Amelioration of depressed cardiopulmonary reflex control of sympathetic nerve activity by short-term exercise training in male rabbits with heart failure.

The reflex regulation of sympathetic nerve activity has been demonstrated to be impaired in the chronic heart failure (CHF) state compared with the normal condition (Liu JL, Murakami H, and Zucker IH. Circ Res 82: 496-502, 1998). Exercise training (Ex) appears to be beneficial to patients with CHF and has been shown to reduce sympathetic outflow in this disease state (Hambrecht R, Hilbrich L, Erbs S, Gielen S, Fiehn E, Schoene N, and Schuler G. J Am Coll Cardiol 35: 706-713, 2000). We tested the hypothesis that Ex corrects the reduced cardiopulmonary (CP) reflex response to volume expansion in the CHF state. Normal, normal with Ex, CHF, and CHF with Ex (CHF-Ex) groups (n = 10-21) of male New Zealand White rabbits were studied. CHF was induced by chronic ventricular pacing. Rabbits were instrumented to record left ventricular end-diastolic pressure (LVEDP), left ventricular end-diastolic diameter (LVEDD), and renal sympathetic nerve activity (RSNA). Experiments were carried out with the animals in the conscious state. Volume expansion was performed with 6% dextran in normal saline at a rate of 5 ml/min to approximately 20% of estimated plasma volume without any significant effect on mean arterial pressure being exhibited. The relationships between RSNA and LVEDP and between RSNA and LVEDD were determined by linear regression; the slopes served as an index of CP reflex sensitivity. Normal rabbits exhibited a CP reflex sensitivity of -8.4 +/- 1.5%delta RSNA/mmHg. This value fell to 0.0 +/- 1.3%delta RSNA/mmHg in CHF rabbits (P < 0.001). Ex increased CP reflex sensitivity to -5.0 +/- 0.7%delta RSNA/mmHg in CHF-Ex rabbits (P < 0.05 compared with CHF). A similar trend was seen when related to the change in LVEDD. Furthermore, resting RSNA expressed as a percentage of maximum RSNA in response to cigarette smoke was also normalized by Ex in rabbits with CHF. Ex had no effect on these parameters in normal rabbits. These data confirm an impairment of CP reflex sensitivity and sympathoexcitation in CHF vs. normal animals. Ex substantially restored both CP reflex sensitivity and baseline RSNA in CHF animals. Thus Ex beneficially affects reflex regulation in CHF, thereby lowering resting sympathetic nerve activity.

A possible indirect sympathomimetic action of metformin in the arterial vessel wall of spontanously hypertensive rats.

The antidiabetic drug metformin (MF) typically achieves only micromolar levels in plasma with normal therapeutic use. However, it is also known to accumulate in various tissues up to several times higher after standard oral dosing and we now have evidence from both in vivo and in vitro experiments with spontaneously hypertensive rats (SHR) that millimolar levels stimulate release of norepinephrine (NE) from vascular sympathetic nerve endings (SNEs). As shown in the present work with SHR tail arterial tissue (rich in SNEs), the known vasodilator effect of millimolar levels of MF on the smooth muscle (even if contracted with a nonadrenergic agonist), is attenuated by the presence of the SNEs unless phentolamine (an alpha receptor blocker) is present. We reasoned that the mechanism for this apparent NE-releasing action of MF is not exocytotic release as that would require depolarization of the neuronal cell membranes in SNEs, and MF at millimolar levels is known to repolarize (not depolarize) membranes of other cells. Thus, we tested the possibility that MF releases NE by an indirect sympathomimetic-like action. Such an action should be amplified by monoamine oxidase inhibitors (e.g. iproniazid) and blocked by NE-carrier inhibitors (e.g. desipramine). Accordingly, we found that the abovementioned attenuating effect of intact SNEs on MF's relaxation of SHR tail arterial tissue (compared to tissues in which SNEs were experimentally removed with 6-hydroxydopamine) was amplified nearly 3-fold by iproniazid (p<0.05) and blocked by desipramine (p<0.05). These results support an indirect sympathomimetic action of MF and raise the question whether commonly used antidepressants with properties similar to iproniazid and desipramine might alter MF's beneficial vasodilatory (and thus antihypertensive) effectiveness in diabetic patients with hypertension.

