow ratio to 0.87 +/- 0.06 from 1.24 +/- 0.08. Subendocardial dysfunction persisted during recovery, at a time when transmural blood flow distribution returned to baseline, suggesting myocardial stunning. At the least intense level of exercise studied, the endo/epi blood flow ratio did not fall (1.27 +/- 0.14), but increases in heart rate (+73 +/- 8 beats per minute) and LV systolic (+35 +/- 8 g/cm2) and diastolic (+27 +/- 3 g/cm2) wall stresses were observed, and subendocardial wall thickening fell significantly (-0.21 +/- 0.08 mm, p less than 0.05). With anticipation of exercise, subendocardial wall thickening was not changed. However, subendocardial dysfunction was even evident after 10 beats, i.e., the first 3 seconds of exercise, at a time when LV pressures and stresses had not increased. After beta-adrenergic receptor blockade with propranolol, the most intense level of exercise was associated with lesser increases in systolic and diastolic LV wall stresses, heart rate, and LV dP/dt, and the endo/epi blood flow ratio was no longer reduced below unity (1.17 +/- 0.09). In addition, there were no decreases in subendocardial or full wall thickening, and myocardial stunning was no longer observed. Thus, the subendocardial hypoperfusion and depression in subendocardial wall thickening observed during exercise in dogs with LV hypertrophy was prevented by pretreatment with beta-adrenergic receptor blockade. Furthermore, the subendocardial dysfunction occurred rapidly, before alterations in LV systolic or diastolic wall stress or an alteration in the endo/epi blood flow ratio.(ABSTRACT TRUNCATED AT 400 WORDS)
Adrenergic beta-Antagonists↗
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↗
Abnormalities in intracellular calcium regulation and contractile function in myocardium from dogs with pacing-induced heart failure.
24 d of rapid ventricular pacing induced dilated cardiomyopathy with both systolic and diastolic dysfunction in conscious, chronically instrumented dogs. We studied mechanical properties and intracellular calcium (Ca2+i) transients of trabeculae carneae isolated from 15 control dogs (n = 32) and 11 dogs with pacing-induced cardiac failure (n = 26). Muscles were stretched to maximum length at 30 degrees C and stimulated at 0.33 Hz; a subset (n = 17 control, n = 17 myopathic) was loaded with the [Ca2+]i indicator aequorin. Peak tension was depressed in the myopathic muscles, even in the presence of maximally effective (i.e., 16 mM) [Ca2+] in the perfusate. However, peak [Ca2+]i was similar (0.80 +/- 0.13 vs. 0.71 +/- 0.05 microM; [Ca2+]o = 2.5 mM), suggesting that a decrease in Cai2+ availability was not responsible for the decreased contractility. The time for decline from the peak of the Cai2+ transient was prolonged in the myopathic group, which correlated with prolongation of isometric contraction and relaxation. However, similar end-diastolic [Ca2+]i was achieved in both groups (0.29 +/- 0.05 vs. 0.31 +/- 0.02 microM), indicating that Cai2+ homeostasis can be maintained in myopathic hearts. The inotropic response of the myopathic muscles to milrinone was depressed compared with the controls. However, when cAMP production was stimulated by pretreatment with forskolin, the response of the myopathic muscles to milrinone was improved. Our findings provide direct evidence that abnormal [Ca2+]i handling is an important cause of contractile dysfunction in dogs with pacing-induced heart failure and suggest that deficient production of cAMP may be an important cause of these changes in excitation-contraction coupling.
Animals↗
Alterations in left ventricular diastolic function in conscious dogs with pacing-induced heart failure.
We investigated in conscious dogs (a) the effects of heart failure induced by chronic rapid ventricular pacing on the sequence of development of left ventricular (LV) diastolic versus systolic dysfunction and (b) whether the changes were load dependent or secondary to alterations in structure. LV systolic and diastolic dysfunction were evident within 24 h after initiation of pacing and occurred in parallel over 3 wk. LV systolic function was reduced at 3 wk, i.e., peak LV dP/dt fell by -1,327 +/- 105 mmHg/s and ejection fraction by -22 +/- 2%. LV diastolic dysfunction also progressed over 3 wk of pacing, i.e., tau increased by +14.0 +/- 2.8 ms and the myocardial stiffness constant by +6.5 +/- 1.4, whereas LV chamber stiffness did not change. These alterations were associated with increases in LV end-systolic (+28.6 +/- 5.7 g/cm2) and LV end-diastolic stresses (+40.4 +/- 5.3 g/cm2). When stresses and heart rate were matched at the same levels in the control and failure states, the increases in tau and myocardial stiffness were no longer observed, whereas LV systolic function remained depressed. There were no increases in connective tissue content in heart failure. Thus, pacing-induced heart failure in conscious dogs is characterized by major alterations in diastolic function which are reversible with normalization of increased loading condition.
