Renal and systemic vascular conductances in renal wrap hypertension in rabbits

The contribution of renal vascular conductance to the fall in total peripheral conductance during the development of renal wrap hypertension was determined in conscious rabbits. Measurements were made 28 days after renal wrap (n = 9) or sham operation (n = 8). Blood pressure was about 50 mmHg higher in the wrapped group as compared to the sham-operated group. This was due to a fall in total peripheral conductance of about 42%. Cardiac output was not significantly different between wrap and sham groups. Renal vascular conductance was 0.42 ml/min per mmHg lower in the wrap compared to the sham-operated group (P less than 0.001). Total peripheral conductance was 3.93 ml/min per mmHg lower in the wrap compared to the sham group (P less than 0.01). The reduction in renal vascular conductance in wrapped rabbits, which is probably due to compression caused by the thickening renal capsule, accounts for about 10% of the fall in total peripheral conductance. We suggest that this mechanically induced reduction in renal conductance is involved in the initiation and maintenance of the hypertension, but is only a minor contributor to the overall change in blood pressure.     

Structural factors increase blood pressure through the interaction of resistance vessel geometry with neurohumoral and local factors: estimates in rabbits with renal cellophane-wrap hypertension with intact effectors and during neurohumoral blockade

BACKGROUND : The structural changes in hypertension include narrowing of the lumen of the large resistance vessels and an increase in their wall thickness : lumen ratio. Their haemodynamic role has been controversial. OBJECTIVE : To examine resting haemodynamics and the responses to graded drug-induced changes in tone in renal cellophane-wrap (wrap) and sham-operated (sham) rabbits, when their neurohumoral effectors were intact and during high-level blockade. METHODS : Each rabbit was implanted with a flow probe for measuring cardiac output, had catheters inserted for drug infusions, and underwent mean arterial pressure (MAP) measurements. Resting values were determined and we infused graded doses of dilator and constrictor drugs: acetylcholine or adenosine; angiotensin II or methoxamine. The dilator and constrictor dose-response curves were combined into a single relationship for MAP, cardiac output, total peripheral conductance (TPC) and heart rate; total peripheral resistance (TPR) was estimated as 1/TPC. RESULTS : Throughout the range of vascular tone and with intact effector function, MAP was greater and TPC lower in wrap than in sham rabbits, and cardiac output was the same in both groups. The ratios of wrap : sham slopes of the log dose-response regression lines were 0.47 for TPC, 2.04 for TPR and 1.89 for MAP. Thus MAP and TPR responses were enhanced to the same degree in wrap rabbits. During neurohumoral block, baroreflex-mediated heart rate responses were abolished. In addition, resting vascular tone was lower than with intact effectors in both wrap and sham rabbits; however, the ratios of wrap : sham slopes for TPC and TPR were similar to those with intact effectors, whereas the ratio for the slope for MAP was slightly smaller, although still enhanced. CONCLUSION : In wrap hypertension, the enhanced MAP and TPR responses are in accord with an interaction between vascular geometry and the sum of altered neurohumoral + local activity, plus a rarefaction component.     

Inhibition of the Na+/H+ exchanger attenuates the deterioration of ventricular function during pacing-induced heart failure in rabbits

Aims: Inhibition of the Na+/H+-exchanger (NHE) preserves myocardial morphology and function in rat and mouse models of hypertrophy and failure. The mechanism(s) involved in such cardioprotective effects remain(s) unclear, but might involve blockade of increased protein kinase activity as observed in untreated hearts. Methods and results: We investigated the functional, morphological and biochemical consequences of NHE-inhibition with BIIB722 in rabbits with pacing-induced heart failure (HF). In sham rabbits treated with placebo (n = 9) or BIIB722 (30 mg/kg/day po, n = 9), LV end-diastolic diameter (LVEDD) and systolic fractional shortening (FS, %) remained unchanged. In HF rabbits (n = 9), LVEDD increased and FS decreased from 31.5 +/- 1.4 to 8.1 +/- 0.9 (p < 0.05) at 3 weeks of LV pacing (400 bpm). Apoptosis, fibrosis and myocyte cross-sectional area as well as p38MAPK phosphorylation and iNOS protein expression were significantly increased in HF compared to sham rabbits. The activity of the 90 kDa NHE-kinase was greater in HF than in sham rabbits. In HF rabbits receiving BIIB722 prior to (18.1 +/- 2.2, n = 9) or following 1 week (15.5 +/- 1.6, n = 7) of pacing, FS at 3 weeks was better preserved than in untreated HF rabbits (p < 0.05). Apoptosis, fibrosis, myocyte cross-sectional area, p38MAPK phosphorylation and iNOS protein expression were significantly reduced in HF rabbits receiving BIIB722. Conclusion: NHE-inhibition attenuates the functional, morphological and biochemical derangements of pacing-induced HF in rabbits.     

