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Biomedical subjects

G F Merrill

Publications and source records attributed to G F Merrill.

At least 55 records · Page 3Linked to original sources
PubMed1987

Pressure-dependent vasoactive effects of histamine in the coronary circulation.

Twenty-one isolated, perfused, spontaneously rhythmic guinea pig hearts (Langendorff preparation) were used to investigate the effects of coronary perfusion pressure (CPP) on the coronary vasoactive response to a continuous infusion of histamine. Heart rate (HR), coronary perfusate flow (CPF), left ventricular pressure, dp/dtmax, oxygen extraction, and myocardial oxygen consumption (MVO2) were measured at constant CPP of 40 (n = 9), 53 (n = 6), and 65 cm H2O (n = 6) in the absence and presence of continuous intracoronary infusion of histamine [0.9 +/- 0.2 microgram/(min X g)]. At 40 cm H2O histamine caused significant coronary vasodilation. At 65 cm H2O histamine caused significant coronary vasoconstriction. At an intermediate pressure of 53 cm H2O histamine had no effect on CPF. At all three pressures HR, left ventricular pressure, dp/dtmax, and oxygen extraction increased significantly in response to histamine. MVO2 was unchanged by histamine at 65 cm H2O (flow was reduced but extraction increased. MVO2 increased modestly but significantly at 53 cm H2O (12% increase; flow unchanged but extraction increased), and increased prominently at 40 cm H2O (50% increase; flow and extraction increased). We conclude that the coronary vascular effects of continuously infused histamine are dependent on the preexisting, steady-state level of CPP in the isolated perfused guinea pig heart.

Animals↗
PubMed1987

Histamine-induced changes in coronary circulation and myocardial oxygen consumption: influences of histamine receptor antagonists.

The effects of histamine and selected H1 and H2 histamine receptor antagonists on cardiac inotropic and chronotropic activity, coronary perfusate flow (CPF), and myocardial oxygen consumption (MVO2) were studied in isolated guinea pig hearts perfused at constant pressure. Data were collected at the end of a 3-min infusion period at steady state. Cardiac performance increased significantly whereas CPF decreased during histamine infusion. MVO2 remained constant owing to a significant increase in myocardial oxygen extraction. Diphenhydramine attenuated the coronary vasoconstriction but potentiated the positive inotropic response. Cimetidine attenuated the inotropic and chronotropic responses but had no effect on coronary vasoconstriction. In combination, the histamine antagonists attenuated the changes in heart rate, contractility, and CPF. The histamine-induced increase in myocardial oxygen extraction was accompanied by a significant increase in MVO2 in the presence of diphenhydramine. The ratio of the change in oxygen extraction to the change in oxygen consumption caused by histamine was significantly increased by diphenhydramine. This compensated for a histamine-induced decrement in the ratio of the change of CPF to the change in oxygen consumption. Cimetidine had no effect on the changes in coronary flow, oxygen consumption, or the above ratios. Thus, histamine causes direct coronary vasoconstriction via an H1 receptor mechanism, cardiac positive inotropy by an H2 receptor mechanism, and cardiac positive chronotropy by combined H1 and H2 mechanisms. In the presence of a histamine-induced decrease in myocardial oxygen supply, increments in oxygen demand are met by increased oxygen extraction.

Animals↗
PubMed1987

Introns are inconsequential to efficient formation of cellular thymidine kinase mRNA in mouse L cells.

TK mRNA levels were determined in mouse L cells transformed with intron deletion mutations of the chicken TK gene. Whether normalized per cell, per integrated gene, or per internal control signal, intron deletion did not diminish the efficiency of TK mRNA formation in transformed L cells. The results demonstrated that introns are not required for efficient biogenesis of cellular mRNA in transformed mouse L cells.

Animals↗
PubMed1986

Structural and functional analysis of an alternatively spliced chicken TK messenger RNA.

