Adaptation of coronary microvascular exchange in arterioles and venules to exercise training and a role for sex in determining permeability responses

Abstract

Studies of physical performance and energy metabolism during and following exercise have shown significant sex-specific musculoskeletal adaptations; less is known of vascular adaptations, particularly with respect to exchange capacity. In response to adenosine (ADO), a metabolite produced during exercise, permeability (P(s)) of coronary arterioles from female pigs changed acutely; the magnitude and direction of the change (Delta P(s)) were determined by training status. In the present study P(s) to albumin was assessed in arterioles (n = 138) and venules (n = 24) isolated from hearts of male (N = 27) and female (N = 59) pigs in the exercise training group (EX). We evaluated the hypothesis that coronary microvessel exchange adapts to endurance exercise training not by altering basal P(s), per se, but by elevating P(s) on exposure to ADO. In contrast, training resulted in a reduction of basal P(s) in all arterioles, and in venules from males, with no change in venules from EX females. Exposure to ADO resulted in the predicted increase in P(s) except for venules from EX males where P(s) was reduced. Delta P(s) responses of arterioles to mediators of adenylyl cyclase (isoproterenol)- and guanylyl cyclase (atrial natriuretic peptide)-signaling pathways were attenuated in EX pigs relative to pigs in the sedentary group. The adaptation of EX arterioles involves an upregulation of a nitric oxide-dependent pathway since nitric oxide synthase inhibition blocks Delta P(s) by ADO. Thus adaptation of microvascular exchange capacity to endurance exercise training not only occurs but also involves multiple mechanisms that differ in arterioles and venules with their relative contribution to net flux being a function of sex.

Fig. 1

Assessment of endurance exercise training (EX) in age-matched Yucatan miniature swine of both sexes. A: resting heart rate (HR; beats/min) in naive [pretraining (Pre)] females (F) was higher than males (M) (**P < 0.05, EX F significantly different from EX M); following 16 wk endurance exercise training, HR fell [*P < 0.05, Pre ≠ posttraining (Post)], in both F and M pigs and the sex difference in HR was maintained. B: duration of exercise stress test administered to pigs before (Pre) initiation of training regime and following 16 wk of training (Post) for the EX M and F pigs. Although the training regime resulted in a significantly increased duration (*P < 0.05), there were no discernible sex differences. C: change in HR between the stress test administered prior (HR_Pre) and following (HR_Post) the 16-wk regime for the pigs at rest and the four stages of work (S1, 5 min at 5 km/h, 0% grade; S2, 10 min at 5 km/h, 10% grade; S3, 10 min at 6.9 km/h, 10% grade; and S4, 9.7 km/h, 10% grade until exhaustion). *P < 0.05, significant difference; **P < 0.05, EX F significantly different from EX M. SED, sendentary; bpm, beats/min.

Fig. 2

Basal permeability (Basal P_s) to porcine serum albumin (PSA) is plotted (means ± SE) for arterioles and venules isolated from the hearts of EX female and male pigs. Basal P_s was lower in venules from the hearts of EX M than in EX F pigs (*P < 0.05). P_s of coronary venules was greater than those of the arterioles (**P < 0.05) whether the data were combined or separated by sex. The gray-shaded bars represent the mean data from SED littermates (25). Numbers in bars represent number of animals.

Fig. 3

Concentration-response relationship of the permeability responses, ΔP_s, of isolated coronary arterioles from a mixed population of 7 (3 F and 4 M) EX pigs. The data (means ± SE) are plotted as the ratio of the P_s during suffusion with adenosine (ADO, in M) ( $P_{\text{s}}^{\text{ADO}}$) relative to basal permeability to PSA ( $P_{\text{s}}^{\text{Control}}$) over the range of 10⁻⁹ to 10⁻⁵ M. *P < 0.05, significant response ( $P_{\text{s}}^{\text{ADO}}/P_{\text{s}}^{\text{Control}}\ne 1$). Comparison of the concentration-response for the age- and sex-matched SED pigs is given by the broken gray line (Ref. 25). N, number of hearts.

Fig. 4

ΔP_s of arterioles and venules isolated from the hearts of EX pigs are plotted as the ratio of the P_s during suffusion with 10⁻⁵ M ADO ( $P_{\text{s}}^{\text{ADO}}$) relative to basal permeability to PSA ( $P_{\text{s}}^{\text{Control}}$). Data are given as means ± SE. *P < 0.05, significant response ( $P_{\text{s}}^{\text{ADO}}/P_{\text{s}}^{\text{Control}}\ne 1$); **P < 0.05, significant differences between females and males; ***P < 0.05, significant differences between arterioles and venules. The responses of the age- and sex-matched SED pigs (Ref. 25) are represented by the light gray bars.

Fig. 5

The influence of exercise adaptation on responses thought to be mediated primarily by adenylyl cyclase (using isoproterenol; A) and by guanylyl cyclase [using atrial natriuretic peptide (ANP); B] was explored in arterioles isolated from the hearts of age- and sex-matched SED and EX pigs. Data are given as the means ± SE of the ratio of P_s to α-lactalbumin measured in the presence of the drug ( $P_{\text{s}}^{\text{Test}}$) relative to its absence ( $P_{\text{s}}^{\text{Control}}$). Ratios > 1 represent increases in P_s; values < 1 indicate a reduction in P_s. with *P < 0.05, significant difference from 1; **P < 0.05, significant difference with training status. n, Number of microvessels.

Fig. 6

A role for a contribution of nitric oxide to the P_s response of female EX pig arterioles to ADO. A: a significant reduction (*P < 0.05) in P_s from basal levels is observed following blockade of nitric oxide synthase with 10⁻⁵ M N^G-monomethyl-L-arginine (L-NMMA). B: in 10 additional arterioles, ADO first induces a significant increase (*P < 0.05) in P_s, which was then abolished by the presence of L-NMMA (**P < 0.05).