Attenuation of the vasopressor effect of angiotensin II, vasopressin and alpha 1-adrenergic stimulation by bradykinin

The role of circulating bradykinin in the regulation of cardiovascular homeostasis was studied in the normotensive conscious rat using a competitive antagonist of bradykinin at the receptor level. This antagonist (B4162) was administered intravenously as a bolus dose of 400 micrograms. This dose was shown to effectively block the hypotensive effect of exogenous bradykinin (2.5 micrograms) for at least 5 min. The bradykinin antagonist was administered at the end of an infusion of angiotensin II (1 ng/min, n = 5, or 12.5 ng/min, n = 6), of methoxamine (0.5 micrograms/min, n = 5, or 4 micrograms/min, n = 6), of lysine vasopressin (0.25 mUI/min, n = 11) or of saline (10 microliter/min, n = 7). The bradykinin antagonist did not change the mean arterial pressure of the control rats. The low doses of angiotensin II and of methoxamine did not have an effect on mean blood pressure. The bradykinin antagonist however increased mean blood pressure of these rats within 1 min by 10 +/- 2 (p less than 0.01, mean +/- SEM) and by 12 +/- 3 (p less than 0.01) mmHg, respectively. The large dose of angiotensin II raised mean blood pressure from 127 +/- 3.6 to 142 +/- 4.9 mmHg and that of methoxamine from 130 +/- 2 to 146 +/- 5 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Renal Denervation on the Development of Cellophane-Wrap Hypertension in Rabbits

The development of hypertension in rabbits with bilateral cellophane wrapping of the kidneys was studied in animals with and without surgical denervatton of the kidneys. Mean arterial pressure was measured before and 14 and 28 days after surgery. After 14 and 28 days of wrapping, mean arterial pressure had increased 12 ± 3 mmHg and 31 ± 3 mmHg in rabbits with innervated kidneys and 7 ± 2 mmHg and 26 ± 2 mmHg in rabbits with denervated kidneys, respectively. The increases in arterial pressure were significantly less in the denervated animals. In sham wrap animals, renal denervation also resulted in significantly lower arterial pressure than in sham wrap+sham denervated rabbits. Noradrenaline concentration of denervated kidneys averaged only 4% of that measured in kidneys subjected to sham denervation. The results show that renal denervation slightly attenuated the degree of hypertension developed following renal wrapping. Since renal denervation produced a similar small decrease in arterial pressure in normotensive rabbits it is suggested that the effect is non-specific and probably due to loss of efferent renal sympathetic nerves.     

Adrenocorticotrophin-induced hypertension in the rat: haemodynamic, metabolic and morphological characteristics

Adrenocorticotrophin (ACTH) administration has been systematically studied in man and sheep. It raises systolic blood pressure (SBP) in the rat, but this has been little studied. ACTH was injected once daily at 0.5 mg/kg for 12 days in male Sprague-Dawley rats (n = 19). Sham-injected animals were studied in parallel (n = 15). ACTH increased SBP from 94 +/- 4 to 121 +/- 4 mmHg (P less than 0.001), significantly greater (P less than 0.02) than sham injection. The SBP of ACTH-treated rats was significantly higher than that of sham-injected rats when the same animals were measured by both the tail-cuff method (ACTH, 126 +/- 3 mmHg; sham, 99 +/- 3 mmHg) and direct arterial cannulation (ACTH, 137 +/- 2 mmHg; sham, 123 +/- 3 mmHg): P less than 0.005 and P less than 0.001, respectively. There was a loss of body weight, and increased water intake and urine output in ACTH-treated animals compared with both control (P less than 0.001) and sham treatments (P less than 0.02). ACTH increased plasma [Na] (sham, 140 +/- 1 mmol/l; ACTH, 145 +/- 1 mmol/l; P less than 0.001) and urinary Na excretion compared with control (P less than 0.01) and sham injection (P less than 0.05), and also decreased plasma [K] (sham, 4.6 +/- 0.2 mmol/l; ACTH, 3.3 +/- 0.8 mmol/l; P less than 0.01) and increased urinary K excretion (P less than 0.01) compared with control. SBP in adrenalectomized animals (n = 10) was unchanged by ACTH. ACTH increased adrenal, renal, cardiac and brain weights compared with sham injection (P less than 0.05). There were no significant changes in vascular morphology, although ACTH treatment increased glomerular epithelial cell droplets and abolished the adrenal zona glomerulosa.     