The nucleotide sequence of independent cDNA clones revealed that TK transcripts can undergo alternative splicing within the 3' nontranslated portion of the message. The most abundant mRNA is 2.1 kb in length and is colinear with the underlying genomic sequence for at least the first 1052 bases of its 3' nontranslated region. A less abundant mRNA, 1.3 kb in length, differs from the larger mRNA in that an 863 base intron is spliced from the 3' nontranslated region. The possibility that removal of the alternatively spliced intron allows the small mRNA to persist in postreplicative cells was investigated in two ways. First, the levels of large and small TK mRNA in tissues expressing differential growth rates was determined. Second, the pattern of TK enzyme expression during differentiation was analyzed in muscle cells transformed with recombinant TK genes lacking the 3' nontranslated intron. Both lines of experimentation indicated that the small TK mRNA was as dependent as the large TK mRNA on the replicative state of the cell.

Animals↗
PubMed1986

Differential effects of adenosine and verapamil on histamine vascular contractions.

The present study was undertaken to compare the effects of adenosine and verapamil on histamine-induced contractions in rabbit vascular smooth muscle. Ring segments of rabbit femoral artery were isometrically mounted and contractile responses to histamine (10(-7) to 10(-4) M) were recorded. Verapamil (10(-5) to 10(-4) M) and adenosine (10(-5) to 10(-4) M) produced significant (P less than 0.05) shifts to the right of the histamine dose-response curve in normal physiological salt solution (PSS). Adenosine (10(-4) M) had no effect on the contractile responses to histamine in calcium-deplete PSS but significantly (P less than 0.01) increased the rate of relaxation (-dT/dt, 16.1 +/- 2.3 mg/s before adenosine, 53.7 +/- 7.0 mg/s during adenosine). In calcium-free PSS, verapamil (10(-4) M) had no effects on histamine-induced contractions, nor did it affect the spontaneous rate of relaxation. These findings suggest that the relaxant responses to adenosine, like verapamil, are partially mediated through blockade of external calcium influx, while adenosine, unlike verapamil, appears to have an additional intracellular mode of action.

Adenosine↗
PubMed1986

Adenosine deaminase attenuates canine coronary vasodilation during systemic hypoxia.

The hypothesis that adenosine mediates the coronary vasodilatory response to hypoxia was tested by determining if intracoronary infusion of the adenosine degrading enzyme, adenosine deaminase (ADA), would attenuate this response. Efficacy of ADA was also evaluated by examining its effect on the coronary responses to exogenous adenosine and to 20-s myocardial ischemia. Experiments were conducted in 14 anesthetized, open-chest dogs ventilated 3-5 min with 3% O2-5% CO2-92% N2 to induce systemic hypoxia. Under control, pre-ADA conditions, hypoxia (arterial PO2 19 +/- 2 mmHg) caused left anterior descending (LAD) coronary blood flow to increase from 100 +/- 12 to 382 +/- 47 ml X min-1 X 100 g-1 (+282%). After infusion of ADA (5 U X kg-1 X min-1 for 8-10 min) into the LAD, equally severe hypoxia (arterial PO2 18 +/- 3 mmHg) caused a significantly smaller increase in LAD flow, 79 +/- 9 to 234 +/- 41 ml X min-1 X 100 g-1 (+195%). Oxygen consumption in the LAD perfusion field was unchanged by hypoxia before ADA but fell significantly during hypoxia after ADA. ADA also attenuated significantly the coronary vasodilatory response to exogenous adenosine and to 20-s ischemia. The results of this investigation demonstrate a significant role of adenosine in the coronary vasodilatory response to systemic hypoxia.

Adenosine↗
PubMed1985

Evidence of histamine-induced myocardial ischaemia: reversal by chlorpheniramine and potentiation by atherosclerosis.

The effects of histamine on coronary vasomotor tone and on myocardial blood flow distribution were studied in the anaesthetised rabbit in the absence of histamine H1-receptor blockade and calcium channel blockade. Two groups of rabbits were used, those fed a normal diet and those fed a high cholesterol diet (2%) for 8 to 12 weeks. Continuous recordings of standard limb lead electrocardiograms (ECG) were obtained, and all animals were pretreated with cimetidine, an H2-receptor blocker, to minimise the intervening systemic effects of histamine. In the absence of H1-receptor blockade, histamine produced a marked (40 to 50%) reduction in coronary blood flow without significantly affecting other cardiovascular variables. This effect was seen uniformly across the free wall of the left ventricle, ie endo-epi flow ratios did not significantly change. Concomitant with the coronary vasoconstriction were significant depressions (greater than or equal to 0.1 mV) of the ECG ST-segment and elevation of cardiac tissue lactate and lactate:pyruvate ratio. These histamine-mediated responses were independently abolished by chlorpheniramine (1.5 mg X kg-1 iv) and verapamil (0.5 mg X kg-1 iv). Atherosclerosis reduced the average dose of histamine needed to induce these ischaemic changes from 55 +/- 6 to 34 +/- 6 micrograms X kg-1 X min-1 (p less than 0.05). These findings suggest that in the H2-receptor blocked rabbit coronary vascular bed histamine causes tissue ischaemia by an H1-receptor mechanism. The decrement in myocardial blood flow appears to involve activation of plasma membrane calcium channels and is sensitive to atherosclerosis.

