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. 2010 Aug 31;588(Pt 20):4007–4016. doi: 10.1113/jphysiol.2010.192492

Coronary vasoconstrictor responses are attenuated in young women as compared with age-matched men

Afsana Momen 1, Zhaohui Gao 1, Abigail Cohen 1, Tamreen Khan 1, Urs A Leuenberger 1, Lawrence I Sinoway 1
PMCID: PMC3000588  PMID: 20807793

Abstract

Recent work in humans suggests coronary vasoconstriction occurs with static handgrip with a time course that suggests a sympathetic constrictor mechanism. These findings are consistent with animal studies that suggest this effect helps maintain transmural myocardial perfusion. It is known that oestrogen can attenuate sympathetic responsiveness, however it is not known if sympathetic constrictor responses vary in men and women. To examine this issue we studied young men (n = 12; 28 ± 1 years) and women (n = 14; 30 ± 1 years). Coronary blood flow velocity (CBV; Duplex Ultrasound), heart rate (ECG) and blood pressure (BP; Finapres) were measured during static handgrip (20 s) at 10% and 70% of maximum voluntary contraction. Measurements were also obtained during graded lower body negative pressure (LBNP; activates baroreflex-mediated sympathetic system) and the cold pressor test (CPT; a non-specific sympathetic stimulus). A coronary vascular resistance index (CVR) was calculated as diastolic BP/CBV. Increases in CVR with handgrip were greater in men vs. women (1.25 ± 0.49 vs. 0.26 ± 0.38 units; P < 0.04) and CBV tended to fall in men but not in women (−0.9 ± 0.9 vs. 1.7 ± 0.8 cm s−1; P < 0.01). Changes in CBV with handgrip were linked to the myocardial oxygen consumption in women but not in men. CBV reductions were greater in men vs. women during graded LBNP (P < 0.04). Men and women had similar coronary responses to CPT (P = n.s.). We conclude that coronary vasoconstrictor tone is greater in men than women during static handgrip and LBNP.

Introduction

It has long been suggested that the incidence of atherosclerotic coronary artery disease is lower in women than men. The causes of this difference are not well defined. One potential factor may be the influences of the female sex hormone, oestrogen. Oestrogen can lower lipids (Mendelsohn & Karas, 1999), attenuate atherosclerotic plaque development and prevent vascular injury (Rauscher et al. 2003). It can also reduce vascular contractility (Collins et al. 1993), enhance coronary artery dilatation (Collins et al. 1994; Chester et al. 1995), and reduce sympathetic nerve activity (Vongpatanasin et al. 2001; Weitz et al. 2001).

However, despite evidence showing less large-vessel coronary disease in women than in men, a number of studies suggest that the incidence of exertional angina is in fact similar or slightly higher in women than men (Hemingway et al. 2008). Other reports indicate that 50% of women who were evaluated for chest pain had angiographically normal coronary arteries (Shaw et al. 2009). The mechanisms of developing of ischaemic heart disease in women with normal coronary arteries are not known.

Recently, we have observed that coronary vasoconstriction occurs within 20 s of initiating handgrip exercise in healthy humans (Momen et al. 2009). Of note, the majority of volunteers were male in this prior work (8 men and 3 women). These findings suggest that similar to observations in animals (Young et al. 1987; Longhurst, 1990), sympathetic coronary constrictor mechanisms are operative in healthy humans. Several animal studies have suggested that coronary vasoconstriction may be beneficial during exercise. For example, Huang and Feigl demonstrated that adrenergic sympathetic coronary vasoconstriction in exercising dogs helps to maintain uniform transmural perfusion by redistributing blood from the outer epicardial to the inner subendocardial layer (Huang & Feigl, 1988). Similarly, Chilian and Ackell suggested that α-adrenergic-mediated coronary vasoconstriction, especially in the outer layer, helps to maintain perfusion throughout the myocardial layers (Chilian & Ackell, 1988). Accordingly, these observations suggest that a lack of alpha constriction in the coronary arteries could predispose the inner myocardial layer to ischaemic injury when metabolic demand is high, such as during exercise. However, these previous animal reports did not specify the sex of the experimental animals.

