Changing the temperature, frequency of stimulation and calcium concentration altered the dose-response curves for isoproterenol and histamine on guinea pig and rabbit papillary muscles. Basal developed force, maximal developed force and sensitivity to the agonists were all affected. Increasing the temperature stepwise from 25° to 42° resulted in a progressive decrease in BDF and sensitivity to the agonists. The response of MDF was different in the guinea pig and rabbit. In the guinea pig, MDF was not affected by changing the temperature, and the size of the response to isoproterenol and histamine was similar. In the rabbit, the largest MDF response was seen at 37.5° when the calcium concentration was maintained at 2.2 mM. At this calcium concentration the response to histamine was less than that to isoproterenol at each temperature, although the difference was not significant. Increasing the frequency of stimulation stepwise from 0.5 to 4 Hz in the guinea pig, and 0.2.to 3 Hz in the rabbit affected the dose-response curves in a slightly different manner. In both species, BDF was reduced by low frequency stimulation. At other frequencies BDF was not changed. With isoproterenol, the MDF was only reduced by high frequency stimulation, and the sensitivity increased stepwise with increasing frequency. With histamine, the MDF was reduced by both low and high frequency stimulation. In the rabbit the response to histamine was consistently less than that to isoproterenol. The sensitivity to histamine was not affected by changing the frequency in the guinea pig, but was increased by high frequency stimulation in the rabbit. Increasing the calcium content stepwise from 1.5 to 8 mM in the guinea pig, and 0.5 to 6 mM in the rabbit resulted in a progessive increase in BDF, MDF and sensitivity. In both species, the increase in MDF appeared to reach a maximum between 2.2 and 6 mM calcium. In the rabbit this effect was less noticeable in situations where the frequency or temperature was also reduced. The response to histamine was reduced compared to that of isoproterenol. We postulate that the response to histamine is reduced in rabbit papillary muscles due to stimulation of H₁- receptors in this tissue. It has been shown that stimulation of β and H₂- receptors results in an increase in cyclic AMP, while stimulation of H₁- receptors has no effect on cyclic AMP. The increase in cyclic AMP may enhance calcium binding by the SR resulting in an augmented response.. In the guinea pig papillary muscle which contains β- and H^- receptors, the inotropic responses to isoproterenol and histamine are similar, while in the rabbit papillary muscle which contains 3- and H₁- receptors, the response to histamine is reduced compared to that of isoproterenol. This difference may be due to the lack of cyclic AMP involvement in the response to histamine in this tissue. Use of the calcium antagonist D600 produced a decrease in the sensitivity of rabbit papillary muscles to isoproterenol, but did not depress the MDF. There was no difference in the sensitivity to histamine. D600 therefore could not distinguish any difference in dependence on extracellular calcium between isoproterenol and histamine in this tissue. Isoproterenol stimulated an increase in ⁴⁵Ca content of rabbit right ventricle strips at 2 minutes after administration. No effect could be detected at any other time, nor when histamine was used. It is sugges- ted that at times greater than 2 minutes any increase in ⁴⁵Ca content induced by isoproterenol was masked by a "pool saturation" phenomenon, and that this increase which was detected is consistent with a difference in the mechanism of action of isoproterenol and histamine in rabbit ventricular muscle. / Pharmaceutical Sciences, Faculty of / Graduate

Hui, Lai Shan. / Thesis (M.Sc.)--Chinese University of Hong Kong, 1988. / Bibliography: leaves 83-87.

Thesis (M.Sc. (Physiology))--Mahidol University, 1979.

Thesis (doctoral)--Universität Hamburg, 1980.