Animals↗
Endothelium and blood flow mediated vasomotion in the conscious dog.
Numerous in vitro studies have demonstrated the important role of the vascular endothelium on the vasoactivity of vascular smooth muscle. Experimentation, particularly in conscious animals, is required to study the integrated role of endothelium in the regulation of vascular tone. This article reviews some of the evidence demonstrating endothelium mediated vasodilation and inhibition of vasoconstriction by the endothelium in the chronically instrumented conscious animal. Furthermore, a role for endothelial cells has been shown in the mechanism of blood flow-mediated vasodilation. Finally, the endothelium, through elaboration of constricting factors, e.g., endothelin, can also induce potent vasoconstriction. In the conscious animal endothelin elicits markedly differing degrees of vasoconstriction among the various regional vascular beds.
Animals↗
Beta-adrenergic receptor regulation in the heart in pathophysiologic states: abnormal adrenergic responsiveness in cardiac disease.
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Animals↗
Effects of atrial natriuretic factor on blood flow distribution and vascular resistance in conscious dogs.
Systemic and regional hemodynamic responses to atrial natriuretic factor (ANF) administered by either bolus or infusion were examined in conscious dogs in the presence and absence of ganglionic blockade. In intact dogs, bolus injection of ANF (9 micrograms/kg), which increased plasma ANF by 100,913 +/- 12,330 pg/ml, initially reduced mean arterial pressure (7 +/- 1%) and total peripheral (-31 +/- 2%), coronary (-28 +/- 3%), mesenteric (-19 +/- 2%), renal (-36 +/- 2%), and iliac (-24 +/- 2%) vascular resistances. During the recovery period, resistance rose in the total peripheral (+13 +/- 3%), coronary (+19 +/- 5%), mesenteric (+7 +/- 2%), and iliac (+42 +/- 8%) beds but did not rise in the renal bed. At 15 min after infusion of ANF (0.3 micrograms.kg-1.min-1 x 30 min), which increased plasma ANF by 4,296 +/- 869 pg/ml, resistance rose in the total peripheral (+19 +/- 3%), coronary (+17 +/- 2%), mesenteric (+23 +/- 7%), and iliac (+40 +/- 11%) beds but remained slightly depressed in the renal bed (-8 +/- 5%). Ganglionic blockade with hexamethonium did not modify substantially the pattern of change of regional vascular resistances to ANF. Thus in conscious dogs, ANF under steady-state conditions was found to elicit direct vasoconstriction in most regional vascular beds and minor vasodilation in the renal vascular bed. However, after bolus administration of ANF, which results in extremely high plasma ANF levels, transient vasodilation occurs in all regional vascular beds. These data suggest that the distribution of ANF receptors, which elicit vasodilation, differs in regional vascular beds, and that in most vascular beds, except those of the kidney, these receptors require extremely high levels of ANF to be activated.
Animals↗
Alterations in myocardial contractility in conscious dogs with dilated cardiomyopathy.
We investigated the changes in left ventricular (LV) geometry and myocardial contractility in eight conscious chronically instrumented dogs studied before and after the development of dilated cardiomyopathy induced by rapid ventricular pacing. Significant increases (P less than 0.01) were observed in cardiac dimensions in both the LV long and short axes and in end-diastolic volume (control: 53 +/- 1 ml; cardiomyopathy: 76 +/- 2 ml) and end-systolic volume (control: 27 +/- 2 ml; cardiomyopathy: 56 +/- 7 ml). This was associated with the left ventricle assuming a more spherical shape with LV long-to-short axis ratio falling from 1.59 +/- 0.05 to 1.47 +/- 0.04 (P less than 0.05). Both isovolumic (LV dP/dt) and ejection phase indexes (LV mean velocity of circumferential fiber shortening, corrected LV short-axis diameter at point of maximum shortening, and LV ejection fraction) were depressed by 50%. The end-systolic elastance was also depressed significantly (control: 16.6 +/- 0.7 g.cm-2.ml-1; cardiomyopathy: 10.1 +/- 1.7 g.cm-2.ml-1, P less than 0.02). However, cardiac output was maintained at 3 wk due to a compensatory tachycardia (+31 +/- 3 beats/min), plasma volume expansion (+295 +/- 68 ml, P less than 0.05), and greater reliance on the Frank-Starling mechanism. However, in an additional four dogs studied at 4-5 wk, cardiac output fell significantly (P less than 0.05). Thus rapid ventricular pacing results in dilated congestive cardiomyopathy in conscious dogs characterized by globally depressed myocardial systolic function and changes in LV shape.
Animals↗
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↗
Changes in diastolic cardiac function in developing and stable perinephritic hypertension in conscious dogs.