It is not known whether the sympathetic coronary vasoconstrictor responses to exercise differ in men and women. Studies in both animals (Schmitt & Kaufman, 2003) and healthy humans (Ettinger et al. 1998) suggest that oestrogen may reduce the sympathetic responses seen with muscle contraction. It has also been reported that oestrogen enhances dilator sensitivity of coronary vessels by increasing the production of endothelium-derived nitric oxide (Thompson et al. 2000). Moreover, endothelium-derived relaxing factors are found to interact with α2-adrenergic receptors and attenuate vasoconstriction (Ohyanagi et al. 1992). Thus, it is conceivable that women would show less coronary vasoconstriction than men during bouts of exercise.

In this report we tested this hypothesis by examining coronary vascular responses in healthy men and women during handgrip exercise. In addition, two other protocols were employed: lower body negative pressure (LBNP) to evoke baroreflex-mediated sympathetic activation (Khan et al. 2002) and the cold pressor test (CPT) to evoke non-specific sympathetic activation (Sterns et al. 1991). We used non-invasive Doppler ultrasound technology to examine coronary blood flow velocity (CBV) in a beat-by-beat fashion. The primary objective of these studies was to determine whether coronary vascular responses to these different sympathoexcitatory stimuli varied in men and women. We report that coronary vasoconstriction is less in women than men during short bouts of handgrip exercise and during LBNP.

Methods

Study population

A group of 12 healthy young men (age 28 ± 1 years, mean BMI 23 ± 1 kg m−2) and 14 healthy young women (age 30 ± 1 years, mean BMI 22 ± 1 kg m−2) were studied. Eight men and three women were also studied in a previous report (Momen et al. 2009). Subjects were non-smokers, normotensive and on no medication. However, 9 out of 14 women were taking contraceptives during the study. Each subject signed an informed written consent that was approved by the Institutional Review Board at the Hershey Medical Center. All studies performed were in compliance with the Declaration of Helsinki. A physical examination was performed prior to conducting the study protocols.

All protocols were performed in the Penn State General Clinical Research Center in Hershey. Subjects were lying supine on a bed during the study. Between the protocols, the subjects rested for 15 min. The protocol sequence was the same in all subjects tested. In three women, only the LBNP protocol was tested.

Measurements

Blood pressure (BP) and heart rate (HR)

BP (Finapres, Ohmeda, Madison, WI, USA) and HR (electrocardiogram) measurements were obtained throughout the protocols. Resting BP obtained by Finapres was verified with an automated sphygmomanometer (Dinamap, Critikon, Tampa, FL, USA).

Myocardial oxygen consumption (Inline graphic)

Inline graphic was calculated applying the following formula (Rooke & Feigl, 1982; Chilian et al. 1986):

graphic file with name tjp0588-4007-m1.jpg

where SBP is the systolic blood pressure.

Coronary blood flow velocity (cm s−1)

Blood flow velocity in the left anterior descending (LAD) coronary artery was measured with duplex ultrasound (HDI 5000, ATL Ultrasound, Bothell, WA, USA). A linear-array high-frequency transducer (7–10 MHz) with a 6 MHz pulsed Doppler frequency was used for these studies. With the subjects in the left lateral decubitus position, the LAD was scanned along the left midclavicular line in the 4th or 5th intercostal space. The distal segment of the LAD near the cardiac apex was identified with colour flow mapping, and the focal zone was then set at the depth of the LAD. The insonation angle to the artery was ≤60 deg. The velocity range was set at 0–30 cm s−1. The sample volume was adjusted to cover the size of the vessel. Care was taken to avoid Valsalva manoeuvers by the subjects during the bouts of handgrip. The Doppler tracing of the diastolic portion of each cardiac cycle was analysed using HDI 5000 ATL software to obtain mean coronary diastolic blood velocity. Due to the limited spatial resolution at the depth of the coronary arteries and the small vessel size, we did not attempt to make measurements of coronary artery diameter. However, it has been documented that changes in coronary flow velocity reliably reflect changes in absolute blood flow (Doucette et al. 1992; Di Mario et al. 2000; Serruys et al. 2000; Hirata et al. 2004). Hence, CBV was used as an index of coronary blood flow. Beat-to-beat BP was recorded and analysed with a Power Lab Chart software suite (ADInstruments). Mean diastolic BP was obtained off-line from the Power Lab chart by determining average BP during the diastolic component of the cardiac cycle. Therefore, for each cardiac cycle, diastolic velocity and the corresponding diastolic BP were obtained. An index of coronary vascular resistance (CVR) was calculated by dividing corresponding diastolic BP by CBV and was expressed in arbitrary units.