An inexpensive meter to measure differences in electrical resistance in the rat vagina during the ovarian cycle.

The inherent electrical resistance of the rat vaginal wall rises markedly near the beginning of estrus and then falls again to low levels for the remainder of the ovarian cycle. Accordingly, special instruments have been developed to measure such resistances (within seconds) on simply inserting a small probe fitted with a pair of recording electrodes into the vagina (i.e., the MK-10A impedance checker and the EC40 estrus cycle monitor). As described herein, these two instruments are far more convenient for monitoring individual cycles than more laborious methods in which vaginal smears are inspected for changes in numbers of cornified (C), nucleated (N), and leukocytic (L) cells. However, they are also expensive and their use has essentially remained uncited in the literature. Thus we sought to determine whether a simple, inexpensive electrical meter (with resistance-measuring capacity), as commonly used by professional electricians, would serve the same purpose. We chose a standard multifunctional meter (model 22-178, RadioShack) and attached leads to it fabricated from the internal wiring of a shielded audio cable (model 42-2387A, RadioShack), one male terminal of which was used as a vaginal probe. In rats from which vagina smears revealed cell numbers in the order of C > N > L (typical of early estrus) electrical resistances were high, 488 +/- 130 k Omega (18 rats). In rats from which vagina smears revealed all other possible cell distributions, electrical resistances (combined) were much lower (P < 0.05), 124 +/- 23 k Omega (32 rats). Thus readily accessible, inexpensive electrical meters may be useful in assessing the status of estrus in female rats, either to improve reproductive efficiencies and/or for other purposes involving experiments in which such information is desirable.

Opposing adrenergic actions of intravenous metformin on arterial pressure in female spontaneously hypertensive rats.

OBJECTIVE: Intravenous (i.v.) injection of the antidiabetic drug metformin rapidly lowers mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR). However, if autonomic ganglia or alpha-adrenoceptors are first blocked then metformin rapidly raises MAP in SHR. This study was conducted to further characterize the adrenergic mechanisms of these opposing i.v. actions of the drug. METHODS: Conscious, undisturbed female SHR with indwelling vascular catheters were used to measure acute effects of i.v. metformin (100 mg/kg; before and after sustained ganglionic blockade, GB, with chlorisondamine, 5 mg/kg) on: (1) circulating levels of catecholamines, (2) MAP after pharmacologic modulation of beta- as well as alpha-adrenoceptors and (3) all the above in the absence as well as presence of the adrenal medulla. RESULTS: Plasma norepinephrine (NE) and epinephrine (E) levels (pg/ml) were rapidly increased by i.v. metformin (8 SHR, p < 0.05) both before GB (delta NE = +146 +/- 41; delta E = +119 +/- 31) and after GB (delta NE = +79 +/- 24; delta E = +120 +/- 32). Similar increases in plasma NE (though not E) were seen in SHR without adrenal medullae. Blockade of beta-adrenoceptors with propranolol (pro; 3 mg/kg, 8 SHR) enhanced the rapid depressor response to i.v. metformin before GB (delta MAP, mmHg: -38 +/- 4 with pro vs -17 +/- 3 without pro; p < 0.05) and attenuated the rapid pressor response to i.v. metformin after GB (delta MAP, mmHg: +8 +/- 3 with pro vs +30 +/- 4 without pro; p < 0.05). Results were similar in SHR without adrenal medullae. Finally, if baseline MAP under GB was raised back to hypertensive levels with i.v. infusion of either NE or phenylephrine then i.v. metformin did not raise but rather reduced MAP in SHR. CONCLUSION(S): The acute depressor action of i.v. metformin in female SHR (1) is most likely due to a direct vasodilator action which includes inhibition of alpha-receptor-mediated vasoconstriction and (2) is buffered by an acute beta-receptor-mediated pressor action likely due to a direct metformin-induced release of NE from postganglionic sympathetic nerve endings.

Acute vasorelaxant effects of metformin and attenuation by stimulation of sympathetic agonist release.

