摘要:

Summary: The effects of forskolin and seven derivatives on cardiac functions were investigated by using the Langendorff technique and the results compared with the respective potencies obtained from adenylate cyclase and binding studies. In the isolated heart, forskolin increased all parameters measured in the same concentration range as demonstrated by identical EC50 values for increasing contractile force (270 nmol/L), heart rate (276 nmol/L). and coronary flow (249 nmol/L). Compared with its analogs, forskolin was the most potent agonist followed by 7-desacetylforskolin-7-ethylcarbonate, 7-desacetyl-7-pro-pionylforskolin. 14,15-dihydroforskolin. and 7-desacetyl-forskolin. An identical order of potencies was obtained when these compounds were tested for their ability to inhibit [3H [forskolin binding and stimulate adenylate cyclase in a myocardial preparation. While the K, values derived from the binding experiments (386 nmol/L for forskolin) were similar to the respective EC50 values for the cardiac stimulatory effects, the ED50 values for adenylate cyclase stimulation were about 30-fold higher, e.g., 10 μmol/L for forskolin. Derivatives modified in position 9 of the molecule (1,9-dideoxyforskolin, 9,14-epoxy-15-hydroxyforskolin, and 7-desacetylforskolin-6.7:l,9-dicarbonate) had no effect on the isolated heart nor in adenylate cyclase or binding studies. This identical structure-activity profile observed in the three systems used suggests that the cardiac effects of forskolin are elicited by the one specific binding site described in this study.

ISSN:0160-2446    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: To investigate the antianginal action of nitroglycerin and nifedipine, systemic and right heart pressures, cardiac output, oxygen consumption, and radionuclide left ventricular ejection fraction and volume were measured in 14 men with stable effort angina and a positive exercise electrocardiogram. Exercise tests were performed on a semiupright bicycle ergometer on no therapy and after intravenous nitroglycerin and sublingual nifedipine, which lowered mean arterial pressure by 20 mm Hg. Exercise tolerance improved from 50 ± 4 to 61 ±5 W on nifedipine and to 79 ± 4 W on nitroglycerin (p < 0.01, nitroglycerin vs. nifedipine). At submaximal workloads, both drugs decreased arterial pressure and ventricular volumes, but heart rate was higher on nifedipine. At peak exercise on nitroglycerin (79 W). oxygen consumption, cardiac index, heart rate, and rate-pressure product were significantly increased over peak control and nifedipine values, while systolic pressure and end-di-astolic volume were unchanged. Nitroglycerin reduced pulmonary wedge pressure more and systemic diastolic pressure less than nifedipine, so the coronary perfusion gradient was reduced by nifedipine and maintained by nitroglycerin. Also, there was less angina and ST-segment depression after nitroglycerin compared to control or nifedipine, and the left ventricular diastolic pressure-volume relationship was improved only by nitroglycerin. This suggests that the action of nitroglycerin in reducing ischemia is not only due to reduced myocardial oxygen demand, but that myocardial oxygen delivery may also be increased.

ISSN:0160-2446    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: The effect on blood pressure of the dihydro-pyridine derivative nicardipine was studied in 87 essential hypertensive patients aged 25–77 years. A total cumulative dose of 8.75 mg nicardipine was administered over a 30-min period by continuous intravenous infusion. The dose was doubled every 10 min from 1.25 to 5.0 mg. The mean blood pressure fall and the heart rate rise were both dose-related. At 30 min, mean blood pressure fell by 18.9 ± 7.5% vs. baseline values (p < 0.001), heart rate increased by 28.0 ± 11.8% (p < 0.001), and the renin level by 20.7 ± 32.5% (p < 0.001). The blood pressure fall was correlated positively with age(r= 0.521; p < 0.001) and negatively with the rise in heart rate(r =-0.308; p < 0.01) and renin level(r= −0.205; p = 0.05). After eliminating the linear effects of age by the partial correlation method, blood pressure fall and the initial renin level were no longer correlated(r = -0.046. NS), whereas the positive correlation between age and blood pressure fall persisted after eliminating the effect of renin(r= 0.464; p < 0.001). The slope of the regression line for the heart rate rise vs. the blood pressure fall was taken to reflect the baroreflex sensitivity. This sensitivity was negatively correlated to age (r = −0.515; n = 51; p < 0.001) in the 51 of the 87 patients for whom it could be calculated. We conclude that the baroreflex triggering is the main factor limiting the blood pressure fall induced by the calcium-channel blocker nicardipine. The decline in baroreflex sensitivity with age may explain why these blockers are more effective in older than younger patients.