The effects of developing perinephritic hypertension (2-3 weeks) and a more stable period of perinephritic hypertension (approximately 14 weeks) were examined on indexes of left ventricular (LV) diastolic function in conscious, chronically instrumented dogs. The complete period of diastole was studied using indexes of isovolumic relaxation (tau), early filling (LV +dD/dt), and stiffness (myocardial stiffness and chamber stress/diameter ratio). During developing hypertension, increased LV end-diastolic pressure, LV end-diastolic stress, peak filling rate, myocardial stiffness, and the stress/diameter ratio increased (p less than 0.05); the time constant tau was not changed. These changes were associated with preserved baseline levels of coronary blood flow (radioactive microspheres) but an impaired coronary vasodilator response to adenosine. Acute administration of phenylephrine in the normotensive dogs caused increases in systolic and diastolic stress and resulted in increases in myocardial stiffness and in the stress/diameter ratio similar to values observed in developing hypertension. During stable hypertension, LV end-diastolic stress, peak filling rate, and both parameters of late-diastolic function (myocardial stiffness and stress/diameter ratio) returned toward control values, but the isovolumic relaxation time constant was increased. Quantitative histological evaluation revealed no increase in stainable connective tissue in dogs with stable hypertension compared with control dogs, and hydroxyproline concentration was not increased in the subendomyocardium, midmyocardium, or subepimyocardium of the dogs with chronic perinephritic hypertension. Thus, in developing hypertension, major alterations in diastolic function were observed that were not structurally related, since these changes 1) could be induced in normal dogs by increasing preload and afterload acutely with phenylephrine and 2) were improved during the ensuing stable period of hypertension.
Adenosine↗
Relative roles of cardiac and arterial baroreceptors in vasopressin regulation during hemorrhage in conscious dogs.
To determine the relative roles of cardiac and sinoaortic baroreceptors in mediation of arginine vasopressin (AVP) release, hemorrhage was performed in five groups of conscious splenectomized dogs: 1) all nerves intact; 2) either chronic surgical or acute pharmacological (intrapericardial lidocaine) cardiac denervation (CD); 3) chronic sinoarotic denervation (SAD); 4) combined chronic sinoartic denervation plus either chronic or acute cardiac denervation (SAD + CD); and 5) all nerves intact, but with ganglionic blockade. Hemorrhage (0.5 ml/min/kg) reduced mean arterial pressure similarly in the intact and CD groups. Decreases in mean arterial pressure were augmented in SAD, SAD + CD, and ganglion-blocked groups compared with responses in intact and CD groups. There were no differences in responses of plasma AVP to hemorrhage in the intact and CD groups, but the AVP response was significantly blunted in the SAD + CD group as compared with SAD alone. When compared during the early stage of hemorrhage, at the same reduction in mean arterial pressure, the rise in AVP was greater in the ganglion-blocked group than in the SAD + CD group, but was less than in the intact group. With a protocol to reduce mean arterial pressure by 20 mm Hg over the same period (42 +/- 0.6 minutes) in four of the groups, the blood volume required to reduce mean arterial pressure by 20 mm Hg was similar in the intact (20 +/- 1 ml/kg) and CD (21 +/- 1 ml/kg) groups, but was less in the SAD (12 +/- 1 ml/kg) and SAD + CD (12 +/- 1 ml/kg) groups. Again, similar increases were observed in AVP between the intact (50 +/- 9 pg/ml) and CD (51 +/- 9 pg/ml) groups, whereas increases in AVP were diminished in the SAD (11 +/- 3 pg/ml) and SAD + CD (7 +/- 2 pg/ml) groups. In the presence of an AVP antagonist, decreases in mean arterial pressure and increases in total peripheral resistance with hemorrhage were affected similarly in both the intact and CD groups, whereas hemodynamic impairment by AVP blockade was less marked in the SAD and SAD + CD groups. These results indicate that cardiac receptors are not the major regulators of AVP release during progressive hemorrhage in conscious dogs. However, when the complicating influences of sinoaortic reflexes were eliminated, a modest role for cardiac receptors was uncovered.
Animals↗
Acetylcholine-induced coronary vasoconstriction and vasodilation in tranquilized baboons.