Abstract Adrenomedullin (AM) is a 52-amino acid peptide which is produced in many tissues, including adrenal medulla, lung, kidney and heart. Intravenous administration of AM causes a long-lasting hypotensive effect, accompanied with an increase in the cardiac output in experimental animals. This study was aimed to examine whether AM has any direct effects on myocardial function. In addition to the myocardial contractility, the effects of AM on coronary vascular tone and A-type natriuretic peptide (ANP) release from atria and B-type natriuretic peptide (BNP) gene expression in the ventricles were studied in the perfused rat heart preparation. In spontaneously beating hearts, AM had no effects on the heart rate, but dose-dependently increased the developed tension (DT) with an EC50 of 7 x 10-11 nmol/l, reflecting a potent positive inotropic effect. The lower the initial resting tension, the higher was the elevation in DT. In paced hearts, a protein kinase A inhibitor, H-89, had no effect on AM-induced inotropic effect, and AM did not increase the cAMP content of the ventricular myocardium. In contrast, the inhibitors of sarcoplasmic reticulum Ca2+ stores, ryanodine and thapsigargin, as well as a protein kinase C inhibitor, staurosporine, significantly attenuated the inotropic response to AM. L-type Ca2+ channel blocker, diltiazem, also suppressed the AM-induced elevation in DT. Moreover, AM increased the duration of myocyte action potentials between 10 mV and - 50 mV in isolated rat atria, consistent with an increase in L-type Ca2+ channel current during the plateau. Inotropic effect of endothelin-1 (ET-1), another locally acting peptide, was enhanced by inhibiting the myocardial nitric oxide (NO) synthesis by Nω-nitro-L-arginine methyl ester (L-NAME) in perfused rat heart. The AM-induced inotropic action was unaltered by L-NAME treatment. When AM and ET-1 were administrated in combined infusion, the inotropic response was significantly smaller than that following the infusion of the peptides alone. This attenuated response was more than overcome by infusion of L-NAME, although the individual responses to AM and ET-1 were not modulated by L-NAME at the doses used in the combination. Consistent with its vasodilator action, AM dose-dependently dilated the coronary arteries of the perfused heart. The effect of AM was not dependent on NO under basal conditions or in coronary arteries constricted with ET-1. Furthermore, AM enhanced the stretch-induced release of ANP from the right atrium, but did not affect the ventricular BNP expression induced by ET-1. In conclusion, AM exerts regulatory actions on the heart by increasing cardiac contractility, dilating coronary arteries and modulating stretch-induced ANP release. The inotropic effect of AM was independent of cyclic AMP, but may involve activation of protein kinase C, Ca2+ influx through L-type Ca2+ channels and the release of Ca2+ from the sarcoplasmic reticulum. Endogenous NO production did not modulate the inotropic effect of AM, although the effect of ET-1 was suppressed. Combined administration of AM and ET-1 produced a weak inotropic response most likely because of a potentiated synthesis of NO. Finally, AM had a coronary vasodilator effect and augmented the stretch-induced ANP release in the right atrium.

Like any muscle, cardiac contraction is evoked by action potentials. In the healthy heart, atrial and ventricular activation occur through impulse conduction via the rapid conduction system. Normal cardiac function requires a highly synchronized series of mechanical events occurring in the atria and the ventricles. This synchronization is achieved by rapid conduction of action potentials through the electrical conduction system, which leads to coordinated mechanical activation and deactivation of the myocardium — a process known as electromechanical coupling. As a result of this coordinated electromechanical coupling, the left ventricle functions efficiently as a pump. On the contrary, asynchronous electrical activation leads to asynchronous contraction. The presence of a bundle branch block or other intraventricular conduction delay can worsen heart failure due to systolic dysfunction by causing ventricular dyssynchrony, thereby inducing regional loading disparities and reducing the efficiency of contraction. Consistent with the idea that ventricular dyssynchrony exacerbates left ventricular dysfunction is the observation that a variety of hemodynamic benefits follow the correction of dyssynchrony with cardiac resynchronization therapy (CRT) using biventricular pacing. With decades of research on electromechanical coupling in the heart, it is now recognized that (1) cardiac dyssynchrony worsens ventricular efficiency and contributes to the progression of systolic heart failure; (2) cardiac dyssynchrony can be accurately assessed by echocardiography; (3) cardiac dyssynchrony independently predicts worse prognosis in patients with systolic heart failure; and (4) CRT has established as an effective treatment for systolic heart failure, leading