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Biomedical subjects

J T Herlihy

Publications and source records attributed to J T Herlihy.

At least 19 recordsLinked to original sources
PubMed2001

Gene expression of cyclooxygenase in the aging heart.

Cyclooxygenase (COX) is the key rate-limiting enzyme in the prostaglandin synthetic pathway. Two isoforms of COX have been identified: a constitutive COX-1 and an inducible COX-2, which is activated in response to various stimuli. We investigated the changes of COX-1 and COX-2 in rat heart during aging. We measured the age-related changes in the mRNA and protein levels of COX by using reverse-transcription polymerase chain reaction and Western blotting, respectively. COX-2 mRNA and protein levels increased with age, whereas those of COX-1 showed no change. The COX activity determined by prostaglandin E(2) production increased with age. Because the COX-catalyzed arachidonate cascade is an important source of reactive oxygen species (ROS) generation, changes in ROS generation and lipid peroxidation were also assessed. The amount of ROS generated by the COX pathway increased with age, as did the total ROS generation and lipid peroxidation. These results show that COX-2 activity increases with age, partially because of elevated transcriptional expression and protein content, and they suggest that increased COX-2 can play a role in oxidative alterations in the aged heart.

Aging↗
PubMed1999

Modulation of cardiac mitochondrial membrane fluidity by age and calorie intake.

The aim of the present study was to determine the effects of dietary restriction (DR) on the age-related changes in membrane fluidity, fatty acid composition and free radical damage of mitochondrial membranes obtained from the rat left ventricle. Mitochondrial membrane preparations were obtained from the left ventricles of 6- and 24-month-old, male, Fischer 344 rats that were allowed to eat throughout their life either ad lib (Group A) or only 60% of the amount consumed by the ad lib fed group (Group B). Our results show that the membrane fluidity of the 24 month Group A hearts was less than that of the 6 month group A hearts. No differences in membrane fluidity were observed between the 6 and 24 month DR groups. The fatty acid composition of the mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty acid was higher in the older group, although linoleic acid (18:2) was lower. DR eliminated the differences. No statistically significant difference in the overall polyunsaturated fatty acid content was noted. However, the peroxidizability index was higher in the membranes of the 24 month Group A hearts but not in the 24 month Group B hearts. Finally, the degree of lipid damage, as assessed in vitro by the induced production of reactive oxygen species, was elevated in the 24 month Group A hearts. No difference was observed between the young and old DR groups. Considered together, these results suggest that DR maintains the integrity of the cardiac mitochondrial membrane fluidity by minimizing membrane damage through modulation of membrane fatty acid profile.

Aging↗
PubMed1998

Food restriction alters the age-related decline in cardiac beta-adrenergic responsiveness.

The responsiveness of the heart to beta-adrenergic receptor stimulation declines with age. The aim of this study was to determine whether food restriction (FR), the most effective means of retarding the aging processes, affects the loss of beta-adrenergic responsiveness. Male Fisher 344 rats, fed either ad libitum (Group A) or allowed to eat only 60% of what Group A rats consumed (Group B), were sacrificed at 4, 11 or 22-28 months of age. The hearts were isolated and perfused via the Langendorff method. Ventricular pressure-volume curves were constructed to determine the optimal volume for pressure development and concentration-response curves to isoproterenol were obtained at this optimal volume. Interestingly, the ventricular pressure-volume curve for 4 month Group B lay to the left of all the other groups, suggesting that hearts from younger FR rats possessed higher contractility than the other groups. In the unstimulated heart, aging was associated with a slower relaxation phase of contraction and FR further slowed the relaxation. The maximum response of the heart to isoproterenol declined with age and the decline was unaffected by FR. The concentration-response curves of hearts from older rats were generally shifted to the right of the younger animals, while FR shifted the curves to the left toward greater sensitivity to beta-adrenergic stimulation. The EC50s for isoproterenol increased with age, indicating a decrease in the responsiveness of the heart to beta-adrenergic receptor stimulation. In contrast, FR decreased the isoproterenol EC50, suggesting an enhanced responsiveness. These results demonstrate that FR can retard some aging changes (loss in beta-adrenergic responsiveness), while it enhances others (increase in relaxation times).

Adrenergic beta-Agonists↗
PubMed1997

Effect of life-long food restriction on cardiac myosin composition.

