Endothelium-derived hyperpolarizing factor in coronary microcirculation: responses to arachidonic acid.

In coronary resistance vessels, endothelium-derived hyperpolarizing factor (EDHF) plays an important role in endothelium-dependent vasodilation. EDHF has been proposed to be formed through cytochrome P-450 monooxygenase metabolism of arachidonic acid (AA). Our hypothesis was that AA-induced coronary microvascular dilation is mediated in part through a cytochrome P-450 pathway. The canine coronary microcirculation was studied in vivo (beating heart preparation) and in vitro (isolated microvessels). Nitric oxide synthase (NOS) (N(omega)-nitro-L-arginine, 100 microM) and cyclooxygenase (indomethacin, 10 microM) or cytochrome P-450 (clotrimazole, 2 microM) inhibition did not alter AA-induced dilation. However, when a Ca(2+)-activated K(+) channel channel or cytochrome P-450 antagonist was used in combination with NOS and cyclooxygenase inhibitors, AA-induced dilation was attenuated. We also show a negative feedback by NO on NOS-cyclooxygenase-resistant AA-induced dilation. We conclude that AA-induced dilation is attenuated by cytochrome P-450 inhibitors, but only when combined with inhibitors of cyclooxygenase and NOS. Therefore, redundant pathways appear to mediate the AA response in the canine coronary microcirculation.

Mechanism of coronary vasodilation to insulin and insulin-like growth factor I is dependent on vessel size.

Insulin and insulin-like growth factor I (IGF-I) influence numerous metabolic and mitogenic processes; these hormones also have vasoactive properties. This study examined mechanisms involved in insulin- and IGF-I-induced dilation in canine conduit and microvascular coronary segments. Tension of coronary artery segments was measured after constriction with PGF(2alpha). Internal diameter of coronary microvessels (resting diameter = 112.6+/-10.1 microm) was measured after endothelin constriction. Vessels were incubated in control (Krebs) solution and were treated with N(omega)-nitro-L-arginine (L-NA), indomethacin, or K(+) channel inhibitors. After constriction, cumulative doses of insulin or IGF-I (0.1-100 ng/ml) were administered. In conduit arteries, insulin produced modest maximal relaxation (32 +/- 5%) compared with IGF-I (66+/-12%). Vasodilation was attenuated by nitric oxide synthase (NOS) and cyclooxygenase inhibition and was blocked with KCl constriction. Coronary microvascular relaxation to insulin and IGF-I was not altered by L-NA, indomethacin, tetraethylammonium chloride, glibenclamide, charybdotoxin, and apamin; however, tetrabutylammonium chloride attenuated the response. In conclusion, insulin and IGF-I cause vasodilation in canine coronary conduit arteries and microvessels. In conduit vessels, NOS/cyclooxygenase pathways are involved in the vasodilation. In microvessels, relaxation to insulin and IGF-I is not mediated by NOS/cyclooxygenase pathways but rather through K(+)-dependent mechanisms.

Reexamination of tympanic membrane temperature as a core temperature.

Controversies surrounding tympanic temperature (Tty) itself and techniques for measuring it have dampened the potential usefulness of Tty in determining core temperature (operationally defined here as the body temperature taken at a deep body site). The present study was designed to address the following questions. 1) Can a tympanic membrane probe be made that is safer and more reliable than its predecessors? 2) Why is the effect of facial cooling and heating on Tty so inconsistent in reports from different laboratories? 3) Is Tty still useful as a measure of core temperature? Data from this study, obtained with a modified thermocouple probe, suggest that the widely reported facial skin cooling effect on Tty is most probably due to thermal contamination from the surrounding ear canal wall and/or suboptimal contact of the probe sensor with the tympanic membrane because 1) Tty that fell during facial cooling was increased to the precooling level by the repositioning of the probe sensor; 2) Tty determined by using a probe with a larger sensor area (the sensor soldered to a steel wire ring)tended to fall in response to facial cooling, whereas Tty determined with a thermally insulated probe ring did not; and 3) Tty obtained under careful positioning of the insulated probe was relatively insensitive to facial cooling or heating. Because Tty was practically identical to esophageal temperature (Tes) in the steady state, i.e., 36.83 +/- 0.20 (SD) degrees C for Tty and 36.87 +/- 0.16 degrees C for Tes at room temperature (n = 11), and because facial cooling had little effect on both Tty and Tes (36.86 +/- 0.17 degrees C for Tty and 36.86 +/- 0.26 degrees C for Tes during facial or scalp skin cooling), we support the postulate that Tty is a good measure of core temperature. The temperature transient in response to foot warming was detected 5 min (n = 2) faster with Tty than with Tes. Thus, with further improvements in the design of the probe. Tty can become a standard for determination of core body temperature.