to improved symptomatic status and better survival. / Concerning the subject of cardiac dyssynchrony there are still a lot of unanswered questions which are important to complete understanding of disease mechanisms of heart failure and hence to develop better treatment strategies. First, patients with heart failure but with a preserved ejection fraction (HFPEF) constitutes about half of the heart failure occurrence. Yet, it is not completely understood whether cardiac dyssynchrony, as a potential pathogenic mechanism and therapeutic target, is present in these patients. Second, the heart and circulation is a dynamic system. Nevertheless, scarce data exists on how cardiac dyssynchrony alters in response to exercise and other hemodynamic stressors in patients with heart failure. The potential clinical significance of dynamic dyssynchrony is unknown. Furthermore, identification of precipitating factors of acute hemodynamic decompensation in heart failure is important to prevent recurrent acute exacerbation and hospitalization. Cardiac dyssynchrony has been suspected to be an insidious, potentially correctable trigger of acute decompensated heart failure (ADHF), but scientific evidence is limited. Last but not least, about 30% of the CRT recipients did not respond to the treatment. It was proposed that inadequate optimization of atrioventricular (AV) synchronization is the most common contributory factor, hence the routine practice of AV optimization after CRT implantation. But again, electromechanical coupling is a dynamic process. It is uncertain, however, whether AV optimization should be performed at rest or during exercise to achieve optimal hemodynamic and clinical benefit. / In Part I of this thesis, I will review the literature on heart failure, cardiac dyssynchrony, and exercise impact on the cardiovascular system. In Chapter 1, the definition, clinical classification, and epidemiology of heart failure, as well as the biomechanical model for heart failure progression will be discussed. In Chapter 2, the literature on the normal and pathological electromechanical coupling mechanism, the clinical implication of dyssynchrony in heart failure, and the effect of CRT will be reviewed. In Chapter 3, I will discuss the current understanding of the physiologic effect of exercise, heart rate and stress on cardiac function and synchronicity. In Part II, the hypotheses (Chapter 4) and general objectives (Chapter 5) of the studies included in this thesis will be specified. In Part III, I will describe in detail the general methodology used inthese studies including the study population involved (Chapter 6), the echocardiographic techniques (Chapter 7), and the exercise/pharmacological stress protocols (Chapter 8) used in these studies. / Part IV will be a thorough and logical reporting of the background, methods, findings, discussion, and conclusion of each of the clinical studies of this thesis. Chapter 9, 10 and 11 will focus on patients with preserved ejection fraction and Chapter 12 and 13 will attempt to fill the gap of knowledge of cardiac dyssynchrony in patients with systolic heart failure. / In the study discussed in Chapter 9, the prevalence of left ventricular mechanical dyssynchrony in coronary artery disease with preserved ejection fraction was evaluated. Ninety-four consecutive patients with chronic coronary artery disease and preserved ejection fraction (≥50%) were evaluated using echocardiography with tissue Doppler imaging and compared to 217 patients with depressed ejection fraction and (<50%) and 117 healthy subjects. Left ventricular systolic and diastolic dyssynchrony were determined by measuring the standard deviations of peak systolic (Ts-SD) and early diastolic myocardial (Te-SD) velocities, respectively, using a six-basal/six-mid-segmental model. In patients with coronary artery disease and preserved ejection fraction, both Ts-SD (32.2±17.3 compared with 17.7±8.6 ms; p<0.05) and Te-SD (26.2±13.6 compared with 20.3±8.1 ms; p<0.05) were significantly prolonged when compared with controls, although they were less prolonged than patients with coronary artery disease and depressed ejection fraction (Ts-SD, 37.8±16.5 ms; and Te-SD, 36.0±23.9 ms; both p<0.005). Patients with preserved ejection fraction who had no prior myocardial infarction had Ts-SD (32.9±17.5 ms) and Te-SD (28.6±14.8 ms) prolonged to a similar extent (p=NS) to those with prior myocardial infarction (Ts-SD, 28.4±16.8 ms; and Te-SD, 25.5±15.0 ms). Patients with class III/IV angina or multi-vessel disease were associated with more severe mechanical dyssynchrony (P<0.05). Furthermore, the majority of patients with mechanical dyssynchrony had narrow QRS complexes in those with preserved ejection fraction. This is in contrast with patients with depressed ejection fraction in whom systolic and diastolic dyssynchrony were more commonly associated with wide QRS complexes. / In Chapter 10, focus will be shifted to patients with acute coronary syndrome complicated by acute HFPEF. One hundred two patients presenting with