Hypotensive effects of captopril on physical properties of the arterial system in young and adult rats.

We determined the acute effects of the angiotension converting enzyme inhibitor captopril on the arterial mechanics in rats at different ages, based on the exponentially tapered T-tube model. Male Wistar-Kyoto rats aged 4 and 12 months were individually referred to as young (n = 8) and adult rats (n = 8) and were anesthetized and thoractomized. The pulsatile aortic pressure and flow signals before and after the administration of captopril (20 mg/kg, i.p.) were measured by a high-fidelity pressure sensor and an electromagnetic flow probe, respectively. In each age group, captopril showed little change in basal heart rate as well as cardiac output. However, captopril produced a drop of 15% in mean aortic pressure in young and a fall of 12% in adult rats. In addition. captopril reduced total peripheral resistance by 21% in young and by 23% in adult animals. As for the pulsatile nature of the arterial system, captopril had increased wave transit time of the lower body circulation of 10% in young and of 12% in adult rats. By contrast, captopril reduced wave reflection factor by 22% in young and by 25% in adult animals. In conclusion, the converting enzyme inhibitor captopril has a stiffness-decreasing effect on Windkessel vessels and a dilated effect on resistance arterioles in either young or adult rats. No age dependence of vascular response and reflex tachycardia to captopril has been found in rats between 4 and 12 months.

Mechanical effects of liriodenine on the left ventricular-arterial coupling in Wistar rats: pressure-stroke volume analysis.

1. In a recent in vivo study, liriodenine, an aporphine alkaloid, has been identified as a prominent anti-arrhythmic agent that can prevent rats' sudden deaths, even at the dose as low as 10(-7) g kg(-1). The aim of this study was to determine whether liriodenine at its effective anti-arrhythmic dose of 10(-7) g kg(-1) had effects on the left ventricular (LV)-arterial coupling in Wistar rats. 2. LV pressure and ascending aortic flow signals were recorded to construct the ventricular and arterial end-systolic pressure-stroke volume relationships to calculate LV end-systolic elastance (E(es)) and effective arterial volume elastance (E(a)), respectively. The optimal afterload (Q(load)) determined by the ratio of E(a) to E(es) was used to measure the optimality of energy transmission from the left ventricle to the arterial system. 3. Liriodenine at the dose of 10(-7) g kg(-1) showed no significant changes in basal heart rate (HR), cardiac output (CO), LV end-systolic pressure (P(es)), E(a), E(es), and Q(load). 4. By contrast, liriodenine at the dose of 10(-6) g kg(-1) produced a significant fall of 2.0% in HR and a significant rise of 5.8% in CO, but no significant change in P(es). Moreover, liriodenine administration of 10(-6) g kg(-1) to rats significantly decreased E(es) by 8.5% and E(a) by 10.6%, but did not change Q(load). 5. We conclude that liriodenine at the dose of 10(-7) g kg(-1) has no effects on the mechanical properties of the heart and the vasculature and the matching condition for the left ventricle coupled to its vasculature in rats. Even at 10 times the effective anti-arrhythmic dose, liriodenine shows no effects on the efficiency of energy transferred from the left ventricle to the arterial system.

Effects of food restriction on systolic mechanical behavior of the ventricular pump in middle-aged and senescent rats.

