Healthy ageing of cloned sheep

The health of cloned animals generated by somatic-cell nuclear transfer (SCNT) has been of concern since its inception; however, there are no detailed assessments of late-onset, non-communicable diseases. Here we report that SCNT has no obvious detrimental longterm health effects in a cohort of 13 cloned sheep. We perform musculoskeletal assessments, metabolic tests and blood pressure measurements in 13 aged (7–9 years old) cloned sheep, including four derived from the cell line that gave rise to Dolly. We also perform radiological examinations of all main joints, including the knees, the joint most affected by osteoarthritis in Dolly, and compare all health parameters to groups of 5- and 6-year-old sheep, and published reference ranges. Despite their advanced age, these clones are euglycaemic, insulin sensitive and normotensive. Importantly, we observe no clinical signs of degenerative joint disease apart from mild, or in one case moderate, osteoarthritis in some animals. Our study is the first to assess the long-term health outcomes of SCNT in large animals

Calcium entry blockade and agonist-mediated forearm vasoconstriction in hypertensive patients. Difference between nicardipine and verapamil.

The interference by nicardipine and verapamil with the response to vasoactive stimuli, such as lower body negative pressure and angiotensin II, has been evaluated in the forearm of hypertensive patients. Forearm blood flow was monitored during the intraarterial infusion of either drug at rates equieffective on basal flow. Nicardipine blunted the peak forearm vasoconstrictor action of lower body negative pressure and a comparable result was obtained when angiotensin II was administered intraarterially. In spite of a comparable increase in forearm flow, nicardipine was more potent than verapamil in inhibiting vasoconstriction following both stimuli. Thus, nicardipine suppressed regional vascular reactivity, probably by blockade of the influx of extracellular calcium, in response to receptor activation, since both alpha-adrenergic and angiotensin II receptor-mediated vasoconstrictor responses were attenuated. However, the results of the comparison with an unrelated calcium entry blocker, such as verapamil, may suggest that nicardipine, and possibly other dihydropiridine derivatives, preferentially antagonize agonist-mediated vasoconstriction in the human forearm

Calcium entry blockade and agonist-mediated vasoconstriction in hypertensive patients.

The effects of two chemically unrelated calcium channel blockers--nicardipine and verapamil--on vascular responses to exogenous norepinephrine were evaluated in uncomplicated hypertensive patients. Each drug was infused into the brachial artery at rates that did not affect systemic blood pressure or heart rate, and forearm blood flow was measured using strain gauge venous plethysmography. Nicardipine 1 microgram/100 ml forearm tissue/min dilated the forearm arterioles and antagonized the vasoconstrictor effect of norepinephrine, whereas verapamil 1 microgram/100 ml tissue/min was ineffective, even though both drugs relaxed basal tone to the same extent. The difference between nicardipine and verapamil was also evident when reflex forearm vasoconstriction was elicited by the application of a lower body negative pressure and the drugs were infused intra-arterially at 1 and 3 micrograms/100 ml tissue/min, respectively. To evaluate whether a comparable behavior might also hold for nonsympathomimetic agents, increasing doses of angiotensin II were administered to the forearm vascular bed after pretreatment with either nicardipine or verapamil. Both drugs increased forearm blood flow, but only nicardipine antagonized the effect of angiotensin II in the forearm, showing that the impairment of vasoconstrictor mechanisms was not dependent on a specific receptor. Important differences seem to exist between nicardipine and verapamil with regard to agonist-mediated vasoconstriction in hypertensive patients, which is consistent with the heterogeneity of calcium channel blockers as a pharmacological class. Preferential antagonism of a series of vasoconstrictor stimuli may characterize the vasodilatory and, possibly, the antihypertensive effect of nicardipin

Atrial natriuretic factor as a vasodilator agent in hypertensive patients.

To investigate the role of Atrial Natriuretic Factor (ANF) in modulating arteriolar tone in hypertension, a synthetic 25 AA human ANF-analogue (anaritide) was infused intraarterially in the forearm vascular bed of five patients with mild hypertension. A dose-dependent increase in blood flow (plethysmographic technique) was seen at rates covering a thousand-fold range (0.008, 0.08, 0.8, 8.0 micrograms/dl tissue/min x 15 minutes each). At the lowest infusion rate, the forearm blood flow increment was associated with changes in local venous ANF concentrations comparable with those reported during biological stimuli in hypertensive man and consistent with an ANF physiologic role in forearm arterioles of hypertensive patients. However, at local venous concentrations greater than 1000 pg/ml, ANF did not relax forearm vessels by more than about one-fourth of the total forearm vasodilator capacity (as assessed through a maximally active ischemic stimulus). These data confirm the low potency of ANF as an endogenous vasodilator, although vasodilator potency is not a necessary requirement for physiologic systems involved in the regulation of muscular vascular tone. Systemic arterial pressure, heart rate, and contralateral flow did not change during the study in spite of the markedly increased peripheral ANF levels recirculating from the local forearm administration. This behavior indicates that arteriolar vasodilation is apparently not the main mechanism of action of ANF on systemic hemodynamics in hypertensive patients