To determine the effects of acetylcholine on the coronary bed in the baboon and whether the effects preceded or followed the action of acetylcholine on ventricular function, eight adult baboons (Papio anubis) were instrumented to measure left ventricular (LV) and mean arterial pressures, LV dP/dt, regional myocardial function, and coronary blood flow. Acetylcholine was injected locally through a catheter positioned in the coronary artery ostium using fluoroscopic guidance in intact sedated baboons. With heart rate held constant, intracoronary acetylcholine (0.5 micrograms/kg) reduced coronary blood flow by 82 +/- 4% from a baseline value of 34 +/- 4 ml/min without a significant change in mean arterial pressure and with a reduction in LV dP/dt of only 12 +/- 3%. The decrease in coronary blood flow occurred before either LV dP/dt or regional myocardial function fell in the region of the heart receiving acetylcholine. After the intense coronary constriction, a later phase characterized by dilation was observed. The changes in coronary blood flow with acetylcholine were unaffected by combined alpha- and beta-adrenoceptor blockades but were abolished by muscarinic blockade. Low doses of acetylcholine elicited only coronary vasodilation. All doses of acetylcholine, administered directly into the iliac artery, also elicited only iliac vasodilation. Intracoronary acetylcholine in conscious dogs also induced only coronary vasodilation, whereas in conscious calves at higher doses, initial vasoconstrictor responses were observed, which also preceded reductions in regional myocardial function. These results suggest that the controversy surrounding the effects of acetylcholine can be reconciled on the basis of species, vascular bed studied, and dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
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↗
Effects of selective cardiac denervation on collateral blood flow after coronary artery occlusion in conscious dogs.
The extent to which cardiac nerves regulate responses to myocardial ischemia remains controversial. Our data in conscious dogs indicate that neither selective posterior left ventricular (LV) wall denervation nor selective ventricular denervation, leaving the atria intact, modifies the effects of coronary artery occlusion (for 24 h) on regional myocardial function and infarct size as compared to normally innervated dogs. Since hemodynamic changes were similar among the three groups after coronary artery occlusion, it is possible to speculate that responses of collateral blood flow to the ischemic zone were also not modified by chronic selective cardiac denervation. To address this, individual samples were selected and included in either the infarcted (TTC negative) or salvaged (TTC positive) group. The infarcted and salvaged samples were paired according to blood flow levels of 0.1-0.2, 0.2-0.3, or 0.3-0.4 ml/min/g at either 5 min, 1 h, 3 h, or 6 h after coronary artery occlusion. The results demonstrated similar patterns of myocardial blood flow in tissue samples within the area at risk after coronary artery occlusion in the animals, regardless of whether the ischemic zone was innervated or denervated. While blood flow rose in ischemic tissue that ultimately was salvaged, and tended not to rise over the 24 h monitoring period in tissue samples that became necrotic, no differences could be discerned on the basis of intact or absent innervation of the ischemic zone. Thus, chronic absence of cardiac nerves does not affect regulation of ischemic zone blood flow following coronary artery occlusion in conscious dogs.
Animals↗
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↗
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↗
Exercise-induced subendocardial dysfunction in dogs with left ventricular hypertrophy.
The effects of treadmill exercise on regional myocardial blood flow and function were examined in 10 adult, conscious dogs with left ventricular hypertrophy (LVH) induced by aortic banding in puppies, which resulted in a left ventricular (LV) weight/body weight ratio of 8.5 +/- 0.3. Data were compared with results from eight control dogs with an LV weight/body weight ratio of 4.9 +/- 0.2. At rest, LV systolic and end-diastolic pressures were significantly greater (p less than 0.01), and mean arterial pressure was significantly less (p less than 0.05) in LVH dogs. Mean myocardial blood flow (control dogs, 0.98 +/- 0.11 ml/min/g; LVH dogs, 1.16 +/- 0.06 ml/min/g) and the transmural blood flow distribution at baseline, as assessed by endocardial/epicardial blood flow ratio (control, 1.35 +/- 0.12; LVH, 1.21 +/- 0.09), were similar in the two groups. During exercise to a target heart rate (240 beats/min), LVH dogs demonstrated greater (p less than 0.01) increases in LV systolic and end-diastolic pressures. In control dogs, as expected, exercise augmented velocity of circumferential fiber shortening (16 +/- 9%) and shortening fraction (15 +/- 5%), but in LVH dogs, exercise reduced the velocity of circumferential fiber shortening (-14 +/- 6%) and shortening fraction (-17 +/- 5%). Exercise also increased full wall thickening (35 +/- 5%), subendocardial wall thickening (66 +/- 10%), and subepicardial wall thickening (44 +/- 9%) in control dogs. In LVH dogs, exercise increased subepicardial wall thickening (31 +/- 9%) and reduced subendocardial wall thickening (-40 +/- 7%); full wall thickening did not change (-11 +/- 9%). This was associated with a fall in endocardial/epicardial flow ratio to 0.72 +/- 0.05 (p less than 0.01) in LVH dogs. The subendocardial dysfunction persisted late into recovery, at a time when the transmural blood flow distribution had returned to baseline; this occurrence suggested myocardial stunning. Thus, in dogs with LVH, selective subendocardial hypoperfusion and profound selective depression in subendocardial wall thickening are observed during exercise. The subendocardial dysfunction persisted into recovery despite resolution of the perfusion abnormality.
Animals↗