Previous work from our laboratory has revealed that the intrinsic contractility of the left ventricle is depressed in rats at 24 months, and the ventricular internal resistance shows declines with age. The aim of this study was to determine whether food restriction (FR) delays the development of age-related changes in left ventricular (LV) contractility and internal resistance. Male Fischer 344 rats that began FR at the ages of 12 and 18 months were fed on alternate days for 6 months and compared with age-matched ad libitum (AL)-fed rats. Rats studied at the ages of 18 and 24 months were referred to as middle-aged and senescent rats, respectively, and were anesthetized and thoracotomized. We measured LV pressure and ascending aortic flow waves by using a high-fidelity pressure sensor and an electromagnetic flow probe, respectively. The elastance-resistance model was used to generate Emax and Qmax to describe the physical properties of the left ventricle; Emax is the maximal systolic elastance to represent the myocardial contractility; Qmax is the theoretical maximal flow to be inversely related to the LV internal resistance. Neither age nor diet affected basal heart rate, LV end-systolic pressure, or cardiac output. Emax normalized to LV weight (Emaxn) exhibited a decline from 941.9+/-62.7 mmHg/ml-g to 690.2+/-57.5 mmHg/ml-g with age in AL-fed rats but not FR rats. Qmax showed an increase with age from 36.55+/-2.78 ml/s to 44.22+/-2.62 ml/s in AL-fed rats or from 36.01+/-2.09 ml/s to 43.52+/-2.74 ml/s in FR rats. There was no effect of diet on Qmax. In conclusion, FR prevents or delays the reduction in myocardial contractility that occurred between 18 and 24 months of age in AL rats. However, FR does not affect the age-related changes in ventricular internal resistance.

Involvement of apoptosis during deciduomal regression in pseudopregnant hamsters effect of progesterone.

We determined whether fragmentation of genomic DNA, apoptosis, occurs during deciduomal regression in pseudopregnant hamsters and the effect of progesterone on the apoptotic processes. Artificially induced deciduoma were obtained on different days of pseudopregnancy and separated into mesometrial and antimesometrial tissues. The deciduomal cell cycle progression and population profiles of both sides were compared by flow cytometry. The proportion of sub-G1 peak, which was correlated with the apoptotic cells, were about 10% on day 8 and reached to 40% in both tissues on day 10. Exogenous progesterone treatment by daily injection (2 mg; s.c.) on and after day 8 reduced the percentage of low molecular weight DNA in both tissues on day 10 and day 12 as compared to the nontreated control one, respectively. The appearance of DNA ladder was also delayed at least 24 h by progesterone administration. The intensity of DNA fragmentation was more pronounced in antimesometrial deciduoma. In situ 3'-end labeling of apoptotic cells further substantiated the apoptotic process. The apoptotic cells first appeared in the luminal region in antimesometrial deciduoma on day 8 and spreaded all over the entire deciduomal tissue on day 10. Progesterone treatment stimulated deciduomal proliferating cell nuclear antigen (PCNA) expression, maintained deciduoma until day 14 and retarded the differentiation and regeneration of the uterine epithelium.

Age-related changes in pumping mechanical behavior of rat ventricle in terms of systolic elastance and resistance.

Both the maximal systolic elastance (Emax) and the theoretical maximal flow (Qmax) can quantify the systolic mechanical behavior of the ventricular pump. Physically, Emax can reflect the intrinsic contractility of the myocardium as an intact heart. The quantity in (Qmax is inversely related to the internal resistance of the left ventricle. How great the effects of age are on these Emax and Qmax has never been examined, however. This study was to determine the ventricular pumping mechanics in terms of the systolic elastance and resistance in male Fischer rats at 6, 12, 18, and 24 months of age. We measured left ventricular (LV) pressure and ascending aortic flow waves using a high-fidelity pressure sensor and an electromagnetic flow probe, respectively. Those two parameters that characterize the systolic pumping mechanics of the left ventricle are obtained by making use of an elastance-resistance model. The basic hemodynamic condition in those animals with different ages is characterized by (i) no significant change in cardiac output and (ii) a decrease in basal heart rate, LV end-systolic pressure, as well as effective arterial volume elastance. Changes that take place in the left ventricle with age include a decline in Emax and an increase in Qmax especially at 24 months. These results demonstrate that the impaired intrinsic contractility of an aging heart may be compensated to some extent by the diminished ventricular internal resistance. Such compensation in aging rats may maintain normal blood flow essential for the metabolic needs of tissues and/or organs before heart dysfunction and failure occur.

Acute effects of methoxamine on left ventricular-arterial coupling in streptozotocin-diabetic rats: a pressure-volume analysis.