We recently discovered 1) that intravenous injection of the antidiabetic drug metformin in the rat rapidly reduces arterial pressure elevations maintained by the alpha-adrenoceptor agonist phenylephrine (PE) and 2) that direct administration of metformin to isolated rat tail arterial tissue rings rapidly relaxes PE-induced contractions. To further characterize this potential direct vasodilator action, we examined effects of metformin on contractions induced not only by PE but also by norepinephrine (NE) and by nonadrenergic agonists (5-hydroxytryptamine, 5HT; arginine vasopressin, AVP). Also, because the rat tail artery contains abundant adrenergic nerve endings we conducted these tests not only in arterial rings with nerve endings intact but in rings in which they had been removed by pretreatment with 6-hydroxydopamine. In intact rings, metformin at levels from approximately 0.2 to 20 mmol/L rapidly relaxed half-maximal contractions induced by PE and NE similarly and to a markedly greater degree than contractions induced by 5-HT (p<0.05). Metformin did not relax AVP-induced contractions. In addition, removal of adrenergic nerve endings facilitated metformin's relaxant effects (p<0.05). Thus, the acute vasodilator action of metformin appears 1) to be selectively more powerful on arterial smooth muscle contractions induced adrenergically versus nonadrenergically and 2) to be buffered by a possible metformin-induced release of endogenous NE from adrenergic nerve endings. Such results were not seen during relaxation produced by either the calcium channel inhibitor nifedipine or the nitrovasodilator nitroprusside suggesting that metformin's effects are mediated by other mechanisms.

4-Aminopyridine antagonizes the acute relaxant action of metformin on adrenergic contraction in the ventral tail artery of the rat.

The ability of metformin (MF) to acutely relax phenylephrine (PE)-induced contraction in the isolated rat tail artery is reported to be accompanied by repolarization of the arterial smooth muscle cell (SMC) membranes. These membranes contain potassium (K) channels which if opened could mediate such repolarization and resultant relaxation. We have shown that the acute relaxation of rat tail arterial tissue rings by graded levels of MF > or = 0.24 mmol/L is markedly antagonized by a high concentration of tetraethylammonium (TEA; 10 mmol/L) which nonselectively inhibits nearly all K channels. Thus, we tested effects of more selective inhibitors of K channels in the same tissue. We also tested MF for relaxation of contractions induced by high levels of extracellular K. To avoid confounding variables, we also conducted these tests in arterial rings in which endothelium and sympathetic nerve endings had been removed. In the absence of K channel inhibition, half-maximal PE-induced contractions were rapidly relaxed by all levels of MF with an EC50 of 1.7+/-0.2 mmol/L (n=8 rings). 1 mmol/L 4-aminopyridine (4AP) which only inhibits voltage-operated and ATP-sensitive K channels markedly antagonized this relaxation, shifting the EC50 for MF to 7.5+/-0.7 mmol/L (n=8; p < 0.05). TEA at 1 mmol/L (which only inhibits calcium-activated K channels), barium at 20 micromol/L (which only inhibits inward rectifier K channels) and glyburide at 5 micromol/L (which only inhibits ATP-sensitive K channels) did not alter this relaxation. Finally, MF failed to relax contractions produced by elevations of extracellular K to levels high enough to abolish the K gradient across arterial SMC membranes. Thus, acute relaxation of rat tail arterial smooth muscle by MF may be dependent on the transmembrane K gradient and mediated at least in part by specific activation of K efflux through 4AP-sensitive voltage-dependent K channels in arterial SMC membranes.

Disparate effects of antidiabetic drugs on arterial contraction.