Animals↗
PubMed1984

Genetic and physical analysis of the chicken tk gene.

Several aspects of the structure of the chicken thymidine kinase gene (tk) have been resolved as a result of genetic experiments and nucleotide sequencing. Deletion mapping established the locations of two functional boundaries in a region thought to correspond to the 5' terminus of the gene. One such boundary coincides with a transcriptional promoter, and the other coincides with the translation start codon of the chicken tk polypeptide. Similar deletion mapping assays identified a functional boundary at the 3' terminus of the gene. DNA sequence analysis confirms the prediction that this 3' region encodes the carboxyl terminus of the tk polypeptide. A recombinant cDNA clone complementary to genomic tk sequences was isolated. A comparison between genomic and cDNA sequences reveals the locations of six intervening sequences and allows prediction of the complete amino acid sequence of the chicken tk polypeptide.

Amino Acid Sequence↗
PubMed1984

tk Enzyme expression in differentiating muscle cells is regulated through an internal segment of the cellular tk gene.

Thymidine kinase (tk) enzyme expression is shut down when cultured skeletal muscle cells terminally differentiate. This regulation is mediated by a rapid and specific decline in the abundance of cellular tk mRNA. tk-deficient mouse myoblasts were transformed to the tk-positive phenotype by using both the cellular tk gene of the chicken and the herpesvirus tk gene. Myoblasts transformed with the cellular tk gene effectively regulate tk enzyme activity upon terminal differentiation. Conversely, myoblasts transformed with the herpesvirus tk gene continue to express tk enzyme activity in postreplicative muscle cells. A regulated pattern of expression is retained when the promoter of the cellular tk gene is replaced by the promoter of the herpesvirus tk gene. Moreover, the cellular tk gene is appropriately regulated during terminal muscle differentiation when its 3' terminus is removed and replaced by the terminus of the viral tk gene. Thus, the element of the cellular tk gene sufficient to specify its regulation is entirely intragenic.

Animals↗
PubMed1983

Comparative effects of adenosine and nifedipine in rabbit vascular smooth muscle.

The calcium channel blocker nifedipine attenuates the coronary response to adenosine infusion and reactive hyperemia in dogs. Other evidence indicates adenosine may dilate vascular smooth muscle with a mechanism similar to the calcium channel blockers. In isolated rabbit femoral arterial rings, we studied the interaction of adenosine and nifedipine in mediating vascular relaxation. We also compared the actions of adenosine and nifedipine in relaxing norepinephrine- and K+-stimulated tension, and Ca2+-free contractions in an effort to elucidate differences in the specificity of the two agents. Nifedipine (10-25 micrograms/L) was without effect on adenosine-mediated relaxation of femoral arteries. Adenosine exhibited a greater ability to relax NE-induced contractions and contractions in Ca2+-free medium than did nifedipine. Conversely, nifedipine attenuated K+-induced contractions more effectively than adenosine. These results suggest that adenosine and nifedipine have different cellular actions and that part of adenosine-mediated relaxation may operate intracellularly. Furthermore, the negative interaction of nifedipine and adenosine in vivo suggests that these agents might act differently in an in vitro setting.

Adenosine↗
PubMed1982

Differential effect of adenosine and hypoxia on potassium-induced dilation in the isolated, perfused guinea pig heart.

