DNA damage and aging on hematopoietic stem cells: Impact of oxidative stress in ApoE-/- mice.

The effects of aging on ROS production and DNA damage were assessed in hematopoietic stem cells (HSCs) from apolipoprotein E-deficient (ApoE-/-) mice (2-, 12- and 24-month-old), a traditional experimental model of atherogenic dyslipidemia. HSCs from aged ApoE-/- mice were associated with increased ROS levels, leading to loss quiescence, DNA damage, apoptosis and telomere shortening. The concurrence of lack of ApoE and aging result in exhaustion and senescence of HSCs accompanied by increased oxidative stress and inflammation. Therefore, our data open avenues to a better understanding of age-related changes and genetic factors, which may synergistically compromise the efficacy of aged HSC recovery and/or transplantation.

Lesions in rostral ventromedial or rostral ventrolateral medulla block neurogenic hypertension.

Neurogenic hypertension results from the removal of inhibitory baroreceptor afferent input to vasomotor systems in the central nervous system. We sought to determine whether the bilateral destruction of neurons in the rostral ventrolateral or rostral ventromedial medulla, made using microinjections of N-methyl-D-aspartic acid (30 nmol in 200 nL), would block the acute increase in arterial pressure after sinoaortic deafferentation in pentobarbital-anesthetized rats. Bilateral lesions of the rostral ventrolateral or rostral ventromedial medulla decreased mean arterial pressure (107 +/- 4 to 78 +/- 5 and 115 +/- 3 to 94 +/- 3 mm Hg, respectively). In rostral ventrolateral or rostral ventromedial medulla lesioned rats, sinoaortic deafferentation failed to increase arterial pressure. Sham lesions or lesions placed rostral to the rostral ventrolateral or rostral ventromedial medulla did not significantly lower arterial pressure. Subsequent sinoaortic deafferentation significantly increased mean arterial pressure (109 +/- 3 to 145 +/- 4 and 109 +/- 5 to 141 +/- 3 mm Hg, respectively). In eight rats we used an infusion of angiotensin II to return arterial pressure to control levels after lesion of the rostral ventrolateral (n = 4) or rostral ventromedial (n = 4) medulla. In these animals, sinoaortic deafferentation failed to increase arterial pressure. We conclude that neurons in the rostral ventrolateral and rostral ventromedial medulla are involved in the normal maintenance of arterial pressure and the development of hypertension after sinoaortic deafferentation in pentobarbital-anesthetized rats.

Role of periaqueductal gray matter in hypertension in spontaneously hypertensive rats.

We performed experiments to study the effects of electrolytic lesions of periaqueductal gray matter on mean blood pressure, heart rate, and cardiac baroreflex in adult male spontaneously hypertensive rats. Cardiac baroreflex was assessed by the administration of randomly assigned doses of phenylephrine (0.3 to 5.0 micrograms/kg i.v.) or sodium nitroprusside (1.5 to 5.0 micrograms/kg i.v.) to unanesthetized rats. Bilateral lesions of the periaqueductal gray matter (0.5 mA/5 s) were then performed with rats under sodium pentobarbital anesthesia (35 mg/kg i.p.). Twenty hours after lesion, cardiac baroreflex was retested. Baroreflex data were analyzed by sigmoidal curve fitting. Lesion rats (n = 12) showed a significant decrease in both the gain (delta = -0.89 +/- 0.38 beats per minute [bpm]/mm Hg, P < .05) and curve midpoint (delta = -15 +/- 6 mm Hg, P < .05) of the cardiac baroreflex. Moreover, despite a moderate increase in heart rate (delta = 34 +/- 10 bpm, P < .01), resting mean blood pressure was significantly decreased 24 hours after the lesions (delta = -19 +/- 5 mm Hg, P < 01). No significant changes in cardiac baroreflex were observed in sham-lesion rats (n = 12). Histological examination showed circumscribed bilateral damage of dorsolateral periaqueductal gray matter. Dorsolateral periaqueductal gray matter is an area of the brain putatively related to fear and anxiety. It also projects onto premotor sympathetic neurons in the medulla. Although electrolytic lesions damage neurons as well as fibers of passage, these data suggest that dorsolateral periaqueductal gray matter has a far greater influence on resting cardiovascular control in spontaneously hypertensive rats than was previously suspected.