Type II diabetic patients and others with insulin resistance are at risk for development of hypertension characterized by elevated peripheral vascular resistance and loss of insulin's normal vasodilating activity. Oral antidiabetic drugs have recently been recognized to have disparate effects on arterial pressure in such patients and in related rodent models. Sulfonylureas (e.g., glyburide), which stimulate insulin secretion, have been reported either to increase or not to affect arterial pressure, whereas nonsulfonylurea agents with insulin-sensitizing properties, the biguanide metformin and various thiazolidinediones (eg, pioglitazone), have been reported to decrease arterial pressure in humans and rodents. To help elucidate these disparate effects, we investigated these agents for direct actions on arterial vascular contractility and its sensitivity to insulin. Preincubation of intact rat tail arterial tissue rings for 2 hours with known therapeutically effective antidiabetic concentrations of metformin and pioglitazone significantly attenuated the force of contractions produced by either potassium (membrane depolarization) or norepinephrine ([NE] adrenergic receptor activation). Glyburide did not influence these contractions. Preincubation with metformin also induced an attenuating (vasodilating-like) action of insulin on arterial tissue rings contracted by potassium. Conversely, glyburide induced an accentuating action of insulin on potassium-mediated contractions. These results are consistent with measures of vascular function obtained in the past after oral administration of the drugs, which suggested but did not prove that they may exert direct effects on arterial vascular contractility. Thus, metformin and thiazolidinediones may decrease arterial pressure partly by direct vasorelaxant mechanisms, with metformin having an additional effect of inducing vasorelaxation by insulin. In contrast, sulfonylureas may directly induce a paradoxical vasoconstrictor response to insulin.

Interactive effects of insulin with dihydrotestosterone on adrenergic tone in isolated rat tail arterial rings.

Reversal of sex-related differences in incidence of vascular diseases in Type II diabetics suggests that high circulating insulin may reverse normal differences in vascular actions of sex steroids. We have found that a high concentration of insulin can reverse small inhibitory actions of low estradiol on adrenergic tone in isolated arterial rings. Thus, we measured effects of high insulin on actions of dihydrotestosterone on adrenergic tone and specificity of these effects with respect to time of exposure to the steroid and its concentration. In the first of two studies, tail arterial rings from 16 male rats were incubated for 2 h with either dihydrotestosterone (0.0012 mumol/ L), insulin (0.5 mU/mL), dihydrotestosterone plus insulin, or vehicles. Rings were then contracted with norepinephrine administered cumulatively from 10(-9) to 10(-4) mol/L. Contractile responses to norepinephrine from 10(-7) to 10(-4) mol/L were increased by dihydrotestosterone in the absence (P < .05) but not in the presence of insulin. Also, norepinephrine's EC50 was reduced by dihydrotestosterone in the absence (P < .05) but not in the presence of insulin. In a second study (with rings from 12 more rats), the same low level of dihydrotestosterone failed to affect norepinephrine contractions acutely (that is, within 6 min), whereas much higher levels (12 and 120 mumol/L) rapidly inhibited the same contractions, independent of 2-h preincubation with insulin. Thus, prolonged exposure to a low physiological level of dihydrotestosterone enhances adrenergic tone, whereas acute exposure to high levels inhibits it. In addition, a high level of insulin specifically blunts the delayed enhancing effect of the low dihydrotestosterone. These results suggest possible mechanisms underlying sex-related differences in arterial vascular tone and the potential impact of hyperinsulinemia on such differences.

Differential inhibitory effects of antidiabetic drugs on arterial smooth muscle cell proliferation.

We compared three drugs representing different classes of antidiabetic pharmacology (glyburide, a sulfonylurea; pioglitazone, a thiazolidinedione; and metformin, a biguanide) in terms of their direct effects on proliferation of cultured arterial smooth muscle cells (SMC). Rat aortic SMC were seeded at 4 x 10(4)/35 mm well. After 24 h, they were treated every 2 to 4 days for 2 weeks with 5% fetal bovine serum (FBS) in normal culture medium containing either drug vehicles or a low and a high but nontoxic level of glyburide (0.5 and 2.5 mumol/L), pioglitazone (1 and 5 mumol/L), and metformin (20 and 100 mumol/L). Vehicle-treated cells increased from 2 +/- 0 to 6 +/- 1 to 42 +/- 3 to 210 +/- 14 (cells per well x 10(4); 5 wells each) from day zero to 4 to 9 to 14. From day 9 to 14 these cell numbers were decreased an average of 20% by the 2.5 mumol/L glyburide (P < .05) and 43% by the 5 mumol/L pioglitazone (P < .05). The low levels of glyburide and pioglitazone and both the low and high levels of metformin failed to influence cell numbers. In a second experiment, even half the abovementioned high level of pioglitazone (2.5 mumol/L) still exerted a markedly greater antiproliferative effect on aortic SMC than a high level of 2.0 mumol/L glyburide (P < .05). In addition, neither drug's antiproliferative effect was influenced by a high level of insulin added to the medium (10 mU/mL). Similarly, a small but significant stimulatory effect of this high insulin on cell proliferation (P < .05) was not significantly affected by these two drugs (although pioglitazone tended to inhibit it). These results suggest that thiazolidinediones may be more useful antidiabetic agents than sulfonylureas and biguanides in inhibiting abnormal arterial SMC proliferation associated with atherosclerosis and postangioplastic restenosis which are common in diabetic patients.