This study examined the effects of age and dietary manipulations on the cardiac myosin isozyme composition of male Fischer 344 rats. In hearts from ad libitum-fed rats, aged 6-24 months, the myosin isozyme profile shifted with age from the fast, V1, to the slow, V3, isoform. Life-long food restriction (FR) (60% of ad libitum intake) as well as short-term FR (4 months) initiated at 16 months of age enhanced the age-related shift. Isocaloric reduction in the carbohydrate consumption of the rat from 2/3 to 1/3 of total calories had no effect on the isozyme profile, suggesting that FR acts via a decrease in calorie intake alone. The effect of FR on the cardiac myosin isozyme composition reported here shares several characteristics with the well-known effect of FR on life span extension, i.e., it (a) persists as long as FR is applied (life span extension is proportional to FR duration), (b) depends upon calorie reduction rather than a decrease in a specific dietary component, and (c) can be induced even when FR is initiated later in life. Suggesting that alterations in cardiac performance may be involved, the results may provide some clue as to the mechanism by which FR retards the aging processes.

Aging↗
PubMed1997

Effect of long-term food restriction on cardiac mechanics.

Food restriction (FR) is the only known intervention capable of increasing mammalian life span. It not only increases longevity, but reduces the incidence of a broad spectrum of age-related pathologies, including cardiomyopathy, and retards the physiological decline associated with aging. Previous work from this laboratory has shown that long-term FR affects the contractile machinery of the heart, shifting the cardiac myosin profile from the fast, V1 isoform to the slow, V3 isoform. The aim of the present study was to determine whether FR also induces changes in cardiac mechanics. Isolated, isovolumically beating hearts were examined from four groups of rats: 1) ad libitum-fed rats killed at 10-13 mo of age, 2) FR rats offered only 60% of the calories consumed by ad libitum-fed rats and killed at the same age, 3) young ad libitum-fed rats having the same heart weights as the FR rats, and 4) ad libitum-fed rats subjected to short-term FR, i.e., for the last 3 wk of life, and also killed at 10-13 mo of age. Both short- and long-term FR profoundly and to approximately the same extent affected cardiac mechanics. Hearts from FR rats developed much higher pressures than hearts from the ad libitum-fed rats under conditions of low-calcium perfusate. This difference disappeared, however, when contractility was enhanced by either calcium or isoproterenol. FR prolonged both contraction and relaxation times. Long-term ad libitum-fed rats (adult, 10-13 mo of age) had a lower isoproterenol sensitivity than the young ad libitum-fed rats (10 wk of age). Both short- and long-term FR restored the sensitivity to isoproterenol. In summary, FR profoundly affects many aspects of cardiac mechanics, enhancing some age-related changes (prolongation of the contraction and relaxation times), attenuating another (increasing the isoproterenol sensitivity), and, finally, inducing some unique changes unrelated to age (increased pressure development under low-calcium perfusate).

Aging↗
PubMed1996

Exercise and diet modulate cardiac lipid peroxidation and antioxidant defenses.

Free radical metabolism can be altered by several interventions, including dietary restriction (DR) and exercise. Most of the previous work has focused on the liver and skeletal muscle. The following experiments were performed to determine whether long-term DR and chronic exercise affect free radical metabolism and change the status of the antioxidant defenses of the heart. Rats were subjected to DR and/or endurance exercise for 18.5 months and were sacrificed along with their ad lib fed and sedentary controls. Both DR and exercise decreased the malondialdehyde content of cardiac mitochondria, indicating a decrease in lipid peroxidation damage. The antioxidant enzymes in the cytosol, superoxide dismutase, selenium dependent glutathione peroxidase, and glutathione S-transferase were all increased by DR. Catalase activity was unaffected by DR but was increased by exercise. The following results demonstrate that long-term DR and exercise modulate the extent of free radical damage in the heart and enhance the antioxidant defense system.

Animals↗
PubMed1994

Tachycardia heart failure alters rabbit aortic smooth muscle responsiveness to angiotensin II.

