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(Hypertension. 2002;39:348.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Heart Rate and Blood Pressure Quantitative Trait Loci for the Airpuff Startle Reaction

Rebecca L. Jaworski; Martin Jirout; Shamara Closson; Laura Breen; Pamela L. Flodman; M. Anne Spence; Vladimir Kren; Drahomira Krenova; Michal Pravenec; Morton P. Printz

From the Department of Pharmacology, University of California at San Diego (R.L.J., M.J., S.C., L.B., M.P.P.), La Jolla; Department of Pediatrics, University of California at Irvine (P.L.F., M.A.S.); Institute of Biology and Medical Genetics, Charles University (M.J., V.K., D.K.), Prague; and Institute of Physiology Czech Academy of Sciences (M.P.), Prague, Czech Republic.

Correspondence to Dr Morton P. Printz, Department of Pharmacology, University of California, San Diego, 9500 Gilman Dr 0636, La Jolla CA, 92093-0636. E-mail mprintz{at}ucsd.edu

	Abstract

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The airpuff startle reaction is a probe of sensori-autonomic processing and is useful for studies of genetic control of stress-induced cardiovascular activity. Using a Wistar-Kyoto-Spontaneously Hypertensive Rat F2 cross, we reported an airpuff-elicited strain-dependent and trial-dependent bradycardia, the absence of which cosegregated with hypertension. Here, we use the mapping power of the HXB-BXH recombinant inbred rat strains (n=23) to locate quantitative trait loci (QTL) for this and associated cardiovascular phenotypes. Rats (12 weeks old), with indwelling femoral arterial catheters, were subjected to repeated airpuff startle stimuli (100 ms, 12.5 psi, 28 trials). Basal mean arterial pressure (MAP), delta MAP, and delta heart rate response to airpuff stimuli were analyzed as the average over 28 trials. There was a significant strain effect on the cardiovascular phenotypes measured. One QTL for the bradycardia elicited by the first airpuff stimulus was identified on chromosome 2 (D2rat 62/63; logarithm of odds [LOD] 2.9) mapping near a reported blood pressure locus. Further QTL were identified for basal MAP (RN08), stimulus-elicited tachycardia on trials 2 to 5 (RNO1 and RNO10), and delta MAP (RNO6). Our results indicate that chromosomes 1, 2, and 10 are involved in heart rate responses to airpuff startle stimulus, and chromosomes 6 and 8 are involved in pressor responses. This study is the first to identify stress-related heart rate loci and provides additional support for our prior cosegregation results. Furthermore, we have established the utility of this experimental paradigm to identify loci responsible for cardiovascular regulation during stress in genetic hypertensive models.

Key Words: behavior • blood pressure • bradycardia • tachycardia • heart rate • genomics

	Introduction

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Stress and stress responses have been postulated to have a causal relationship in the development of hypertension in susceptible organisms. Cohen and Obrist¹ suggested that the cardiovascular responses to a behavioral stressor result in adjustments in cardiac output, and thereby cardiovascular function, and that repeated stress, via repeated increases in arterial pressure, may result in hypertension, a concept formalized by Folkow.² Furthermore, individuals with a family history of high blood pressure exhibited heightened cardiovascular responses to physical and psychological stress when compared with those with a negative family history of hypertension.³ More recently, it was posited that the stress response predicts later development of hypertension.⁴ Similar results have been obtained with animal models. The spontaneously hypertensive rat (SHR) exhibits increased stress responses and hyperreactivity compared with normotensive controls.^5,6 Animals exposed to repeated stress develop high blood pressure that is maintained even after discontinuation of the stress.⁷ As Van Den Buuse et al⁸ have suggested, increased cardiovascular output during mental stress may be related to increased sympathetic outflow. However, McCarty and Gold⁶ have argued that increased sympathetic activity is independent of hypertension. In support of this, Grossman et al⁹ have proposed that stress effects on the cardiovascular system in the borderline hypertensive rat model reflect deficiencies in the parasympathetic nervous system, not hyperactivity of the sympathetic nervous system.

