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Background: Adult hypertension is a well-established risk factor for stroke in young adults (aged <55 years), and the effects are even more deleterious than at an older age. However, data are limited regarding the association between adolescent hypertension and the risk of stroke in young adulthood., Methods: A nationwide, retrospective cohort study of adolescents (aged 16-19 years) who were medically evaluated before compulsory military service in Israel during 1985 to 2013. For each candidate for service, hypertension was designated after constructed screening, and the diagnosis was confirmed through a comprehensive workup process. The primary outcome was ischemic and hemorrhagic stroke incidence as registered at the national stroke registry. Cox proportional-hazards models were used. We conducted sensitivity analyses by excluding people with a diabetes diagnosis at adolescence or a new diabetes diagnosis during the follow-up period, analysis of adolescents with overweight, and adolescents with baseline unimpaired health status., Results: The final sample included 1 900 384 adolescents (58% men; median age, 17.3 years). In total, 1474 (0.08%) incidences of stroke (1236 [84%] ischemic) were recorded, at a median age of 43 (interquartile range, 38-47) years. Of these, 18 (0.35%) occurred among the 5221 people with a history of adolescent hypertension. The latter population had a hazard ratio of 2.4 (95% CI, 1.5-3.9) for incident stroke after adjustment for body mass index and baseline sociodemographic factors. Further adjustment for diabetes status yielded a hazard ratio of 2.1 (1.3-3.5). We found similar results when the outcome was ischemic stroke with a hazard ratio of 2.0 (1.2-3.5). Sensitivity analyses for overall stroke, and ischemic stroke only, yielded consistent findings., Conclusions: Adolescent hypertension is associated with an increased risk of stroke, particularly ischemic stroke, in young adulthood., Competing Interests: Disclosures None.

Background and Purpose: There is a continuous rise in the prevalence of adolescent obesity and incidence of stroke among young adults in many Western countries, but the association between them is unclear., Methods: A nationwide population-based study of 1 900 384 Israeli adolescents (58% men; mean age, 17.3 years) who were evaluated before mandatory military service during 1985 and 2013. Body mass index was classified according to the US Center for Disease Control and Prevention percentiles. Primary outcome was a first stroke event as recorded by the Israeli National Stroke Registry between 2014 and 2018. Cox proportional hazard models were applied., Results: There were 1088 first stroke events (921 ischemic and 167 hemorrhagic; mean diagnosis age, 41.0 years). Adolescent body mass index was significantly associated with a graded increase in the risk for any stroke, ischemic stroke, but less so with hemorrhagic stroke. The hazard ratios for the first ischemic stroke event were 1.4 (95% CI, 1.2–1.6), 2.0 (95% CI, 1.6–2.4), and 3.4 (95% CI, 2.7–4.3) for the 50th to 84th percentile, overweight and obese groups, respectively, after adjustment for sex, age, and sociodemographic confounders with the 5th to 49th body mass index percentile group as the reference. The respective hazard ratios after further adjustment for diabetes status were 1.3 (1.1–1.5), 1.6 (1.3–2.0), and 2.4 (1.9–3.1). Results persisted when the cohort was divided by diabetes status and when ischemic stroke before age 30 was the outcome., Conclusions: High adolescent body mass index was associated with ischemic stroke in young adults with or without diabetes. The rising prevalence of adolescent obesity may increase the future burden of stroke in young adults.