Sex hormone modulation of ventricular hypertrophy in sinoaortic denervated rats.

The influence of sex hormones on the development of left ventricular hypertrophy was investigated in baroreceptor-denervated rats. A significant increase (p less than 0.01) in the left ventricular weight/body weight ratio was observed in male but not in female rats 15 days after operation, compared to age- and sex-matched sham-operated rats. This differential hypertrophy occurred despite the development of a significant elevation in arterial blood pressure in both sexes. Castration prior to sinoaortic denervation did not change the level of arterial hypertension but caused a significant reduction (p less than 0.01) in left ventricular weight in male rats and a significant increase (p less than 0.01) in female rats. The pretreatment of male and female sinoaortic denervated and castrated rats with testosterone resulted in ventricular hypertrophy similar to that observed in intact male sinoaortic denervated rats. Pretreatment with estradiol, however, suppressed the left ventricular hypertrophy in intact male rats but did not change the normal ventricular mass observed in intact female sinoaortic denervated rats. These results indicate that the development of left ventricular hypertrophy in sinoaortic denervated rats is modulated by sex hormones, and that testosterone exerts a facilitatory and estradiol an inhibitory action.

Time course of changes in sigmoidal-fitting baroreceptor curves in one-kidney, one clip hypertensive rats.

The present study examined the time course of changes in baroreceptor reflex function by means of sigmoidal curve-fitting analysis in conscious, unrestrained renovascular one-kidney, one clip (1K1C) rats at 1, 3, 7, 15, 30, and 60 days after renal artery clipping. The reflex heart rate responses were elicited by alternate intravenous bolus injections of phenylephrine (change, +5 to +50 mm Hg) and sodium nitroprusside (change, -5 to -50 mmHg). Atropine methylnitrate and atenolol were given to evaluate the responses mediated by the cardiac sympathetic or vagal component, respectively. The average baroreceptor reflex gain (sensitivity) decreased progressively (day 1, 3.35 +/- 0.3 beats per minute [bpm] per millimeter of mercury), reaching a maximal attenuation in the 30-day 1K1C group (1.83 +/- 0.5 bpm/mm Hg) compared with sham rats (approximately 4.60 bpm/mm Hg). The data showed a decreased vagal activity contributing to the attenuation of the baroreceptor gain only in the 30-day 1K1C group. In contrast, the cardiac sympathetic component of the baroreceptor reflex was significantly decreased in all 1K1C groups (from 2.10 +/- 0.4 to 0.50 +/- 0.2 bpm/mm Hg) compared with the respective sham groups (from 3.80 +/- 0.3 to 3.10 +/- 0.4 bpm/mm Hg). These results suggest that a reduced contribution of the sympathetic component to the baroreceptor heart rate reflex may be the main cause of the progressive attenuation of the baroreceptor reflex sensitivity observed in conscious 1K1C hypertensive rats.

Central nervous system and the pathogenesis of hypertension. Sites and mechanisms.

A large body of evidence indicates that the central nervous system plays an essential role in the pathogenesis of hypertension. However, in many cases the specific brain regions involved and the mechanisms by which these regions promote hypertension are not known. In recent years, research in this and other laboratories has attempted to determine the mechanisms by which neural and humoral signals arising in response to pathological conditions (often occurring in the periphery) interact with the central nervous system to produce hypertension. In this article, we illustrate the coupling of peripheral and central factors in the pathogenesis of hypertension by examining the central actions of angiotensin II and mineralocorticoids in the expression of renal hypertension and mineralocorticoid-salt hypertension, respectively. We also review recent data from this laboratory illustrating the involvement of medullary vasomotor centers in the development of neurogenic hypertension after sinoaortic deafferentation and in the maintenance of hypertension in the spontaneously hypertensive rat.