Reduction of aortic wall motion inhibits hypertension-mediated experimental atherosclerosis

Hypertension is a well-known risk factor for coronary artery disease and carotid and lower extremity occlusive disease. Surgically induced hypertension in hypercholesterolemic animals results in increased aortic wall motion and increased plaque formation. We tested the hypothesis that reduction in aortic wall motion, despite continued hypertension, could reduce plaque formation. New Zealand White rabbits (n=26) underwent thoracic aortic banding to induce hypertension and were fed an atherogenic diet for 3 weeks. In 13 rabbits, a segment of aorta proximal to an aortic band was externally wrapped to reduce wall motion. All animals were fed an atherogenic diet for 3 weeks. Four groups were studied: 1, coarctation control (no wrap, n=7); 2, coarctation with loose wrap (n=6); 3, coarctation with firm wrap (n=7); and 4, control (noncoarcted, n=6). Wall motion, blood pressure, and pulse pressure were measured at standard reference sites proximal and distal to the coarctation by use of intravascular ultrasound. Quantitative morphometry was used to measure intimal plaque. Mean arterial pressure and cyclic aortic wall motion were equally increased proximal to the aortic coarctation in all 3 coarcted rabbit groups compared with the control group (P:<0.001). Wall motion in the segment of aorta under the loose and firm wraps was no different from the control value. The external wrap significantly reduced intimal thickening in the 4 groups by the following amounts: group 1, 0.30+/-0.03 mm(2); group 2, 0.06+/-0.02 mm(2); group 3, 0. 04+/-0.02 mm(2); and group 4, 0.01+/-0.01 mm(2) (P:<0.001). Localized inhibition of aortic wall motion in the lesion-prone hypertensive aorta resulted in significant reduction in intimal plaque formation. These data suggest that arterial wall cyclic motion may stimulate cellular proliferation and lipid uptake in experimental atherosclerosis.     

Mechanism of syncope in patients with positive adenosine triphosphate tests

OBJECTIVES: We prospectively evaluated the mechanism of syncope in patients with positive adenosine triphosphate (ATP) tests (defined as the induction of atrioventricular [AV] block with a ventricular pause >/=6 s after an intravenous bolus of 20 mg ATP). BACKGROUND: Patients with unexplained syncope tend to have more positive ATP tests results than those without syncope. METHODS: An implantable loop recorder (ILR) was inserted in 36 ATP-positive patients (69 +/- 10 years; 22 women; median of 6 syncopal episodes); 15 of them also had a positive response to tilt testing. RESULTS: During the follow-up of 18 +/- 9 months, 18 patients (50%) had syncopal recurrence and 16 (44%) had an electrocardiographically documented episode: AV block (n = 3: paroxysmal in 2 and permanent in 1), AV block followed by sinus arrest (n = 1), sinus arrest (n = 5), sinus bradycardia <40 beats/min (n = 2), normal sinus rhythm (n = 2), sinus tachycardia (n = 1), rapid atrial fibrillation (n = 1), and ectopic atrial tachycardia (n = 1). Bradycardia was documented in a total of 11 cases (69%), and a long ventricular pause (4 to 29 s) was present in eight cases (50%). All three patients with ILR-documented AV block had previously had a negative tilt test, whereas seven of eight with ILR-documented sinus bradycardia or sinus arrest had previously had a positive tilt test. CONCLUSIONS: In patients with adenosine-sensitive syncope, the mechanism of syncope is heterogeneous, although bradycardia is the most frequent finding. Adenosine triphosphate-induced AV block predicts AV block as the mechanism of spontaneous syncope in only a few tilt-negative patients.     

