Spontaneous transient outward K(+) currents (STOCs) elicited by Ca(2+) sparks and steady-state K(+) currents modulate vascular reactivity, but effects of artery size, diabetic dyslipidemia, and exercise on these differentially regulated K(+) currents are unclear. We studied the conduit arteries and microvessels of male Yucatan swine assigned to one of three groups for 20 wk: control (C, n = 7), diabetic dyslipidemic (DD, n = 6), or treadmill-trained DD animals (DDX, n = 7). Circumflex artery blood flow velocity obtained with intracoronary Doppler and lumen diameters obtained by intravascular ultrasound enabled calculation of absolute coronary blood flow (CBF). Ca(2+) sparks were determined in pressurized microvessels, and perforated patch clamp assessed K(+) current in smooth muscle cells isolated from conduits and microvessels. Baseline CBF in DD was decreased versus C. In pressurized microvessels, Ca(2+) spark activity was significantly lower in DD versus C and DDX (P < 0.05 vs. DDX). STOCs were pronounced in microvessel (approximately 35 STOCs/min) in sharp contrast to conduit cells ( approximately 2 STOCs/min). STOCs were decreased by 86% in DD versus C and DDX in microvessels; in contrast, there was no difference in STOCs across groups in conduit cells. Steady-state K(+) current in microvessels was decreased in DD and DDX versus C; in contrast, steady-state K(+) current in conduit cells was decreased in DDX versus DD and C. We conclude that steady-state K(+) current and STOCs are differentially regulated in conduit versus microvessels in health and diabetic dyslipidemia. Exercise prevented diabetic dyslipidemia-induced decreases in baseline CBF, possibly via STOC-regulated basal microvascular tone.

Previous studies have documented increased K+ permeability of arterial smooth muscle in hypertension and suggested a role in altered arterial contractile function. To characterize the mechanisms responsible for these alterations, we determined the contribution of K+ current (IK) components to whole cell IK in freshly dispersed myocytes and tetraethylammonium (TEA)-induced contractile responses in mesenteric arteries of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Tetraethylammonium produced a larger tonic contractile response in SHR with a lower threshold compared to WKY (ie, 0.1 v 1 mmol/L), which was due in part to the larger Ca2+ current in SHR. Whole cell IK recorded by perforated patch methods was similar at a holding potential (HP) of -60 mV (IK60), but were larger in SHR when recorded from a HP of -20 mV (IK20). The selective blocker iberiotoxin (IbTX) was used to separate the contribution of voltage- (Kv) and calcium-dependent (KCa) components of IK60. The IK60 and IK20 component inhibited by 100 nmol/L IbTX (ie, KCa) was larger in SHR than in WKY myocytes, whereas the IbTX-insensitive IK60 component (ie, Kv) was larger in WKY. In the presence of IbTX, 1 and 10 mmol/L TEA inhibited a larger fraction of IK60 in SHR myocytes compared with WKY. The activation properties of the TEA-sensitive and TEA-insensitive Kv components determined by fitting a Boltzmann activation function to the current-voltage data, exhibited both group and treatment differences in the half maximal activation voltage (V0.5). The V0.5 of the TEA-sensitive Kv component was more positive than that of the TEA-insensitive component in both groups, and values for the V0.5 of both TEA-sensitive and TEA-insensitive components were more negative in SHR than WKY. These results show that SHR myocytes have larger KCa and smaller Kv current components compared with WKY. Furthermore, SHR myocytes have a larger TEA-sensitive Kv component. These differences may contribute to the differences in TEA contractions, resting membrane potential, Ca2+ influx, and KCa current reported in hypertensive arteries.