The effects of heart failure on the responsiveness of aortic smooth muscle tissue to various vasoactive agents were examined. Heart failure was induced in rabbits by sustained rapid ventricular pacing (400 beats/min) for 6-7 wk. After the rabbits were killed, strips of thoracic aorta were prepared and mounted in tissue baths. Responsiveness of these aortic strips to potassium depolarization and cumulative additions of vasoactive agents was determined. Aortic strips from control and tachycardia heart failure (THF) rabbits developed similar maximum forces to stimulation by potassium depolarization (0.77 +/- 0.08 vs. 0.96 +/- 0.16 kg/cm2), calcium chloride (0.71 +/- 0.09 vs. 0.88 +/- 0.06 kg/cm2), and phenylephrine (0.90 +/- 0.08 vs. 1.14 +/- 0.09 kg/cm2). The maximum relaxation to isoproterenol was also unaffected by THF (0.08 +/- 0.02 vs. 0.07 +/- 0.01 kg/cm2). In contrast, the maximum response of aortic strips from THF rabbits to angiotensin II was significantly lower than control (0.37 +/- 0.07 vs. 0.069 +/- 0.09 kg/cm2). With regard to aortic smooth muscle sensitivity, no differences in the concentrations at which 50% of the maximal response is achieved (EC50) were observed between THF and control strips for calcium chloride (0.10 +/- 0.01 vs. 0.16 +/- 0.04 mM), isoproterenol (51.5 +/- 13.5 vs. 51.0 +/- 5.4 nM), and phenylephrine (65.2 +/- 12.3 vs. 92.5 +/- 18.0 nM). However, THF was associated with a significant increase in the EC50 value for angiotensin II response (2.03 +/- 0.25 vs. 0.58 +/- 0.05 nM). These results demonstrate that THF is associated with a specific and significant reduction in the sensitivity and maximal responsiveness of aortic smooth muscle to angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1994

Dietary restriction modulates the norepinephrine content and uptake of the heart and cardiac synaptosomes.

The present study was designed to examine the effects of long-term dietary restriction on cardiac sympathetic nerves and neurotransmitter. The food intake of male, 6-week-old Fischer 344 rats was reduced to 60% of the intake of control rats fed ad libitum. The body and heart weights of rats diet restricted for 4.5 months were less than those of the ad libitum fed animals, while the heart weight to body weight ratios were higher. The norepinephrine (NE) content of hearts from restricted rats (1073 +/- 84 ng/g wet wt) was higher than controls (774 +/- 38 ng/g wet wt), although the total amount of NE per heart was unchanged. Similarly, the cardiac synaptosomal P2 fraction from restricted rats possessed a higher NE content (24.1 +/- 2.4 ng/mg protein) than the P2 fraction of ad libitum fed controls (13.7 +/- 1.3 ng/mg protein). The desmethylimipramine-sensitive norepinephrine uptake of the P2 fraction from restricted rats was significantly higher than that of control rats (9.44 +/- 1.33 vs 4.75 +/- 0.35 ng/mg protein/hr). The NE uptakes of the two groups were similar when uptake was normalized to endogenous NE levels. These results demonstrate that long-term dietary restriction affects cardiac sympathetic nerve endings and suggest that part of the beneficial action of life-long dietary restriction on the age-related decline in cardiovascular regulation may be related to changes in cardiac sympathetic nerves.

Animals↗
PubMed1993

Long-term caloric restriction improves baroreflex sensitivity in aging Fischer 344 rats.

The effects of aging and caloric restriction on mean arterial pressure (MAP), heart rate (HR), and baroreflex sensitivity were determined in young (7-9 months) and old (22-24 months) awake, male Fischer 344 rats which had been either ad libitum fed or calorie restricted (60% of the ad libitum calories). The MAP of young rats was higher than that of old rats. The MAP of old ad libitum fed rats was higher than that of old restricted rats with no effect of diet in young rats. The HR of restricted rats was lower than ad libitum fed rats with no significant age effect. Reflex bradycardia to hypertensive episodes was greater in restricted than in ad libitum fed rats. Reflex tachycardia to hypotensive episodes was greater in young than in old rats and greater in calorie restricted than in ad libitum fed rats. These findings demonstrate that caloric restriction alters the age-associated decline in several hemodynamic parameters.

Aging↗
PubMed1992

Long-term calorie restriction enhances baroreflex responsiveness in Fischer 344 rats.