Evidence for a sympatholytic effect of mibefradil in the pithed rat preparation

OBJECTIVE: The T-type prevalent calcium channel blocker mibefradil (MIB) was shown to possess N-type calcium channel blocking properties. As this particular type of calcium channel is known to be crucially involved in the neuronal release of noradrenaline, we have investigated whether MIB could be a sympatholytic drug. METHODS: To evaluate the sympathoinhibitory action, the effects of 3 and 10 micromol/kg MIB on the tachycardic effect of electrical stimulation of the preganglionic cardioaccelerator nerves in the pithed rat were investigated. The effect of MIB on the dose-response curve of externally applied noradrenaline was also studied. To compare the results with a classic L-type calcium channel blocker, the experiments were repeated with 3 and 10 micromol/kg verapamil (VER). RESULTS: The maximal increase in heart rate in response to electrical nerve stimulation was 96 +/- 7 bpm (control, n = 6), 70 +/- 6 bpm (3 micromol/kg MIB, n = 8), 57 +/- 6 bpm (10 micromol/kg MIB, n = 5), 93 +/- 5 bpm (3 micromol/kg VER, n = 6) and 46 +/- 7 bpm (10 micromol/kg VER, n = 5). The tachycardic response to electrical stimulation at 1, 5 and 10 Hz was completely blocked by 5 mg/kg intravenous guanethidine. The maximal increase in heart rate in response to noradrenaline was 96 +/- 4 bpm (control, n = 6), 103 +/- 6 (3 micromol/kg MIB, n = 6), 42 +/- 9 bpm (10 micromol/kg MIB, n = 5), 73 +/- 5 bpm (3 micromol/kg VER, n = 5) and 40 +/- 7 bpm (10 micromol/kg VER, n = 6). Under control conditions and in the presence of 3 micromol/kg MIB and VER the maximal effect of noradrenaline was reached at 0.1 micromol/kg whereas in the presence of 10 micromol/kg MIB and VER it was reached at a dose of 1 micromol/kg. MIB at a dose of 3 micromol/kg was significantly more effective in reducing the chronotropic response to electrical stimulation compared with externally applied noradrenaline. For VER the opposite holds true. These differences were not observed with doses of 10 micromol/kg MIB and VER. CONCLUSION: Mibefradil, besides its direct effect on cardiac T- and L-type calcium channels, reduces the release of noradrenaline from sympathetic nerve endings, most probably by inhibition of presynaptic N-type calcium channels. In the model used this effect is only observable at relatively low concentrations, most probably because of the direct cardiodepressant action of MIB provoked by L-type channel blockade.     

Tissue plasminogen activator (alteplase) in acute massive pulmonary embolism. A pilot study

Twenty six patients with acute (less than 5 days) pulmonary embolism (PE) confirmed by bilateral pulmonary angiography with a Miller index greater than 15 were given tissue plasminogen activator (Alteplase) (rt-PA) intravenously (n = 20) or directly into the pulmonary artery (n = 6). The dosage was 100 mg/7 hours (bolus 10 mg + 40 mg/2 hours + 50 mg/5 hours). Heparin (5000 IV as a bolus and 1000 IV/hour) was associated in all cases. The Miller index decreased from 24 +/- 1 (n = 26) before treatment to 12 +/- 1 (n = 25) (p less than 0.001) after 100 mg of Alteplase, and from 25 +/- 0.4 (n = 14) to 22 +/- 0.5 (n = 14) (p less than 0.001) after 50 mg. The mean pulmonary arterial pressures fell from 30 +/- 2 mmHg to 21 +/- 2 mmHg after 50 mg (n = 26) (p less than 0.001) and to 14 +/- 1 (n = 25) (p less than 0.001) after 100 mg of Alteplase. A decrease in mean pulmonary artery pressures (-22%, p less than 0.001) and total pulmonary resistances (-29%, p less than 0.001) was obtained after one hour of thrombolysis in 12 monitored patients. There were no fatalities. Severe haemorrhage occurred in 6 cases. Therefore, Alteplase induced a rapid dissolution of recent intrapulmonary thrombi without inacceptable haemorrhagic complications. Its action could be particularly beneficial in patients with right ventricular failure due to life threatening pulmonary embolism.     