Effects of pioglitazone on calcium channels in vascular smooth muscle.

Pioglitazone, an insulin-sensitizing, antidiabetic agent, has blood pressure-lowering effects in insulin-resistant hypertensive rats and attenuates growth factor-induced increases of intracellular Ca2+ in rat aortic vascular smooth muscle cells. To determine whether modulation of voltage-dependent Ca2+ channels plays a role in this association, we investigated the effects of pioglitazone on voltage-dependent current in cultured rat aortic (a7r5) and freshly dissociated rat tail artery vascular smooth muscle cells. Both cell types were studied with whole-cell patch-clamp techniques. Current through L-type Ca2+ channels was elicited with a voltage ramp in the presence of Ba2+ substituted for Ca2+. T-type Ca2+ current was studied using a two-pulse protocol that enabled the isolation of transient current. In a7r5 vascular smooth muscle cells, 2-minute application of pioglitazone (5 and 10 mumol/L) reduced L-type current by 7.9 +/- 1.0% (n = 8) (mean +/- SEM, number of cells) and 14.5 +/- 3.0% (n = 9) (P < .01, two-tailed paired t test), respectively. In contrast, 2-minute application of pioglitazone had no significant effect on T-type Ca2+ current. In freshly dissociated tail artery vascular smooth muscle cells, 2-minute application of 10 mumol/L pioglitazone had an insignificant effect (4.8 +/- 5.6% reduction); however, 25 mumol/L pioglitazone reduced L-type current by 27.3 +/- 7.2% (n = 5) (P < .01). Two-minute application of 0.1% or 0.2% dimethyl sulfoxide (vehicle) alone had no significant effects on currents in either type of vascular smooth muscle cell.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of oral calcium and potassium on endothelium-dependent relaxation in hypertensive rats.

High oral potassium (K) decreases stroke incidence in aging high salt-fed stroke-prone spontaneously hypertensive rats (SHRSP). We have seen high oral Ca increase stroke incidence in aging high salt-fed SHRSP without increasing blood pressure (BP) but with signs of K wasting. Therefore, we sought to determine whether high oral Ca suppresses the previously reported oral K-related enhancement of arterial endothelium-dependent relaxation as seen in younger high salt-fed SHRSP before the appearance of strokes. Four groups of female SHRSP were fed high-salt diets containing either low (0.4%) or high (1.6%) K with low (0.4%) and high (1.6%) Ca from age 1 to 4 mos. High oral K decreased BP independent of Ca intake (P < 0.05). High oral Ca did not affect BP. In contrast to aging SHRSP, high oral Ca neither increased urinary excretion nor decreased plasma concentration of K in these young adult SHRSP. However, high (vs. low) oral K only significantly reduced the half-maximal effective dose for acetylcholine-induced relaxation of aortic rings from rats fed low (18 +/- 3 vs. 38 +/- 6 nM, P < 0.05) not high Ca (25 +/- 5 vs. 31 +/- 3 nM). Neither oral K nor Ca affected nitroprusside-induced relaxation. Thus high oral Ca by itself does not impair endothelium-dependent relaxation in young adult high salt-fed SHRSP, but yet it suppresses the enhancing effect of high oral K on such relaxation and does so without altering BP, K balance, or endothelium-independent relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced bradycardia but not renal sympathoinhibition during hemorrhage in rats with area postrema lesions.