We determined the acute effects of methoxamine, a specific alpha1-selective adrenoceptor agonist, on the left ventricular-arterial coupling in streptozotocin (STZ)-diabetic rats, using the end-systolic pressure-stroke volume relationships. Rats given STZ 65 mg x kg(-1) iv (n = 8) were compared with untreated age-matched controls (n = 8). A high-fidelity pressure sensor and an electromagnetic flow probe measured left ventricular (LV) pressure and ascending aortic flow, respectively. Both LV end-systolic elastance E(LV,ES) and effective arterial elastance Ea were estimated from the pressure-ejected volume loop. The optimal afterload Q(load) determined by the ratio of Ea to E(LV,ES) was used to measure the optimality of energy transmission from the left ventricle to the arterial system. In comparison with controls, diabetic rats had decreased LV end-systolic elastance E(LV,ES), at 513 +/- 30 vs. 613 +/- 29 mmHg x mL(-1), decreased effective arterial elastance Ea, at 296 +/- 20 vs. 572 +/- 48 mmHg x mL(-1), and decreased optimal afterload Q(load), at 0.938 +/- 0.007 vs. 0.985 +/- 0.009. Methoxamine administration to STZ-diabetic rats significantly increased LV end-systolic elastance E(LV,ES), from 513 +/- 30 to 602 +/- 38 mmHg x mL(-1), and effective arterial elastance Ea, from 296 +/- 20 to 371 +/- 28 mmHg x mL(-1), but did not change optimal afterload Q(load). We conclude that diabetes worsens not only the contractile function of the left ventricle, but also the matching condition for the left ventricular-arterial coupling. In STZ-diabetic rats, administration of methoxamine improves the contractile status of the ventricle and arteries, but not the optimality of energy transmission from the left ventricle to the arterial system.

Impaired vascular dynamics in normotensive diabetic rats induced by streptozotocin: tapered T-tube model analysis.

This study is to explore the changes of arterial mechanical properties in streptozotocin (STZ)-diabetic rats, based on the exponentially tapered T-tube model. Rats given STZ 65 mg kg(-1)i.v. are compared with untreated weight- and age-matched controls. A high-fidelity pressure sensor and electromagnetic flow probe measured pulsatile pressure and flow waves in the ascending aorta, respectively. Diabetic rats exhibit isobaric vasodilatation that is characterized by an increase in cardiac output and no significant changes in aortic pressure. Total peripheral resistance of diabetic rats is lower than that of weight- and age-matched controls. Diabetic rats have higher total peripheral compliance (2.86+/-0.70 microl mm Hg(-1)) than do weight- (1.77+/-0.34 microl mm Hg(-1)) and age-matched (1.87+/-0.69 microl mm Hg(-1)) controls. Aortic characteristic impedance is reduced from 0.017+/-0.003 mm Hg min kg ml(-1)in weight- and 0.020+/-0.004 mm Hg min kg ml(-1)in age-matched controls to 0.010+/-0.004 mm Hg min kg ml(-1)in diabetic rats. Moreover, diabetic rats show shorter wave transit time in lower body circulation (17.86+/-1.91 ms) than do weight- (20.45+/-1.91) and age-matched (23.05+/-2.04 ms) controls. Under isobaric vasodilatation, the decreased resistance and increased compliance in peripheral circulation suggest that the contractile dysfunction of the smooth muscle cells may occur in resistance arterioles in diabetes. With unaltered aortic pressure, an impairment in aortic distensibility of STZ-diabetic rats is manifest on the reduced wave transit time rather than on the diminished aortic characteristic impedance.

Effects of food restriction on mechanical properties of arterial system in adult and middle-aged rats.