In 13 isolated, perfused guinea pig hearts we determined the coronary flow responses to abrupt elevation of perfusate potassium levels (final concentration 12-16 mM) in the absence and presence of adenosine, and during hypoxic perfusion. Control diastolic coronary flow and spontaneous heart rate averaged 7.85 +/- 0.26 ml/min/g and 249.6 +/- 2.4 beats/min, respectively. Potassium infusion (12-16 mM) in the absence of other intervention did not alter coronary flow significantly. Repeat potassium elevation in the presence of 0.05 and 0.1 microM adenosine (threshold dilating doses) produced respective flow increases of 58 and 43% above normokalemic flow (p less than 0.05). Paradoxically, during hypoxic perfusion (70%, O2 or 45% O2 in the gas phase) potassium did not elevate flow and, in some instances, constricted the vessels. Myocardial oxygen consumption and effluent potassium levels did not change with adenosine or hypoxic perfusion. These results suggest two points: (1) an interaction between potassium ion and adenosine may be important in the regulation of coronary flow and (2) hypoxic dilation in the coronary vasculature may act via a mechanism different from that of adenosine.

Adenosine↗
PubMed1982

Adenosine coronary vasodilation and sympathetic adrenergic vasoconstriction during altered PCO2.

We used the open-chest, anesthetized dog to investigate the possible influence of blood PCO2 on alpha-adrenergic constriction (ansa subclavia stimulation) of previously dilated (adenosine infusion into the left anterior descendens LAD) coronary vessels. During hypercapnia, LAD flow was increased to a significantly greater degree by adenosine than during normocapnia. Adenosine infusion during hypocapnia was least effective in dilating the coronary vasculature. Ansa stimulation at the peak of the adenosine response attenuated LAD flow by 7 and 33 percent respectively during hypo- and hypercapnia. Although there was a significant effect of PCO2 on the vascular response to adenosine, the ability of the adrenergic nerves to attenuate this response in the presence of an altered PCO2 seemed to relate to this pre-existing level of coronary tone.

Adenosine↗
PubMed1981

Coronary circulation in hearts from hibernating, normothermic, and cold-acclimated hamsters.

We have investigated the influence of temperature, acute global ischemia, adenosine administration, and alterations in perfusion pressure on the coronary circulation of isolated, perfused spontaneously beating hearts from hibernating, normothermic, and cold-acclimated (nonhibernating) hamsters. No differences in heart rates were observed among groups at either 9 or 38 degrees C. Hearts from hibernating hamsters showed some differences in autoregulatory capacity at both the low and normal temperatures. All hearts exhibited similar responses to 30 s of global ischemia at both temperatures, with a marked reduction in the response at 9 degrees C. Similarly, the magnitude of the vasculature response to adenosine (250 micrograms) at 38 and 9 degrees C was equal in both normothermic and hibernating hearts perfused at 38 degrees C. Responses were abolished in all groups at 9 degrees C. We conclude that the altered ability of hibernating hearts to autoregulate is possibly due to intrinsic differences initiated by hibernation, while the responses to adenosine, and global ischemia are largely temperature-dependent effects.

Acclimatization↗
PubMed1981

Cardiac output distribution before and after endotoxin challenge in the rooster.

Cardiac output and its distribution to selected organs was studied using radiolabeled microspheres in unanesthetized, restrained white Leghorn roosters before and 3 h after an Escherichia coli endotoxin challenge. Cardiac output was not significantly altered in either control or endotoxin-treated animals, nor was there a difference in cardiac output between the two groups. Systemic arterial pressure decreased by 37% in the endotoxin group from 187 +/- 14 to 117 +/- 9 mmHg, thus reflecting a marked reduction in total peripheral resistance. The fraction of cardiac output perfusing the heart, adrenals, and liver (hepatic arterial) was not altered by the challenge. Conversely, the percent of total blood flow received by the kidneys, pancreas, and gut (proventriculus and duodenum) was significantly (P less than 0.05) reduced during endotoxemia. Absolute flow to the brain was also decreased. These findings demonstrate that in the rooster endotoxin-induced systemic arterial hypotension is a sufficient stress to cause a redistribution of blood flow, and that the brain in this species (unlike its counterpart in mammals) probably regulates its blood supply passively during periods of hypotension. Conversely, the reduced blood supply to such organs as the gut, pancreas, and kidney following the endotoxin challenge is similar to changes seen in the more commonly studied mammals during experimental endotoxemia.

Animals↗
PubMed1981

The influence of concurrently administered theophylline, ouabain and hypocapnia on coronary flow perturbations in the perfused guinea pig heart.