Diet influences many aspects of cardiovascular function. Restriction of caloric intake represents a major nonpharmacological means of reducing blood pressure. The aim of the present work was to determine the effects of long-term calorie restriction on mean arterial pressure (MAP) and baroreflex responsiveness of the conscious, normotensive, nonobese Fischer 344 male rat. From 6 wk of age rats ate either ad libitum or 60% of the amount consumed by those eating ad libitum. Calorie restriction had no effect on MAP of rats 12-14 mo of age; the MAP for the ad libitum fed and calorie-restricted groups were 114.6 +/- 1.6 and 111.6 +/- 0.8 mmHg, respectively. Basal heart rate (HR), however, was reduced from 396 +/- 6 beats/min in the libitum-fed group to 333 +/- 5 beats/min in the calorie-restricted group. Administration of sodium nitroprusside (SNP) (both as bolus and constant infusion) and phenylephrine (PE) (bolus alone) elicited tachycardia and bradycardia in both groups. The calorie-restricted group exhibited greater baroreflex responsiveness to hypotensive stress than did the ad libitum-fed group. For constant infusion of SNP, the baroreflex gain of the calorie-restricted group (-5.43 +/- 0.56 beats.min-1.mmHg-1) was significantly greater than that of the ad libitum-fed group (-2.14 +/- 0.19 beats.min-1.mmHg-1). Bolus injections of SNP elicited similar results. Calorie restriction only minimally altered the baroreflex responsiveness to hypertensive stress elicited by bolus injections of PE, although the relationship between HR and MAP was shifted to the left in the calorie-restricted group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Long-term food restriction depresses serum thyroid hormone concentrations in the rat.

Long-term food restriction exerts an anti-aging action in rodents. The mechanism underlying its modulation of aging processes is unknown but changes in endocrine systems have been postulated as couplers of food restriction to aging. The effects of long-term food restriction on the serum concentrations of thyroid hormones were examined in 6-month-old, male Fischer 344 rats. For 4.5 months a Food Restricted group was fed 60% of the amount consumed by an Ad Libitum group. Food restriction did not alter the 24-h mean T4 concentration but reduced the 24-h mean T3 concentration from 95 +/- 1 to 87 +/- 3 ng/dl. The Ad Libitum group exhibited diurnal rhythms in both serum T4 and T3 concentrations, with peak values for each hormone at 1000 h. Although food restriction eliminated the 1000 h peak for both thyroid hormones, it abolished the diurnal variation only for T3. The dietary-induced changes in serum T4 and T3 are consistent with a role for these hormones in the anti-aging action of food restriction.

Aging↗
PubMed1989

Metabolic rate and aging: effects of food restriction and thyroid hormone on minimal oxygen consumption in rats.

Metabolic rate (MR) is widely regarded as an important component of aging processes. Decreased MR has been suggested as a possible mechanism of the life-prolonging action of food restriction in rodents and recent reports show lowered plasma levels of tri-iodothyronine (T3), a regulator of MR, in food restricted rodents. In order to study the relationship between MR, food restriction, thyroid status and aging we measured the Minimal Oxygen Consumption (MOC) of barrier-raised Fischer 344 male rats fed ad libitum (Group A) or fed a diet restricted to 60% of ad libitum intake (Group R). Oxygen consumption (VO2) was also measured over 24 hr to establish the relationship between MOC and VO2 under usual living conditions. Results show: (i) MOC declines with age in both groups of rats; (ii) there is no difference in MOC of Groups A and R rats; (iii) MOC of Group R rats is significantly more sensitive to doses of injected T3 than MOC of Groups A rats at all ages; and (iv) MOC of both groups of rats is significantly lower than the lowest VO2 recorded under usual living conditions. The results indicate that a decrease in MR is not the mechanism by which food restriction retards aging processes in rodents. The results also suggest no change in thyroid status due to restriction of food although there is increased sensitivity to T3 in food restricted rats.

Aging↗
PubMed1989

Effects of preload and eicosanoid synthesis inhibition on rat aortic smooth muscle sensitivity.

Concentration-response curves to serotonin and phenylephrine were obtained from aortic strips subjected to low (0.75 g) and high (3.0) preloads in the presence and absence of eicosanoid synthesis inhibitors. The sensitivity of the strips to both agonists was greater in the high preload strips. The cyclooxygenase inhibitor, indomethacin (28 microM), shifted the serotonin concentration-response curves to the right. However, the preload effect still remained. The lipoxygenase inhibitor, nordihydroguaiaretic acid (10 microM), not only decreased sensitivity to serotonin and phenylephrine, but eliminated the preload effect as well. These results suggest that 1) both cyclooxygenase and lipoxygenase metabolites affect the sensitivity of isolated arterial smooth muscle to vasoactive agents, and 2) lipoxygenase, but not cyclooxygenase, metabolites may play a role in the effect of preload on arterial smooth muscle sensitivity.