The mechanisms by which sympathetic function is augmented in chronic heart failure (CHF) are not well understood. A previous study from this laboratory (Circ Res. 1998;82:496-502) indicated that blockade of nitric oxide (NO) synthesis resulted in only an increase in renal sympathetic nerve activity (RSNA) when plasma angiotensin II (Ang II) levels were elevated. The present study was undertaken to determine if NO reduces RSNA in rabbits with CHF when Ang II receptors are blocked. Twenty-four New Zealand White rabbits were instrumented with cardiac dimension crystals, a left ventricular pacing lead, and a pacemaker. After pacing at 360 to 380 bpm for approximately 3 weeks, a renal sympathetic nerve electrode and arterial and venous catheters were implanted. Studies were carried out in the conscious state 3 to 7 days after electrode implantation. The effects of a 1-hour infusion of sodium nitroprusside (SNP; 3 microgram . kg-1. min-1) on RSNA and mean arterial pressure (MAP) were determined before and after Ang II blockade with losartan (5 mg/kg) in normal and CHF rabbits. Changes in MAP were readjusted to normal with phenylephrine. Before losartan, SNP evoked a decrease in MAP and an increase in RSNA in both groups that was baroreflex-mediated, because both MAP and RSNA returned to control when phenylephrine was administered. In the normal group, losartan plus SNP caused a reduction in MAP and an increase in RSNA that was 152.6+/-9.8% of control. Phenylephrine returned both MAP and RSNA back to the control levels. However, in the CHF group, losartan plus SNP evoked a smaller change in RSNA for equivalent changes in MAP (117.1+/-4.1% of control). On returning MAP to the control level with phenylephrine, RSNA was reduced to 65.2+/-2.9% of control (P<0. 0001). These data suggest that endogenous Ang II contributes to the sympathoexcitation in the CHF state and that blockade of Ang II receptors plus providing an exogenous source of NO reduces RSNA below the elevated baseline levels. We conclude that both a loss of NO and an increase in Ang II are necessary for sustained increases in sympathetic nerve activity in the CHF state.

Increasing evidence suggests that endogenous NO inhibits sympathetic outflow in anesthetized animals. However, in a recent study from this laboratory, we were unable to find any evidence of increased renal sympathetic nerve activity (RSNA) in response to blockade of NO synthesis in conscious rabbits. Because angiotensin II (Ang II) increases sympathetic outflow, one factor for this discrepancy may be the difference in the resting level of Ang II, which may be lower in well-trained conscious animals. In the present study, the effects of blockade of NO synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg IV) on resting RSNA with and without a background intravenous infusion of Ang II (10 ng.kg(-1).min(-1)) was investigated in conscious rabbits. Intravenous administration of L-NAME (30 mg/kg) caused an increase in mean arterial blood pressure (MAP, from 80.4+/-2.9 to 92.8+/-2.5; P=.0001) and a decrease in RSNA (from 100+/-0% to 53.4+/-8.6%, P=.0016). When the elevated blood pressure was returned to control by infusion of hydralazine (0.01 to 0.06 mg.kg(-1).min(-1)), RSNA returned to the level before L-NAME administration. During a sustained infusion of Ang II (10 ng.kg(-1).min(-1)), L-NAME increased MAP from 89.2+/-2.9 to 109.0+/-4.3 mm Hg (P=.0101) and decreased RSNA from 100.0+/-0% to 53.7+/-7.5% (P=.0013). Under this circumstance, however, when the MAP was returned to the level that existed before the administration of L-NAME, RSNA increased significantly above the level that existed before the administration of L-NAME (164.5+/-17.7% versus 100+/-0%, P=.0151). The enhancement of the sympathetic response by Ang II was completely blocked by the AT1 receptor antagonist, losartan. In contrast, during a background infusion of phenylephrine, which increased MAP to the same level as produced by Ang II, L-NAME had no effect on RSNA when MAP was returned to the control level. Nomega-Nitro-D-arginine methyl ester had no effect on MAP and RSNA. Intravenous infusion of Ang II alone for 75 minutes had no effect on RSNA when MAP was returned to control levels. These data suggest that an elevated level of Ang II is critical for the inhibitory effect of NO on sympathetic outflow in conscious rabbits and imply that these two substances have a major impact on the regulation of sympathetic outflow.