Study protocols

Protocol 1: Short bouts of static handgrip

Eleven men and 11 women participated in this protocol. The protocol was designed to examine the effects of gender on coronary vascular responses during short bouts of handgrip exercise. During these short bouts of handgrip exercise, sympathetic neural constrictor mechanisms, such as central command and/or muscle mechanoreflexes are likely to be activated (Kaufman & Forster, 1996; Waldrop et al. 1996; Herr et al. 1999). Before beginning the handgrip exercise, a maximum voluntary contraction (MVC) of the exercising arm was determined in each subject with a handgrip dynamometer (Stoelting, Wood Dove, IL, USA). After obtaining the baseline data for HR, BP and CBV for ∼5 min, each subject then completed 20 s bouts of static handgrip exercise at 10% and 70% of their respective MVC. Each subject received visual feedback of the amount of tension generated during handgrip. Each bout of exercise was preceded by ∼1 min rest period.

Protocol 2: Cold pressor test (CPT)

This protocol was designed to evaluate the effects of non-specific sympathetic drive on coronary flow responses. Eleven men and 10 women participated in this protocol. HR, BP and CBV data were obtained at rest and during 90 s of submersion of one hand up to the wrist in iced water.

Protocol 3: Graded LBNP

These protocols were designed to disengage baroreflexes and activate the sympathetic system. The LBNP protocols were designed to determine whether the effects of baroreflex-mediated sympathetic activation on coronary flow responses differ in men and women. Eleven men and 12 women participated in this protocol. Subjects’ lower body was positioned inside a sealed wooden chamber (up to the level of the umbilicus). After baseline HR, CBV and BP were recorded over 5 min, negative pressure was then applied in a graded manner beginning with −10 mmHg and increasing to −30 mmHg for 3 min at each level. BP, HR and CBV were recorded continuously throughout the protocol. A similar order was maintained for all subjects. The experiment was terminated early if the subjects developed presyncopal symptoms such as lightheadedness, dizziness, nausea, diaphoresis, visual disturbances or a sudden fall in BP.

Statistical analysis

All data are presented as mean ± s.e.m. Repeated measure two-way analysis of variance was applied to determine the gender influence on multiple variables during different interventions. Tests of simple effects were also performed to compare haemodynamic responses between men and women at respective time periods in each intervention. Differences between genders for resting data were assessed using Student's t test. A P < 0.05 was considered statistically significant.

Results

Baseline data

Baseline data with respect to BP, CVR and CBV were similar in men and women. Resting HR was higher in women than men (Table 1).

Table 1.

Demographic and resting haemodynamic measurements in men (n = 12) and women (n = 14)

Men Women P <
N 12 14
Age (years) 28 ± 1 30 ± 1 n.s.
BMI (kg m−2) 23 ± 1 22 ± 1* 0.047
MVC (kg) 35 ± 1 23 ± 1* 0.001
CBV (cm s−1) 17.4 ± 1.5 16.8 ± 1.3 n.s.
CVR (units) 4.07 ± 0.33 5.07 ± 0.40 n.s.
BP (mmHg) 71.5 ± 2.6 76.4 ± 1.9 n.s.
HR (beats min−1) 53.2 ± 2.8 62.6 ± 2.8* 0.027
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Values are expressed as mean ± s.e.m. BMI, body mass index; MVC, maximum voluntary contraction; CBV, coronary blood flow velocity; CVR, coronary vascular resistance; BP, diastolic blood pressure; HR, heart rate. * indicates significant differences (P value < 0.05) between men vs. women.

Gender influences on coronary haemodynamics during short bouts of handgrip

During handgrip, CVR increased in 9 out of 11 men and 7 out of the 11 women studied. However, the average changes from baseline in CVR were greater in men than in women (P < 0.04; Table 2). Moreover, unlike their male counterparts, CBV tended to increase in women especially during handgrip at 70% MVC (P < 0.004; Fig. 1A and Table 2). Of note, the increase in blood flow velocity was linearly linked to the changes in myocardial oxygen consumption in the women (Fig. 1B). BP and HR responses were similar in the men and women (Table 2).

Table 2.