In our laboratory, the airpuff-elicited startle reaction is used as a probe of stress-autonomic coupling. The airpuff stimulus is a mild, multimodal stressor with acoustic and tactile components allowing examination of both somatic motor and autonomic processing. Following an airpuff startle stimulus, a rat exhibits a motor response, an increase in mean arterial pressure, and a heart rate response with trial-dependent and strain-dependent bradycardia and tachycardia components.^10,11 Relative to La Jolla Wistar-Kyoto (WKY/LJ) or vendor Sprague-Dawley (Charles River Labs, Worcester, Mass) and Brown-Norway (BN) (Harlan, Indianapolis, Ind) rats, the SHR exhibit greater pressor, motor, and tachycardia responses. However, SHR lack the early trial bradycardia response observed in these normotensive strains.^11,12,13 This early trial bradycardia is a component of the orienting response and is not due to a baroreceptor reflex, because sino-aortic denervation does not abolish it.¹² Our earlier studies suggested an association of the absence of early trial bradycardia with hypertension in the SHR. For example, while the early trial bradycardia was present in both young SHR and WKY/LJ, it was not evident in adult SHR,¹² and analysis of an F2 and back-cross (WKY/LJxSHR) found that elevated blood pressure cosegregated with the absence of the orienting bradycardia.^14,15

The goal of the present study was to determine quantitative trait loci (QTL) for expression of the early trial bradycardia and other cardiovascular responses to the airpuff startle stimulus. To determine inheritance patterns for a phenotype by linkage analysis, segregating populations is necessary.¹⁶ We therefore used the trait-mapping power of a set of recombinant inbred rat strains (RIS) derived from the normotensive Brown Norway-Lx/Cub congenic and the hypertensive SHR/Ola (HXB-BXH reciprocal cross).¹⁷ Each RI strain, prepared by brother-sister mating of F2 progeny for more than 20 generations, represents an inbred "replica" of its F2 progenitors. The number of recombinations each individual strain has undergone in the process of its creation accounts for the increased mapping power of RIS in comparison with F2 crosses. Other advantages of RIS are the possibilities of cumulative genotyping and phenotyping and studying a particular genotype under different environmental conditions.^17,18 The HXB-BXH set of recombinant inbred strains has been used to identify numerous QTL for cardiovascular and metabolic phenotypes.^19,20,21 We hypothesized these RIS would facilitate analysis of the airpuff startle-stimulus bradycardia and other startle-related cardiovascular traits and that one or more loci would exhibit linkage to loci for basal or stress-activated blood pressure regulation.

	Methods

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Animals and Airpuff Startle Stimulus
Twenty-three HXB-BXH RIS were used in this study. These RIS were developed in Prague and rederived in our La Jolla colony. All animal protocols were reviewed and approved by the UCSD Institutional Animal Care and Use Committee. Under halothane-oxygen anesthesia, 11- to 12-week-old animals were implanted with indwelling femoral arterial catheters as previously described.¹² Briefly, a PE-10 fused PE-50 catheter was inserted into the femoral artery and advanced into the abdominal aorta. The catheter, filled with heparinized saline, was secured in place, plugged, tunneled under the skin, and exteriorized at the nape of the neck. Following surgery, animals were housed 1 per cage on a 12-hour light-dark cycle. Food and water were available ad libitum and 3 days’ recovery was allowed before testing.

Animals were moved from the vivarium to a lit and ventilated chamber with a 70-dB background noise. Startle testing was conducted in a 10-cm diameter plastic cylinder secured to a stabilimeter and placed within a startle chamber (San Diego Instruments) as described.^12,13 Background white noise was maintained at 70 dB. Catheters were attached, via PE-50 tubing, to a manometer-calibrated Statham P23 pressure transducer. The transducer signal was conditioned and analyzed by a Gould 2400S (Gould) for determination of pulsatile and mean arterial pressure and the pressure waveform analyzed by an EKG/Biotach for determination of beat-to-beat heart rate. Analog pressure signals at 400 Hz were averaged in blocks of 40 to yield 0.1-second values. Prestimulus values were defined as the average of multiple measurements (ten 0.1-second values) from the 1-second period preceding each airpuff stimulus. Responses to the airpuff were defined relative to the prestimulus value as the average change in heart rate and mean arterial pressure occurring within the 5-second period after stimulus delivery. Animals could move horizontally within the chamber but could not rear or avoid the airpuff. A 30-minute stabilization period preceded the onset of the airpuff startle stimuli. Twenty-eight airpuff stimuli (100 millisecond, 12.5 psi) were delivered at 55-second intervals, which permitted cardiovascular parameters to return to prestimulus basal values between trials.¹¹ All animals were experimentally naive at testing. All testing took place between 0800 hours and 1300 hours.