Cardiac and arterial baroreflex control of the circulation is abnormal in both human and experimental heart failure. Ventricular vagal afferents mediate mechanical and chemical reflexes, which result in bradycardia and hypotension. The aim of the present study was to evaluate the changes that occur in ventricular mechanoreflexes and chemoreflexes in a conscious canine model of chronic heart failure. Dogs were instrumented for the measurement of left ventricular pressure, left atrial pressure, arterial pressure, and heart rate. Vascular occluders were placed on the ascending thoracic aorta, on the descending thoracic aorta, and on the thoracic inferior vena cava. A chronic left circumflex coronary artery catheter was also implanted. Finally, a pacing lead was secured to the left ventricular free wall. After recovery from surgery (10 to 14 days), the dogs were subjected to complete arterial baroreceptor denervation. The responses to vascular occlusions and intracoronary administration of prostacyclin (PGI2) were carried out before and after heart failure was induced by chronic cardiac pacing at 250 beats per minute. PGI2 was used as a chemical stimulus for ventricular afferents; ascending aortic occlusion was used as a mechanical stimulus. Before chronic pacing, ascending aortic occlusion resulted in a decrease in heart rate of 36.1 +/- 12.3 beats per minute (mean +/- SD, P < .001). After heart failure was induced, the heart rate response to ascending aortic occlusion was almost completely abolished. The slope of the linear relation between pulse interval and left ventricular end-diastolic pressure was reduced by 90.5% from a control value of 11.3 +/- 6.9 ms/mm Hg after heart failure had been induced.(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously demonstrated a decrease in baroreceptor discharge sensitivity in dogs with experimental heart failure. In the present study, we determined the sensitivity of the carotid sinus baroreceptor reflex in dogs with pacing-induced heart failure. The carotid sinus baroreceptor reflex sensitivity was determined by pressurizing one carotid sinus with all other baroreceptor and cardiopulmonary receptor inputs removed. The data were analyzed by plotting carotid sinus pressure-mean arterial pressure curves and carotid sinus pressure-renal sympathetic nerve activity curves in the two groups of dogs. The peak arterial pressure during carotid hypotension was significantly depressed in dogs with heart failure compared with normal dogs (107.1 +/- 5.7 versus 139.8 +/- 7.0 mm Hg, p less than 0.001). Mean arterial pressure range, renal sympathetic nerve activity range, and peak slope were significantly decreased in the heart-failure group. To determine if this depression was completely due to depression of baroreceptor discharge per se, or to alterations in central or end-organ responsiveness, similar experiments were performed by stimulating the carotid sinus nerve and evaluating frequency, voltage, and duration of stimulation on the resultant mean arterial pressure and renal sympathetic nerve activity. As was the case with carotid sinus pressurization, electrical stimulation caused a significantly smaller change in mean arterial pressure in heart-failure dogs compared with the normal dogs. However, there was no significant difference between normal and heart-failure dogs for the renal sympathetic nerve activity-electrical stimulation curves. These data strongly suggest that the depressed carotid sinus baroreceptor reflex in heart failure is not solely the result of depressed baroreceptor responsiveness but may be related to poor end-organ responses and normal central control of renal sympathetic outflow.

The autonomic components of the baroreflex control of heart rate were evaluated in conscious mongrel dogs before and after 4-6 weeks of ventricular pacing (250 beats/min). Arterial baroreflex sensitivity (BRS) was determined by the slopes of linear regression of pulse interval versus the preceding systolic arterial pressure in response to bolus injections of either phenylephrine or nitroglycerin. BRS was significantly depressed in the heart failure state [nitroglycerin slope, 5.0 +/- 2.7 (mean +/- SD) versus 16.6 +/- 5.1 msec/mm Hg, p less than 0.005; phenylephrine slope, 15.0 +/- 14.8 versus 32.0 +/- 26.7 msec/mm Hg, p less than 0.005]. There was no depression in BRS in dogs that were used as time controls or were acutely paced for 30 minutes. After beta 1-adrenergic blockade with metoprolol, the resting heart rate in the heart failure state was depressed more than in the normal state (-17.0 +/- 5.0% versus -3.2 +/- 3.4%, p less than 0.001). Atropine significantly increased resting heart rate more in the normal state than in the heart failure state (115.8 +/- 36.7% versus 25.4 +/- 14.5%, p less than 0.005). Thus, dogs in the heart failure state appear to have high resting cardiac sympathetic tone and low resting vagal tone. For nitroglycerin administration, metoprolol depressed BRS by 47.6 +/- 26.3% in the normal state and by 63.6 +/- 58.5% in the heart failure state. Atropine decreased the BRS by 86.7 +/- 7.8% in the normal state and by 39.5 +/- 30.2% in the heart failure state.(ABSTRACT TRUNCATED AT 250 WORDS)

