Cardiovascular effects of cocaine in anesthetized and conscious rats

This study examined the cardiovascular and respiratory effects of cocaine and procaine in anesthetized and conscious rats. Intravenous cocaine (0.16-5 mg/Kg) elicited a rapid, dose dependent increase in mean arterial pressure of relatively short duration. In pentobarbital anesthetized (65 mg/Kg, i.p.) animals, the pressor phase was generally followed by a more prolonged depressor phase. These effects on arterial pressure were generally accompanied by a significant tachypnea and at larger doses (2.5 and 5 mg/Kg, i.v.), bradycardia. Procaine (0.31 and 1.25 mg/Kg, i.v.) produced similar cardiovascular and respiratory effects (depressor phase, tachypnea) in pentobarbital anesthetized animals. In conscious-restrained animals, both cocaine and procaine (1.25 mg/kg, i.v.) produced pressor responses. The subsequent depressor response was, however, absent in both cases. The cardiovascular effects of cocaine (0.25-1 mg/Kg, i.v.) in urethane anesthetized (1.25 g/Kg, i.p.) animals were essentially similar to those observed in conscious animals. Procaine (1mg/Kg) did not produce any significant cardiovascular effects in urethane anesthetized animals, but did elicit tachypnea. Reserpine pretreatment (10 mg/Kg, i.p.) did not significantly attenuate the pressor response in urethane anesthetized animals. Phentolamine pretreatment (3 mg/Kg, i.v.) did significantly antagonize the pressor effect in urethane anesthetized animals. These results suggest that: the depressor phase is likely due to a interaction between local anesthetic activity (cocaine and procaine) and barbiturate anesthesia, the cardiovascular effects of cocaine in conscious animals are more similar to those observed in urethane anesthetized rats than in pentobarbital anesthetized rats and the pressor effect in urethane anesthetized rats is apparently due to a reserpine resistant catecholaminergic mechanism.     

Cardiovascular responses to intrathecal administration of endomorphins in anesthetized rats

Endomorphins (EMs), the endogenous, potent and selective mu-opioid receptor agonists, have been shown to decrease systemic arterial pressure (SAP) in rats after intravenous (i.v.) administration. In the present study, cardiovascular responses to intrathecal (i.t.) injection of EMs were investigated in urethane-anesthetized rats. It is noteworthy that EMs elicited decreases in SAP and heart rate (HR) in a dose-dependent manner; 10-300nmol/kg were injected intrathecally. Furthermore, these vasodepressor and bradycardic effects were significantly antagonized by naloxone (0.5mg/kg, i.t.). Interestingly, i.t. (5mg/kg) or i.v. (50mg/kg) administrations of N(omega)-nitro-l-arginine methylester (l-NAME) attenuated the vasodepressor and bradycardic effects. Moreover, pretreatment of the rats with muscarinic receptor antagonist atropine (2mg/kg, i.v.) and alpha-adrenoceptor antagonist phentolamine (1mg/kg, i.v.) significantly reduced the vasodepressor effects of EMs. Nevertheless, pretreatment with beta-adrenoceptor antagonist propranolol (2mg/kg, i.v.) could only block the bradycardia effects induced by EMs, but had no significant effects on the hypotension. In summary, all the results suggested that i.t. administration of EMs decreased SAP and HR which were possibly mediated by the activation of opioid receptors in the rat spinal cord. In addition, nitric oxide (NO) release in both the spinal cord and in peripheral tissues might regulate the cardiovascular activities of EMs, and the muscarinic receptor and adrenoceptor played an important role in the regulation of the cardiovascular responses to i.t. administration of EMs.     

Cardiovascular responses to melanocortin 4-receptor stimulation in conscious unrestrained normotensive rats

In the present studies, we used a non-selective melanocortin MC3/4 receptor agonist (HP228) and a novel selective melanocortin MC4 receptor (MC4-R) agonist (MK-cpd1) to study the cardiovascular, temperature, locomotor and feeding responses to melanocortin receptor stimulation in comparison to sibutramine in rats instrumented with a telemetry transmitter. Moreover, norepinephrine turnover rates in heart and brown adipose tissue were determined. HP228 (1, 3 and 10mg/kg, i.p.) reduced 24h food intake dose-dependently and increased heart rate and mean arterial pressure (maximal differences: +60+/-8beats/min and +8+/-1mmHg, means+/-S.E.M., p<0.001 and p<0.01, respectively). After 10mg/kg HP228 showed a three-fold increase in norepinephrine turnover in the heart. The selective MC4-R agonist MK-cpd1 tended to decrease 24h food intake only at the highest dose tested (10mg/kg, i.p., p=0.06) and increased both heart rate (+17+/-4 and +22+/-5beats/min at 3 and 10mg/kg, p<0.01) and mean arterial pressure (+4+/-1mmHg at 10mg/kg, p<0.05). Sibutramine reduced food intake at all doses tested (1, 3 and 10mg/kg, i.p.). It did not change mean arterial pressure significantly, and increased heart rate only at the highest dose tested (+36+/-6beats/min, p<0.05). If also observed in humans, the pharmacological profile of MC4-R agonists would not offer a significant therapeutic advantage over currently used appetite suppressants such as sibutramine.     