L-arginine partially reverses established adrenocorticotrophin-induced hypertension and nitric oxide deficiency in the rat

BACKGROUND: L-arginine treatment prevents adrenocorticotrophin (ACTH) induced hypertension in the rat. This study examined whether L-arginine treatment could reverse established ACTH hypertension and its effects on markers of decreased NO activity. METHODS: Sixty-four male Sprague-Dawley rats were randomly divided into 6 groups given 12 days of treatment: (1) sham (0.9% NaCl, 0.5 ml/kg, subcutaneously, sc, n = 16); (2) ACTH (0.5 mg/kg/day, sc, n = 16); (3) sham + L-arginine (0.6% in food, from treatment day 8 onwards, n = 10); (4) ACTH + L-arginine (n = 10); (5) sham + D-arginine (0.6% in food, from T 8 onwards) (n = 6); and (6) ACTH + D-arginine (n = 6). Systolic blood pressure, water intake, urine volume, and body weight were measured every second day. At the end of the experiments, plasma and urinary nitrate/nitrite (NOx), plasma amino acid concentrations (in groups 1-4), and urinary cyclic guanosine monophosphate (cGMP) concentrations were measured. RESULTS: Sham, sham + L-arginine, and sham + D-arginine treatments did not affect blood pressure. ACTH increased systolic blood pressure (from 121 +/- 1 to 147 +/- 2 mmHg, p < 0.001, pooled control vs treatment day 12, mean +/- sem), and this was partially reversed by L-arginine (group 4: from 141 +/- 2 on day 8 to 133 +/- 1 mmHg on day 12, n = 10, p < 0.001). In contrast, D-arginine did not affect blood pressure in ACTH-treated rats (group 6). ACTH increased water intake and urine volume and decreased body weight, and L-arginine administration did not alter these parameters. ACTH decreased plasma citrulline (group 1 vs 2: 115 +/- 7 vs 67 +/- 6 micro M/L, n = 16, p < 0.001) and NOx concentrations (group 1 vs 2: 8.3 +/- 0.8 vs 4.5 +/- 0.6 microM/L, n= 10, p < 0.001) and these decreases were reversed by L-arginine treatment (group 4: citrulline 98 +/- 9 micro M/L, NOx 9.1 +/- 1.6 micro M/L, group 2 vs 4, both p < 0.05). ACTH produced marked increases in urinary cGMP excretion (group 1 vs 2: 0.5 +/- 0.1 vs 1.9 +/- 0.4 nmol/24 h, p < 0.01). CONCLUSION: Supplementation with L-arginine partly reversed established ACTH-induced hypertension and restored plasma NOx and citrulline concentrations to levels seen in sham-treated rats. These data are consistent with previous studies suggesting that functional NO deficiency has a role in ACTH-induced hypertension in rats.     

Adrenergic inhibition of endogenous acetylcholine release on postganglionic cardiac vagal nerve terminals

OBJECTIVE: The aim was to examine the adrenergic modulation of endogenous acetylcholine (ACh) release from vagal nerve terminals in the in vivo heart. METHODS: Using dialysis technique in anesthetized cats, we investigated the influence of exogenous noradrenaline on dialysate ACh response. Dialysis probes were implanted in the left ventricular myocardium and perfused with Krebs-Henseleit buffer containing eserine (10(-4) M) at 3 microl/min. Dialysate ACh concentration was measured as an index of ACh release from cardiac vagal nerve terminals. The dialysate ACh response to vagal nerve stimulation was examined before and after local administration of noradrenaline (10(-5) M) through dialysis probes. RESULTS: Noradrenaline significantly attenuated the dialysate ACh response to vagal nerve stimulation (10 Hz) from 9.5+/-1.8 to 5.4+/-1.2 nM (n=7). In the presence of the alpha-adrenergic antagonist phentolamine (10(-4) M), noradrenaline did not attenuate the dialysate ACh response (from 9.8+/-2.7 to 9.4+/-2.8 nM, n=6). The N-type Ca2+ channel blocker omega-conotoxin GVIA (10(-5) M) significantly attenuated the dialysate ACh response from 9.6+/-1.2 to 4.5+/-0.7 nM (n=8). In the presence of omega-conotoxin GVIA, noradrenaline did not attenuate the dialysate ACh response (from 3.8+/-1.4 to 3.5+/-1.3 nM, n=7). CONCLUSIONS: Our results suggest the presynaptic adrenergic inhibition of ACh release on postganglionic cardiac vagal nerve terminals. Adrenergic inhibition of Ca2+ influx through the N-type Ca2+ channels could play a predominant role in the decrease in ACh release.     