Animals↗
PubMed1989

Phenylarsine oxide inhibition of endocytosis: effects on asialofetuin internalization.

The aim of this work was to establish to what extent the concentrations over which phenylarsine oxide (PAO) inhibits oxygen consumption and decreases cellular ATP content overlap with those used to inhibit protein internalization. The effects of PAO (1-100 microM) on 125I-labeled asialofetuin internalization, oxygen consumption, ATP content, and lactate dehydrogenase (LDH) latency of isolated rat hepatocytes were determined. Ten micromoles/liter PAO blocked 125I-asialofetuin internalization but had no effect on ATP content up to 20 min, only a slight inhibition (18%) on oxygen consumption, and no effect on LDH latency. Higher concentrations of PAO had increasingly deleterious effects on the parameters. These results show that higher concentrations of PAO severely affect the energy stores as well as integrity of the hepatocyte. We concluded that 1) use of PAO requires careful evaluation of its effects in each experimental preparation and 2) it should be possible to establish time and concentration parameters for use of PAO as an inhibitor of endocytosis while minimizing the influence of its other cellular actions.

Adenosine Triphosphate↗
PubMed1989

In vitro adsorption losses of arachidonic acid and calcium ionophore A23187.

Arachidonic acid (AA) is often utilized in in vitro studies to label cellular pools of AA or to elicit cellular responses dependent on eicosanoid production. Because of the hydrophobic nature of AA, organic diluents such as ethanol or dimethyl sulfoxide are utilized in preparing concentrated solutions. The fate of AA when added to aqueous medium is not generally considered because of the dilution of the AA, although some investigators utilize bovine serum albumin (BSA) to solubilize as well as to trap AA and its hydrophobic metabolites. These experiments demonstrate a rapid and progressive decline in AA concentration when added to aqueous media in tissue baths and in glass test tubes. The extent of the decline was greater in the tissue baths than in the test tubes. The calcium ionophore A23187, which is used to stimulate AA metabolism, is also hydrophobic, and its concentration also decreased when added to aqueous media. The decline in the concentration of both AA and A23187 was due to adsorption to the container walls. The presence of 1% BSA in the aqueous solution attenuated and even eliminated the decline in the concentration, indicating binding of the two agents to the protein. However, the presence of BSA in culture medium inhibited the A23187-induced stimulation of AA metabolites in baboon aortic smooth muscle cells. These results underscore the complexities arising from the in vitro use of hydrophobic substances in biological systems.

Adsorption↗
PubMed1987

Modulation of vascular smooth muscle sensitivity by preload and eicosanoid synthesis inhibition.

An increase in preload from 0.75 to 10 g caused an increase in the sensitivity of rabbit aortic strips to phenylephrine, serotonin, and KCl. Several eicosanoid synthesis inhibitors were utilized to determine whether production of endogenous eicosanoids contributed to the change in muscle sensitivity. Quinacrine (10 microM), indomethacin (10 and 50 micrograms/ml), meclofenamate (50 and 100 micrograms/ml), 5,8,11,14-eicosatetraynoic acid (ETA, 50 and 100 micrograms/ml), and nordihydroguaiaretic acid (NDGA, 10 microM) all shifted the concentration-response curves of various agonists to the right, indicating a decrease in the sensitivity of the muscle to these agents. Thromboxane synthesis inhibition by 1 microM (E)-3-[4-(1-imidazolylmethyl]phenyl-2-propenoate (OKY 046) exerted no effect on sensitivity. Indomethacin at both concentrations caused a parallel shift in the high and low preloaded strips but was unable to alter the influence of preload on sensitivity. A similar effect was observed with the lower concentrations of meclofenamate and ETA. NDGA and higher concentrations of meclofenamate and ETA not only shifted the sensitivity in both high and low preloaded strips but also eliminated the preload effect. These results indicate that cyclooxygenase and lipoxygenase metabolites both alter aortic smooth muscle sensitivity to contractile agents and suggest that lipoxygenase metabolites may play a role in the change in sensitivity seen with preload.

5,8,11,14-Eicosatetraynoic Acid↗