Genetic Analysis
All RIS were genotyped from the La Jolla colony and a new framework-marker-based linkage map of RIS was constructed (to be reported elsewhere). Interval mapping for all the traits of interest was performed using Map Manager QTX.²² Before interval mapping, the distribution of each trait was tested for normality. In those cases where the distribution did not follow normality, a simple function was used to transform the data. A test of 10,000 permutations was applied to each individual trait to establish the significance of the logarithm of odds (LOD) values generated by the interval mapping. Suggestive and significant values correspond to =0.63 and 0.05, respectively.

Data Analysis
A variety of traits were analyzed. Basal heart rate and mean arterial pressure (MAP) were calculated as 1 value across all 28 trials. The average change in heart rate at 1.9±0.05 seconds poststimulus was calculated individually for trials 1 through 5 since prior studies established that the most significant changes in heart rate and MAP occurred at 1.9±0.5 seconds.²³ The average airpuff-elicited (delta) change in MAP was calculated as the average across all 28 trials. Strain differences in phenotype were compared with 1-way analysis of variance (ANOVA) for basal heart rate, basal MAP, and average delta MAP, and by 2-way ANOVA with repeated measures for trials 1 through 5 delta heart rate (strain-by-trial variance).

	Results

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There was a significant strain effect for basal MAP (range: 103±2 to 145±4 mm Hg: P0.001) and basal heart rate (range: 314±5 to 404.9±5 bpm; P0.001). There was also a significant strain effect for the trial 1 bradycardia at 1.9±0.05-seconds poststimulus (Figure 1a; P0.001). Similarly, there was a significant strain effect in "later" trial tachycardia on trials 2 through 5 (Figure 1b; representative example of trial 2 to 5 tachycardia; P0.001; strain-x-trial-interaction P0.001). Finally, the average delta MAP varied significantly among RIS (range: 2.66±1.8 to 16±1.6 mm Hg; P0.001).

View larger version (52K): [in this window] [in a new window]   Figure 1. a, Strain distribution of early trial bradycardia. The heart rate response to airpuff startle stimulus on trial 1 is related to the orienting response cardiac deceleration. This trait is rapidly extinguished and absent by trials 2 to 5 depending on strain. The trait was normally distributed with a significant interstrain difference (23 strains; P0.001). Data expressed as mean±SEM. b, Strain distribution of trial 5 tachycardia. This is a representative example of the tachycardia response to the airpuff startle stimulus that is first evident on trial 2 in most strains. By trial 5, the bradycardia is no longer present and only tachycardia is observed in all strains. This trait was normally distributed and varied significantly among strains (P0.001). Data expressed as mean±SEM.

A significant QTL for the early trial bradycardia was identified on RNO2 (D2Rat62-D2Rat247, LOD 2.9; Figure 2a). According to analyses, the BN allele effect in that region enhanced the bradycardia. Two significant QTL for tachycardia were identified on RNO1 and RNO10 (RNO1: D1Rat287-D1Rat292, LOD 3.08; RNO 10: D10Rat26-D10Rat267, LOD 2.4; Figure 2b and 2c). Also, a suggestive QTL for tachycardia on trial 5 was identified on RNO3 (D3Rat180-D3Rat35, LOD 1.8). According to analyses, the effect of the BN allele in the region of the QTL on RNO1 and RNO10 reduced the tachycardia response to the airpuff startle stimulus, while the BN allele in the region of the QTL on RNO3 increased the tachycardia response to airpuff startle stimulus. A significant QTL was identified for basal MAP on RNO8 (D8 mgh9-D8rat40, LOD 1.8;Figure 3a); the BN allele had a blood pressure lowering effect. Finally, a significant QTL was identified for the average delta MAP on RNO6 (D6Rat80-D6Rat171, LOD 2.5; Figure 3b); here, the BN allele decreased the delta MAP.