acute coronary syndrome (ejection fraction ≥50%) and 104 healthy controls were studied using tissue Doppler imaging: group 1 (n=55) had HFPEF on presentation and group 2 (n=47) had no clinical HFPEF. Te-SD was found to be greater in group 1 (33±13 ms) than group 2 (21±9 ms) (p<0.001), and diastolic mechanical dyssynchrony was evident in 35% of patients in group 1 but in only 9% in group 2 (p<0.001). Worsening of the diastolic dysfunction grade was associated with a parallel increase in Te-SD (grades 0, 1, 2, and 3: 16±3 ms, 21±5 ms, 28±9 ms, and 41±17 ms, respectively; p<0.001). Te-SD correlated negatively with mean early diastolic basal myocardial velocity (Em) (r=-0.56, p<0.001) and positively with peak mitral inflow velocity of the early rapid-filling wave/Em (r=0.69, p<0.001). Multivariate analysis identified peak mitral inflow velocity of the early rapid-filling wave/Em as the only variable independently associated with HFPEF [odd sratio (OR)=1.48, p=0.001]. When peak mitral inflow velocity of the early rapid-filling wave/Em was excluded from the model, Te-SD (OR=1.13, p<0.001) and mean Em (odds ratio=0.37, p<0.001) became independently associated with HFPEF. / In Chapter 11, I will evaluate the impact of hemodynamic stress on left ventricular dyssynchrony and the relationship and predictive value of dynamic changes of left ventricular dyssynchrony on hypertensive HFPEF. In this study, a total of 131 subjects including 47 hypertensive HFPEF patients, 34 hypertensive patients with left ventricular hypertrophy without HFPEF, and 50 normal controls were studied by dobutamine stress echocardiography with tissue Doppler imaging. In normal controls, systolic and diastolic dyssynchrony did not develop during stress. The prevalence of resting systolic (36.2% vs. 38.2%, p=0.85) and diastolic (34.0% vs. 29.4%, p=0.66) dyssynchrony was similar in patients with HFPEF and left ventricular hypertrophy. During stress, the prevalence of systolic and diastolic dyssynchrony increased dramatically to 85.1% and 87.2%, respectively, in patients with HFPEF, but only 52.9% and 58.8% in patients with left ventricular hypertrophy (p<0.005). In HFPEF group, stress-induced increase in mean systolic basal myocardial velocity (Sm) was significantly blunted (2.8±2.0 vs. 4.2±2.4 cm/s, p=0.004), and the increase was abolished for mean Em (-0.3±2.5 vs. 2.4±3.4 cm/s, p<0.001). On multivariate analysis, stress-induced changes in mean Em (OR=0.69, p=0.004) and mean Sm (OR=0.56, p=0.004), and diastolic (OR=4.6, p=0.005) and systolic dyssynchrony during stress (OR=4.3, p=0.038) were independent determinants for occurrence of HFPEF. / In Chapter 12, the role of dyssynchrony in patients with systolic heart failure presentating with acute decompensation (ADHF) will be studied. In this study, it was hypothesized that acute left ventricular systolic dyssynchrony might be a hidden triggering mechanism for ADHF. Echocardiography with tissue Doppler imaging was performed in 145 subjects with systolic heart failure (ejection fraction <50%), including 84 consecutive patients presented with ADHF requiring hospitalization, comparing them to 61 chronic stable heart failure patients who had no heart failure exacerbation or hospitalization in the past 6 months. The ADHF group was observed to have higher heart rate on admission than patients with stable heart failure (82±15 vs 68±13 bpm, P<0.001), greater left ventricular wall thicknesses and mass (all P<0.05), and mitral regurgitation was more common (71% vs 46%, P<0.0001; ERO=0.12±0.11 vs 0.02±0.04 cm2, P<0.0001), but the overall severity of mitral regurgitation was mild or moderate. Despite no difference in ejection fraction, the ADHF group had significantly lower mean Sm (2.7±0.9 cm/s vs 3.0±0.9 cm/s, P=0.04). The Ts-SD was significantly prolonged in the ADHF group compared to patients with stable heart failure (44.7±16.6 vs 33.4±17.7 ms, P=0.0001). Significant left ventricular systolic dyssynchrony was evident in 75% (63 of 84) of patients of the ADHF group, compared to only 44% (27 of 61) of patients with chronic stable heart failure (P=0.0002). / In Chapter 13, I will focus on the role of dynamic AV dyssynchrony during exercise in patients with systolic heart failure who receive CRT. AV delay in CRT recipients are typically optimised at rest. However, there are limited data on the impact of exercise-induced changes in heart rate on the optimal AV delay and left ventricular function. In this study, AV delays were serially programmed in 41 CRT patients with intrinsic sinus rhythm at rest and during two stages of supine bicycle exercise with heart rates at 20 bpm (stage I) and 40 bpm (stage II) above baseline. The optimal AV delay during exercise was determined by the iterative method to maximise cardiac output using Doppler echocardiography. Results were compared to physiological change in PR intervals in 56 normal controls during treadmill exercise. The optimal AV delay was progressively shortened (p<0.05) with escalating exercise level (baseline: 123±26 ms vs. stage I: 102±24 ms vs stage