The effects of food restriction on the mechanical properties of the vasculature were determined in Long-Evans male rats with different ages. Rats that began food restriction at the ages of 6 months and 12 months were fed on alternate days for 6 months. Rats at the ages of 12 and 18 months were referred to as adult and middle-aged rats and were anesthetized and thoracotomized. The exponentially tapered T-tube model was employed to relate pulsatile pressure and flow signals measured in the ascending aorta. In each age group, food restriction elicited a decrease in body weight as well as basal heart rate but showed no significant change in cardiac output. Arterial blood pressure, total peripheral resistance, and aortic characteristic impedance were not affected by food restriction in middle-aged rats. However, adult food-restricted rats exhibited lower mean arterial blood pressure (99.1 +/- 3.1 mmHg) than did adult ad libitum-fed rats (110.7 +/- 3.0 mmHg). Total peripheral resistance was reduced from 0.645 +/- 0.045 mmHg-min-kg/ml in adult ad libitum-fed rats to 0.492 +/- 0.030 mmHg-min-kg/ml in adult food-restricted rats. Moreover, aortic characteristic impedance of adult food-restricted rats (0.014 +/- 0.001 mmHg-min-kg/ml) was lower than that of adult ad libitum-fed rats (0.024 +/- 0.002 mmHg-min-kg/ml). Neither age nor diet exerted effects on wave transit time and produced no changes in aortic distensibility. In conclusion, food restriction may elicit significant changes in the mechanical properties of both Windkessel vessels and resistance arterioles in adult rats, but not in middle-aged rats.

Recovery of high potassium-evoked dopamine release after depolarization challenge in the striatum of young and old male rats.

The aim of this study was to assess the recovery of high potassium-evoked dopamine (DA) release after depolarization challenge in young (3-4 months) and old (21-25 months) male Wistar rats. Recovery of DA release was evaluated by comparison of the peak responses of DA release induced by two serial high potassium stimulations. Concentric microdialysis probes were stereotaxically implanted in the lateral striatum of rats, and microdialysis was commenced 24 h after surgery. Using a low flow rate of perfusion (1 microl/min), all rats received 2 x 20 min infusions of 100 mM potassium solution separated by either 60 or 140 min. No difference in the basal DA concentration or the potassium-evoked DA release or its recovery was seen between the two groups. Our results suggest that the vesicular DA store recovers rapidly after high potassium challenge in both young and old rats.

Age-related changes of arterial mechanical properties in rats: analysis using exponentially tapered T-tube model.

This study was designed to explore the changes of mechanical properties in the rat's arterial system at different ages by using the exponentially tapered T-tube model. Long-Evans male rats at the ages of 6, 12, and 18 months were anesthetized and thoractomized. Rats at the ages of 6, 12, and 18 months were individually referred to as young, adult, and middle-aged rats. The pulsatile pressure and flow signals in the ascending aorta were measured by a high-fidelity pressure sensor and electromagnetic flow probe, respectively. Model parameters, such as aortic characteristic impedance, vascular tapering index, wave transit time, and arterial load compliance, were inferred from the aortic pressure and flow signals to describe the pulsatile nature of blood flows in the vasculature. The static hemodynamic condition in those animals with different ages was characterized by (i) no change in cardiac output and (ii) a decrease in heart rate, arterial blood pressure, as well as total peripheral resistance. As for the pulsatile nature of the arterial system, the wave transit time remained unaltered, indicating there was no change in the aorta's distensibility of rats at those three different ages. The arterial load compliance, which describes the buffering nature of a hollow vessel, also remained unchanged. On the contrary, there was a significant fall in aortic characteristic impedance in those age-related rats. The decline of aortic characteristic impedance without a significant change in arterial distensibility suggests that lumen growth of the aorta and large arteries may occur in rats up to middle age.

Dissociation of the restoration of copulatory behavior and the testicular morphology in old male rats with fetal brain grafting.