View larger version (22K): [in this window] [in a new window]   Figure 2. This figure represents the likelihood ratio plots for the early trial bradycardia and representative plots for the trial 2 to 5 tachycardia in response to the airpuff startle stimulus (solid line) and the additive effect of the BN-allele (dotted line). a, A significant QTL for the early trial bradycardia on chromosome 2 is centered at D2Rat62/63 (LOD 2.9). b, A significant QTL for the tachycardia response to airpuff startle stimulus on chromosome 1 is located at D1Rat69 (LOD 3.08). c, A significant QTL for tachycardia on chromosome 10 is located at D10Rat145 (LOD 2.3).

View larger version (19K): [in this window] [in a new window]   Figure 3. This figure represents the likelihood ratio plots for basal and airpuff startle stimulus-elicited change in MAP (solid line) and the additive effect of the BN-allele (dotted line). a, The plot for chromosome 8 illustrates a significant QTL for basal MAP located at D8Rat9/D8Rat219 (LOD 1.8). b, The plot for chromosome 6 illustrates a significant, novel QTL for the delta MAP to airpuff startle stress located at D6Rat80 (LOD 1.9).

	Discussion

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This is the first report of a QTL for the early trial bradycardia associated with the airpuff startle stimulus. Similarly, we believe it is the first report to identify independent chromosomal regions for bradycardia versus tachycardia in response to a mild stressor. Singh et al²⁴ have shown that heart rate variability is heritable and has a genetic component that is independent of reflex responses. Furthermore, Kreutz et al,²⁵ using a total genome screen, found linkage between the marker for Scn2a1 on chromosome 3 and both basal heart rate and salt-induced changes in heart rate in an F2 (SHRSPxWKY) cross. In the current study, we find a suggestive QTL for the airpuff-elicited tachycardia on trial 5 near the region of chromosome 3 identified by Kreutz et al.²⁵

Kreutz et al²⁵ did not find any correlation between basal heart rate and blood pressure in their F2 cross and we also do not find a significant correlation between basal blood pressure and early trial bradycardia across the RIS. However in our RIS set, Pravenec et al¹⁹ identified a basal blood pressure QTL on RNO2 which exhibits linkage (P<0.0001) with our early trial bradycardia QTL. The inability to identify a blood pressure locus on RNO2 in this study and the lack of a significant, across strain blood pressure-heart rate correlation may be due to differences in methodology. Additionally, in an F2 WKYxSHR cross, Samani et al²⁶ identified a blood pressure QTL, encompassing the ATP-1alpha1 gene, in the same region of RNO2 as our QTL for early trial bradycardia. Finally, independently, we have found in RNO2 congenics (WKY/LJxSHR), that an SHR segment (21cM) of RNO2, when introgressed on a WKY/LJ background, resulted in increased blood pressure; this segment contains the site of our new bradycardia QTL (A. Alemayheu and M.P. Printz, unpublished observations, 2001). This evidence, along with our previous cosegregation analysis,¹⁵ strongly suggests that deficits in the early trial bradycardia are linked to a locus for blood pressure regulation.

Our earlier studies revealed that the early trial bradycardia was mediated by the parasympathetic nervous system. We and others have reported that both peripheral and central cholinergic blockade abolished the early trial bradycardia, while treatment with atenolol or celiprolol had no effect in those strains that exhibit the bradycardia.^12,13,27,28 As the SHR has been reported to have a deficit in both the central cholinergic system¹³ as well as the early trial bradycardia,^12,13 it would be of interest to examine the genomic sequence for cholinergic genes in the areas of our QTLs, and such analyses are underway.

