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Nankervis, Craig A., and Philip T. Nowicki. Role of endothelin-1 in regulation of the postnatal intestinal circulation. Am. J. Physiol. Gastrointest. Liver Physiol. 278: G367-G375, 2000.--Newborn intestine is uniquely prone to vasoconstriction in response to a wide variety of perturbations. To test the hypothesis that endothelin (ET)-1 is an important factor in this process, we determined the effects of exogenous ET-1 administration and blockade of endogenous ET-1 in vivo and in vitro in 3- and 35-day-old swine. Intramesenteric artery administration of exogenous ET-1 to vascularly isolated in vivo gut loops ([10.sup.-9] M/kg bolus) caused vasoconstriction and reduced gut [O.sub.2] uptake similarly in these age groups. Selective blockade of [ET.sub.A] or [ET.sub.B] receptors with BQ-610 or BQ-788, respectively, in vascularly isolated in vivo gut loops had no effect on gut vascular resistance or [O.sub.2] uptake in either age group; within in vitro gut loops, BQ-610 significantly increased vasoconstriction when perfusion pressure was reduced below baseline, but only in 3-day-old animals; i.e., it impaired the autoregulatory response to perfusion pressure reduction. Exogenous ET-1 significantly decreased capillary perfusion within in vitro gut loops, as evidenced by a decrease in capillary filtration coefficient, but only in 3-day-old animals; furthermore, blockade of endogenous ET-1 activity with BQ-610 significantly enhanced capillary filtration coefficient in 3-day-old animals and increased [O.sub.2] extraction ratio. ET-1 did not depress intestinal metabolic rate, as evidenced by its effect on the [O.sub.2] uptake-blood flow relationship; it did compromise tissue oxygenation because of its effects on intestinal [O.sub.2] transport. ET-1 concentration in mesenteric venous effluent exceeded arterial concentration, but only in 3-day-old intestine, suggesting production of ET-1 by newborn intestine. We conclude that ET-1 exerts an age-dependent effect on intestinal hemodynamics in postnatal intestine, having a greater impact in 3- than in 35-day-old intestine. swine; newborn intestine; intestinal circulation physiology

Lambers, Donna S., Suzanne G. Greenberg, and Kenneth E. Clark. Functional role of angiotensin II type 1 and 2 receptors in regulation of uterine blood flow in nonpregnant sheep. Am. J. Physiol. Heart Circ. Physiol. 278: H353-H359, 2000.--The objective was to determine the receptor subtype of angiotensin II (ANG II) that is responsible for vasoconstriction in the nonpregnant ovine uterine and systemic vasculatures. Seven nonpregnant estrogenized ewes with indwelling uterine artery catheters and flow probes received bolus injections (0.1, 0.3 and 1 [micro]g) of ANG II locally into the uterine artery followed by a systemic infusion of ANG II at 100 mg [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1] for 10 min to determine uterine vasoconstrictor responses. Uterine ANG II dose-response curves were repeated following administration of the ANG II type 2 receptor ([AT.sub.2]) antagonist PD-123319 and then repeated again in the presence of an ANG II type I receptor ([AT.sub.1]) antagonist L-158809. In a second experiment, designed to investigate the mechanism of ANG II potentiation that occurred in the presence of [AT.sub.2] blockade, nonestrogenized sheep received a uterine artery infusion of L-158809 (3 mg/min for 5 min) prior to the infusion of 0.03 [micro] g/min of ANG II for 10 min. ANG II produced dose-dependent decreases in uterine blood flow (P [is less than] 0.03), which were potentiated in the, presence of the [AT.sub.2] antagonist (P [is less than] 0.02). Addition of the [AT.sub.1] antagonist abolished the uterine vascular responses and blocked ANG II-induced increases in systemic arterial pressure (P [is less than] 0.01). Significant uterine vasodilation (P [is less than] 0.01) was noted with [AT.sub.1] blockade in the second experiment, which was reversed by administration of the [AT.sub.2] antagonist or by the nitric oxide synthetase inhibitor [N.sup.[Omega]] -nitro-L-arginine methyl ester. We conclude that the [AT.sub.1]- receptors mediate the systemic and uterine vasoconstrictor responses to ANG II in the nonpregnant ewe. [AT.sub.2]-receptor blockade resulted in a potentiation of the uterine vasoconstrictor response to ANG II, suggesting that the [AT.sub.2]-receptor subtype may modulate uterine vascular responses to ANG II potentially by release of nitric oxide. PD-123319; L-158809; pregnancy