Cardiovascular responses to oxygen inhalation after hemorrhage in anesthetized rats: hyperoxic vasoconstriction

Oxygen inhalation is recommended for the initial care of trauma victims. The improved survival seen in early hemorrhage is normally associated with an increase in blood pressure. Although clinical use of oxygen can occur late after hemorrhage, the effects of late administration have not been specifically examined. Anesthetized rats were studied using an isobaric hemorrhage model with target pressures of either 70 or 40 mmHg. At various times after hemorrhage, the feedback control of the blood pressure was stopped and the inspired gas was changed from room air to 100% oxygen. The results show that shortly after hemorrhage to 70 mmHg, oxygen inhalation results in an increase in mean arterial blood pressure of 60 +/- 3 mmHg, which is associated with a large increase in total peripheral resistance from 0.89 +/- 0.05 to 1.25 +/- 0.1 peripheral resistance units. The blood pressure response is essentially unchanged with time, and it is not altered by a 10-min exposure to N(G)-nitro-l-arginine methyl ester. At a target pressure of 40 mmHg, the initial blood pressure response to oxygen is the same, but it gradually decreases as the animal develops a lactic acidosis. We conclude that the therapeutic value of oxygen needs to be separately evaluated for late hemorrhage.     

Cardiovascular responses to substance P in the nucleus tractus solitarii: microinjection study in conscious rats

The cardiovascular effects of substance P (SP) microinjections in the nucleus tractus solitarii (NTS) were evaluated in conscious rats. We chose this model because it is an effective way to access some of the cardiovascular effects of neurotransmitters in the NTS without the inconvenience of blunting pathways with anesthetic agents or removing forebrain projections by decerebration. The cardiovascular responses to SP injections were also evaluated after chronic nodose ganglionectomy. We found that, in conscious rats, SP microinjections into the NTS induced hypertension and tachycardia. Unilateral and bilateral SP injections into the NTS caused a slow increase in blood pressure and heart rate that peaked 1.5-5 min after injection and lasted for 20-30 min. Nodose ganglionectomy increased the duration of the pressor and tachycardic effects of SP and enhanced the pressor response. These data show that SP in the NTS is involved in pressor pathways. The supersensitivity to SP seen after nodose ganglionectomy suggests that vagal afferent projections are involved in those pressor pathways activated by SP in the NTS.     

Cardiovascular responses to an isosterically modified prostaglandin analog in conscious dogs

The cardiovascular effects of oral and intravenous administration of 0.05 and 0.1 mg/kg of the isosterically modified prostaglandin (PG) analog, (+)- 4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-thiazolidinyl] propyl) benzoic acid were ascertained in conscious mongrels. After 0.05 mg/kg p.o., mean arterial pressure (MAP), obtained from indwelling catheters, fell from 105 +/- 1 to 100 +/- 4 mm Hg and total peripheral resistance (TPR) decreased from 0.062 +/- 0.006 to 0.039 +/- 0.002 mm Hg/ml/min. Cardiac output (CO), measured via electromagnetic flow probes, rose from 1.8 +/- 0.2 to 2.6 +/- 0.1 l/min and heart rate from 109 +/- 13 to 128 +/- 8 beats/min. The 0.1 mg/kg p.o. dose produced similar results. Intravenous injection of 0.1 mg/kg immediately dropped MAP from 103 +/- 6 to 58 +/- 3 mm Hg and TPR from 0.049 +/- .006 to .014 +/- .002 mm Hg/ml/min. CO climbed from 2.3 +/- 0.2 to 5.3 +/- 0.5 l/min and HR increased from 126 +/- 9 to 254 +/- 14 beats/min. Stroke volume was not affected by either oral or intravenous administration of the PG analog. Pretreatment with 100 micrograms/kg timolol blunted the CO and HR responses to 0.1 mg/kg iv of the PG analog without affecting the depressor response. Metaraminol infused during injection of 0.1 mg/kg iv of the PG analog diminished all responses. When compared to the cardiovascular effects of hydralazine and nitroprusside, the profile of the PG analog activity closely resembled that produced by the arterial vasodilator, hydralazine; in contrast, nitroprusside (which also dilates veins) reduced stroke volume, but did not significantly affect HR. In conclusion, dilation of the resistance vessels by the PG analog decreased MAP and TPR and reflexly elevated CO and HR in conscious dogs.     