Orthostatic blood pressure changes and arterial baroreflex sensitivity in elderly subjects

BACKGROUND: orthostatic hypotension in elderly people is often attributed to diminished afferent baroreflex sensitivity, but this has not been demonstrated. We examined the hypothesis that postural change in blood pressure is related to baroreflex sensitivity, independent of the confounding effect of baseline blood pressure. METHODS: we studied 25 active, untreated elderly subjects free of postural symptoms (mean age 70 +/- 1 years): 16 with hypertension (clinic blood pressure 194 +/- 6/98 + 3 mmHg) and nine normotensive controls (clinic blood pressure 134 + 3/77 + 3 mmHg). We assessed baroreflex sensitivity from the heart rate and blood pressure responses to the Valsalva manoeuvre and a pressor and depressor stimulus (bolus phenylephrine injection or sodium nitroprusside infusion respectively). Subjects were then passively tilted to 60 degrees and maximum changes in systolic blood pressure, heart rate, forearm blood flow and forearm vascular resistance recorded. RESULTS: maximum change in systolic blood pressure with head-up tilt was correlated with supine systolic blood pressure (r = 0.60, P = 0.001). Maximum change in systolic blood pressure with orthostasis was greater in the hypertensive subjects (45 +/- 4 mmHg versus 29 +/- 6, P = 0.04) and the heart rate increment was less (16 +/- 2 bpm versus 24 +/- 4, P = 0.02). The increase in forearm vascular resistance with tilt was similar in the two groups (47 +/- 11 versus 38 +/- 7 units, P = 0.52). All three methods of assessing baroreflex sensitivity showed a reduction in the hypertensive subjects (all P < or = 0.02). Lower values of baroreflex sensitivity were related to greater falls in systolic blood pressure with tilt, after adjustment for the baseline level of systolic blood pressure. CONCLUSIONS: we found a relationship between baroreflex sensitivity and the systolic blood pressure fall with orthostasis, even after adjustment for prevailing systolic blood pressure. Despite equivalent changes in forearm vascular resistance with tilt, greater falls in systolic blood pressure were seen in hypertensive subjects than in normotensive controls, due in part to an inadequate baroreflex-mediated heart rate response. The postural fall in blood pressure often observed in elderly hypertensive subjects may be related to the reduced baroreflex sensitivity seen in this condition.     

Inositol phosphate formation in arterial smooth muscle from rabbits with perinephritis hypertension

Total inositol phosphate formation was measured in the aorta and femoral artery from rabbits at 1, 2 and 6 weeks after kidney wrapping, at which times the mean arterial pressures were 88 +/- 4, 96 +/- 3 and 126 +/- 7 mmHg against a control pressure of 74 +/- 3 mmHg. Noradrenaline-stimulated (10(-7) to 10(-4) mol/l) inositol phosphate formation was increased in the aorta and femoral artery from hypertensive rabbits at 2 weeks (aorta noradrenaline 10(-6) mol/l sham, 105 +/- 14%; hypertensive, 164 +/- 20% of control). Noradrenaline-stimulated inositol phosphate formation was unchanged at 1 and 6 weeks in the aorta. Endothelin-stimulated inositol phosphate formation was unchanged at 2 weeks. Basal inositol phosphate formation was not significantly different in normotensive and hypertensive animals. In perinephritis hypertension there is an alteration in phosphatidylinositol metabolism in arterial smooth muscle. This occurs at the time when the blood pressure is rising rapidly. This alteration may affect a specific phosphatidylinositol pool that is linked to the alpha-adrenoceptor but not to the endothelin receptor.     

Continuous, low dose of hydralazine, reduces acute hypoxic pulmonary hypertension without a corresponding fall in systemic arterial pressure