II: 70±22 ms, p<0.05). AV delay optimisation led to a significantly higher cardiac output than without optimisation did during stage I (6.2±1.2 l/min vs. 5.2±1.2 l/min, p<0.001) and stage II (6.8±1.6 l/min vs. 5.9±1.3 l/min, p<0.001) exercise. A linear inverse relationship existed between optimal AV delays and heart rates in CRT patients (AV delay=241-1.61 x heart rate, R²=0.639, p<0.001) and healthy controls (R²=0.646, p<0.001), but the slope of regression was significantly steeper in CRT patients (p<0.001). / In conclusion, the works included in this thesis provide new evidence that left ventricular mechanical dyssynchrony is common in patients with coronary artery disease and preserved ejection fraction, even in patients without prior myocardial infarction or evidence of eletromechanical delay. In particular, left ventricular diastolic mechanical dyssynchrony may impair diastolic function and contribute to the pathophysiology of HFPEF during acute coronary syndrome. Moreover, dynamic dyssynchrony and impaired myocardial longitudinal function reserve during stress may contribute importantly to the pathophysiology of hypertensive HFPEF. In patients with heart failure and reduced ejection fraction, a high prevalence of left ventricular systolic dyssynchrony during acute decompensation suggests that acute or dynamic left ventricular systolic dyssynchrony may be an important precipitating factor and a potential therapeutic target. Progressive shortening of hemodynamically optimal AV delay with increasing heart rate during exercise suggests that dyssynchrony is dynamic and there may be a need for programming of rate-adaptive AV delay in CRT recipients to optimise clinical response. I believe this work will provide new understanding of the prevalence, mechanism, and clinical significance of cardiac dyssynchrony in heart failure. / Lee, Pui Wai. / Thesis (M.D.))--Chinese University of Hong Kong, 2015. / Includes bibliographical references (leaves 138-174). / Title from PDF title page (viewed on 24, October, 2016).

Thesis (Ph.D.)--University of Florida, 2004. / Typescript. Title from title page of source document. Document formatted into pages; contains 133 pages. Includes Vita. Includes bibliographical references.

Mammalian myocardial contractility is believed to be regulated by the amount of calcium contained in a highly labile superficial calcium pool. The purpose of the first part of this study was to determine the role of such sites in the positive inotropic effect of isoproterenol. Lanthanum, an ion known to be restricted to the extracellular space and which displaces the superficially-bound calcium, was selected as a tool for this investigation. In Langendorff preparations of the guinea pig heart, lanthanum decreased the basal contractility index (+dP/dtmax) in a concentration-dependent fashion (0.05-3 µM) and blocked the inotropic response of isoproterenol in a non-competitive manner (0.25-3 µM). Three µM lanthanum: 1) reduced basal contractility and the maximum response to isoproterenol by 97 and 95%, respectively; 2) had no significant effect (p>0.05) on basal and isoproterenol-induced cyclic AMP levels; and 3) had no effect on the kd of [³H]nitrendipine binding, but reduced the Bmax by 31%. While 1 µM lanthanum reduced basal contractility and the maximum response to isoproterenol by 90 and 70%, respectively, it had no effect on [³H]nitrendipine binding. These results suggest that the effects of such low concentrations of lanthanum (≤3 µM) are not related to a direct action on the calcium channels and are not mediated by an inhibition of isoproterenol stimulation suggest that superficially-bound calcium is required for the inotropic response of isoproterenol. The purpose of the second part of this study was to elucidate the biochemical nature of the superficial calcium binding sites, the sialic acids in particular, in the inotropic response of cardiotonic agents. To determine the role of the glycocalyx residues of sialic acids in excitation-contraction coupling and the inotropic response to cardiotonic agents, I studied the effect of removal of the sialic acids following neuraminidase treatment on the response to ouabain, isoproterenol, calcium and reduced extracellular sodium in Langendorff preparations of adult guinea pig hearts. Neuraminidase treatment (0.01 U/ml, 1 h) reduced the magnitude of the positive inotropic response to 2.5x10⁻⁷M ouabain and the maximum response to 5x10⁻⁷ M ouabain by about 46 and 30%, respectively, but did not prevent ouabain toxicity. Neuraminidase treatment did not affect the contractility produced by calcium concentration alterations up to 5 mM calcium or the positive inotropic effect produced by lowering external sodium to as low as 80 mM. The inotropic response to as high as 10⁻⁸ M isoproterenol was also not affected. The contractility response developed to calcium concentrations greater than 5 mM and to 5x10⁻⁸ M isoproterenol were significantly reduced (p<0.05) by neuraminidase treatment. The content of sialic acids in neuraminidase-treated hearts used in the above concentration-response reduced by 70.7, 66.1, 65.6 and 66.2%, respectively. Neuraminidase treatment had no effect on basal (Na⁺-K⁺)ATPase and Mg²⁺ -ATPase activities of (Na⁺-K⁺)ATPase-containing membrane preparations of the guinea pig left ventricle. Neuraminidase treatment neither influenced the sensitivity of the enzyme (Na⁺-K⁺)ATPase to ouabain inhibition nor did it affect the characteristics of [³H]ouabain binding to the preparation. These results suggest that the sialic acids of the glycocalyx in the guinea pig left ventricle play an important role in part of the inotropic response to subtoxic concentrations of ouabain. / Pharmaceutical Sciences, Faculty of / Graduate