Hypotensive hemorrhage inhibits renal sympathetic nerve activity (SNA) and heart rate (HR) in rats. The area postrema (AP) is reported to modulate autonomic responses to arginine vasopressin (AVP) and may be a site where circulating AVP influences SNA and HR during hypotensive hemorrhage. We found a similar renal sympathoinhibition in AP-lesioned (APX) and sham-lesioned (Sham) rats during hypotensive hemorrhage and a greater bradycardia in APX compared with Sham rats. Further inhibition of renal SNA with AVP infusion was not observed in APX rats, although the bradycardic action of AVP infusion was comparable to that in Sham rats. Thus the AP attenuates bradycardia but not renal sympathoinhibition during hypotensive hemorrhage in normal rats. Nonetheless, an intact AP permits further reduction in renal SNA during infusion of AVP. If AVP contributes to hypotensive hemorrhage-induced renal sympathoinhibition, its action may occur at sites other than the AP or at the AP where such action is counterbalanced by sympathoexcitatory factor(s) also activated during hypotensive hemorrhage. Finally, enhanced bradycardia during hypotensive hemorrhage in APX rats suggests it may not be the site of action for AVP-induced bradycardia in intact rats.

Sex-specific effects of an insulin secretagogue in stroke-prone hypertensive rats.

Glyburide, an insulin secretagogue and an insulin-sensitizing agent, lowers blood pressure in normal male and female dogs when administered acutely. Because insulin resistance may contribute to spontaneous hypertension in rats, we sought to determine if long-term administration of glyburide (5 mg/kg per day by diet, age 5 weeks to 5 months) would lower blood pressure in male and female stroke-prone spontaneously hypertensive rats. Arterial (aortic) rings from these rats were incubated with insulin in vitro (100 mU/mL) 1 hour before and during phenylephrine-induced contraction to determine if long-term glyburide administration improves vascular sensitivity to the intrinsic vasodilator action of insulin. Glyburide, however, significantly increased blood pressures and ratios of heart weight to body weight in 5-month-old female rats (+20 mm Hg diastolic, P < .05), with no significant change noted in male rats (+4 mm Hg diastolic). Glyburide increased plasma insulin levels (twofold, P < .04) in female but not in male rats. Glyburide did not affect plasma glucose or catecholamine levels. After incubation with insulin, aortic to rings from glyburide-treated female rats demonstrated more than 40% greater contractile responsiveness the phenylephrine compared with aortic rings from control female rats (P < .04). This insulin-dependent increase in phenylephrine-induced contraction consisted of a reversal in the in vitro action of insulin, from attenuation to accentuation of such contraction (P < .05). This change was not seen in male rats. Neither gender, glyburide, nor insulin influenced acetylcholine-induced relaxation of phenylephrine-induced contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Partial protection from salt-induced stroke and mortality by high oral calcium in hypertensive rats.

BACKGROUND AND PURPOSE: Repeated demonstration of an antihypertensive effect of high oral calcium in stroke-prone spontaneously hypertensive rats led us to determine whether it also protects such rats from premature mortality and stroke-related lesions. METHODS: Female stroke-prone rats (11-13 per diet) were fed high- and low-calcium (2.0% and 0.4%, respectively) diets with both high and low salt (7.0% and 0.3%, respectively) content from age 4 weeks until spontaneous death. In addition to life span, other variables measured included blood pressures, plasma chemistries, and histological characterization of stroke-related lesions. RESULTS: Life span was increased from 51 +/- 4 to 68 +/- 1 weeks (p less than 0.05) by high versus low oral calcium in rats fed high-salt diets; it was further increased to greater than or equal to 82 weeks (p less than 0.05) in rats fed low-salt (+/- added calcium) diets. As seen previously, high oral calcium attenuated salt-induced hypertension but did not affect blood pressure in rats fed low-salt diets. High versus low oral calcium exerted contrasting effects (p less than 0.05) on brain lesions (hemorrhages and infarctions) in rats fed high-salt diets, decreasing lesion size (242 +/- 21 versus 712 +/- 276 microns per rat [diameters seen in histological sections]) but increasing lesion number (8.9 +/- 2.4 versus 3.4 +/- 2.2 per rat); it exerted little influence on the few brain lesions that appeared in rats fed low-salt diets. CONCLUSIONS: High oral calcium may protect stroke-prone hypertensive rats from early salt-induced mortality at least partially by decreasing severity (size) of stroke-related lesions, an effect which may relate to decreased blood pressure. However, this protection may be limited by increased number (incidence) of such lesions, an effect which suggests that high oral calcium may increase the number of brain vessels susceptible to stroke-related injury independent of change in blood pressure.