Noninvasive ambulatory 24-hour blood pressure in patients with high normal blood pressure and exaggerated systolic pressure response to exercise.

Few studies have investigated the significance of abnormal increases in systolic pressure during exercise in patients with high normal blood pressure and its correlation with 24-hour ambulatory blood pressure monitoring and left ventricular structure. This study was performed in 30 sedentary subjects (42 +/- 4 years old) with high normal blood pressure. Fifteen subjects presenting < 220 mm Hg systolic pressure during ergometric exercise were compared with 15 others with systolic pressure > or = 220 mm Hg. Average 24-hour (systolic, 127 +/- 5 versus 142 +/- 4 mm Hg, P < .01; diastolic, 82 +/- 4 versus 92 +/- 3 mm Hg, P < .01), daytime (systolic, 130 +/- 6 versus 144 +/- 4 mm Hg, P < .01; diastolic, 84 +/- 4 versus 92 +/- 4 mm Hg, P < .01), and nighttime (systolic, 116 +/- 7 versus 132 +/- 6 mm Hg, P < .01; diastolic, 72 +/- 6 versus 85 +/- 6 mm Hg, P < .01) ambulatory blood pressure monitoring values were significantly higher in subjects with an exaggerated blood pressure response to exercise. No significant differences were observed in left ventricular morphology. These findings indicate that subjects presenting high normal blood pressure and exaggerated systolic pressure during exercise show significantly high ambulatory blood pressure monitoring values that are not associated with left ventricular hypertrophy.

Chronic lesion of rostral ventrolateral medulla in spontaneously hypertensive rats.

We studied the effects of chronic selective neuronal lesion of rostral ventrolateral medulla on mean arterial pressure, heart rate, and neurogenic tone in conscious, unrestrained spontaneously hypertensive rats. The lesions were placed via bilateral microinjections of 30 nmol/200 nl N-methyl-D-aspartic acid. The restimulation of this area with N-methyl-D-aspartic acid 15 days postlesion failed to produce a pressor response. One day postlesion, the resting mean arterial pressure was significantly decreased in lesioned rats when compared with sham rats (100 +/- 7 versus 173 +/- 4 mm Hg, p less than 0.05). Fifteen days later, the lesioned group still showed values significantly lower than the sham group (150 +/- 6 versus 167 +/- 5 mm Hg, p less than 0.05). No significant heart rate differences were observed between the sham and lesioned groups. The ganglionic blocker trimethaphan (5 mg/kg i.v.) caused similar reductions in mean arterial pressure in both lesioned and sham groups. The trimethaphan-induced hypotension was accompanied by a significant bradycardia in lesioned rats (-32 +/- 13 beats per minute) but a tachycardia in sham rats (+33 +/- 12 beats per minute) 1 day postlesion. Therefore, rostral ventrolateral medulla neurons appear to play a significant role in maintaining hypertension in conscious spontaneously hypertensive rats. Spinal or suprabulbar structures could be responsible for the gradual recovery of the hypertension in the lesioned rats.

Identification of cardiovascular neurons in the rostral ventromedial medulla in anesthetized rats.

Recent studies have identified a region in the rostral ventromedial medulla (RVMM) of rats that appears to be involved in cardiovascular function. Since these studies used either microinjection of lidocaine or electrical stimulation, the exact contribution of intrinsic neurons as opposed to fibers of passage could not be determined. The present study was performed to map the location of neurons in RVMM from which changes in mean arterial pressure could be elicited by the microinjection of the excitatory amino acid analogue N-methyl-D-aspartic acid (NMDA) (20 ng/50 nl), which selectively activates cell bodies in barbiturate-anesthetized rats. Microinjection of NMDA into RVMM most often (53%) elicited pressor responses (31 +/- 7 mm Hg). On the basis of these responses, RVMM was determined to encompass a large portion of the nucleus gigantocellularis 0.5-1.5 mm lateral to the midline, 0.5-3.5 mm above the ventral surface, and extending from the rostral to the caudal pole of the facial nucleus. Depressor responses (-21 +/- 3 mm Hg) were found at all levels of RVMM but were most concentrated and of the largest magnitude in the rostral and caudal poles of RVMM. Microinjection of the inhibitory neurotransmitter glycine (500 mM) was used to determine whether neurons in RVMM were contributing to the maintenance of arterial pressure. Microinjection of glycine decreased arterial pressure (-15 +/- 2 mm Hg) throughout most of RVMM. Unexpectedly, increases in mean arterial pressure (24 +/- 3 mm Hg) were elicited by microinjection of glycine into the same region in RVMM in which NMDA most frequently elicited pressor responses.(ABSTRACT TRUNCATED AT 250 WORDS)

