12-lipoxygenase in porcine coronary microcirculation: implications for coronary vasoregulation.

Noncyclooxygenase metabolites of arachidonic acid (AA) have been proposed to mediate endothelium-dependent vasodilation in the coronary microcirculation. Therefore, we examined the formation and bioactivity of AA metabolites in porcine coronary (PC) microvascular endothelial cells and microvessels, respectively. The major noncyclooxygenase metabolite produced by microvascular endothelial cells was 12(S)-hydroxyeicosatetraenoic acid (HETE), a lipoxygenase product. 12(S)-HETE release was markedly increased by pretreatment with 13(S)-hydroperoxyoctadecadienoic acid but not by the reduced congener 13(S)-hydroxyoctadecadienoic acid, suggesting oxidative upregulation of 12(S)-HETE output. 12(S)-HETE produced potent relaxation and hyperpolarization of PC microvessels (EC(50), expressed as -log[M] = 13.5 +/- 0.5). Moreover, 12(S)-HETE potently activated large-conductance Ca(2+)-activated K(+) currents in PC microvascular smooth muscle cells. In contrast, 12(S)-HETE was not a major product of conduit PC endothelial AA metabolism and did not exhibit potent bioactivity in conduit PC arteries. We suggest that, in the coronary microcirculation, 12(S)-HETE can function as a potent hyperpolarizing vasodilator that may contribute to endothelium-dependent relaxation, particularly in the setting of oxidative stress.

Inhalation of amyl nitrite and the measurement of left ventricular outflow velocity: studies in normal, young adults.

Amyl nitrite inhalation is useful in the identification of patients with provocable left ventricular (LV) outflow tract obstruction. However, there are no prospective studies that assess the normal change in LV outflow velocity during this intervention. Eighteen normal subjects (mean age, 34+/-5 years; 9 men and 9 women) inhaled amyl nitrite during measurement of LV outflow velocity. Peak velocity increased from 109+/-16 cm/s to 144+/-24 cm/s (P<0.001). There were no significant gender differences in velocity measurements at baseline or at peak. Our study provides prospective data that may be useful when evaluating young adults for LV outflow tract obstruction with Doppler echocardiography during amyl nitrite inhalation.

Functional status of the oldest-old in a home setting.

The purpose of this cross-sectional study was to examine six domains of functioning: physical, mental, social, spiritual, economic and activities of daily living. The primary inclusion criteria at the time of recruitment were that participants be over the age of 85, be cognitively intact, and be living in a home setting. Instruments used for the study included the Older Americans Resource Survey (OARS), Mini-Mental Status Examination (MMSE), Geriatric Depression Scale (GDS), Spiritual Well Being Scale (SWBS). Fifty subjects, mean age 89 years, lived alone (65%) or with their spouse (22%) in their homes. Person's correlation analysis found significant relationships among physical, mental, social, economic and activities of daily living. Good to excellent functioning was found in the mental (82%) and social (82%) domains. Highest functional impairments were identified with ability to carry out activities of daily living (72%) and in the domains of physical functioning (55%). Common chronic illnesses reported were arthritis (56%), hypertension (46%) and cardiac problems (30%). The average daily use of prescribed drugs was three times and over-the-counter use was once per day. Eleven per cent of subjects were mildly (7%) or moderately (4%) depressed. Subjects reported that they needed visiting nurses (29%), home health aids (20%) and help with shopping (24%) and transportation (24%). The data suggest that multidimensional assessment is necessary to identify nursing interventions that will regain, maintain or enhance functioning among oldest-old people.

Adrenergic and nonadrenergic regulation of hindlimb blood flow during stress in rats.

A conditioned emotional response paradigm was established to determine the roles of adrenergic and nonadrenergic neurotransmitters in the hemodynamic responses during stress in conscious rats. The alpha adrenoceptor antagonists, prazosin (alpha-1-selective) or phentolamine (nonselective), blocked the stress-induced increase in mean arterial pressure (MAP), but not the increase in iliac blood flow or the decrease in iliac vascular resistance. Stress-induced iliac dilation was eliminated by the nonselective beta-adrenoceptor antagonist sotalol. In rats treated with prazosin plus sotalol, stress increased MAP but did not alter iliac vascular resistance. In contrast, stress did not increase MAP after complete adrenergic blockade with phentolamine plus sotalol yet did decrease iliac vascular resistance. Bilateral adrenal demedullation (ADM) did not affect the hemodynamic responses during stress, but ganglionic blockade eliminated them in both intact rats and in rats subjected to ADM. The stress-induced vasodilation in rats with ADM was not altered by sotalol, in direct contrast to intact rats. Finally, in rats with ADM, neither atropine nor sotalol (individually or when combined) altered any of the hemodynamic responses elicited by stress. The data suggest that during a conditioned emotional response: 1) adrenal catecholamines are not critical to the hemodynamic responses; 2) the increase in MAP is mediated by alpha-1 and alpha-2 adrenoceptor activation and 3) most critically, the hindquarter vasodilation is mediated by the release of neural adrenergic and nonadrenergic, noncholinergic factors.

Quipazine increases renin release by a peripheral hemodynamic mechanism.

Systemically administered serotonin (5-HT) agonists have been suggested to act centrally to increase plasma renin activity (PRA) and arterial pressure (AP). To test this hypothesis, hemodynamic responses were determined in conscious male rats after intracerebroventricular (i.c.v.) or intravenous (i.v.) administration of the direct 5-HT agonist quipazine. When administered i.v., quipazine increased AP and PRA, and decreased renal blood flow (RBF); doses of quipazine i.c.v. that increased AP to a similar degree failed to increase PRA. The increase in PRA elicited by i.v. quipazine was not blocked by propranolol, suggesting non-neural mechanisms. The increase in AP and decrease in RBF elicited by i.v. quipazine were not eliminated by prazosin, enalapril, or a V1-vasopressin antagonist administered alone or in combination. LY 53857, a 5-HT2 antagonist that enters the central nervous system (CNS), blocked all responses to i.v. quipazine. In contrast, the peripheral 5-HT2 antagonist xylamidine blocked the renin and RBF responses, but only attenuated the pressor response to quipazine. These data suggest that quipazine can act in the CNS to increase AP, but when administered systemically quipazine also activates vascular 5-HT2 receptors to increase AP further and to decrease RBF. The increase in PRA caused by i.v. quipazine is secondary to renal hemodynamics and is unrelated to CNS actions of this drug.

Prazosin unmasks a renin response to intravenous para-chloroamphetamine.

When injected intraperitoneally, p-chloroamphetamine (PCA) causes the acute release of catecholamines and serotonin, increases mean arterial pressure (MAP) and increases plasma renin activity (PRA) in rats. Experiments were designed to determine the dose-response and time-course for the effect of PCA administered intravenously on PRA in conscious, unrestrained rats. It was found initially that intravenous doses of PCA ranging from 0.3 - 6.0 mg/kg caused rapid and marked hypertension, but produced variable effects on PRA for up to 30 minutes after injection. In a second study PCA (0.3 - 6.0 mg/kg) did not alter PRA at 30 or 60 minutes after intravenous injection, but did increase PRA 60 minutes after 10 mg/kg, intraperitoneally. When the hypertension elicited by intravenous PCA was abolished by pretreatment with the alpha 1-adrenoceptor antagonist prazosin (100 micrograms/kg, iv), PCA produced marked elevations in PRA from 15 - 60 minutes. Thus it appeared that the renin response to intravenous PCA was masked by an elevation in MAP; when the vascular response to PCA was blocked, a large increase in PRA was observed.