To test the hypothesis that in the failing volume-overloaded ventricle, the extracellular matrix and fibrillar collagen in particular are major determinants of the architectural remodeling of the myocardium, this histopathological study of the dilated, postmortem canine left ventricle secondary to rapid ventricular pacing or aortocaval fistula was undertaken. Using the picrosirius-polarization technique to enhance collagen birefringence, we sought to examine the structural integrity of the collagen matrix and interstitium. In the dilated failing ventricle secondary to rapid pacing, we found 1) interstitial edema and a disruption or disappearance of collagen fibers that were apparent within 6 hours of pacing, persisted for weeks, and subsequently were associated with muscle fiber disorganization within the endomyocardium, 2) interstitial fibrosis that was present in the midwall and epimyocardium with chronic pacing, and 3) an early remodeling of intramyocardial coronary arteries that included medial swelling with smooth muscle degeneration followed by proliferative lesions involving fibroblasts and a subsequent perivascular and medial fibrosis. Many of these findings were still evident 48 hours after pacing had been discontinued. In contrast, the collagen matrix and interstitium seen with ventricular dilatation secondary to the circulatory overload that accompanies an aortocaval fistula were indistinguishable from that in sham-operated controls. Thus, we conclude that unlike the chamber enlargement and preserved ventricular function that accompany an aortocaval fistula, ventricular dilatation and failure caused by rapid pacing are based on an architectural remodeling of the myocardium. This structural dilatation involves the extracellular matrix and interstitium and appears to be related to altered permeability of intramyocardial coronary arteries. The mechanism or mechanisms involved in the pathogenesis of myocardial remodeling with rapid ventricular pacing require further investigation.

Single-unit carotid sinus baroreceptor activity was recorded in normal and heart-failure (pacing-induced) dogs. The sensitivity of these units was compared between the two groups of dogs. After development of clinical heart failure, the animals were anesthetized, and the left carotid sinus was vascularly isolated and perfused with oxygenated Krebs-Henseleit solution. Single-unit baroreceptor discharge was recorded from the carotid sinus nerve in response to stepwise increases in carotid sinus pressure (CSP). In addition, the carotid sinus diameter was measured with sonomicrometer crystals. In this way, both CSP-discharge and CSP-diameter curves were constructed for both normal and heart-failure dogs. Analysis of these curves demonstrated that the heart-failure group exhibited a significant decrease in peak discharge (48.1 +/- 3.0 vs. 22.2 +/- 2.2 spikes/sec; p less than 0.001) and a significant elevation in threshold pressure compared with the normal animals (91.0 +/- 5.0 vs. 119.1 +/- 4.4 mm Hg; p less than 0.001). The peak slope of the CSP-discharge curve was also significantly lower in the heart-failure group (0.63 +/- 0.06 vs. 0.40 +/- 0.09 spikes/sec/mm Hg; p less than 0.05). In the heart-failure group, perfusion of the carotid sinus with ouabain (0.01 micrograms/ml) caused a significant decrease in threshold pressure and a significant increase in peak discharge frequency, as well as an increase in slope of the CSP-discharge curve. There were no changes in CSP-diameter relations in response to ouabain. This dose of ouabain had no effect on pressure-discharge relations or carotid sinus diameters in normal dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin I2 (PGI2) is known to stimulate ventricular C fiber receptors resulting in a Bezold-Jarisch-like reflex. Also, cardiac receptor stimulation is known to interact with the expression of arterial baroreflexes. Therefore, experiments were performed to determine the effects of left circumflex coronary artery infusion of PGI2 on the baroreflex control of heart rate in conscious instrumented dogs. Dogs were instrumented chronically with an aortic catheter for the measurement of mean aortic pressure, hydraulic occluder cuffs on the descending aorta and inferior vena cava, a left ventricular catheter for the measurement of left ventricular pressure and heart rate, and a nonocclusive catheter in the left circumflex coronary artery. At the time of experimentation, arterial pressure was altered randomly in steps by partially inflating the occluders. Mean arterial pressure-heart curves (baroreflex curves) were constructed by fitting the data to a logistic curve by nonlinear regression. PGI2 infused into the left circumflex coronary artery at doses of 10, 20, and 50 ng/kg/min caused significant (p less than 0.05) inhibition of the maximum heart rate, heart rate range, and maximum slope of the curve compared to the control baroreflex curve obtained during intracoronary infusion of PGI2 vehicle. PGI2 had no significant effect on the minimum heart rate during hypertension. Since PGI2 is known to stimulate left ventricular receptors, these effects were most likely produced via stimulation of cardiac receptors. In additional experiments using beta 1-blockade with metoprolol or cholinergic blockade with atropine methyl bromide, it was shown that PGI2 attenuates baroreflex-mediated tachycardia by preventing parasympathetic withdrawal completely and by attenuating sympathetic stimulation by approximately 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