L-arginine restores the effect of ouabain on baroreceptor activity and prevents hypertension.

In spontaneously hypertensive rats, ouabain exerts an excitatory effect on baroreceptor nerve activity (BNA). The aim of this study was to determine the effects of ouabain on BNA in other experimental models of hypertension and its interaction with nitric oxide. Rats were made hypertensive using the procedures for N(omega)-nitro-L-arginine methyl ester (L-NAME), deoxycorticosterone acetate (DOCA) salt, and 2-kidney, 1 clip (2K1C) hypertension models. In these groups, systolic arterial pressure was 195+/-7, 149+/-6, and 148+/-4 mm Hg, respectively, compared with 110+/-4 mm Hg in normotensive rats. Acute ouabain administration had an excitatory effect on BNA in normotensive rats (37+/-4%), an inhibitory effect in L-NAME hypertensive rats (-60+/-7%), and no effect in DOCA-salt and 2K1C hypertensive rats. The effects of ouabain were not related to arterial pressure levels, and no excitatory effect on BNA was observed in prehypertensive DOCA-salt rats. Long-term administration of L-arginine (3 g x kg(-1) x day(-1)) prevented DOCA-salt (121+/-8 mm Hg) and 2K1C (104+/-4 mm Hg) hypertension, markedly attenuated L-NAME (130+/-9 mm Hg) hypertension, and restored the excitatory effect of ouabain on BNA in these groups to levels similar to the normotensive rats and their respective control groups. We conclude that ouabain has a diverse effect on BNA in experimental models of hypertension, and it can be normalized by L-arginine. The data also indicate that nitric oxide may play a pivotal role in mediating the excitatory effect of ouabain on BNA, and we speculate that a therapeutic combination of ouabain and L-arginine may be beneficial in secondary hypertension.

Adenovirus-mediated gene delivery to hypothalamic magnocellular neurons in mice.

Vasopressin is synthesized by magnocellular neurons in supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei and released by their axon terminals in the neurohypophysis (NH). With its actions as an antidiuretic hormone and vasoactive agent, vasopressin plays a pivotal role in the control of body fluids and cardiovascular homeostasis. Because of its well-defined neurobiology and functional importance, the SON/PVN-NH system is ideal to establish methods for gene transfer of genetic material into specific pathways in the mouse central nervous system. In these studies, we compared the efficiency of transferring the gene lacZ, encoding for beta-galactosidase (beta-gal), versus a gene encoding for green fluorescent protein by using replication-deficient adenovirus (Ad) vectors in adult mice. Transfection with viral concentrations up to 2 x 10(7) plaque-forming units per coverslip of NH, PVN, and SON in dissociated, cultured cells caused efficient transfection without cytotoxicity. However, over an extended period of time, higher levels (50% to 75% of the cells) of beta-gal expression were detected in comparison with green fluorescent protein (5% to 50% of the cells). With the use of a stereotaxic approach, the pituitary glands of mice were injected with Ad (4 x 10(6) plaque-forming units). In material from these animals, we were able to visualize the expression of the beta-gal gene in the NH and in magnocellular neurons of both the PVN and SON. The results of these experiments indicate that Ad-Rous sarcoma virus promoter-beta-gal is taken up by nerve terminals at the injection site (NH) and retrogradely transported to the soma of the neurons projecting to the NH. We conclude that the application of these experimental approaches will provide powerful tools for physiological studies and potential approaches to deliver therapeutic genes to treat diseases.