ISSN:0160-2446    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: In intact anesthetized dogs, we measured myocardial potassium uptake, as calculated from the aor-tocoronary sinus difference in potassium concentration and myocardial blood flow, before and during (3-adren-ergic stimulation with isoproterenol. Isoproterenol (10 and 30 ng/kg/min, n = 16) lowered arterial potassium concentration from 3.48 + 0.08 mmol/L by 0.20 ± 0.07 and 0.32 ± 0.06 mmol/L, coronary sinus potassium from 3.45+0.08 mmol/L by 0.20 + 0.06 and 0.35 ± 0.06 mmol/L, increasing myocardial potassium uptake from 1.94 ± 0.99 μmol/min to 2.33 ± 0.97 and 5.36 + 1.29 μmol/min. Unselective β blockade (propranolol 0.1 mg/kg) significantly attenuated the fall in arterial and coronary sinus serum potassium and the increase in myocar dial potassium uptake. Selective β1blockade (metoprolo 0.1 mg/kg) did not significantly influence these effects We conclude that β-adrenergic stimulation increases myocardial potassium uptake, lowering serum potassium in the coronary bed, in addition to causing a systemic hypokalemia. This effect is mediated predominantly by β2adrenoceptors.

ISSN:0160-2446    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: ABBOTT-54741 was identified as a full α-adrenergic agonist; its interaction with the β-adrenergic receptor was compared to that of norepinephrine. ABBOTT-54741 lacks affinity for α1-adrenergic receptors. In radioligand binding studies, the affinity of ABBOTT-54741 for α-adrenoceptors (as measured against3H-pra-zosin binding) was K1, – 401 nM, and that for norepinephrine was 388nM.The affinity of ABBOTT-54741 for α2-adrenoceptors (as measured against3H-rauwolscine binding) was greater than that of norepinephrine (KIA−7 nM; K1,NE= 37 nM). In vitro. ABBOTT-54741 exhibits high potency in vascular preparations (ED50NE./KIAin rabbit aorta – 12.9; in phenoxyhen/amine-treated dog saphenous vein 188.5). In rabbit pulmonary artery, it shows greater potency for the presynaptic than postsynaptic receptors, corroborating the observations of selectivity obtained in binding studies. The observations in vivo reflect that in isolated tissues. In different species (dog. rat) and via different routes of administration (i.v., p.o., i.e.v.. and nasal), ABBOTT-54741 exhibits cardiovascular effects reflecting the stimulation of both α1- and α2adrenoceptors consistently with much greater potency than norepinephrine or any other α agonist known to the authors.