Influence of PCPA, shock level, and home-cage conditions on shock-induced aggression.

In a series of experiments, the effect of parachlorophenylalanine (PCPA) on shock-induced fighting was assessed rats raised and maintained under either a 12-hr alternating light-dark cycle (LD) or constant light conditions (LL). PCPA increased shock-induced aggression only in LL groups when testing was accomplished using a 2 mA shock; PCPA resulted in increased aggression in groups from the LD condition only when testing was done at 1 mA. A procedure that used castrated and intact cagemates to manipulate home-cage social experience provided evidence for a role for social experience in determining differences between LL and LD reared rats in shock-induced aggression. However, these data also suggested that home-cage social experience was not a factor in the lighting condition influence on the effect of PCPA on shock-induced aggression. Finally, a separate experiment demonstrated that diurnal rhythms in shock-induced aggression were disrupted by handling and vehicle injection in the control procedures, so the possible role of serotonin in diurnal rhythms of aggression behavior could not be assessed.

Influence of home-cage lighting conditions on shock-induced fighting.

A series of experiments was conducted to assess the influence of home-cage lighting conditions on shock-induced aggression in rats. The first two experiments tested rats six times within 24 hr and demonstrated that subjects maintained on a light/dark (LD) cycle fought more than rats maintained on a 24-hr light schedule (LL). In addition, a periodic trend could be identified in the data of the LD groups but not in the data of the LL groups. The second two experiments assessed the effects of castration on this lighting effect. Castration of adults did not influence the lighting effects, but castration of weanling rats eliminated the group difference between LL and LD groups. However, the LD rats castrated at weaning did show the periodic trend characteristic of all of the LD groups tested within 24 hr. Two additional experiments assessed the effects of time of testing in between-subjects designs. Time of testing was a significant variable in the LD groups but unimportant in the LL groups. A final experiment demonstrated that the difference between the LD and LL groups does not emerge in a daily testing procedure.

Influence of colony lighting conditions on home-cage spontaneous aggression.

In a series of experiments the effects of colony lighting conditions on home-cage aggression were examined, and the relation among measures of home-cage aggressive behavior and shock-induced aggression were determined. In each experiment rats were maintained under either a light/dark (LD) cycle or a continous light (LL) schedule. Experiments 1A and 1B indicated that for cages of LD rats the highest rates of home-cage aggression occurred during the dark segment of the light cycle whereas the lowest rates of aggression characterized the light segment. In contrast, the rate of home-cage aggression was low and constant across time periods for cages of LL rats. Reflecting these differences between lighting conditions, regression analyses in Experiment 1B identified a periodic trend following the fundamental sine curve in the home-cage aggression data from cages of LD rats but not in the data from cages of LL rats. In Experiment 2 the relation between individual differences in home-cage aggression and shock-induced aggression and shock-induced aggression was found to be time dependent for pairs of LD rats. Correlations based on scores of home-cage aggression and shock-induced aggression obtained during the dark segment were positive and statistically significant. Correlations of these two aggressive behaviors based on scores obtained during the light segment were not statistically significant. For pairs of LL rats, no time-dependent pattern in the relation of home-cage aggression to shock-induced aggression was observed.