Effects of chlorthalidone on ventricular hypertrophy in deoxycorticosterone acetate-salt hypertensive rats.

Diuretics have been the mainstay of long-term treatment of hypertension, but there is no evidence suggesting that diuretics may be effective in reducing cardiac hypertrophy associated with hypertension. Thus, the present study was carried out to elucidate if long-term treatment with chlorthalidone (8 mg per animal per day added to food) affects the development of and reverses the ventricular hypertrophy in deoxycorticosterone acetate (DOCA) (8 mg/kg SC twice a week)-salt hypertensive rats. Chlorthalidone was given to one group during all 20 days of DOCA administration (preventive regimen) and to another group 20 days after DOCA treatment was initiated until the 40th day (therapeutic regimen). Chlorthalidone was found to reduce or prevent the development of ventricular hypertrophy, as assessed by a reduction in ventricular mass and cardiac protein as well as arterial hypertension. Both chlorthalidone regimens prevented the increase or induced a significant decrease in the plasma concentration of sodium and in cardiac sympathetic tone, which were both increased in DOCA-salt-treated rats. These data provide evidence that long-term chlorthalidone treatment is effective in preventing or reducing ventricular hypertrophy along with arterial hypertension. However, whether this is due to a reduction in plasma sodium or other additional mechanisms, such as a reduction in cardiac sympathetic tone, remains to be determined.

Heated humidification or face mask to prevent upper airway dryness during continuous positive airway pressure therapy.

STUDY OBJECTIVES: The objectives of this study were (1) to evaluate the way in which nasal continuous positive airway pressure (CPAP) therapy influences the relative humidity (rH) of inspired air; and (2) to assess the impact on rH of the addition of an integrated heated humidifier or a full face mask to the CPAP circuitry. DESIGN: The studies were performed in 25 patients with obstructive sleep apnea syndrome receiving long-term nasal CPAP therapy and complaining of nasal discomfort. During CPAP administration, temperature and rH were measured in the mask either during a night's sleep for 8 patients or during a daytime study in which the effects of mouth leaks were simulated in 17 patients fitted with either a nasal mask (with or without humidification) or a face mask alone. SETTING: University hospital sleep disorders center. MEASUREMENTS AND RESULTS: Compared with the values obtained with CPAP alone, integrated heated humidification significantly increased rH during the sleep recording, both when the mouth was closed (60 +/- 14% to 81 +/- 14%, p < 0.01) and during mouth leaks (43 +/- 12% to 64 +/- 8%, p < 0.01). During the daytime study, a significant decrease in rH was observed with CPAP alone. Compared with the values measured during spontaneous breathing without CPAP (80 +/- 2%), the mean rH was 63 +/- 9% (p < 0.01) with the mouth closed and 39 +/- 9% (p < 0. 01) with the mouth open. The addition of heated humidification to CPAP prevented rH changes when the mouth was closed (82 +/- 12%), but did not fully prevent the rH decrease during simulation of mouth leaks (63 +/- 9%) compared with the control period (80 +/- 2%, p < 0. 01). Finally, attachment of a face mask to the CPAP circuitry prevented rH changes both with the mouth closed (82 +/- 9%) and with the mouth open (84 +/- 8%). CONCLUSIONS: These data indicate that inhaled air dryness during CPAP therapy can be significantly attenuated by heated humidification, even during mouth leaks, and can be totally prevented by using a face mask.

Time course of cardiac sympathetic and vagal tone changes in renovascular hypertensive rats.