Angina pectoris is characterized by chest pain that results when the demands of the heart muscle for oxygen are exceeded by the capacity of the coronary arteries to supply blood, the ischemic threshold. Clinical experience has shown that angina may result from exercise, but it also may result from mental stress. In the November 28, 1991 issue of The New England Journal of Medicine, researchers measured the response of the coronary arteries to mental stress. Heart patients were asked to perform arithmetic calculations while the researchers subjected them to interruptions and annoyances. Visual observation of the coronary arteries using angiography revealed that many of the smooth artery segments, regions of artery not affected by atherosclerosis, either dilated in response to the mental stress or remained about the same. In contrast, regions of the arteries that were already partially obstructed by atherosclerosis constricted in many patients during the mental stress. It should be emphasized, however, that the amount of constriction observed in this study is unlikely to be the cause of the heart muscle ischemia and the angina that is associated with mental stress. Narrowing of the vessels does not necessarily mean a decrease in blood flow, since the rate of blood flow can speed up to result in the same net flow. Far greater obstructions are required before a serious impairment of blood flow results. The net flow of blood into the heart muscle is the sum of the interaction of a variety of physiological factors. One possibility is that, while the effects of mental stress on the larger arteries may be easily observed, it may be that the smaller arteries are responsible for obstructing the adequate flow of blood. Many of the smaller arteries are too small to be visible on angiography. Heart disease is a very complex problem, and the more that is learned about the physiology of cardiovascular disease, the more complex it seems to become. (Consumer Summary produced by Reliance Medical Information, Inc.)

The medical profession and the general public are both aware that heart attacks are more common in the morning than at any other time of day. Many different research studies have examined physiological factor that vary during the normal daily cycle and may contribute to the variations in the risk of heart attack. In the October 3, 1991 issue of The New England Journal of Medicine, researchers have added to this growing body of information by demonstrating that the arteries are more constricted in the morning and therefore provide more resistance to blood flow. These researchers have shown that this constriction seems to by modulated by alpha-adrenergic receptors, specific hormone receptors that operate as a part of the sympathetic nervous system. These findings are important, but much more needs to be learned about the daily changes in heart attack risk. The present study was conducted using healthy volunteers; do the same factors influence the cardiovascular systems of people with high blood pressure? Are the same physiological influences at work in patients with coronary artery disease? Furthermore, while it is plausible that the increase in blood vessel resistance in the morning may affect the risk of heart attack, it is far from certain whether it actually does play a role in the onset of a heart attack. A heart attack results from the interplay of many different factors, and the factors that are most important in accounting for the increased heart attack incidence in the morning remain to be identified. Unfortunately, the results of the present study provide no hints that might be useful in preventing heart attacks. Prevention is critical; the majority of heart attack deaths occur before the patient can be brought to a hospital. About 500,000 deaths each year, a full quarter of all deaths in the United States, are attributed to heart attacks. ("Heart attack" is an imprecise term which includes both myocardial infarction and sudden cardiac death.) Of these deaths, about 300,000 occur before the patient reaches the hospital. Medicine may go a long way simply by encouraging the reduction of risk factors such as smoking and high cholesterol. It may be possible to further reduce the rate of heart attacks by identifying the factors that not only set the stage for the heart attack, but initiate the actual event. (Consumer Summary produced by Reliance Medical Information, Inc.)

The CYP450 hydroxylase pathway contributes to P2X receptor-mediated afferent arteriolar vasoconstriction. Am J Physiol Heart Circ Physiol 281: H2089-H2096, 2001.--This study was conducted to test the hypothesis that the cytochrome P-450 (CYP450) metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to the afferent arteriolar response to P2 receptor activation. Afferent arteriolar responses to ATP, the P2X agonist, [alpha],[beta]-methylene ATP and the P2Y agonist UTP were determined before and after treatment with the selective CYP450 hydroxylase inhibitor, N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) or the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE). Stimulation with 1.0 and 10 [micro]M ATP elicited an initial preglomerular vasoconstriction of 12 [+ or -] 1% and 45 [+ or -] 4% and a sustained vasoconstriction of 11 [+ or -] 1% and 11 [+ or -] 2%, respectively. DDMS or 20-HEDE significantly attenuated the sustained afferent arteriolar constrictor response to ATP. [alpha],[beta]-Methylene ATP (1 [micro]M) induced a rapid initial afferent vasoconstriction of 64 [+ or -] 3%, which partially recovered to a stable diameter 10 [+ or -] 1% smaller than control. Both DDMS and 20-HEDE significantly attenuated the initial vasoconstriction and abolished the sustained vasoconstrictor response to [alpha],[beta]-methylene ATP. UTP decreased afferent diameter by 50 [+ or -] 5% and 20-HEDE did not change this response. In addition, the ATP-induced increase in the intracellular [Ca.sup.2+] concentration in preglomerular microvascular smooth muscle cells was significantly attenuated by 20-HEDE. Taken together, these results are consistent with the hypothesis that the CYP450 metabolite 20-HETE participates in the afferent arteriolar response to activation of P2X receptors. ATP; UTP; [alpha],[beta]-methylene adenosine trisphosphate; afferent arterioles; renal microcirculation; 20-hydroxyeicosatetraenoic acid

A study was conducted to analyze the impact of infusions of atrial, B-type and C-type natriuretic peptide (BNP) in normal conscious dogs. Each natriuretic peptide was infused at step-up doses to increase circulating levels of the infused peptide from -2 to 20-fold. Experimental results indicated that the infusion of homologous BNP caused dose-related, reversible mesenteric vasoconstriction.

A study was conducted on the mechanistic foundations for postnatal intestinal vasoconstriction during systemic hypotension. The effects of intestinal response to blood flow and pressure were examined. Data from comparing responses of 3-day-old and 35-day-old swines were analyzed. The findings confirmed the mediation by angiotensin II and endothelin-I and the vascular regulatory control of intestinal vasoconstriction during systemic hypotension.