Improvement of copulatory activity has been reported in aged male rats bearing the fetal preoptic area (POA), however, whether the fetal POA graft has any effect on the gonad of aged male rats has not been established. In the present study, the testicular histology and the sexual behavior were studied in 20 old (18-19 months) Long-Evans male rats after fetal brain transplantation. Animals were divided into three groups: (1) POA-grafted group (n = 6): fetal POA neurons were grafted into the POA, (2) COR-grafted group (n = 7): fetal cerebral cortex tissue was grafted into the POA and (3) SHAM-grafted group (n = 7): the POA of rats received glucose-saline injection. Thirty days after the grafting, only those bearing POA graft showed an increase in mount frequency and intromission frequency. Sixty days after fetal brain grafting, testicular morphology was examined. Testicular volume was measured and paraffin sections (8 microns) of the testis were stained with Hematoxylin-Eosin. Seminiferous tubular diameter and epithelial height were analyzed quantitatively. No significant changes in testicular volume, seminiferous tubular diameter and epithelial height were observed in all three groups. The shrunk testicular morphology in the aged male rats cannot be restored by fetal POA grafting. These results suggest that copulatory behavior and testicular morphology may be dissociated in old male rats.

Effects of age on open-field behavior of male rats.

As age advances, the performance of animal behavior declines gradually. The purpose of this study was to investigate the onset of age-related changes in open-field behavior of rats from a wide age spectrum. Male Long-Evans rats, ranging from 2 to 22 months, were placed in an open-field apparatus during the dark phase for a cumulative period of 28 min. Data were collected for the following parameters of open-field behavior: horizontal activity (HA), total distance (TD), stereotypy count (SC), vertical activity (VA), movement time (MT) and margin time (MGT). The highest value of HA, TD, SC and MT was found in rats at the age of 3 months. After 3 months, the values for these parameters gradually declined, subsequently reaching statistical significance by 6 months (HA, TD and SC) or 8.5 months (MT) of age. Maximum activity of VA occurred at 8.5 months of age and thereafter gradually declined with increasing age, however, no significantly statistical difference was reached as compared to the highest value. In contrast, the values for MGT gradually declined after 2 months of age, thereby reaching statistical significance by 11 months of age. These results indicate that the onset of age-related decline in open-field behavioral parameters can differ and the age-related changes in open-field behavior depends on observational parameters.

Involvement of alpha- and beta-adrenoceptors in antinociception at the lumber spinal level in mice.

To study the role of the adrenergic receptors in the regulation of nociceptive transmission in male albino mice, the antinociceptive activity of adrenergic drugs was tested with a tail-flick method. Subarachnoid infusion of phenylephrine and clonidine into T13-L1 of spinal cord produced a dose-dependent elevation of the nociceptive threshold in sodium pentobarbital anesthetized mice. The inhibitory effect of alpha-adrenoceptor agonists was antagonized by pretreatment with alpha-adrenoceptor antagonists. Isoproterenol also increased the nociceptive threshold significantly. The antinociceptive effect of isoproterenol was reversed by pretreatment with beta antagonist, propranolol. These findings suggest that spinal adrenergic receptors of both alpha and beta types probably are involved in the inhibition of nociceptive transmission.

Mechanisms of adrenaline-induced antinociception in mice.

Infusion of adrenaline into the upper lumbar subarachnoid space in lightly anesthetized mice produced a significant elevation of the nociceptive threshold as quantitated by tail flick test. The antinociceptive effect of adrenaline was dose-dependent and antagonized equally by pretreatment with either alpha-1 selective antagonist prazosin or alpha-2 selective antagonist yohimbine at a dose of 0.05 microgram/5 microliter/mouse. This antinociceptive effect of adrenaline was also blocked by pretreatment with beta antagonist propranolol or opiate antagonist naloxone at higher doses, i.e., 0.5 microgram and 1.0 microgram/5 microliter/mouse, respectively. These results suggest that the antinociceptive mechanisms of adrenaline at the lumbar spinal level in the mouse seem to be mediated not only through alpha- and beta-adrenergic pathways but also through opiate system.

The effect of microinjection of amino acids into the nucleus tractus solitarius on the diving bradycardia in the rat.