Administration of hydralazine in patients with pulmonary hypertension has been reported to cause excessive systemic vasodilatation, limiting its clinical utility (N Engl J Med 1982; 306: 1326). We studied the effects of hydralazine on hypoxic pulmonary vasoconstriction (HPV) in chronically instrumented sheep and evaluated whether different methods of intravenous administration could prevent severe systemic hypotension. Mean left atrial, pulmonary and systemic arterial pressures (Pla, Ppa and Psa mmHg), cardiac output (CO, l/min, electromagnetic flowmeter) and heart rate were measured continuously. Systemic (SVR) and pulmonary vascular resistances (PVR) were calculated by Psa/CO and (Ppa-Pla)/CO, respectively. Following a 30 min baseline period, we initiated hypoxia with mixture of 10% oxygen in nitrogen. After 20 min of hypoxia we then performed the following two experiments: Group A-Hydralazine (10 micrograms/kg/min) was infused continuously for a further 20 min of hypoxia (n = 6); Group B-Hydralazine (400 micrograms/kg) was administered as a single bolus, followed by an additional 20 min of hypoxia (n = 6). In both Groups A and B, hypoxia produced a prominent pulmonary hypertensive response. Continuous infusion of hydralazine (Group A) significantly decreased the hypoxic values of Ppa and PVR from 25.1 +/- 1.1 to 21.7 +/- 1.6 mmHg (p less than 0.01) and from 4.82 +/- 0.50 to 4.17 +/- 0.40 mmHg/l/min (p less than 0.05), respectively. In Group B, hydralazine as a bolus also significantly decreased HPV, with Ppa dropping from 20.9 +/- 0.9 to 18.3 +/- 1.5 mmHg (p less than 0.05) and PVR falling from 4.98 +/- 0.55 to 4.34 +/- 0.53 mmHg/l/min (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial salvage after regional beta-adrenergic blockade

The aim of the study was to determine whether regional beta-adrenergic blockade via the coronary sinus limited myocardial damage after coronary artery occlusion in the canine model. Accordingly, open-chest anesthetized dogs were randomly allocated to one of three groups: a control group and groups treated with propranolol (in doses of 0.02, 0.2, and 2.0 mg/kg) given either intravenously or via the coronary sinus. The hypoperfused zone (i.e., risk area) and the extent of myocardial damage were assessed by autoradiography and triphenyltetrazolium chloride staining, respectively. Myocardial damage expressed as a percent of the hypoperfused zone was 84 +/- 5% in the control group (n = 9) and 78 +/- 7% (0.02 mg/kg, n = 7, NS), 63 +/- 6% (0.2 mg/kg, n = 7, p less than 0.05), and 62 +/- 7% (2.0 mg/kg, n = 9, p less than 0.02) in the groups receiving intravenous propranolol and 73 +/- 6% (0.02 mg/kg, n = 7, NS), 58 +/- 7% (0.2 mg/kg, n = 7, p less than 0.01), and 44 +/- 9% (2.0 mg/kg, n = 9, p less than 0.001) in groups receiving propranolol via the cardiac veins. There was a significant enhancement of myocardial salvage with increasing doses of propranolol delivered via the cardiac veins (linear regression trend, p less than 0.05). In contrast, myocardial damage expressed as a percent of the hypoperfused zone remained comparable with propranolol doses of 0.2 and 2.0 mg/kg administered intravenously (linear regression trend, NS). In conclusion: (1) regional beta-adrenergic blockade via the cardiac veins afforded significant myocardial salvage and (2) the regional administration of propranolol resulted in significant reduction of myocardial damage in a dose-dependent fashion.     

Whole body autoregulation in reduced renal mass hypertension.

Whole body autoregulation in conscious rats can be shown in the absence of the rapid acting neural and hormonal controllers of blood pressure. It is hypothesized that this phenomenon is responsible for the gradual rise of vascular resistance observed in volume-dependent forms of hypertension such as reduced renal mass-salt-induced hypertension. To examine the hypothesis, we evaluated the gain of whole body autoregulation at various stages of reduced renal mass hypertension to determine if acute autoregulatory capacity is altered during chronic hypertension. Rats underwent reduced renal mass surgery (nephrectomy plus 70% reduction of remaining kidney) and were studied at 2 (n = 8), 4 (n = 6), and 6 (n = 7) weeks after high salt diet. Control rats (n = 6) underwent nephrectomy and sham surgery and were studied after 2 weeks of high salt diet. All reduced renal mass rats showed progressive hypertension (2 weeks, 136 +/- 5; 4 weeks, 157 +/- 8; and 6 weeks, 171 +/- 10 mm Hg) compared with sham rats (113 +/- 4 mm Hg). We observed an increase in basal level of total peripheral resistance index after neurohumoral blockade in reduced renal mass rats (2 weeks, 1.64 +/- 0.06; 4 weeks, 1.79 +/- 0.10; and 6 weeks, 1.89 +/- 0.09 mm Hg.100 g-1.min-1.ml-1) compared with sham rats (1.56 +/- 0.10 mm Hg.100 g-1.min-1.ml-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of a bradycardic agent on the isolated blood-perfused canine heart