ISSN:0160-2446    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: This study investigated the plasma concentrations of human atrial natriuretic peptide (hANP) of blood samples obtained from the aorta and coronary sinus (CS) in 19 male patients (mean age of 52.8 ± 2.1 years) with ischemic heart disease before and during atrial pacing. The plasma concentrations of hANP were measured by radioimmunoassay, and the secretion rate of hANP was calculated on the basis of the CS-aorta difference in plasma hANP concentration and the CS flow rate recorded at blood sampling. Before atrial pacing, aortic plasma hANP concentration showed a significant positive correlation with mean pulmonary capillary wedge pressure (r = 0.67, p < 0.002) or mean pulmonary artery pressure (r – 0.71, p < 0.001), and a significant negative correlation with left ventricular ejection fraction (r = −0.50, p < 0.05). During atrial pacing, aortic plasma hANP concentration increased from 67 ± 13 (SEM) to 151+33 pg/ml (p < 0.01), CS plasma hANP concentration from 727 ± 121 to 1205 ± 228 pg/ml (p < 0.01), and the hANP secretion rate from 45.4 ± 14.8 to 86.8 ± 28.2 ng/min (p < 0.05, n = 12). The aortic plasma hANP concentration was significantly correlated with the CS plasma hANP concentration (r = 0.81. p < 0.001) or the hANP secretion rate (r = 0.70, p < 0.001). When the patients were divided into the old myocardial infarction group (n = 10) and the angina pectoris group (n = 9), the aortic plasma hANP concentration was significantly higher in the former than in the latter before pacing (p < 0.05). The change in aortic plasma hANP concentration during pacing was significantly smaller in the infarction group than in the angina group (p < 0.05). These results suggest that the secretion rate of hANP determines the circulating level of hANP at rest and during atrial pacing and that the secretion of hANP is influenced by cardiac function.

ISSN:0160-2446    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: The relationship between halothane concentration and tachyphylaxis to sodium nitroprusside (SNP) was studied in a rabbit model. Three groups of six rabbits (groups A, B. and C) were anesthetized with halothane at 0.75, 1.0, and 1.25 vol% end-tidal, respectively. SNP-in-duced hypotension was maintained for 135 min or until a cumulative total dose of 12 mg/kg had been infused (defined as “marked tachyphylaxis‘”). Plasma norepinephrine (NE). epinephrine (EP1) levels, and plasma renin activity (PRA) were measured. Initial mean arterial pressure (MAP) (72 + 2 mm Hg). heart rate (325 + 12 beats/min), and the amount of SNP required to induce 409f hypotension (19 + 4 μg/kg/min) did not differ significantly among the three groups. In group A. live out of six animals exhibited “marked tachyphylaxis.” In group B. only one animal showed “marked tachyphylaxis”; the remaining five required a dose rate of 104 -+- 38 μg/kg/min at 135 min to maintain a 40% reduction in MAP. In group C, none of the animals showed “marked tachyphylaxis”; the dose rate of SNP required after 135 min was 29±14 μg/kg/min. In all groups, SNP dose rate was found to best correlate (p <. 0.0005, r – 0.79) with NE levels and not with PRA or arterial blood pH. This implies that reflex sympathetic activation is the measured mediator of SNP tachyphylaxis. Halothane blunted the tachyphylaxis (sympathetic response) to SNP-induced hypotension at higher concentrations.

ISSN:0160-2446    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: Alinidine is a new bradycardic agent that interferes with ion channels and the ifpacemaker current. To determine if alinidine had antiischemie effects unrelated to its bradycardic action, myocardial metabolism was studied during a pacing-stress test in 20 patients with coronary artery disease and angina pectoris, before and after intravenous infusion of alinidine (10 mg. n= 10; 50 mg, n= 10). When compared to the control pacing-stress test, the low dose of alinidine had no significant effect on aortic pressure, coronary sinus flow (-3%, NS), myocardial oxygen extraction, or myocardial lactate uptake. After the high dose of alinidine. aortic pressure and coronary sinus flow remained unchanged but the arteriocoronary sinus difference in oxygen content increased (12.2 ± 1.3 to 12.7 ± 1.4 ml/100 ml; p < 0.0002) above the values observed during the control pacing-stress test, while both the chemical lactate extraction fraction ( – 19 ± 30 to 15 ± 21%. p < 0.025) and the L-[ l-14C]lactate extraction fraction increased. Accordingly, the net myocardial lactate uptake (corrected for production) had increased from 14 ± 32 during the control pacing-stress test to 29 ± 24 μmol/min during the pacing repeated after the high dose of alinidine (p < 0.05). After the high dose of alinidine, the free fatty acid uptake also rose slightly ( ± 23%, NS) and the alanine production was reduced in 7 of 10 patients (-3.6 ± 1.7 to −1.4 ± 0.6 μmol/min: NS). Thus, independently of its effects on the sinus rhythm, administration of a high dose of alinidine improved oxygen extraction and reduced the signs of anaerobic metabolism during high-demand ischemia.