Haemodynamic measurements in men and women during 20 s graded handgrip, cold pressor test (CPT) and graded lower body negative pressure (LBNP)

Men Women
Handgrip protocol 10% MVC
 CBV −0.9 ± 0.5 (−4 ± 2)% 1.3 ± 0.8 (8 ± 5)%
 CVR 0.21 ± 0.09 (6 ± 2)% −0.17 ± 0.28 (−3 ± 5)%
 BP 0.8 ± 0.7 (1 ± 1)% 1.6 ± 1.4 (2 ± 2)%
 HR 1.5 ± 1.3 (3 ± 2)% 0.6 ± 1.1 (1 ± 2)%
 CBV −0.9 ± 0.9 (−6 ± 5)% 1.7 ± 0.8* (13 ± 6)%
Handgrip protocol 70% MVC
 CVR 1.25 ± 0.49 (28 ± 9)% 0.26 ± 0.38* (7 ± 5)%
 BP 12.4 ± 2.8 (17 ± 4)% 14.2 ± 2.4 (19 ± 3)%
 HR 10.7 ± 1.3 (18 ± 2)% 12.1 ± 2.9 (22 ± 5)%
CPT
 CBV 3.5 ± 1.2 (17 ± 5)% 1.6 ± 0.9 (9 ± 5)%
 CVR 0.31 ± 0.27 (6 ± 5)% 0.20 ± 0.18 (6 ± 4)%
 BP 18.0 ± 3.2 (22 ± 4)% 9.6 ± 2.1* (14 ± 4)%
 HR 5.0 ± 1.5 (9 ± 3)% 5.4 ± 1.9 (8 ± 3)%
LBNP −10 mmHg
 CBV −3.4 ± 0.9 (−18 ± 5)% −0.2 ± 1.6 (−4 ± 8)%
 CVR 1.11 ± 0.41 (25 ± 8)% 0.80 ± 0.40 (12 ± 8)%
 BP −0.4 ± 1.2 (−1 ± 1)% 0.0 ± 1.2 (0 ± 1)%
 HR −1.3 ± 0.8 (−2 ± 1)% 0.0 ± 0.4 (0 ± 1)%
LBNP −30 mmHg
 CBV −5.5 ± 1.2 (−25 ± 5)% −0.3 ± 1.6* (−2 ± 9)%
 CVR 1.64 ± 0.47 (40 ± 9)% 0.50 ± 0.39 (9 ± 8)%
 BP 0.0 ± 1.5 (0 ± 2)% 1.5 ± 2.2 (2 ± 3)%
 HR 6.3 ± 2.1 (12 ± 4)% 8.0 ± 2.8 (11 ± 4)%
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Values are expressed as mean ± s.e.m. MVC, maximum voluntary contraction for handgrip exercise. All haemodynamic data (BP, diastolic blood pressure (mmHg); HR, heart rate (beats min−1); CBV, coronary blood flow velocity (cm s−1); CVR, coronary vascular resistance index (units)) are presented as changes from the respective baseline (delta data); % change from the respective baseline data are shown in parentheses. The data are shown in different interventions including graded handgrip protocol, cold pressor test (CPT) and graded lower body negative pressure (LBNP). *P < 0.05, indicating significant gender main effect for respective indices.

Figure 1. Coronary blood flow velocity responses and linear regression analysis during static handgrip.

Figure 1

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A, coronary blood flow velocity responses (y-axis) during short bouts of graded static handgrip at 10% and 70% of maximum voluntary contraction (MVC; x-axis). Delta data are expressed as means ± s.e.m. P value for 2-way ANOVA: Note, gender effect value (P < 0.004) represents significant differences in coronary blood flow velocity responses between men (n = 11) and women (n = 11). B, linear regression analysis data showing coronary blood flow velocity responses (delta data; on y-axis) and changes in calculated myocardial oxygen consumption values (Inline graphic; x-axis) during handgrip at 70% MVC in men (left panel) and women (right panel). Note, significant linear relationship between changes in coronary blood flow velocity and changes in Inline graphic are only found in women.

Gender influences on coronary haemodynamics during 90 s CPT

BP, HR and CBV were increased during CPT (Table 2 and Fig. 2A). HR and CBV responses were similar in men and women. Increases in BP tended to be greater in men than women (P < 0.04; Table 2). However, as noticed in the handgrip protocol, a linear relationship between increases in CBV and increases in myocardial oxygen consumption was found in the women but not in the men (Fig. 2B).

Figure 2. Coronary blood flow velocity responses and linear regression analysis during cold pressor test.