Bradycardic agents could limit the consequences of myocardial ischemia via two mechanisms: by decreasing myocardial oxygen demand (MVO2) and by increasing diastolic coronary blood flow (CBF). We investigated whether the benzazepinone UL-FS 49 affects only sinus node cells or also smooth muscle and/or myocardial cells. To avoid confounding interactions with the periphery, we performed experiments on 11 isolated, blood-perfused canine hearts. Injection of UL-FS 49 (1 mg/kg i.c.) significantly reduced heart rate (HR) from 104 +/- 7 to 93 +/- 7 min-1 (mean +/- SEM) and increased stroke volume (n = 6: 9.8 +/- 1.1 vs. 13.2 +/- 1.6 ml), so that cardiac output remained unchanged (n = 6: 1.1 +/- 0.1 vs. 1.2 +/- 0.1 l/min). The contractile state, assessed by isovolumic peak systolic pressure, was unaltered by UL-FS 49 (n = 5: 72 +/- 6 vs. 72 +/- 6 mmHg). At a constant coronary arterial pressure (CAP) of 80 mmHg, mean CBF was slightly decreased (102 +/- 11 vs. 97 +/- 10 ml/[min.100 g]) by UL-FS 49, such that mean coronary resistance remained unchanged (0.9 +/- 0.1 vs 1.0 +/- 0.1 mmHg.min.100 g/ml). The slight decreases in arteriovenous oxygen content difference (n = 6: 6.6 +/- 0.7 vs. 6.5 +/- 0.7 ml/100 ml) and in CBF lead to a calculated, significant decrease in MVO2 (n = 6: 6.9 +/- 0.5 vs. 6.0 +/- 0.4 ml.100 g/min). In conclusion, UL-FS 49 at the dose used decreases MVO2 by reducing HR in isolated canine hearts. In the absence of negative inotropic and vasodilating effects, cardiac output is maintained via increased stroke volume, and CAP will likely be preserved in situ. Thus, this specific bradycardic agent could be useful in treating ischemic myocardial disease.     

Facilitation of sympathetic neurotransmission by phosphatidylinositol-4,5-bisphosphate-dependent regulation of KCNQ channels in rat mesenteric arteries

Sympathetic nerves regulate vascular tone by releasing neurotransmitters into the vasculature. We previously demonstrated that bradykinin facilitates sympathetic neurotransmission in rat mesenteric arteries. Although little is known about the intracellular mechanism modulating this neurotransmission, recent cell line experiments have shown that the KCNQ channel, which is inhibited by the depletion of membrane phosphatidylinositol-4,5-bisphosphate (PIP(2)), participates in the control of neurotransmission by bradykinin. In the present study, we examined the mechanism regulating neurotransmitter release from rat perivascular sympathetic nerves. Excitatory junction potentials (EJPs) elicited by repetitive nerve stimulation (1?Hz, 11 pulses, 20?μs, 20-50?V), a measure of sympathetic purinergic neurotransmission, were recorded with a conventional microelectrode technique in rat mesenteric arteries. Bradykinin (10(-7)?mol?l(-1)) significantly enhanced the amplitude of EJPs (n=22, P<0.05). This enhancing effect was abolished by N-type calcium-channel inhibition with ω-conotoxin GVIA (2 × 10(-9)?mol?l(-1), n=8). The blockade of phospholipase C with U-73122 (10(-6)?mol?l(-1), n=17) also eliminated the facilitatory effect of bradykinin. In addition, the effects of bradykinin were diminished by the prevention of PIP(2) resynthesis with wortmannin (10(-5)?mol?l(-1) n=7) or KCNQ channel inhibition with XE-991 (10(-5)?mol?l(-1), n=7). On the other hand, depletion of intracellular calcium stores with cyclopiazonic acid (3 × 10(-6)?mol?l(-1), n=6) or the inhibition of protein kinase C with bisindolylmaleimide-I (10(-6)?mol?l(-1), n=9) did not alter the action of bradykinin. These data demonstrate that the hydrolysis of PIP(2) by phospholipase C, which is activated by G(q/11)-coupled receptors, and subsequent KCNQ channel inhibition enhance sympathetic purinergic neurotransmission presumably via the activation of N-type calcium channels in rat mesenteric arteries.