The present study has examined the time course of autonomic tone changes in two-kidney, one-clip (2K1C) and one-kidney, one-clip (1K1C) renal hypertension. In conscious rats, cardiac sympathetic and vagal tone were determined using propranolol and atropine, respectively. The development of renovascular hypertension was accompanied by a significant tachycardia, increase in cardiac sympathetic tone and decrease in cardiac vagal tone. In the isolated perfused heart we observed a reduced chronotropic response to isoproterenol. These alterations were transitory in 2K1C and greater and more persistent in 1K1C renal hypertension. These results show the relative role played by the cardiac sympathetic and vagal systems in the maintenance of tachycardia in renovascular hypertension.

Evidence that the autonomic nervous system plays a major role in the L-NAME-induced hypertension in conscious rats.

The present study was designed to investigate the role of the autonomic nervous system in experimental hypertension induced by chronic administration of N-nitro-L-arginine methyl ester (L-NAME) in the drinking water (1 mg/mL) over 6 days. L-NAME ingestion caused a large rise in resting mean arterial pressure (MAP) (175 +/- 5 mm Hg) and heart rate (HR) (440 +/- 17 beats per minute) compared to nontreated control rats (resting MAP: 112 +/- 2 mm Hg and HR: 345 +/- 8 beats per minute). Ganglionic blockade induced by trimethaphan (5 mg/kg, intravenously) caused a significantly (P < .01) greater decrease in MAP (delta -86 +/- 7 mm Hg) compared to control rats MAP (delta -44 +/- 4 mm Hg). This strongly suggests that the level of central sympathetic tone in L-NAME-treated rats is much greater than in nontreated rats. Using atenolol and atropine alone and combined, the level of resting sympathetic drive to the heart was found to be significantly increased in L-NAME-treated rats compared to control rats. However, vagal tone to the heart was found to be virtually abolished in L-NAME-treated rats compared to control rats. These results indicate that an increase in central sympathetic drive plays an important role in the hypertension induced by chronic inhibition of nitric oxide synthesis with L-NAME.

Inhibition of nitric oxide synthase causes profound enhancement of the Bezold-Jarisch reflex.

The Bezold-Jarisch reflex function was evaluated in rats made hypertensive by the chronic oral intake of a nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, averaging 35 mg/kg/day), for 3, 6, and 12 days (n = 9/group) and in untreated control rats (CR, n = 9/group). L-NAME-treated rats showed a marked hypertension (MAP: 148 +/- 3, 182 +/- 4, and 179 +/- 4 mm Hg, respectively) compared with CR (110 +/- 2 mm Hg). The 6- and 12-day groups showed tachycardia (447 +/- 20 and 466 +/- 13 beats/min, respectively) when compared with CR (355 +/- 10 beats/min). When compared with CR, left ventricular hypertrophy was observed in rats treated with L-NAME for 6 and 12 days. The Bezold-Jarisch reflex, a decrease in heart rate (HR) accompanied by a decrease in diastolic arterial pressure (DAP), was evoked in a dose dependent manner by the intravenous injection of 5-hydroxytryptamine (5-HT, 5 to 10 microg/kg). Relative to responses observed in CR, 5-HT at 10 microg/kg caused a four- to fivefold greater decrease in HR and a two- to threefold greater decrease in DAP in all the L-NAME treatment groups. Using a Langendorff technique, we observed a significant increase in the responsiveness of the pacemaker to acetylcholine (1.25 to 80 microg/mL). These data suggest that the pharmacological inhibition of the nitric oxide synthase causes profound changes in the mechanisms of cardiovascular regulation as shown by a marked enhancement of the Bezold-Jarisch reflex in L-NAME-treated rats. The enhancement of this reflex seems to be in great part due to the hyperresponsiveness of the cardiac pacemaker to cholinergic stimulation.

Deficits of spatial learning and working memory in spontaneously hypertensive rats.