Figure 2

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A, coronary blood flow velocity responses (y-axis) during 90 s cold pressor test (CPT; x-axis). Delta data are expressed as means ± s.e.m. P value for 2-way ANOVA: Note, gender effect value (P = n.s.) represents no significant differences in coronary blood flow velocity responses between men (n = 11) and women (n = 10). B, linear regression analysis data showing coronary blood flow velocity responses (delta data; on y-axis) and changes in calculated myocardial oxygen consumption values (Inline graphic; x-axis) during CPT in men (left panel) and women (right panel). Note, significant linear relationship between changes in coronary blood flow velocity and changes in Inline graphic are only found in women.

Gender influences on coronary haemodynamic responses to LBNP

CBV was reduced during graded LBNP (Fig. 3). The reductions in flow velocity were greater in men than women especially at the higher LBNP level (P < 0.04 from post hoc test). CVR increased during graded LBNP in both men and women. However, no significant differences between men and women with respect to CVR were noted. Increases in HR were also similar in men and women. BP did not change in either group during LBNP (Table 2).

Figure 3. Coronary blood flow velocity responses during graded lower body negative pressure.

Figure 3

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Coronary blood flow velocity responses (y-axis) during graded lower body negative pressure (LBNP) at −10 and −30 mmHg (x-axis). Delta data are expressed as means ± s.e.m. P value for 2-way ANOVA: Note, sex effect value (P < 0.034) represents significant differences in coronary blood flow velocity responses between men (n = 11) and women (n = 12).

Discussion

The important findings in this report are that coronary vasoconstrictor responses to short bouts of handgrip exercise and to LBNP are less in premenopausal women than in age-matched men. These results suggest that reflex sympathetic control of coronary vasomotor tone differs in healthy men and women.

Recent advances in Duplex ultrasound technology have enabled investigators to examine CBV in a safe and non-invasive manner (Hozumi et al. 1998b; Lethen et al. 2003). An important advantage of this method is that it provides beat-by-beat time resolution affording the opportunity to examine the time course of coronary resistance changes to an intervention. The time courses of the coronary vasoconstrictor responses to exercise (i.e. an increase in the coronary resistance index within the first 20 s of handgrip) suggest that certain neural mechanisms, e.g. central command and/or muscle mechanoreflexes (Kaufman & Forster, 1996; Waldrop et al. 1996; Herr et al. 1999), were probably responsible for the presumed sympathetic coronary vasoconstriction. Of note, prior studies performed in decerebrate cats demonstrate that oestrogen attenuates muscle reflexes (Schmitt & Kaufman, 2003) as well as central command (Hayes et al. 2002). Studies in healthy women also have demonstrated that oestrogen lowers muscle reflex-mediated sympathetic nerve activity during exercise (Ettinger et al. 1998). It is also possible that in this report the higher oestrogen levels in women led to higher endothelial nitric oxide levels which antagonized the α2-adrenergic receptor-mediated constrictor effects (Ohyanagi et al. 1992). Of note, coronary vascular beds possess both α1- and α2-adrenergic receptors (Chilian, 1991) and activation of both can lead to coronary vasoconstriction (Woodman & Vatner, 1987).

It should be noted that in this report we did not study the transmural distribution of blood flow. Therefore, we cannot state definitively whether enhanced coronary vasoconstriction seen in men had beneficial effects on transmural myocardial perfusion. Previous animal reports have shown such a beneficial effect (Chilian & Ackell, 1988; Huang & Feigl, 1988; Baumgart et al. 1993). To date, there are no human data available with regard to this issue. We believe this is an area of important future study.