We determined the contribution of the dorsal roots, vagi, and sino-aortic nerves to the renal responses to acute isotonic, isooncotic intravascular volume expansion in the nonhuman primate, Macaca fascicularis. Expansion of the estimated blood volume by 15% produced a significant natriuresis and diuresis. There was no significant difference between the time to peak response for either. Neither dorsal rhizotomy (C6-T7) nor vagotomy and sino-aortic denervation had a significant effect on these responses. We conclude that these pathways are not necessary for eliciting the renal responses to hypervolemia in the nonhuman primate.

The role of the central nervous system in the mechanism(s) involved in acute carotid baroreflex resetting was studied in six conscious, chronically instrumented, aortic-denervated dogs. Dogs were prepared for reversible vascular isolation of the carotid sinuses. Acute baroreflex resetting was induced by holding the left carotid sinus pressure (LCcsp) at a given value for 20 minutes using a pulsatile pressure control system while at the same time keeping the right carotid sinus pressure (RCSP) at a subthreshold level (approximately 40 mm Hg). At the end of the 20 minutes, the LCcsp) was reduced to approximately 20 mm Hg, and a baroreflex (RCSP-mean arterial pressure [MAP]) curve was generated on the right carotid sinus using static-step increases in carotid sinus pressure. At the control LCcsp of 100 mm Hg, the RCSP-MAP baroreflex had a threshold pressure (Pth) of 86.6 +/- 3.1 mm Hg and a set point pressure (Psp) of 104.7 +/- 2.5 mm Hg. Increasing LCcsp) to 140 mm Hg for 20 minutes caused these parameters for the right carotid baroreflex to increase. Pth and Psp increased by 18.4 +/- 4.0 and 14.2 +/- 3.0 mm Hg, respectively (p less than 0.05). The baroreflex curve, therefore, was shifted upward and to the right. Decreasing LCcsp to 60 mm Hg caused Pth and Psp to decrease by 24.7 +/- 5.0 and 18.1 +/- 2 mm Hg, respectively (p less than 0.05). The baroreflex curve was therefore shift downward and to the left. The percent of resetting of Pth and Psp was 46 +/- 9% and 36 +/- 8%, respectively, when LCcsp was 140 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

During the last decade the animal rights movement has garnered widespread support that now threatens the existence of animal research. Current public sentiment demands researcher accountability and documentation of the potential value of animal research that was largely assumed in the past. One way this can be accomplished is through prior review and approval of animal research protocols by the federally mandated institutional animal care and use committee (IACUC). IACUCs, however, face more difficulty in arriving at consistent and ethically correct decisions than human subject review committees or institutional review boards (IRBs). This article explains why and draws a comparison between animal and human subjects review.

Cardiovascular and respiratory effects of intra-left atrial or intra-left ventricular injection of serotonin were studied in conscious dogs (n = 8), anesthetized closed-chest dogs (n = 13) and anesthetized open-chest dogs (n = 9). Serotonin (50-200 microgram), injected as a bolus, resulted in an initial bradycardia and hypotension followed by a delayed tachycardia and hypertension in the conscious dogs. The hypertension was seen as an increase of 21.5 +/- 2.7 (mean +/ SE) mm Hg from a control pressure of 102.5 +/- 1.9 mm Hg, whereas the initial decrease in pressure was 22.6 +/- 1.9 mm Hg. The tachycardia was 23.3 +/- 3.9 beats/min above a control heart rate of 104.9 +/- 3.9 beats/min whereas the bradycardia was 58.5 +/- 3.7 beats/min below control. There was a significant attenuation of the hypotension in both groups of anesthetized dogs. In fact, no hypotension was elicited in the open-chest anesthetized dogs. Open-chest anesthetized dogs showed only a hypertensive response (mean increase 67.2 +/- 5.5 mm Hg). Stimulation of respiration was seen in all groups of dogs. In conscious dogs there was a 214.8 +/- 15.4% increase in respiratory depth and a 20.8 +/- 3.1 breaths/min increase in respiratory rate. Atropine significantly reduced the bradycardia and abolished the hypotension in conscious dogs. Bilateral cervical vagotomy did not abolish the response in open-chest anesthetized dogs. We conclude that the so-called "hypertensive coronary chemoreflex" is altered dramatically by the state of the preparation and by anesthesia.