ISSN:0160-2446    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: The β-adrenergic system has been explored in cardiac hypertrophy (CH) by combining an in vitro study of the inotropic effect of isoproterenol (ISO) and of fors-kolin (FSK) and binding assays using radioactive pindolol. C'H was obtained within 4–6 weeks by banding the abdominal aorta which results in an increase in left ventricular (LV) weight [743 + 14 and 1.098 ± 24 mg in sham-operated (SH) and in CH. respectively, p < 0.011 and in the LV wt/body wt ratio (2.14 +0.05 and 3.24 + 0.05. p< 0.001). The inotropic effect was evaluated on an isolated Langendorff heart preparation whose coronary How was normalized per gram of tissue either by using different constant coronary pressures (75 and 110 mm Hg in SH and in CH, respectively) or different constant coronary Hows (15 and 20 ml min−1in SH and CH. respectively). Binding assays were performed usingl25I pindolol, a rather crude preparation of sarcolemma and a LKjAND program for calculation, (i) The inotropic responsiveness to both ISO and FSK is depressed by 30% in CH. at any drug concentration, without change in EC50whatever the technique used to perfuse the tissue. The time course of the process is slower but, in the case of ISO, remains biphasic. (ii) Binding assays show a normal affinity (Kd100 pM) while receptor density is depressed (32 + 3 and 25 ± 2 fmol mg protein−1, p < 0.05 or 3,287 ± 312 and 2,000 ± 163 fmol/g fresh tissue, p < 0.01, in SH and CH. respectively). The total number of receptors per LV is unchanged. In conclusion: (i) the inotropic response to β agonist is impaired in compensated CH in rat: and (ii) this impairment is not entirely explained by a change in β receptors whose total number per LV remains unmodified in spite of a diminution of its density. In addition, the inotropic response to FSK, an activator of the C subunit of adenylate cyclase, is also depressed suggesting a change at a postreceptor level.

ISSN:0160-2446    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Summary: To determine whether adrenoceptor changes in genetic hypertension occur primary or secondary to blood pressure elevation, we measured cardiac and renal α1,- (by [125I]Be 2254 binding) and β1- and β2-adrenoceptors (by ( – )-[125I]iodocyanopindolol binding) densities in various rat models of acquired hypertension (Dahl S rats on a high-sodium diet. 1-clip-1-kidney (1C-IK) renal hypertensive and DOCA-salt hypertensive rats) in comparison with genetically identical age-matched untreated rats. In addition, α1-adrenoceptors were assessed in spontaneously hypertensive rats (SHR) and in SHR treated with the immunosuppressant cyclosporin A. In heart, no clear pattern of changes in α1- or β1and β2-adrenoceptors was obtained. In kidney, however. β1- and β2-adrenoceptors were increased in all models of hypertension, and a good correlation between renal β-adrenoceptors and systolic blood pressure was found. In contrast, renal β-adrenoceptors were only increased in SHR but not in any form of acquired hypertension. Thus, renal α1-adrenoceptor increases probably occur secondary to blood pressure elevation, whereas α1-adrenoceptor increases appear to be associated with genetic hypertension. Because renal α-adrenoceptors are linked to tubular sodium reabsorption. we suggest that an increase in renal α1,- (and α2)-adrenoceptors may be a very early step in the development of genetic hypertension.

ISSN:0160-2446    

出版商:OVID    

年代:1989

数据来源: OVID