Cardiovascular responses to an isosterically modified prostaglandin analog in conscious dogs

The cardiovascular effects of oral and intravenous administration of 0.05 and 0.1 mg/kg of the isosterically modified prostaglandin (PG) analog, (+)-4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-thiazolidinyl]propy} benzoic acid were ascertained in conscious mongrels. After 0.05 mg/kg p.o., mean arterial pressure (MAP), obtained from indwelling catheters, fell from 105 ± 1 to 100 ± 4 mm Hg and total peripheral resistance (TPR) decreased from 0.062 ± 0.006 to 0.039 ± 0.002 mm Hg/ml/min. Cardiac output (CO), measured via electromagnetic flow probes, rose from 1.8 ± 0.2 to 2.6 ± 0.1 l/ml and heart rate from 109 ± 13 to 128 ± 8 beats/min. The 0.1 mg/kg p.o. dose produced similar results. Intravenous injection of 0.1 mg/kg immediately dropped MAP from 103 ± 6 to 58 ± 3 mm Hg and TRP from 0.049 ± .006 to .014 ± .002 mm Hg/ml/min. CO climbed from 2.3 ± 0.2 to 0.2 to 5.3 ± 0.5 l/ml and HR increased from 126 ± 9 to 254 ± 14 beats/min. Stroke volume was not affected by either oral or intravenous administration of the PG analog. Pretreatment with 100 μg/kg timolol blunted the CO and HR responses to 0.1 mg/kg iv of the PG analog without affecting the depressor response. Metaramidol infused during injection of 0.1 mg/kg iv of the PG analog diminished all responses. When compared to the cardiovascular effects of hydralazine and nitroprusside, the profile of the PG analog activity closely resembled that produced by the arterial vasodilator, hydralazine; in contrast, nitroprusside (which also dilates veins) reduced stroke volume, but did not significantly affect HR. In conclusion, dilation of the resistance vessels by the PG analog decreased MAP and TPR and reflexly elevated CO and HR in conscious dogs.     

EOG responses in anesthetized freely breathing rats

In mammals, access of odor molecules to the olfactory receptor neurons is controlled by respiratory activity. Thus, anesthetized, freely breathing rats were used to record from the olfactory mucosa in the intact nasal cavity (electroolfactogram or EOG) so as to study global response characteristics to odor stimuli. During alternation of the inspiratory phases of odor sampling and expiratory phases, the response was a succession of individual EOG events synchronized with respiration. These were characterized by a steep decrease that started approximately 100-150 ms after the beginning of inhalation, reached its maximum at the transition between inspiration and expiration and was followed by a slower rise until the next inhalation. They were greater during the first respiratory cycles following odor stimulation onset. Thereafter their amplitudes decreased throughout odor delivery, but a significant EOG signal was still present at the end of short (10 s) and long (60 s) odor presentations. Amplitude increased with odor concentration, but much less than expected from concentration changes. Lastly, for some odors EOG responses persisted well beyond the end of stimulation. These results are in agreement with the respiratory synchronization of mitral cell activities observed during short odor presentations and long duration odor exposures. They underline again the importance of taking into account the respiratory activity in studies on the functioning of the olfactory system.     

Cardiovascular actions of central neuropeptide W in conscious rats

Neuropeptide W (NPW) is a novel hypothalamic peptide that activates the orphan G protein-coupled receptors, GPR7 and GPR8. Two endogenous molecular forms of NPW that consist of 23- and 30-amino acid residues were identified. Intracerebroventricular (i.c.v.) administration of NPW is known to suppress spontaneous-feeding at dark-phase and fasting-induced food intake and to decrease body weight and plasma growth hormone and to increase prolactin and corticosterone; however, little is known about its effect on other physiological functions. We examined the effects of i.c.v. administration of NPW30 (0.3 and 3 nmol) on the mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine and epinephrine in conscious rats. NPW30 (3 nmol) provoked increases in MAP (85.12+/-3.16 to 106.26+/-2.66 mm Hg) and HR (305.75+/-13.76 to 428.45+/-26.82 beats/min) and plasma norepinephrine (138.1+/-18.1 to 297.2+/-25.9 pg/ml) and epinephrine (194.6+/-21.4 to 274.6+/-22.7 pg/ml). Intravenously administered NPW30 (3 nmol) had no significant effects on MAP and HR. These results indicate that central NPW30 increases sympathetic nervous outflow and affects cardiovascular function.     