The purpose of this study was to investigate the nature of the serotonin-induced coronary chemoreflex in the conscious monkey. Ten chronically prepared and four acute monkeys were used in this study. Five chronically prepared animals had catheters in the left atrium, ascending aorta, descending aorta, and, bilaterally, in the common carotid arteries. In addition, Silastic catheters were placed next to both vagi to permit vagal block with 2% lidocaine. Serotonin was injected (12-200 micrograms/kg) into the left atrium, ascending aorta, descending aorta, or, bilaterally, into the carotid arteries while blood pressure, heart rate, and respiratory movements were recorded. Injections of serotonin were associated with hypertension and bradycardia followed by tachycardia, all of which were preceded by a cough response. Atropine blocked the bradycardia, whereas atropine and phentolamine eliminated the cardiovascular components of the reflex. Vagal blockade eliminated the bradycardia but otherwise did not alter the response to left atrial serotonin. Three monkeys were prepared with aortic and left atrial catheters. Subsequently, they were subjected to sinoaortic deafferentation. Serotonin injected into these animals did not alter blood pressure or respiration. The results of this study show that serotonin injected into the left atrium of the conscious monkey produces respiratory and cardiovascular alterations by its effect on aortic and carotid chemoreceptors, and that there is no coronary chemoreflex in the conscious monkey.

Experiments were undertaken to determine the influence of increasing left atrial pressure on renal function in the nonhuman primate. Significant elevations of left atrial pressure, produced by using an intra-atrial balloon, had no effect on salt or water excretion, renal plasma flow, or glomerular filtration rate. There were no significant changes in heart rate or blood pressure. We conclude that, unlike those in the dog, atrial receptors in the nonhuman primate play little or no role in modulating salt and water excretion.

The purpose of this investigation was to determine whether left ventricular receptor stimulation attenuates the arterial baroreflex control of heart rate in the conscious dog and to determine the role of cardiac efferent sympathetic and parasympathetic pathways in any interaction observed. Mean arterial blood pressure-heart rate function curves, which characterized arterial baroreflex control of heart rate, were constructed before (control) and during an infusion of veratrine into the left circumflex coronary artery. Peak sensitivity, the maximum absolute slope along the mean arterial blood pressure-heart rate curve, and heart rate range (maximum minus minimum heart rate) were reduced during intracoronary infusion of veratrine. The mean arterial blood pressure-heart rate relationship also was shifted to a lower pressure during intracoronary infusion of veratrine. In order to study the role of cardiac efferents in this interaction, we constructed mean arterial blood-pressure-heart rate curves during cholinergic blockade, cholinergic blockade plus intracoronary infusion of veratrine, beta 1-adrenergic blockade, and beta 1-adrenergic blockade plus intracoronary infusion of veratrine. The addition of intracoronary infusion of veratrine during cholinergic blockade produced a shift of the mean arterial blood pressure-heart rate curve down the ordinate axis (heart rate) and to a lower pressure; however, peak sensitivity and heart rate range remained unchanged. The addition of intracoronary infusion of veratrine during beta 1-adrenergic blockade resulted in reductions in peak sensitivity and heart rate range. These data indicate that left ventricular receptor stimulation attenuates arterial baroreflex control of heart rate and that the reduction of sensitivity and heart rate range is mediated by parasympathetic motoneurons common to both reflex arcs. On the other hand, resetting to a lower operational set point may be mediated by cardiac sympathetic motoneurons common to both reflex arcs.