We observed less coronary vasoconstriction during LBNP in women than in men. This is an important finding since BP did not change dramatically during LBNP. Thus, we believe it is unlikely that the reduced constrictor responses seen in women during LBNP could have been due to a gender effect on pressure-induced vessel autoregulation (Lott et al. 2009). If this were the case we would have expected similar constrictor responses in men and women. Furthermore, our previous report indicated that reduced CBV seen during LBNP was not due to reduced left ventricular wall stress; it was probably due to baroreceptor-mediated sympathetic vasoconstriction (Momen et al. 2009). It is also possible that the effects of LBNP to reduce left ventricular (LV) wall stress varied in men and women. To address this issue, we performed echocardiographic work in three men and three women during graded LBNP (at −10 and −30 mmHg). Left ventricular dimensions including systolic and diastolic wall thickness were measured during baseline and LBNP with the standard m-mode technique. The average wall stress index was calculated as systolic arterial pressure × mean radius/mean wall thickness. The mean radius and mean wall thickness represents the average of end diastolic and end systolic measurements, respectively (Quinones et al. 1980). A comparable small reduction in wall stress was noted in both groups (delta data LV stress −10.83 ± 13.96 mmHg and −13.64 ± 10.36 mmHg, in men and women, respectively) during LBNP at −10 mmHg. Despite these similar reductions in wall stress, the reduction in coronary blood flow velocity (CBV) in men was greater than women during LBNP at −10 mmHg (Fig. 3). Thus, this greater reduction in CBV in men is not probably explained by a preferentially greater reduction in LV wall stress in men as compared with women. Rather, we believe this reduction was due to reflex sympathetic activation (Baily & Sinoway, 1990). Interestingly, LV wall stress did appear to fall more in men than women at the −30 mmHg level of LBNP (delta data LV stress −34.10 ± 16.46 and −8.10 ± .50 in men and women, respectively). Therefore, it is likely that a reduction in both LV wall stress and sympathetic activation contribute to a greater reduction of CBV in men than women at this level of LBNP. Further studies will be necessary to further address this issue.

We did not see any differences between men and women in terms of coronary vascular responses during a non-specific sympathetic stimulus, the CPT. Based on prior studies (Rusch et al. 1981; Victor et al. 1987), it is possible that during 90 s CPT, sympathetic activation led to similar degrees of β-adrenergic receptor-mediated coronary vasodilatation in men and women.

It is interesting to note that we observed a significant linear relationship between changes in CBV and myocardial oxygen consumption (Inline graphic) during CPT and handgrip in women but not in men (Figs 1 and 2). Previous studies performed in healthy male volunteers found increased myocardial oxygen extraction and decreased coronary sinus oxygen content during heavy bicycle exercise suggesting oxygen delivery to the heart may not always fully match myocardial oxygen demand in men (Kitamura et al. 1972). Additionally, prior studies performed in exercising dogs suggest α-adrenergic receptor blockade improves the relationship between coronary flow and myocardial O2 consumption (Takamura et al. 2002). Thus, it is possible that higher levels of oestrogen in women enhanced nitric oxide release and inhibited α-adrenergic activation during exercise. This in turn would be expected to improve the relationship between Inline graphic and CBV in women. However, it must be emphasized that our findings were obtained during 20 s static handgrip exercises and one should be careful in extrapolating our findings to systemic bouts of dynamic exercise.

Study limitations

With available technology we are currently unable to obtain accurate measurements of coronary artery diameter. This precludes our ability to non-invasively and repeatedly measure coronary artery diameter. However, we believe coronary flow velocity is a useful surrogate for blood flow and it is our strong contention that important information can be gleaned from our experiments. By example, we noted that during static handgrip, coronary flow velocity rose in women (13 ± 6%) and fell in men (−6 ± 5%). We also know that for this difference to be explained purely by diameter changes would require that static handgrip evoked a 7–8% greater level of vessel constriction in women than men. In other words, we would need to see directionally opposite effects on large- and small-vessel responses to handgrip in men and women. We believe this to be highly improbable.

In reports by Bove & Dewey (1985) and Stone and colleagues (Liang & Stone, 1983) attenuated adrenergic coronary constriction has been observed after exercise conditioning. It is interesting to note that even in the presence of exercise conditioning the directional relationship between velocity and diameter is preserved (Liang & Stone, 1983). Of note, Bove and Dewey studied only male dogs (n = 14). Other reports did not specify the sex of the experimental animals.

The transducer we used to obtain coronary blood velocity (CBV) has a frequency range of 7–10 MHz. With this transducer, the distal portion of LAD near the cardiac apex was examined under the guidance of colour flow Doppler mapping. The sample volume (∼2.0 mm) was placed over the colour image of the distal LAD and then pulsed wave Doppler velocity tracings were recorded. The spectral coronary flow velocity pattern is distinctive with a large, prominent diastolic component and a smaller systolic component.