Metabotropic glutamate receptors (mGluRs) in the medulla oblongata have been suggested to be involved in the regulation of autonomic function. The aim of the present study was to examine the localization and expression of four types of mGluRs: mGluR1a, mGluR2/3, mGluR5, and mGluR7 in the dorsal and ventral autonomic nuclei of the medulla of the rat. The four mGluR subtypes studied were differentially distributed in distinct subnuclei in the nucleus of the solitary tract (NTS). mGluR1a immunoreactivity was identified in cell bodies, dendrites, and axonal processes in the intermediate, dorsal lateral, and interstitial subnuclei of the NTS. No mGluR1a immunoreactivity was observed in the commissural or medial NTS subnuclei. Immunoreactivity for mGluR2/3 and mGluR5 as observed in fibers and putative axonal processes in the interstitial, intermediate, and dorsolateral subnuclei of the NTS. In contrast, mGluR7 was expressed primarily in fibers and terminals in the central and commissural NTS subnuclei. Expression of mGluR2/3 was clearly evident in cell bodies, dendrites, and axonal processes within the area postrema. The vagal outflow nuclei were also studied. The dorsal motor nucleus of the vagus (DMN) contained mGluR1a cell bodies, dendrites, and axonal fibers and light mGluR2/3 processes. Throughout the rostral‐caudal extent of the compact and semicompact formation nucleus ambiguus, mGluR1a was found in cell bodies and fibers. Within the caudal and rostral regions of the ventral lateral medulla, mGluR1a was observed in cell bodies and fibers. Cell bodies containing mGluR1a were found adjacent to cells staining positive for tyrosine hydroxylase (TH) in these regions but were not colocalized with the TH staining. However, mGluR1a‐expressing neurons in the ventral lateral medulla did appear to receive innervation from TH‐containing fibers. These results suggest that the mGluR1a‐expressing neurons within the ventral lateral medulla are predominantly not catecholaminergic but may be innervated by catecholamine‐containing fibers. These data are the first to provide a mapping of the different mGluR subtypes within the medulla and may facilitate predictions regarding the function of L‐glutamate neurotransmission in these regions. J. Comp. Neurol. 403:486–501, 1999. © 1999 Wiley‐Liss, Inc.

Exercise training attenuates coronary smooth muscle phenotypic modulation and nuclear Ca 2ϩ signaling. Am J Physiol Heart Circ Physiol 283: H2397-H2410, 2002. First published July 26. 2002 10.1152/ajpheart.00371. 2001.-Physical inactivity is an independent risk factor for coronary heart disease, yet the mechanism(s) of exerciserelated cardioprotection remains unknown. We tested the hypothesis that coronary smooth muscle after exercise training would have decreased mitogen-induced phenotypic modulation and enhanced regulation of nuclear Ca 2ϩ . Yucatan swine were endurance exercise trained (EX) on a treadmill for 16-20 wk. EX reduced endothelin-1-induced DNA content by 40% compared with sedentary (SED) swine (P Ͻ 0.01). EX decreased single cell peak endothelin-1-induced cytosolic Ca 2ϩ responses compared with SED by 16% and peak nuclear Ca 2ϩ responses by 33% (P Ͻ 0.05), as determined by confocal microscopy. On the basis of these results, we hypothesized that sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA) and intracellular Ca 2ϩ stores in native smooth muscle are spatially localized to dissociate cytosolic Ca 2ϩ and nuclear Ca 2ϩ . Subcellular localization of SERCA in living and fixed cells revealed a distribution of SERCA near the sarcolemma and on the nuclear envelope. These results show that EX enhances nuclear Ca 2ϩ regulation, possibly via SERCA, which may be one mechanism by which coronary smooth muscle cells from EX are less responsive to mitogeninduced phenotypic modulation.endothelin-1; sarco(endo)plasmic reticulum Ca 2ϩ -ATPase; electron microscopy; fluorescence microscopy; swine SUBSTANTIAL EVIDENCE EXISTS supporting the role of chronic endurance exercise training in reducing the incidence of coronary heart disease (6, 39), yet the mechanism(s) of exercise-related cardioprotection remains unknown. Coronary heart disease can be subdivided into two general categories: diseases of coronary vessel tone, i.e., acute vasospasm and hypertension, and diseases of vessel injury, i.e., atherosclerosis. Several studies from our laboratory have addressed mechanisms associated with exercise training adaptations (for reviews, see Refs. 10 and 43). However, there are few studies (48) addressing exercise-related coronary smooth muscle adaptations and their relationship to resistance to the development of vascular disease.Atherosclerosis is a complex disease involving an inflammatory-fibroproliferative response that develops from various forms of insult to the endothelium and smooth muscle cells of the artery (38). The phenotypic modulation of smooth muscle cells plays a key role in the development of atherosclerosis and is characterized in part by increased DNA synthesis (34); altered functional receptor expression, including receptors involved in growth factor signaling (29); and subcellular/ ultrastructure morphology (35,38,47). In cells from diseased vessels, Ca 2ϩ regulation is also altered (18) and implicated in increased vessel tone and vasospasm (27, 28). We recently reported that localized Ca 2ϩ signaling...