Adenosine, potassium ions and hydrogen ions are known to be vasoactive in the coronary circulation. Little is known, however, about the combined effects of these chemicals during reactive hyperemia, flow autoregulation or hypoxic hyperemia. Isolated, perfused guinea pig hearts were used to study the influence of simultaneously administered theophylline, ouabain and alkalosis on coronary flow responses (occlusive hyperemia, autoregulation, hypoxic hyperemia) thought to be contributed to by the above chemicals. Retrograde aortic inflow was monitored electromagnetically in the absence and presence of concurrently administered theophylline (5 x 10(-5) M), ouabain (1.4 x 10(-7) M), and alkalosis (perfusate pH 7.69). Upon release of a 30-sec inflow occlusion (in the presence of the above agents) mean peak coronary flow was modestly, but significantly, reduced. Volume flow rate and time for flow to return 50% towards control were reduced in the presence of the above agents, but failed to return to pre-experimental values upon removal of blockers. When perfusion pressure was increased from 65 to 95 cm H2O (antagonists present), coronary myogenic autoregulation was significantly enhanced. Upon decreasing pressure from 95 to 35 cm H2O, in the presence of blockers, calculated coronary resistance fell from 13 +/- 0.6 to 9.5 +/- 0.5 cm H2O/ml/min. The latter value was significantly higher than that seen in the absence of test agents. No difference in the maximum mean coronary flow achieved by hypoxia (20% O2-5% Co2-balance N2) was seen in the absence or presence of blockers. In conclusion, these experiments provide some indirect support for the involvement of the above metabolites in reactive hyperemia and as antagonists of myogenic blood flow autoregulation. Little evidence for their involvement in hypoxic hyperemia is available from this study.

Adenosine↗
PubMed1980

Effect of dichloroacetate on plasma lactic acid in exercising dogs.

Dichloroacetate sodium (DCA) has been shown to reduce circulating levels of lactic acid (LA) under a variety of experimental and clinical conditions. We have examined the effect of DCA on the lactacidemia of exercise in treadmill-exercised dogs. One group of animals (n = 8) was tested at light, moderate, and heavy exercise work loads. Plasma LA, 19 +/- 2mg/dl at rest, increased to 26 +/- 4, 38 +/- 5, and 52 +/- 6 mg/dl during the three workloads, respectively. In the same animals, when identical treadmill tests were conducted after DCA (100 mg/kg, iv), the rise in LA was significantly attenuated. Lactic acid values were 11 +/- 2 mg/dl at rest after DCA and 15 +/- 2, 20 +/- 4, and 23 +/- 3 mg/dl for the light, moderate, and heavy workloads, respectively. Another group of dogs (n = 6) performed prolonged moderate exercise. Under untreated conditions, LA increased from 24 +/- 1 mg/dl at rest, to 41 +/- 6 mg/dl at 10 min, and 50 +/- 5 mg/dl at 50 min. During repeat tests, DCA was given at 12 min when LA was 30 +/- 6 mg/dl. At 50 min, LA was 18 +/- 3 mg/dl or 60% lower than that observed during the untreated run. Because DCA has been shown to increase pyruvate dehydrogenase enzyme activity, these data suggest that this enzyme may be an important factor in LA metabolism during exercise.

Acetates↗
PubMed1980

Potassium and hydrogen ion interaction in the vasculature of the isolated, perfused guinea pig heart.

Potassium and hydrogen ion interactions have been reported in the pial vessels of the cerebral vasculature. Adenosine and hydrogen ion interactions were also found in the coronary circulation. We now report an interaction of perfusate pH and potassium in the coronary vasculature. Isolated, perfused guinea pig hearts were used to investigate the possible influence of perfusate pH on hyperkalemic vasodilatation and on ouabain blockade of the coronary response to hyperkalemia. At perfusate pH 7.45, potassium infusion increased coronary diastolic flow 18%. At pH 7.21, the same concentration of potassium increased flow 35% above control. The coronary vascular response to potassium was modestly diminished at pH 7.65. The duration of the transient vasodilatory response to potassium at low pH was more than doubled relative to pH 7.45. The presence of ouabain in the perfusate significantly (p < 0.05) reduced the dilating action of potassium at pH 7.01 and 7.65. We conclude that the effect of hyperkalemia on coronary flow is pH sensitive but that ouabain blockade of the potassium response is not effected by changes in pH.

Animals↗