The discharge characteristics of type B left atrial receptors were analyzed during alterations in heart rate. Recordings were made from single-fiber preparations of the left cervical vagus of pentobarbital-anesthetized, open-chest dogs. The heart was paced following a sinoatrial crush at frequencies ranging from 60 to 240 beats/min. Left atrial transmural pressure was varied at each heart rate by the intravenous infusion of warm isotonic NaCl. As heart rate was increased there was a progressive decrease in the level of peak "v" wave left atrial pressure. Concomitantly with the decrease in left atrial pressure, the number of spikes per cardiac cycle decreased as did the maximal instantaneous frequency of discharge. A significant positive relationship could be demonstrated with either the discharge per minute [(spikes per cycle) X heart rate] or discharge per cycle vs. the peak "v" wave of the left atrial pressure, regardless of heart rate. The number of impulses that entered the central nervous system per unit of time remained relatively constant at heart rates between 90 and 240/min. It is concluded from these data that the reflex effects which have been attributed in the past to atrial stretch receptor stimulation during clinical episodes of atrial tachyarrhythmias may be better correlated with some aspect of receptor discharge other than frequency or the number of discharges per cycle.

Studies were carried out to determine the contribution of cardiopulmonary receptors to the renal responses to head-out water immersion in the nonhuman primate. Immersion to the suprasternal notch was associated with significant increases in central venous pressure, urine flow, and sodium excretion. The increased sodium excretion was due primarily to a significant increase in the percent of the filtered sodium excreted. Deoxycorticosterone acetate (DOCA) and antiduretic hormone (ADH) had no substantial effects on these responses. The finding of a vasopressin-resistant hyposthenuria is consistent with the natriuresis of immersion being due, at least in part, to a decrease in sodium reabsorption proximal to the diluting segment, possibly the proximal tubule. Bilateral cervical vagotomy had no substantial influence on the renal responses to immersion, demonstrating that cardiopulmonary receptors whose axons traverse the vagus nerves are not necessary for the homeostatic adjustments to central hypervolemia in the primate. Since the renal and cardiovascular responses of the primate to immersion are essentially the same as those seen in man, it is probable that vagal pathways also are not necessary in man. However, it is possible that sympathetic afferents are involved in the natriuresis observed in the primate during immersion.

We characterized the influence of high pressure and low pressure intravascular receptors on renal nerve activity in the pentobarbital sodium-anesthetized nonhuman primate Macaca fascicularis. Epinephrine-induced increases in arterial pressure were used to stimulate high pressure receptors, and intravascular volume expansion was used to stimulate both high and low pressure receptors. In addition, the intravascular mechanoreceptors were stimulated directly by intravenous veratrine administration. All interventions produced large decreases in renal nerve activity in the intact state. Denervation of the carotid sinus or bilateral cervical vagal section dimished, whereas sinoaortic denervation with vagotomy completely abolished all responses of renal activity to these interventions. We conclude that the nonhuman primate possesses very sensitive renal nerve sympathetic reflexes that are modulated by intravascular mechanoreceptors whose afferents traverse the carotid sinus nerves and the vago-aortic trunks. The carotid sinus nerves and the vago-aortic trunks appear to be equally effective in inhibiting renal nerve activity in response to increases in arterial pressure. In addition, there are no afferent pathways mediating intravascular mechanoreceptor modulation of renal nerve activity outside the carotid sinus nerves and the vago-aortic trunks.

The present study was undertaken to determine the effects of intracoronary administration of the veratrum alkaloid veratridine on coronary blood flow and resistance in conscious, chronically instrumented intact and sinoaortic denervated dogs. Ten dogs were instrumented with a Doppler flow probe on the left anterior descending coronary artery. A chronic catheter was placed in the left circumflex coronary artery and in the aorta and left atrium. A Konigsberg pressure cell was placed in the left ventricle, and pacing leads were attached to the left atrium and ventricle. While heart rate was kept constant, bolus intracoronary injections of veratridine (0.1-0.4 microgram/kg) were administered in the unblocked state after beta 1-receptor blockade, after alpha-receptor blockade, and after cholinergic blockade. In the unblocked state, late diastolic coronary resistance fell by 34.7 +/- 5.0%. The maximum response was achieved at a time when arterial pressure was not significantly different from control. After beta 1-blockade, coronary resistance fell by 29.1 +/- 7.9%. After combined alpha- and beta-blockade, coronary resistance fell by 25.4 +/- 6.5% in response to veratridine. The addition of atropine completely blocked the decrease in coronary resistance, changing it by an average of -0.10 +/- 2.5%. The responses in sinoaortic denervated dogs were similar to those in intact animals. The response was abolished by vagotomy. We conclude that cardiac receptor stimulation causes a reflex decrease in coronary resistance in the awake dog that is completely accountable by a cholinergic mechanism.