Hypertension in insulin-resistant Zucker obese rats is independent of sympathetic neural support.

We have previously reported that insulin-resistant Zucker obese rats exhibit hypertension associated with impaired vascular smooth muscle (VSM) Ca2+ transport and proposed that this results from failure of insulin to regulate VSM Ca2+ transport in insulin resistance. However, hypertension in insulin-resistant states is generally attributed to hyperinsulinemia, with a consequent stimulation of sympathetic neural activity. Accordingly, the present study was conducted to determine whether the hypertension observed in Zucker obese rats compared with their lean controls was dependent on either increased sympathetic neural activity or exaggerated vascular reactivity. Intra-arterial blood pressure responses to ganglionic blockade with Ecolid (chlorisondamine chloride) and to graded intravenous injections of angiotensin II and norepinephrine were compared in 6- to 8-wk-old male Zucker rats and their lean controls (n = 10/group). The obese rats exhibited significant hypertension before ganglionic blockade (P less than 0.001), and this difference was largely sustained during ganglionic blockade (P less than 0.005). Furthermore, the obese rats exhibited greater pressor sensitivity to both angiotensin II and to norepinephrine during ganglionic blockade (P less than 0.01). Thus enhanced pressor sensitivity, independent of sympathetic neural activity, appears to support hypertension in Zucker obese rats.

Contrasting hemodynamic effects of high oral calcium in genetic models of salt-sensitive hypertension.

Interest in effects of oral calcium (Ca) on blood pressure is now generally focused on salt-induced hypertension. In this study hemodynamic effects of long-term high oral Ca were examined in two different genetic models of salt-sensitive hypertension, stroke-prone spontaneously hypertensive rats (spSHR) and Dahl salt-sensitive (DS) hypertensive rats. High vs low oral Ca (2.0 vs 0.4% Ca, 8-13 rats/diet) significantly (p less than 0.05) attenuated salt-induced hypertension (7% NaCl intake) in female spSHR (mean arterial pressure = 137 vs 175 mmHg) but aggravated such hypertension in female DS rats (141 vs 124 mmHg). Pressor responsiveness to norepinephrine (NE) and angiotensin (A) II were examined in the same rats. High oral Ca decreased pressor responses to graded intravenous injections of NE and AII in spSHR and increased such responses in DS rats. In spSHR, the decreased pressor responsiveness preceded the antihypertensive effect of high oral Ca. In summary, 2.0 vs 0.4% oral Ca produces contrasting effects on blood pressure in two genetic models of salt-sensitive hypertension (stroke-prone SHR and Dahl salt-sensitive rats). These contrasting effects on blood pressure may be related to differential effects of oral Ca on vascular responsiveness to endogenous vasoconstrictors in these two genetic models of salt-sensitive hypertension.

Area postrema and differential reflex effects of vasopressin and phenylephrine in rats.