As would be anticipated for an organ with multiple movement patterns during contraction (i.e. longitudinal, cross-sectional and rotational), the left ventricle and the LAD coronary artery move noticeably with systole. Often this movement changes the Doppler probe position relative to the distal LAD. Thus, keeping the coronary artery within the sample volume of the Doppler system during both diastole and systole is intrinsically challenging. As most coronary flow occurs in diastole, we elected to focus on obtaining ‘clean’ diastolic flow velocity traces for our measurements. Simply stated cardiac systolic motion (and on occasion translational respiratory movement) does not afford us the opportunity to report whole cardiac cycle mean coronary blood velocity data. Therefore, in this manuscript we report and analyse only the diastolic coronary flow velocity signal.

We should note that there is literature precedent for reporting diastolic flow velocity. Previous reports on animal models examined diastolic coronary flow velocity in calculating diastolic coronary resistance. Liang & Stone (1983) and DiCarlo et al. (1988) used such an approach in animals to evaluate neurohumoral control of the coronary circulation.

Moreover, techniques to measure diastolic flow velocity have been reported in humans with non-invasive Doppler approaches (Momen et al. 2010) as well as with invasive Doppler guidewire approaches (Hozumi et al. 1998a; Caiati et al. 1999; Kim et al. 2000).

A question may also be raised regarding the influence of pressure-related myogenic influences on the observed coronary responses. However, blood pressure increased in both male and female during handgrip and the magnitude of these increments was comparable. Despite this, for a given change in blood pressure, changes in coronary resistance during handgrip were not similar in the two groups. Thus, increases in coronary vasoconstriction during handgrip exercise in men cannot be explained by a greater gender-linked stimulus for myogenic vasoconstriction.

Clinical implications

Reports have shown greater increments in sympathetic activation in men than women during upright posture (Shoemaker et al. 2001; Fu et al. 2005). Consistent with these observations, we noted greater coronary vasoconstriction in men than women during LBNP which was probably due to reflex sympathetic activation. We also noted greater coronary vasoconstriction during short bouts of handgrip which are probably due to activation of cardiac sympathetic nerve activity (Matsukawa et al. 1994; Tsuchimochi et al. 2009).

It should be noted that during daily life activities, several physical activities involve short bouts of isometric muscle contraction in upright posture, e.g. holding, lifting, gripping, etc. Based on our present data, we speculate that enhanced sympathetic coronary vasoconstriction would occur in men but not in women during these physical activities. In men but not in women, this system may help maintain transmural perfusion (Huang & Feigl, 1988; Baumgart et al. 1993) and help prevent ischaemic injury to the myocardium. We speculate that these physiological differences must in some way translate into sex differences in the causes of cardiac muscle ischaemia in men and women.

It must be noted that not all reports suggest such a beneficial effect of α-adrenergic coronary constriction. In a number of prior reports using coronary artery stenosis (Laxson et al. 1989) or left ventricular hypertrophy produced (Duncker et al. 1995) models, increased sympathetic tone was not found to be beneficial. Indeed these animal reports suggest that sympathetic α-adrenergic coronary vasoconstriction during exercise limited transmural blood flow (Laxson et al. 1989). Specific human exercise studies with measurements of transmural blood flow and ventricular function are lacking.

In conclusion, our findings suggest that coronary vasoconstrictor responses are very different in healthy men and women during exercise and LBNP. Our data suggest that in men sympathetic activation plays an important role in blood flow regulation.

Acknowledgments

The authors are grateful to Jennie Stoner for expert manuscript preparation; Cheryl Blaha, Jessica Mast, Jonathon Yoder, Mick Herr, Jon Pollock and Kris Gray for technical assistance; and the staff of the General Clinical Research Center. This work was funded by NIH grants R01 HL070222 (Sinoway), P01 HL077670 (Sinoway), NIH/NCRR grant M01 RR010732 and C06 RR016499, American Heart Association grant 830109N (Momen); this project is also funded, in part, by a grant from the Pennsylvania Department of Health using Tobacco Settlement Funds. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions.

Glossary

Abbreviations

BP

blood pressure

CBV

coronary blood flow velocity

CPT

cold pressor test

CVR

coronary vascular resistance

LAD

left anterior descending coronary artery

LBNP

lower body negative pressure

MVC

maximum voluntary contraction

Author contributions

A.M.: Conception and design, data analysis, interpretation of data and drafting the article. Z.G.: Data acquisition and analysis. A.C. and T. K.: Data analysis. U.A.L.: Conception and design and interpretation of data. L.I.S.: Conception and design, interpretation of data and revising the article critically for important intellectual content. All authors approved the final version of the manuscript. All experiments were done in the General Clinical Research Center.

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