This thesis is mainly concerned with the study of the role of cGMP in regulating contractility in the heart and blood vessels. A novel cGMP lowering agent, LY83583 (6-anilino-5,8-quinolinedione), was employed as a tool to determine the involvement of cGMP in mediating pharmacological and biological responses in the tissues being examined. In the first study, the role of cGMP in atriopeptin II-induced vascular relaxation was investigated. Atriopeptin II is believed to produce its vasorelaxant effect by virtue of its ability to elevate cGMP. However, the ability of the guanylate cyclase inhibitor, methylene blue, to inhibit the atriopeptin II-induced vasorelaxation has not been conclusively demonstrated. In the present study, LY83583 was found to partially prevent the rise in cGMP level caused by atriopeptin II but was without effect on the extent of the relaxation. This lack of correlation between cGMP elevation and relaxation may indicate either functional compartmentalization of the cyclic nucleotide or the existence of a cGMP-independent pathway for relaxation. Alternatively, the attenuated cGMP level may still be sufficient to elicit full relaxation. The inability of atriopeptin II to relax KC1-contracted bovine coronary arteries agrees with other reports in the literature and may indicate that the drug is less effective in antagonizing vascular responses associated with a marked degree of cell membrane depolarization. In the second study, the role of cGMP in mediating the endothelium-dependent inhibition of contractile responses of vascular tissue to alpha adrenoceptor stimulation was examined. There are reports in the literature that EDRF released from the endothelium elevates cGMP and depresses the response of the vessels to vasoconstrictors such as clonidine and norepinephrine. In the present study, LY83583 was used to examine the role of cGMP in mediating this effect. The treatment with LY83583 significantly lowered basal levels of cGMP and markedly enhanced the contractile response of endothelium-containing rat arteries to clonidine and norepinephrine. cGMP measurements indicate that clonidine did not elevate cGMP levels; hence the drug is unlikely to stimulate EDRF release. On the other hand, the depressant action of LY83583 on basal cGMP levels supports the hypothesis that inhibition of contractile responses may be a result of spontaneous release of EDRF, which results in tonic elevation of cGMP. The ability of 8-bromo-cGMP to reverse LY83583-induced enhancement of contractile responses to clonidine and norepinephrine further supports the involvement of cGMP in EDRF-induced vascular relaxation. In the final study, the role of cGMP in regulating cardiac contractility of amphibian ventricles was examined. The importance of cGMP in controlling mammalian cardiac function is controversial. However, a remarkable correlation between cGMP and contractile force has been reported in hypodynamic frog ventricles, and cAMP and cGMP were reported to act in a reciprocal fashion to regulate contractility. The present investigation attempted to verify whether such a relationship actually exists in the frog ventricles. Carbachol elicited a dose-dependent reduction in contractility without altering cGMP levels. On the contrary, sodium nitroprusside (100µM) did not reduce cardiac contractility despite a significant elevation of cGMP. At 1mM sodium nitroprusside, a huge elevation of cGMP and a small reduction in contractile tension were observed. Qualitatively similar results were obtained with a degraded sample of sodium nitroprusside. cAMP/cGMP ratios were not correlated with contractility. Hence, these findings were inconsistent with those found in earlier studies on hypodynamic frog hearts and do not support the proposed role of cGMP as a second messenger. The disparate findings may be caused by differences in experimental design. Alternatively, functional compartmentalization of cGMP (in the case of sodium nitroprusside) and the involvement of other cGMP-independent pathways (in the case of carbachol) cannot be ruled out. All these findings suggest that cGMP may play a more crucial role in regulating vascular than cardiac contractility. / Pharmaceutical Sciences, Faculty of / Graduate

Wang Mei. / "July 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 208-233). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.