To our knowledge, our finding that the bradycardia and tachycardia responses to the airpuff startle stressor are regulated by independent chromosomal regions is unique. The tachycardia response to the airpuff startle stimulus, with 2 significant QTL, 1 each on chromosomes 10 and 1, but none on 2, is mediated by the sympathetic nervous system²⁸ and was shown to be greater in the SHR.^10,11 In the current study, the greatest tachycardia is found in those strains with the highest blood pressure, suggesting that like the bradycardia, there may be linkage between loci for startle-induced tachycardia and blood pressure regulation. A number of QTLs for blood pressure have been reported on RNO10^29,30,31 with interesting candidate genes in that vicinity. The blood pressure QTL linked to the angiotensin-converting enzyme gene on RNO10, identified by Jacob et al,³⁰ maps to the vicinity of our tachycardia QTL, possibly linking the renin-angiotensin system, important to blood pressure regulation and suspected in the pathology of hypertension, to heart rate regulation during (startle) stress. In addition, our tachycardia QTL peak is also near the blood pressure QTL linked to the nitric oxide synthase gene on RNO10, identified by Garrett et al,³¹ suggesting a potential relationship between heart rate and vascular regulation during stress. In the RIS, we also have a weak QTL (data not shown) for basal MAP in the same region as the tachycardia QTL, which further implies that stress related regulation of heart rate and blood pressure are linked. However, the tachycardia response to startle also involves loci independent of blood pressure as the tachycardia QTL on RNO1 does not appear to be related to any blood pressure QTL reported, to date, on this chromosome.^31,32,33 Because other heart rate QTL appear to cosegregate with blood pressure QTL, it is interesting to speculate that the independent tachycardia QTL on RNO1 identifies a behaviorally associated locus for heart rate.

We identified a chromosomal region associated with psychological stress-induced changes in MAP. Extensive review of the literature suggests that this is the first QTL for stress-related changes in MAP identified on RNO6. Stoll et al³⁴ reported a QTL on RNO6 for basal MAP (D6 Mit12-D6 Mit3) based on a radiation-hybrid map; however, this QTL appears unrelated to our locus (peak: D6rat80, HXB-BXH map). The new QTL for the average change in MAP appears to be a novel blood pressure QTL related to behavioral effects on blood pressure regulation and potentially may be involved in repeated stress-mediated development of hypertension.

Similar to the findings of others, we also found a QTL for basal blood pressure on RNO8. Kren et al³⁵ (D8 mit5/D8 mgh9 to D8 mgh6) reported a blood pressure QTL near the dopamine 2 receptor that is near our site, as is a QTL for salt-related changes in mean arterial pressure (D8rat 24) found in studies of the Dahl rat.³⁶ Finally, as others^29,30,31 have reported blood pressure QTLs on RNO10, we also find a weak QTL for basal MAP (data not shown) in the same area in the RIS. These findings point to these chromosomes for candidate gene exploration for basal and stress related blood pressure regulation.

Conclusions
This study has identified both a novel QTL for bradycardia in response to airpuff startle stress, and the direction to which the BN-allele drives the trait. The chromosome 2 QTL is strongly linked with blood pressure, further supporting our original hypothesis that loci for startle-induced changes in heart rate are coinherited with loci for hypertension. Our study has also shown that the bradycardia and tachycardia associated with startle are regulated by independent genomic regions. The finding that the bradycardia response to airpuff startle stimulus is mediated by the parasympathetic nervous system¹³ while the tachycardia response is mediated by the sympathetic nervous system²⁷ now provides insight into the genetics of autonomic regulation during psychological stress. These findings should facilitate the search for candidate genes important to regulation of the autonomic nervous system as well as to the development of hypertension under conditions of behavioral stress.

	Acknowledgments

 
The authors wish to thank Dr Lisa Conti for review of this manuscript. This work was funded by NIH HL 35018 (to M.P.P.) and GA CR 204/98/K015 (to V.K. and D.K.).

Received September 23, 2001; first decision November 7, 2001; accepted November 21, 2001.

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