It is possible that behavioral dysfunction, including cognitive, perceptual and psychomotor impairments in hypertensive subjects, can be the result of the high blood pressure. The aim of this study was to evaluate the performance of the spontaneously hypertensive rats (SHR) in the acquisition and execution of tasks in an 8-arm radial maze. Male Wistar normotensive rats (CON, n = 11) and SHR (n = 12), 3 months old, were first submitted to a series of training sessions to enter each of the 8 arms once in a given session (task acquisition), and errors (revisiting an arm in the same session) were computed. Errors before and after two delay intervals (5 s and 1 h, introduced between the fourth and fifth arm choice) were measured. These delayed tests allowed us to evaluate the working memory in different terms. It was observed that the SHR group made slightly more errors during the acquisition sessions and in the execution of the post-delay of 5-s interval tests, and significantly in the execution of the post-delay of 1-h interval tests compared to the CON. These results show that the SHR has a deficiency in the performance of the radial maze, suggestive of impairment of learning and working memory, mainly for a long-term memory, corroborating the hypothesis about the possible behavioral consequences of hypertension.

Cardiac baroreflex dynamics during the defence reaction in freely moving rats.

To determine the extent of baroreceptor reflex involvement in the cardiovascular changes observed during electrically induced defence reaction, the mean arterial blood pressure (MBP) and heart rate (HR) of conscious intact or sinoaortic baroreceptor denervated (SAD) rats were continuously recorded from indwelling cannulae during a 1-min period of electrical stimulation of the mesencephalic tectum. Electrical stimulation produced stimulus intensity-dependent behaviours including freezing at lower intensities and flight at higher intensities. The cardiovascular responses in intact rats were dependent on both the intensity and duration of the stimulus. A linear increase in MBP was observed with increasing stimulus intensities. However, while a slight bradycardia was observed during the freezing behaviour, a marked tachycardia occurred during flight. Simultaneous increases of MBP and HR were seen throughout the first 15 s of the flight response, after which the HR rapidly fell to baseline levels, whereas the MBP remained at a hypertensive plateau until the end of the stimulus. The baroreflex HR curve showed a parallel shift to the left during the first half of the freezing period, being fully reset 40 s after that. So, while the baroreflex gain remained unchanged, the reflex set point was lowered during the freezing stage of the defence reaction. The experiments with SAD rats corroborated the above data. The baroreceptor denervation reversed the freezing bradycardia to tachycardia. Moreover, the denervation potentiated the flight tachycardia and prevented its later reset. MBP responses of baroreceptor denervated rats did not differ from the sham-operated group. The sustained hypertension, thus, appears to be mediated by mechanisms other than the mere baroreceptor reflex deactivation. (ABSTRACT TRUNCATED AT 250 WORDS)

Effects of verapamil on blood pressure and heart rate in neurogenic hypertensive rats.

The effects of verapamil (220 micrograms/kg per min i.v.) on blood pressure and heart rate were studied in sinoaortic baroreceptor denervated and sham-operated rats. In the conscious animals the verapamil-induced hypotension was accompanied by a significant heart rate increase in the first group (from 352 +/- 7 to 422 +/- 10 beats/min) and a decrease in the second group (from 485 +/- 13 to 400 +/- 9 beats/min). The verapamil-induced tachycardia observed in sham-operated rats was prevented by atropine plus propranolol but not by adrenal demedullation. Tachycardia was present in urethane-anesthetized sham-operated rats, similar to the sinoaortic baroreceptor-denervated rats. After verapamil a significant heart rate reduction was observed in sham-operated but not in sinoaortic baroreceptor-denervated rats. The results in conscious rats suggest that the direct inhibitory action of this drug on sinus node automaticity is suppressed by baroreflex tachycardia and that anesthesia masks this response.

Chlordiazepoxide and morphine reduce pressor response to brain stimulation in awake rats.

The effects of intravenous as well as dorsal midbrain injections of morphine and chlordiazepoxide on the blood pressure rise induced by electrical stimulation of the dorsal periaqueductal gray matter (DPAG) were studied in unanesthetized rats. Chlordiazepoxide applied systemically or locally into the DPAG, as well as locally applied but not systemically injected morphine were found to attenuate the centrally-induced hypertension. These data together with others suggest that benzodiazepines as well as local injections of morphine into the DPAG decrease the aversive effect induced by DPAG stimulation.