In normal rats, baroreflex inhibitions of heart rate (HR) and splanchnic but not lumbar sympathetic neural activity (SNA) are greater when mean arterial pressure (MAP) is increased by intravenous infusion of arginine vasopressin (AVP) compared with phenylephrine (PE) or methoxamine. In normal rabbits, baroreflex inhibitions of HR and lumbar and renal SNA are all greater when MAP is increased by AVP vs. PE. The differential reflex bradycardic and renal sympathoinhibitory effects of AVP vs. PE in rabbits require an intact area postrema. To determine whether differential reflex effects of AVP vs. PE in rats is selective for HR or inclusive of renal SNA and to examine the role of the rat area postrema in such action, we monitored HR and renal SNA in normal (sham operated, n = 8) and area postrema-lesioned (APX, n = 8) rats under chloralose anesthesia during slow increases in MAP (less than 0.3 mmHg/s; 3 min) induced intravenously by AVP (0-16 mU.kg-1.min-1) and by PE (0-8 micrograms.kg-1.min-1). Reflex inhibition of HR (-delta betas.min-1.delta mmHg-1) was greater when MAP was increased by AVP vs. PE in normal rats (-2.7 +/- 0.5 vs. -1.7 +/- 0.1, P less than 0.05), and this difference was absent in APX rats (-2.5 +/- 0.5 vs. +/- -2.2 +/- 0.4). Similarly, maximum bradycardia (-delta beats/min) by AVP vs. PE was greater in normal rats (-64 +/- 8 vs. -48 +/- 7, P less than 0.05) but not in APX rats (-53 +/- 5 vs. -52 +/- 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of renal sympathetic activity and heart rate by vasopressin in hemorrhaged diabetes insipidus rats.

Hypotensive hemorrhage paradoxically decreases renal sympathetic nerve activity (SNA) and heart rate (HR) in normal rats. Interruption of vagal reflexes by cervical vagotomy prevents these inhibitory responses but does not unmask expected increases in either renal SNA or HR. Arginine vasopressin (AVP), which increases markedly during hemorrhage, may also exert an inhibitory action on responses of renal SNA and HR to hemorrhage. We tested the hypothesis that inhibition of renal SNA and HR by hemorrhage is absent in AVP-deficient diabetes insipidus (DI) rats and is restored by intravenous AVP replacement (1 mU.kg-1.min-1 before hemorrhage and 10 mU.kg-1.min-1 during hemorrhage). We also determined whether vagotomy unmasks significant increases in renal SNA and HR during hemorrhage in DI rats and whether AVP replacement prevents these increases. Under chloralose anesthesia, hemorrhage to 50 mmHg mean arterial pressure for 8 min did not decrease renal SNA or HR in AVP-deficient DI rats but decreased (P less than 0.05) renal SNA and HR in normal Long-Evans rats and in DI rats receiving AVP replacement. After vagotomy, hemorrhage increased (P less than 0.05) renal SNA and HR in AVP-deficient DI rats but did not alter renal SNA or HR in Long-Evans rats and AVP-treated DI rats. Thus renal SNA and HR during hemorrhage were consistently higher (P less than 0.05) in AVP-deficient DI rats compared with Long-Evans or AVP-treated DI rats both before and after vagotomy. In addition, vagotomy attenuated the inhibitory action of AVP on the response of HR but not the response of renal SNA to hemorrhage in DI rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal sympathetic nerves attenuate the natriuretic effects of atrial peptide.

Low frequencies of renal sympathetic nerve stimulation increase renal tubular sodium reabsorption without causing renal hemodynamic changes. We tested the hypothesis that the natriuretic responses to synthetic atrial peptides (atriopeptin III [APIII], 24 amino acids) are modulated by the renal tubular actions of the renal nerves. Responses to intravenous infusions of APIII (0.5 and 2.0 micrograms/kg/min) were examined in three groups of chloralose-anesthetized rats. Bilateral renal function studies were done in all three groups in which the right kidney was denervated and the left kidney was either left innervated (group I, n = 10) or the distal portion of the transected left renal nerves was stimulated at 15 V, 1 msec, and 0.5 Hz (group II, n = 8) or 1.0 Hz (group III, n = 8). In groups I, II, and III, diuretic and natriuretic responses to APIII were significantly (p less than 0.05) less in the kidneys with intact innervation or low-frequency (0.5 and 1.0 Hz) renal nerve stimulation than in the denervated kidneys. In conclusion, renal excretory responses to APIII are substantially modulated by the renal tubular actions resulting from low-frequency renal nerve stimulation. We speculate that the decrease in renal excretory responses to atrial peptides in pathophysiologic states such as congestive heart failure, nephrotic syndrome, and cirrhosis may result in part from an increase in the prevailing level of renal sympathetic nerve activity.