Pressor and tachycardic responses to intravenous substance P in anesthetized rats

Intravenous injection of 3–33 nmol/kg of substance P (SP) caused pressor and tachycardic responses in anesthetized rats. The responses were not blocked by a ganglion nicotinic receptor antagonist or by pithing. Pretreatment with reserpine blocked both responses. β-Adrenoceptor blockade attenuated only the tachycardic response, and -adrenoceptor blockade attenuated only the pressor response. These findings indicated that the effects of SP to increase blood pressure and heart rate are due to sympathetic ganglion stimulation. Studies with adrenalectomized rats showed that stimulation of the adrenals by SP contributes to both responses but makes a greater contribution to the tachycardic response. These observations raise the possibility that the tachykinin innervation of sympathetic ganglia and the adrenal medulla may be involved in the local regulation of blood pressure and heart rate.     

Cardiovascular actions of central neuromedin U in conscious rats

Neuromedin U (NMU) is a brain-gut peptide, which peripherally stimulates smooth muscle, increases of blood pressure, alters ion transport in the gut, controls local blood flow, and regulates adrenocortical function. Although intracerebroventricular (i.c.v.) administration of NMU is known to decrease food intake and body weight, little is known about its effect on other physiological functions. We examined the effects of i.c.v. administration of NMU on mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine in conscious rats. Neuromedin U (0.05 and 0.5 nmol) provoked an increase in MAP (93.8 +/- 0.5 to 123.5 +/- 1.7 and 94.7 +/- 0.8 to 132.7 +/- 3.0 mm Hg, respectively) and HR (334.9 +/- 6.0 to 494.1 +/- 6.9 and 346.3 +/- 3.3 to 475.1 +/- 8.9 beats/min, respectively). In contrast, plasma norepinephrine increased only with a high dose of neuromedin U. Intravenously administered NMU (0.5 nmol) elicited a small and short lasting increase in MAP, compared to that by i.c.v. NMU. These results indicate that central neuromedin U regulates sympathetic nervous system activity and affects cardiovascular function.     

Cardiovascular and sympathoadrenal responses to stress in swim-trained rats

Chronic exposure to swim stress (i.e., training) is associated with functional adaptations of the cardiovascular system. On the other hand, repeated exposure to tail shock, an emotional stress, often results in deleterious changes in resting blood pressure and myocardial pathology. We hypothesized that the pathological adaptation following chronic exposure to tail shock was associated with a larger acute physiological response compared with swim stress. Therefore, acute responses to swim and shock stress were compared. A second concern of this study examined the extent to which adaptation to swim training influences responses to predictable tail shock stress. The cardiovascular and sympathoadrenal responses to swim stress, using 1% body wt attached to the tail, were compared with predictable tail shock (0.2-0.4 mA intensity, 1-s duration, 1/min) in two groups of Long-Evans male rats. In the first, 11 rats were studied following 5-7 wk of swim training, consisting of daily 1-h sessions of swimming with 2% body wt attached to their tails. They were compared with an age-matched nontrained (NT) group (n = 8). During swimming, the trained animals showed significantly lower heart rate (387 +/- 10 vs. 449 +/- 18 beats/min) and significantly lower lactate (0.9 +/- 0.09 vs. 2.0 +/- 0.24 mmol/l), epinephrine (332 +/- 57 vs. 739 pg/ml), and corticosterone (32 +/- 10 vs. 62 +/- 9 micrograms/dl) responses. Systolic and diastolic blood pressures were elevated in swim stress by the same degree in trained (167/110 mmHg) and NT (177/116 mmHg) rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular responses to hypoxia and hypercapnia in barodenervated rats

Experiments were performed to examine the role of the arterial baroreceptors in the cardiovascular responses to acute hypoxia and hypercapnia in conscious rats chronically instrumented to monitor systemic hemodynamics. One group of rats remained intact, whereas a second group was barodenervated. Both groups of rats retained arterial chemoreceptive function as demonstrated by augmented ventilation in response to hypoxia. The cardiovascular effects to varying inspired levels of O2 and CO2 were examined and compared between intact and barodenervated rats. No differences between groups were noted in response to mild hypercapnia (5% CO2); however, the bradycardia and reduction in cardiac output observed in intact rats breathing 10% CO2 were eliminated by barodenervation. In addition, hypocapnic hypoxia caused a marked fall in blood pressure and total peripheral resistance (TPR) in barodenervated rats compared with controls. Similar differences in TPR were observed between the groups in response to isocapnic and hypercapnic hypoxia as well. It is concluded that the arterial baroreflex is an important component of the overall cardiovascular responses to both hypercapnic and hypoxic stimuli in the conscious rat.