The role of nucleus tractus solitarius (NTS) in the diving bradycardia was studied in anesthetized rats. The floor of the 4th ventricle of the medulla was exposed and 0.1 microliters of the test agent was injected into NTS bilaterally. The simulated diving (head immersion) for 30 sec was performed before and after the injection. Blood pressure and heart rate were monitored. Before the treatment, heart rate decreased by 51% and blood pressure rose by 23% during the diving in the pooled data (n = 35). Injection of glutamate (0.1-1 mM) or CaCl2 (100 mM) into NTS attenuated the diving bradycardia, but that of GABA (0.1 mM), glycine (0.1 mM), KCl (100 mM) or saline solution did not affect the diving bradycardia significantly. Lesions of NTS also attenuated the diving bradycardia. These data suggest that NTS may play a role in modulation of the diving response.

Cardiovascular responses of rats to electrical stimulation of the fastigial nucleus and local microinjection of amino acids.

The cardiovascular response to electrical stimulation of the fastigial nucleus (FN) and microinjection of L-glutamate, kainic acid, glycine and GABA into the FN of anesthetized rats were studied. Electrical stimulation of FN produced pressor or depressor responses with a decrease or no change in heart rate depending upon the intensity or site of the stimulation. Microinjection of L-glutamate or kainic acid into the FN elicited pressor or depressor response with bradycardia, while that of glycine or GABA did not affect blood pressure or heart rate. L-glutamate or kainic acid microinjected into the FN did not affect epinephrine-induced pressor response, but attenuated the bradycardic response. These results indicate that L-glutamate in the FN may play a role in modulation of the cardiovascular regulation.

Effects of cerebral and myocardial ischemia on diving bradycardia in rats.

The simulated diving in awake rats was performed before, during and after cerebral or myocardial ischemia. Diving bradycardia was attenuated at 1 hr and 3 days, but recovered 7 days after cerebral ischemia. EEG became flat promptly after cerebral ischemia and maintained low amplitude at 1 day, but recovered at 7 days. Diving bradycardia did not change at 1 hr, but was attenuated at 3 and 7 days after myocardial ischemia. A combination of cerebral and myocardial ischemia attenuated diving bradycardia through 1 hr, 3 days and 7 days. The results indicate that either cerebral or myocardial ischemia attenuated diving bradycardia.

Age-dependent changes in the oxygen consumption of the cerebral cortex, hypothalamus, hippocampus, and amygdaloid in rats.

The oxygen consumption of the cerebral cortex, hypothalamus, hippocampus, and amygdala, of both sexes, ranging in age from 21-805 days for male rats and from 21-780 days for the estrus and diestrus female rats, was measured. The oxidative activity of the hypothalamus, hippocampus, and amygdala decreased rapidly from Day 21 until the 4th mo. and stabilized till the 27th mo. in the hippocampus and amygdala and gradually decreased from the 12th mo. to the 27th mo. in the hypothalamus. The cerebral cortex showed a different pattern which kept a constant level from day 21 to 12 mo. of age. There was no statistically significant change in any of the regions at the time of vaginal opening. Low oxidative activity of the hypothalamus and amygdala in old age was still observed in castrated/hypophysectomized male rats compared with young ones. Therefore, the decreased oxygen consumption in old age seems to be due primarily to changes in the brain tissue itself and not due secondarily to changes in the gonadotropin and sex hormone levels. Female rats had higher oxygen consumption values than males in the cerebral cortex, the hypothalamus, and the hippocampus. In the amygdala the males had a higher consumption. Estrus female rats showed significantly higher oxygen consumption than diestrus females only in the hypothalamus.

Effect of verapamil on experimental arrhythmias.

Verapamil 0.25-1.0 mg/kg i.v. did not significantly elevate the ventricular fibrillation threshold in dogs. It did not antagonize the deslanoside arrhythmias, but inhibited transiently the arrhythmias induced by either electrical stimulation of the posterior hypothalamus or bilateral carotid occlusion in cats. Effect of verapamil on the aconitine-induced rapid firing of the isolated atria and ventricles of the young rabbit and chick embryos was also studied with the microelectrode technique. In doses of 5, 10 and 20 microng/ml, it suppressed the rapid firing of the cardiac preparations, with exception of the ventricles of the rabbit. Antiarrhythmic action of verapamil in such high concentration seems to be due to non-specific inhibitions of Na+ channels of the myocardial cells.